bluuebunny/crossref_metadata_2025_split huggingface dataset:
A64 HUMAN INTESINAL ORGANOIDS AS A MODEL FOR GASTROINTESTINAL FUNCTION AND TOXICITY SCREENING
Authors: Stahl M , Leung D , Anderson W , Conlin V , Eaves A , Louis S A , Conder R K 
Published: February 2024

Abstract

Aims
Drug-induced gastrointestinal (GI) toxicity is a common adverse event in clinical trials, with symptoms including diarrhea, ulceration, and inflammation resulting from impaired barrier function. Furthermore, the intestine is a key mediator of both drug absorption and metabolism. The human colon carcinoma cell line (Caco-2) is the most common model used in drug discovery, however, intestinal organoids provide a model that better recapitulates the self-renewal, cellular composition, and function of the intestinal epithelium.This study utilizes human intestinal organoids as a high-throughput model for evaluating intestinal function and toxicity in preclinical drug discovery.

Methods
To assess toxicity, intestinal organoids were treated with two GI-toxic drugs, gefitinib and colchicine, and post-treatment cell viability was compared to Caco-2 control cultures. To assess barrier function, organoid-derived monolayers cultured in Transwell® plates were treated with colchicine and sapitinib, and post-treatment permeability was evaluated using the fluorescent low-permeability markers, 4 kDa FITC-dextran and Lucifer yellow.

Results
Human intestinal organoid cultures exhibited 14-fold greater sensitivity to gefitinib (average organoid IC50 = 0.82 μM, n = 3; Caco-2 IC50 =11.4 μM, n = 2) and 2,238 times greater sensitivity to colchicine (average organoid IC50 = 0.028 μM, n = 3; Caco-2 IC50 = 62.89 μM, n = 6) compared to Caco-2 controls. This 96-well assay was reproducible, producing comparable IC50 concentrations in repeated experiments with cells from the same and different donors (n = 3 donors). Organoid-derived monolayers exhibited ampersand:003E 10-fold (n = 3) increase in permeability to both sapitinib and colchicine compared to Caco-2 cultures, which displayed minimal responses to either drug treatment. Finally, organoid-derived monolayer cultures in transwell® plates can be utilized to quantify drug transport and metabolism by the intestinal epithelium. Using ileal organoid-derived monolayers and Caco-2 cultures, we quantified the active transport of methotrexate by the efflux transporter BCRP, calculating an efflux ratio of 11.46 from the basal to apical chambers. We also quantified CYP3A4 activity of ileal monolayers relative to Caco-2 cultures. Ileal monolayers converted midazolam to hydroxymidazolam ampersand:003E 50-fold (n = 2) more than Caco-2 cultures, which displayed minimal CYP3A4 activity below the limit of detection. Together, these data demonstrate that human intestinal organoids are a valuable tool for high-throughput GI toxicity screening and for evaluating intestinal function in preclinical drug discovery.

Conclusions
Together, these data demonstrate that human intestinal organoids are a valuable tool for high-throughput GI toxicity screening and for evaluating intestinal function in preclinical drug discovery.

Funding Agencies
None
A65 THE YAP-PER: CAN YAP/TAZ MEDIATE EPITHELIAL-IMMUNE CROSSTALK DURING PYLORIC METAPLASIA?
Authors: Sung J , Gregorieff A , Gruenheid S 
Published: February 2024

Abstract

Background
Gastric cancer is one of the leading causes of cancer-related deaths and its prevalence has been associated with infection by Helicobacter pylori. H. pylori persistence leads to chronic inflammation, which results in the elimination of acid-secreting parietal cells and the appearance of abnormal mucus-producing cells at the base of the gastric glands, known as spasmolytic polypeptide/trefoil factor 2-expressing metaplasia (SPEM) cells. The processes driving these alterations in epithelial cell fate during H. pylori infection and their function in regeneration of the gastric epithelium remain unclear. Previous work done in our lab have demonstrated that Hippo signalling, more specifically the transcriptional effectors yes-associated protein 1 (YAP) and transcription coactivator with PDZ-binding motif (TAZ), plays an essential role in controlling cell fate during gastric tissue regeneration in a chemical injury model. In the same model, loss of YAP/TAZ resulted in chronic immune cell infiltration in corpus glands, suggesting an immunomodulatory role for YAP and TAZ.

