bluuebunny/crossref_metadata_2025_split huggingface dataset:
A18 DEVELOPMENT OF CHRONIC ILEITIS IN THE TNFΔARE MOUSE IS ASSOCIATED WITH A LOSS OF MESENTERIC LYVE1+ MACROPHAGES
Authors: Keane K P , Almutairi K , Roizes S , Stephens M , von der Weid P 
Published: February 2022

Abstract

Background
Crohn’s disease (CD) is a form of inflammatory bowel disease that causes transmural inflammation of any part of the gastrointestinal (GI) tract but preferentially the terminal ileum and/or the colon. This chronic inflammation is not limited to the GI tract but also affects the mesentery of inflamed regions where it induces the formation of tertiary lymphoid organs (TLOs). The homeostatic LYVE1+ macrophages (LYmΦ) have been identified in many different organs including the mesentery. They have been shown to typically align along blood vessels where they participate in the control of collagen deposition and during inflammation, regulate vascular permeability and immune cell recruitment. Here we investigate the role of the mesenteric LYmΦ in a transgenic model of CD, the TNFΔARE mouse which develops terminal ileitis over time and expresses similar mesenteric alterations (TLOs) as seen in CD.

Aims
To determine whether the mesenteric LYmΦ population is altered during the development of chronic inflammation in the TNFΔARE mouse and whether they participate in the development of TLOs.

Methods
Confocal immunofluorescent imaging of the terminal ileal mesentery of TNFΔARE mice and littermate controls were preformed to identify changes to the populations of LYmΦ during the development of chronic inflammation. Myeloperoxidase activity was used to assess terminal ileitis.

Results
During the initial stage of ileitis (8 weeks) LYmΦs are present across the terminal ileal mesentery in both TNFΔARE and age-matched WT littermate controls with a subpopulation aligning along the collecting lymphatic vessels of the mesentery (n=6). At 20 weeks, while the ileitis progresses, aggregates of CD45+ cells have formed within the TNFΔARE mice where LYmΦs also accumulate (n=5). At 28 weeks when the ileitis worsens, the LYmΦs are greatly reduced from the terminal ileal mesentery as well as from the CD45+ cell aggregates (n=5). WT littermate controls never develop large CD45+ cell aggregates (n=5 for each time point). Antibodies to the LYVE1 cytosolic and extracellular domains confirmed the loss of the LYVE1 receptor over receptor cleavage, however, there was no correlation of altered collagen-1 deposition within the mesentery at 28 weeks.

Conclusions
Here we show a spatial relationship between LYmΦs and collecting lymphatic vessels as well as a decrease in LYmΦs during the development of chronic ileitis in the TNFΔARE mouse. Whether they contribute to TLO formation, or their loss exacerbates terminal ileitis is still unknown and under current investigation.

Funding Agencies
CCC
A23 ESTIMATING INDIRECT AND OUT-OF-POCKET COSTS IN PEDIATRIC INFLAMMATORY BOWEL DISEASE: A NATION-WIDE CROSS-SECTIONAL ANALYSIS
Authors: El-Matary W , Witt J , Bernstein C N , Jacobson K , Mack D R , Otley A , Walters T , Huynh H Q , deBruyn J , Griffiths A , Benchimol E I 
Published: February 2022

Abstract

Background
Identifying disease-related costs is a crucial step to plan for proper allocation of resources and future healthcare services for persons with inflammatory bowel disease (IBD). Data on pediatric inflammatory bowel disease-associated costs are limited.

Aims
We aimed to estimate indirect and out of pocket (OOP) pediatric IBD-associated costs in Canada.

Methods
In a nation-wide cross-sectional analysis, caregivers of children and young adults (&lt;17 years) with IBD were invited to complete a questionnaire on lost work hours and OOP costs related to IBD in the 4 weeks prior to the survey. Participants were re-invited to periodically answer the same questionnaire every 3–9 months for 2 years. Lost productivity was calculated using the Human Capital method. Costs were reported in 2018 inflation-adjusted Canadian dollars. Predictors of high cost users (top 25%) were examined using negative binomial regression.