Aims
The objectives of this project is to characterize the immunomodulatory function of YAP/TAZ in an in vivo model of acute injury as well as an in vivo model of H. pylori infection.

Methods
Acute injury is induced by high-dose tamoxifen treatment in conditional knock-out (cKO) mice with YAP/TAZ deleted throughout the gastric epithelium. Subsequent immunophenotyping experiments such as flow cytometry and multiplex analysis are performed to characterize the role played by YAP/TAZ in regulating the immune response. For a more biologically relevant model, cKO mice are also infected with H. pylori, and similar immunophenotyping analyses are performed.

Results
Preliminary results showed that the loss of YAP/TAZ resulted in differential type II response as well as chronic B cell infiltration upon tissue injury.

Conclusions
This project aims to provide important insights on immune-epithelial cell interactions important for tissue regeneration and tumorigenesis as well as host-pathogen interactions implicated in H. pylori persistence.

Funding Agencies
CIHRFRQS
A66 EFFECTS OF HYMENOLEPIS DIMINUTA EXTRACELLULAR VESICLES ON MOUSE MACROPHAGES AND THEIR MITOCHONDRIA
Authors: Volk P , Allain T , Khan N , Wang A , Buret A G , McKay D 
Published: February 2024

Abstract

Background
In recent years, extracellular vesicles (EVs) have emerged as important means of intercellular communication and immune modulation between helminth and host. Earlier work revealed that excretory/secretory products from the rat tapeworm Hymenolepis diminuta (HES) have anti-inflammatory properties when applied to macrophages. In this study, we have investigated the immunomodulatory properties of H. diminuta EVs (HEVs) on macrophages.

Aims
1. To isolate and characterize bacterial contaminant-free H. diminuta EVs (Hd-EVs).
2. To determine the effects of Hd-EVs on murine macrophage metabolism and LPS-evoked cytokine production.

Methods
Adult H. diminuta were cultured for 6h in serum-free RMPI and Hd-EVs isolated from the conditioned medium using an exoEasy kit. Hd-EV protein content was measured using a micro-BCA kit, and size and quantity were measured using Nanosight tracking analysis. Murine bone marrow-derived macrophages or the human macrophage THP-1 cell line were treated with LPS (10 ng/ml) ± a crude H. diminuta extract (HdE), HES, or Hd-EVs for 24h. TNF-α levels in the culture medium was measured by ELISA. Macrophage oxidative phosphorylation (OX.PHOS) and glycolysis were measured in real-time using an Agilent Seahorse XF Analyzer.

Results
Analysis of 14 Hd-EV samples revealed 4.1 X 109 - 5.48 X 1010 particles/mL, with Hd-EVs predominantly 100-350 nm in diameter and with a protein content of 64.9-181.6 ng/mL. HdE and HES reduced TNF-α production in LPS-activated macrophages by 39-76% (n=11), while Hd-EVs did not lower TNF-α production. Metabolic analysis suggests that HES and Hd-EVs can up-regulate macrophage glycolysis, while only Hd-EVs exposed macrophages showed increased OX.PHOS (n=6).

Conclusions
We have successfully isolated and begun to characterize EVs from adult H. diminuta. Despite the known abilities of HES, we unexpectedly noted that exposure to Hd-EVs did not result in a statistically significant decrease in macrophage TNF-α release. However, the increase in OX.PHOS macrophages treated with Hd-EVs is something to examine further. The next steps are to determine the contents and immunomodulatory activity of the Hd-EVs, thus advancing knowledge of how helminths can manipulate their hosts.

Funding Agencies
NSERC
Clinical Practice
A67 REDUCING INAPPROPRIATE GAMMA-GLUTAMYL TRANSFERASE TESTING FOR INPATIENTS: A QUALITY IMPROVEMENT INITIATIVE IN LAB WASTE REDUCTION APPLYING THE MODEL FOR CONTINUOUS IMPROVEMENT
Authors: Afzaal T , AlRamdan R , Bualbanat H , Howarth N C , Malhi G , Hudson D , ChinYee I , Teriaky A 
Published: February 2024

Abstract

Background
Review of the literature identifies a rising trend in laboratory testing, with over 30% of tests estimated to be inappropriately repeated. Laboratory overutilization increases healthcare costs, and can lead to overdiagnosis, overtreatment and negative health outcomes. Indications for repeat Gamma Glutamyl Transferase (GGT) testing in adults are limited, particularly repeat testing within the same admission.