Results
Consecutive 243 (82 incident cases) of 262 (92.7%) approached participants completed the first survey with a total of 450 surveys longitudinally completed over 2 years. The annual median indirect costs per patient were $5,951 (IQR $1,812- $12,278), with $5,776 (IQR $1,465-$11,733) for Crohn’s disease (CD) and $6,084 (IQR $2,470-$13,371) for ulcerative colitis (UC) (p=0.77). The annual median per patient OOP costs were $2,925 (IQR $978- $8,125) with $3,021 (IQR $978- $8,125) for CD and $2,600 (IQR $975- $8,125) for UC (p=0.55). Older age (10-17y) at diagnosis (p=0.04) and parents in part-time employment (p=0.01) were predictors of higher indirect costs, while female sex (p&lt;0.001), parents with a lower education level (p&lt;0.001) and lower annual family income (p&lt;0.01) were associated with higher OOP costs.

Conclusions
Indirect and OOP IBD-associated costs are substantial and more likely to affect families with unstable employment and lower annual income. Examining different strategies and interventions to reduce these costs such as virtual platforms, telephone and outreach clinics especially in poor communities and families with low annual income is warranted.

Funding Agencies
CIHRThe Children’s Hospital Research Institute of Manitoba
A24 GENERALIZABILITY OF CROHN’S DISEASE RANDOMIZED CONTROLLED TRIALS COMPARED TO CLINICAL PRACTICE
Authors: Chhibba T , Frolkis A , Ma C 
Published: February 2022

Abstract

Background
There are no curative medical therapies for Crohn’s disease (CD). However, multiple novel treatment options are currently being evaluated in randomized controlled trials (RCTs). Historically, CD populations enrolled in RCTs have not reflected the heterogeneity of patients observed in clinical practice due to strict inclusion/exclusion criteria and protocolized trial procedures do not reflect day-to-day care. These factors have raised concerns that results from pivotal RCTs required for drug approval are poorly generalizable.

Aims
To assess the generalizability of CD RCTs, we evaluated the proportion of CD patients initiating ustekinumab or vedolizumab in clinical care who would have been eligible for enrolment in the corresponding phase 3 registrational induction trial, and the factors impacting trial eligibility.

Methods
This is a retrospective cohort study using data from two ambulatory IBD clinics in Calgary, AB. Our study population included consecutive adult (&gt;=18 years) patients with a confirmed diagnosis of CD, newly initiated on ustekinumab or vedolizumab between January 1, 2018 and January 1, 2020. We then applied the inclusion/exclusion criteria from the phase 3 GEMINI II/III and UNITI I/II induction trials to determine the proportion of patients who would have been trial-eligible. We then tabulated the indications for trial exclusion to determine the characteristics of patients who would not have been reflected in the trial population.

Results
A total of 50 patients were included. The median age was 42.5 years. Most patients non-stricturing non-penetrating disease (44%, 22/50) and ileocolonic disease distribution (48%, 24/50). A total of 66% (33/50) would have been eligible for inclusion in GEMINI II/III and (30/50) 60% would be eligible for inclusion in UNITI I/II. The most common reasons for trial exclusion included extensive surgery (total colectomy/subtotal colectomy) with short bowel or ileostomy (n=12), surgery within 6 months of enrolment (n=3), multiple previous resections (n=2). Four patients were excluded based on intra-abdominal abscess. A total of 13 patients (26%) were temporarily ineligible due to recent biologic switch and would have required an 8-week washout prior to trial enrolment. Only two patients were excluded based on age (&gt;80 years).

Conclusions
Although most patients on ustekinumab or vedolizumab would have been eligible for the respective pivotal trials, patients who have complications of disease, extensive surgery, or altered anatomy are not reflected in current RCTs.

Funding Agencies
None
A27 COMPARATIVE EVALUATION OF THE ABC SCORE TO OTHER RISK STRATIFICATION SCALES IN MANAGING HIGH-RISK PATIENTS PRESENTING WITH ACUTE UPPER GASTROINTESTINAL BLEEDING
Authors: Barkun A N , Kherad O , Restellini S , Almadi M , Martel M 
Published: February 2022

Abstract

Background
The ABC risk score identifies patients at high-risk of mortality in acute lower and upper gastro-intestinal bleeding (UGIB).