Aims
Our aim was to reduce the inappropriate ordering of repeat GGT testing by 25% for all inpatients at the London Health Sciences Centre (LHSC) over a one-year study period.

Methods
An interprofessional team was created to help engage relevant stakeholders, collect baseline data and reassess the indications for GGT testing. A combination of root cause analysis tools, specifically the Ishikawa diagram and Pareto chart, were employed to identify potential factors contributing to the overutilization of GGT testing. After prioritizing potential solutions, intervention bundles were developed, and Plan-Do-Study-Act (PDSA) cycles were created to target correctable factors. In PDSA cycle #1, the process started by eliminating GGT as a laboratory testing option in the three most commonly used admission order care sets. Considering the hierarchy of intervention effectiveness, PDSA cycle #2 involved implementing a computerized Clinical Decision Support (CDS) system to restrict the reordering of GGT tests within 72 hours of the same admission.

Results
Baseline data showed that in 2022, a total of 62,542 GGT tests were ordered, with an average of approximately 5,200 GGT tests ordered per month. Of these, 16.4% were ordered through the top 3 most prevalent admission order care sets, and around 25% of all GGT tests were repeats within 72 hours of admission. Referring to Figure 1, PDSA cycle #1 yielded no significant reduction in GGT testing. PDSA cycle #2 successfully reduced the proportion of repeat GGT tests ordered by 12% within two months of implementation, leading to an estimated annualized cost savings of approximately $37,440.

Conclusions
Our results establish the effectiveness of CDS systems in reducing laboratory testing overutilization, suggesting their superiority to individual care set targeting interventions, and emphasize the potential for cost-effective CDS development in contemporary healthcare.

Funding Agencies
None
A68 PERCEPTIONS OF ADOLESCENTS AND YOUNG ADULTS WITH INFLAMMATORY BOWEL DISEASE REGARDING A BIOPSYCHOSOCIAL TRANSITION INTERVENTION: A QUALITATIVE STUDY
Authors: Allemang B , Browne M , Barwick M , Bollegala N , Fu N , Lee K , Miatello A , Nistor I , Dekker E , Anthony S J , Benchimol E I 
Published: February 2024

Abstract

Background
The transition from the pediatric to adult care healthcare system for adolescents and young adults (AYAs) with inflammatory bowel disease (IBD) is complex. This group requires support to prepare for and adapt to adult care due to the manifestation of the disease, expectations for self-management, and simultaneous life transitions. To address this need, a multi-site randomized controlled trial (RCT) is being conducted to evaluate the impact of a multimodal transition intervention on functional, clinical, and psychosocial outcomes for AYAs with IBD. An embedded qualitative study explored participants’ perspectives of the intervention's acceptability and appropriateness to support the translation of findings into practice.

Aims
Using in-depth individual qualitative interviews with a purposive sample of AYAs in both the intervention and control arms of the RCT, this qualitative study aimed to understand AYAs’ experiences preparing for and undergoing service transitions, developing self-management skills, and engaging with the intervention.

Methods
Semi-structured interviews were held via videoconference with 21 AYAs aged 16-18 years participating in the RCT (intervention arm n=11; control arm n=10) in Toronto, Canada. Purposive sampling was used to recruit AYAs with diverse demographic and clinical characteristics at different stages of the healthcare transition. Interviews were audio-recorded, transcribed verbatim, and analyzed using an inductive approach to reflexive thematic analysis.

Results
The analysis yielded four overarching themes related to 1) individual, familial, and system-level factors promoting transition readiness, 2) areas of strength and areas for growth regarding self-management skill development, 3) perceptions of the multimodal transition intervention, including barriers and facilitators to engagement, and 4) recommendations for future transition care, including refinement of the intervention. Findings to date indicate the criticality of considering AYAs’ support systems, learning styles, and communication preferences when designing and implementing transition interventions. The qualitative data analysis is ongoing, and the full results will be presented.