Aims
We aimed to externally validate the ABC score, while comparing it to other prognostication scales when assessing UGIB patients at high-risk of negative outcomes prior to endoscopy.

Methods
UGIB patients from a national Canadian registry (REASON) were studied, with mortality prediction as primary outcome. Secondary endpoints included prognostication of rebleeding, intensive care unit (ICU) admission, ICU and hospitalization lengths of stay (LOS), and a previously proposed composite outcome measure. Univariable and areas under the Receiver Operating Characteristic Curve (AUROC) analyses compared discriminatory abilities of the ABC score to the AIMS65, Glasgow Blatchford (GBS) and clinical Rockall Scores.

Results
The REASON registry included 2020 patients (89.4% nonvariceal; mean age [± SD] 66.3±16.4 years; 38.4% female). Overall mortality, rebleeding, ICU admission, transfusion and composite score rates were 9.9%, 11.4%, 21.1%, 69.0%, and 67.3% respectively. ICU and hospitalization LOS were 5.4 ± 9.3 days and 9.1 ± 11.5 days, respectively. The ABC score displayed superior 30-day mortality prediction (0.78 (0.73; 0.83)) compared to GBS (0.69 (0.63; 0.75) or clinical Rockall (0.64 (0.58; 0.70) but not AIMS65 (0.73 (0.67; 0.79)). Although most scales significantly prognosticated secondary outcomes in univariable analysis except for ICU LOS, discriminatory abilities on AUROC analyses were poor.

Conclusions
ABC and AIMS65 display similar good prediction of mortality. Clinical usefulness in prognosticating secondary outcomes was modest for all scales, limiting their adoptions when informing early management of high-risk UGIB patients.

Funding Agencies
International Scientific Partnership Program ISPP at King Saud University for funding this research work through ISPP-21–156
A29 ALBUMIN UTILISATION AT A TERTIARY CARE HOSPITAL
Authors: Saad Mohammed A , Goldshtein D , Sarbar S , Wong S , Flemming J 
Published: February 2022

Abstract

Background
Albumin is a colloidal solution with usage guided by recommendations from Canadian Blood Services (CBS). In Ontario, rates of albumin use increased substantially from 2012 to 2018 despite the lack of development of new indications for using over this time frame. Further, we recently found that &gt;50% of albumin usage in patients with cirrhosis were non-evidence based. Albumin usage in other patient populations is not well described.

Aims
Our aim was to describe overall usage of albumin stratified by clinical setting, clinical indication, and dosage at a tertiary care hospital.

Methods
We retrospectively identified all albumin prescriptions during two randomly selected non-consecutive months between 2018 and 2019 at Kingston Health Sciences Centre. Data was abstracted from each hospital chart for indication, prescriber specialty, location of patient, amount of albumin ordered, and concentration (5% or 25%). Albumin prescriptions were then defined as either evidence-based or non-evidence based on published literature and guidelines. Overall cost for albumin during the study period was determined based on CBS pricing ($51.47/ 25gms).

Results
A total of 699 albumin prescriptions were dispensed to 317 individuals over December 2018 and May 2019, with a total of 38,458 grams used. Overall, 36% was prescribed for evidence-based indications. The most common indication was plasmapheresis (32%), non-sepsis volume resuscitation (23%), and cardiac surgery (17%). The majority of albumin was prescribed in dialysis unit (32%), ICU (23%), and cardiac sciences unit (11%). The largest prescribers of albumin were intensivists (26%), followed by nephrologists (17%), and cardiac surgeons (15%). There were differences in utilization based on concentration of albumin. Despite limited evidence of benefit, 25% albumin and 5% albumin were used excessively for volume resuscitation and cardiac surgery respectively. When used for an evidence-based indication, the dosing was incorrect in 45% of orders. A total of $79,176 was spent on albumin during the study period. Importantly, only $28,494 was spent on evidence-based indications with appropriate dosage and concentration.

Conclusions
Overall, there is significant albumin use for indications lacking substantial evidence. This study identifies the clinical contexts in which there is opportunity to reduce non-evidence-based albumin usage and cut unnecessary expenditure. Targeted quality improvement initiatives are underway.

Funding Agencies
None
A33 ENDOSCOPIC ULTRASOUND-GUIDED GASTROJEJUNOSTOMY VERSUS SURGICAL GASTROJEJUNOSTOMY AND ENTERAL STENTING FOR THE TREATMENT OF MALIGNANT GASTRIC OUTLET OBSTRUCTION: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Benchaya J , Chen Y , Martel M , Barkun A N , Wyse J , Ferri L , Miller C S 
Published: February 2022

Abstract

Background
Gastric outlet obstruction (GOO), often encountered in advanced malignancy, is associated with debilitating symptoms and decreased quality of life. Traditional management of this condition has been surgical gastrojejunostomy (SGJ) or enteral stenting (ES). While SGJ is highly effective, it is invasive and associated with high rates of morbidity. ES provides a less invasive approach with a lower risk of adverse events; however, it is associated with a significant risk of stent dysfunction with increased need for reintervention. Endoscopic ultrasound-guided gastrojejunostomy (EUS-GJ) is a novel modality in the management of GOO that aims to endoscopically bypass the obstruction with a lumen-apposing metal stent, with early studies suggesting good effectiveness and safety outcomes; but the data are limited.

Aims
To perform a systematic review and meta-analysis comparing the clinical outcomes of EUS-GJ to more traditional treatments of malignant GOO.

Methods
The study protocol was prospectively registered with the PROSPERO international database. The literature was systematically searched using MEDLINE, EMBASE and Web of Knowledge databases from inception through May 2021. Studies comparing EUS-GJ to ES or SGJ in patients with malignant GOO were included. Meta-analysis was performed with results reported as odds ratios (ORs) with 95% confidence intervals (CIs) using random effects models. The two primary outcomes of interest were clinical success without GOO recurrence and adverse events. Secondary outcome was technical success.

Results
Ten studies with a total of 1016 patients were included. EUS-GJ was associated with higher clinical success without GOO recurrence compared to SGJ or ES [OR: 2.19, 95% CI: 1.18–4.09, heterogeneity: P = 0.10; I2 = 59%]. Subgroup analysis showed higher clinical success without GOO recurrence compared to ES [OR: 5.31, 95% CI: 3.07–9.17], but no significant difference compared to SGJ [OR: 1.69, 95% CI: 0.76–3.72]. EUS-GJ was associated with fewer adverse events compared to SGJ and ES [OR: 0.28, 95% CI: 0.14–0.55] and compared to SGJ alone [OR: 0.20, 95% CI: 0.10–0.37], but no difference was noted when compared to ES alone [OR: 0.53, 95% CI: 0.15–1.87]. EUS-GJ was associated with decreased technical success compared to SGJ and ES [OR: 0.26, 95% CI: 0.09 – 0.75] and SGJ alone [OR: 0.14, 95% CI: 0.04–0.48]; however, there was no difference when compared to ES alone [OR: 0.43, 95% CI: 0.05–3.44].

Conclusions
EUS-GJ provides a robust bypass with lower risk of recurrent obstruction compared to ES and fewer adverse events compared to SGJ. High quality prospective studies are needed to further characterize the role of EUS-GJ in the management of malignant GOO.

Funding Agencies
None
A52 GUT-INNERVATING TRPV1+ NEURONS DRIVE CHRONIC VISCERAL PAIN VIA MICROGLIAL P2Y12 RECEPTOR
Authors: Defaye M , Abdullah N , Iftinca M , Hassan A , Agosti F , Zhang Z , Cumenal M , Zamponi G W , Altier C 
Published: February 2022

Abstract

Background
Long-lasting changes in neural pain circuits precipitate the transition from acute to chronic pain in patients living with inflammatory bowel diseases (IBDs). While significant improvement in IBD therapy has been made to reduce inflammation, a large subset of patients continues to suffer throughout quiescent phases of the disease. Peripheral and central mechanisms contribute to the transition from acute to chronic pain during active disease and clinical remission. Lower mechanical threshold and hyperexcitability of visceral afferents induce gliosis in central pain circuits, leading to persistent visceral hypersensitivity (VHS). In the spinal cord, microglia, the immune sentinels of the central nervous system, undergo activation in multiple models of VHS. Using the Dextran Sodium Sulfate (DSS) model of colitis, we found that microglial G-CSF was able to sensitize colonic nociceptors that express the pain receptor TRPV1. While TRPV1+ nociceptors have been implicated in peripheral sensitization, their contribution to central sensitization via microglia remains unknown.