Conclusions
The perspectives of AYAs with IBD can inform the development and refinement of clinical interventions, ensuring they are tailored to recipients’ unique needs and preferences and promote engagement and skill development during pediatric-adult transitions.

Funding Agencies
CCCThe Leona M. and Harry B. Helmsley Charitable Trust
A72 THE ENDOSCOPIC YIELD OF PRIORITIZED INDICATIONS USING A PROVINCIAL-WIDE COLONOSCOPY REFERRAL FORM
Authors: Barkun A , Ravanbakhsh K , Kim D , Milky G , Stanowski P , Geraci O , Martel M , Menard C , von Renteln D 
Published: February 2024

Abstract

Background
The widespread use of a standardized and validated province-wide colonoscopy referral form (PCRF), regrouping mutually exclusive indications into suggested priority wait time categories, has allowed for a more comprehensive assessment of routine colonoscopy practice

Aims
To validate the Quebec PCRF by better characterizing endoscopic finding yields according to specific clinical indications.

Methods
This retrospective cohort study includes consecutive adult patients with available data from the PCRF from two tertiary hospitals. The primary outcome was the diagnostic rates of colorectal cancer (CRC). Secondary outcomes assessed incidences of clinically significant lesions (CSL) on endoscopy and confirmed at pathology. These are CRC, advanced adenomas, sessile serrated polyps, polyps ≥ 5mm, colitis, colonic strictures, and miscellaneous other findings excluding hemorrhoids and diverticulosis. Descriptive and inferential statistics, and multivariable regression predictive modeling are reported.

Results
Overall, 14,657 patients (mean age 59.2 ± 14.0 years, 50.9% female) were included from September 2018 to August 2022. The most frequent indications for colonoscopy were polyp surveillance (IN13, 20.8%), recent change in bowel habits (IN7, 11.9%), a positive fecal immunochemical test (IN5, 8.3%), a family history of CRC or polyps (first-degree relative) (IN8, 6.4%), and suspected active inflammatory bowel disease (IBD) (IN3, 5.8%). Overall, 40.6% had CSL, including CRCs in 0.8%. CRCs were found more frequently for IN2 (19.7% vs 2.0%, pampersand:003C0.01), IN5 (29.9% vs 8.2%, pampersand:003C0.01), and an unexplained documented iron deficiency anemia (IN6) (11.8% vs 5.2%, pampersand:003C0.01). CSLs were more frequent for IN3 (1.6% vs 5.8%, p=0.04), IN7 (4.7% vs 12.0%, p=0.01), IN8 (0.8% vs 6.5%, p=0.01), IN13 (7.1% vs 20.9%, pampersand:003C0.01), IBD surveillance (IN15, 0.0% vs 4.0%, p=0.02), and surveillance for a significant family history (IN21, 0.0% vs 3.7%, p=0.02).
On multivariable analysis, CRC was significantly associated with IN2 OR=31.8 (4.86; 208.7), IN5 OR=19.2 (3.86; 95.7), and IN6 OR=15.7 (2.37; 78.0) - (all are high priority PCRF referrals with a suggested shorter wait time than for most other indications). CSLs were significantly associated with age (OR=1.03 (1.02; 1.03)), IN2 (OR=2.32 (1.35; 3.99)), IN5 (OR=2.37 (1.74; 3.22)), and IN13 (OR= 1.66 (1.36; 2.02)).

Conclusions
This large cohort study confirms the validity of indications and corresponding prioritization of wait times of a PCRF.

Funding Agencies
CPAC and MSSS
A74 A RARE CASE OF ANTIDEPRESSANT-INDUCED LYMPHOCYTIC COLITIS IN A TEENAGER
Authors: Binaqail A , Morinville V D , Nguyen V 
Published: February 2024

Abstract

Background
The etiopathogenesis of microscopic colitis may reflect an immunological reaction in genetically predisposed individuals exposed to an external stimulus causing gut microbiota disruption. Numerous factors such as smoking, autoimmune diseases, and medications have been linked to this condition in adults. Steroids may be required as therapy. Pediatric cases of microscopic colitis have only rarely been reported.

Aims
Case report.