Aims
Here we investigated the mechanisms of microglia activation to identify centrally acting analgesics for chronic IBD pain.

Methods
Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) expressed in TRPV1-expressing visceral neurons that sense colonic inflammation, we tested whether neuronal activity was indispensable to control microglia activation and VHS. We then investigated the neuron-microglia signaling system involved in visceral pain chronification.

Results
We found that chemogenetic inhibition of TRPV1+ visceral afferents prevents microglial activation in the spinal cord and subsequent VHS in colitis mice. In contrast, chemogenetic activation, in the absence of colitis, enhanced microglial activation associated with VHS. We identified a purinergic signaling mechanism mediated by neuronal ATP and microglial P2RY12 receptor, triggering VHS in colitis. Inhibition of P2RY12 prevented microglial reactivity and chronic VHS post-colitis.

Conclusions
Overall, these data provide novel insights into the central mechanisms of chronic visceral pain and suggest that targeting microglial P2RY12 signaling could be harnessed to relieve pain in IBD patients who are in remission.

Funding Agencies
CCC
A60 THE NEURAL SIGNAL, CALCITONIN GENE-RELATED PEPTIDE (CGRG) ENHANCES A REGULATORY PHENOTYPE IN THE HUMAN IL-4 TREATED HUMAN MACROPHAGE
Authors: Callejas Pina B E , Wang A , Hamed S , Mckay D M 
Published: February 2022

Abstract

Background
Recent studies in pre-clinical models of disease have revealed the ability of murine and human IL-4-treated macrophages (M(IL4)) to promote wound recovery and reduce the severity of colitis. An unbiased RNA-sequence analysis of human blood-derived macrophages revealed increased expression of the RAMP1 chain of the CGRP receptor in IL-4 treated cells, raising the intriguing possibility of neural control of regulatory macrophages in the context of neuroimmune interaction in colitis. Thus, we sought to address if this mRNA signal translated into increased RAMP1 protein, if/how CGPR affected M(IL4) function, and if this applied to macrophages from patients with IBD as well as those from healthy donors.

Aims
To determine if CRGP-RAMP1 signalling in human IL-4 treated macrophages enhances a regulatory phenotype.

Methods
Peripheral blood mononuclear cells from healthy volunteers and individuals with IBD were cultured on plastic (2h, 37°C) and non-adherent cells removed. The adherent cells were cultured with recombinant hM-CSF (10 ng/ml) for 7 days. The resultant macrophages (2.5×105) were differentiated with IL-4 (48h 20 ng/mL) and assessed by qPCR and immunocytochemistry. In other cells, CGRP (10 nM) was added 24h after IL-4 and (1) cAMP (2) cytokines and (3) phagocytosis of inert FITC-beads measured, and (4) the capacity of supernatant from the cells to promote healing in wounded Caco2 epithelial monolayers tested.

Results
Compared to non-treated macrophages (M(0)), M(IL4)s from healthy individuals had increased mRNA for both chains of the CGRP-receptor (i.e. RAMP1 and CLR), and increased surface expression of the receptor as shown by immunostaining and CGRP-evoked cAMP. The IL-4 evoked RAMP1 mRNA was only detected in macrophages from 50% of the patients with active IBD. M(IL4)s treated with CGRP showed enhanced expression of the mannose receptor (CD206, allows detection of bacteria), increase phagocytosis of inert beads/macrophages. Moreover, CGRP increases VEGF and CCL18 expression in M(IL4), and soluble mediators from these cells promoted in vitro epithelial wound repair.

Conclusions
Reduced expression of CGRP and its receptor has been shown in IBD. The findings herein, demonstrating how CGRP-RAMP1 signalling can reinforce and enhance a regulatory, reparatory phenotype in human macrophages reveals another aspect of IBD pathophysiology. We speculate that loss of this neuroimmune axis (i.e. CGRP/Nerve-M(IL4) interaction) has the potential to significantly impair mucosal healing in IBD.

Funding Agencies
CCCAlberta Innovates in Health Innovation