Methods
Retrospective single chart review and literature review of microscopic colitis in children.

Results
A 17-year-old female newly diagnosed with major depression disorder following intentional acetaminophen intoxication was started on sertraline, a selective serotonin reuptake inhibitor (SSRI). Within 2 months from initiation, she began to have non bloody watery diarrhea and had a 5 kg weight loss over a 1-month period . Her laboratory workup only revealed a hypochromic, microcytic anemia. Due to severity of symptoms and reluctance of treating team to discontinue sertraline, she underwent an esophagogastroduodenoscopy and ileo-colonoscopy, both showing grossly normal mucosa. Histological assessment of the colon demonstrated increased intraepithelial lymphocytes, up to 50-60 lymphocytes/100 enterocytes (normal ≤ 20 lymphocytes/100 enterocytes), with associated reactive superficial epithelial changes including goblet cell and mucin depletion, compatible with lymphocytic colitis (Figure1). Sertraline was weaned off, and gastrointestinal symptoms resolved completely. A repeat sigmoidoscopy 5 months later confirmed complete normalization of the histology.

Conclusions
Microscopic Colitis encompasses two disorders, lymphocytic colitis and collagenous colitis, in which the endoscopic appearance is unremarkable, but histological changes are diagnostic. The clinical manifestations of both are similar and typically include chronic non bloody watery diarrhea, weight loss and abdominal pain. Certain medications have been implicated in causing lymphocytic colitis, including SSRIs. SSRIs historically have not been frequently prescribed in pediatrics, but their use has increased in recent years. The complete resolution of symptoms and histology, without the need for any medical therapy, strongly supports that this lymphocytic colitis was caused by sertraline. The association of lymphocytic colitis with sertraline is not well-known among pediatric practitioners: neither the pediatrician nor psychiatrist in our case were aware of such a possibility. This case highlights that medication adverse events, even if rare, should always be considered when chronology is supportive, and at times, simple discontinuation of the drug is sufficient to completely resolve the issue.

Funding Agencies
None
A75 PEDIATRIC ABDOMINAL PAIN PRESENTING TO A HOSPITAL-BASED GI CLINIC: EVOLUTION AND DISPOSITION
Authors: Brill H , Patel R 
Published: February 2024

Abstract

Background
Abdominal pain accounts for 50% of pediatric gastroenterology consultations. While data exists on the possible etiologies of abdominal pain, there is a paucity of data on the natural evolution of abdominal pain while under the care of a Pediatric Gastroenterologist. Given limited access to Pediatric Gastroenterologists and long waiting times for initial consultation for abdominal pain, understanding what interventions ameliorate pain may help Gastroenterologists advise referring physicians while the patient awaits a consultation.

Aims
Primary outcome measure was the percentage of patients who reported at least a 75% subjective improvement of pain over baseline consultation.

Methods
A retrospective chart review between April 2014 and Dec 31, 2022 was taken in a hospital based GI clinic. Subjects referred for assessment of abdominal pain were identified, along with subjects referred for reflux and dysphagia as a comparator group. Subsequent visits were abstracted to identify diagnosis disposition and assess which interventions were tried and to what extent they succeeded. Patient loss to follow up were also measured. Results were summarized using descriptive statistics, and regression modeling will be attempted to identify predictors of response.

Results
393 subjects were referred for abdominal pain and 286 for GERD and dysphagia. 439 (64.7%) reported at least 75% improvement in symptoms. 242 (35.6%) underwent endoscopy, 263 (38.7%) used Proton Pump Inhibitors, and 38 (8.54%) used Polyethylene Glycol-3350. Carbohydrate eliminations of various types were used in 13.5 - 27% of subjects with pain. 193 subjects (28.5%) were ultimately lost to follow up though some did report improvement in symptoms. Only 45 (6.6%) remained in active care by the end of the study while only 13 (1.93%) were transitioned to an Adult Gastroenterologist at 18 years old.

Conclusions
Pediatric Abdominal Pain is primarily a transitory population in the Pediatric GI clinic, with a large number responding to successive interventions. There is also a sizable minority who are lost to follow up. Future studies should attempt to identify the reasons for loss to follow up and ultimate disposition.

Funding Agencies
William Osler Health System Summer Student Research Program