bluuebunny/crossref_metadata_2025 huggingface dataset:
Reconsidering macroeconomic policy prescriptions with meta-analysis
Authors: Gechert Sebastian
Published: February 2022

This paper investigates recent developments in meta-analysis, the tool to quantitatively synthesize research in a certain body of literature. After providing a brief overview on how to do a meta-analysis and discussing recent methodological advancements, I review applied contributions to the field of macroeconomics. It turns out that meta-analyses have often questioned the conventional wisdom and established new consensuses in fiscal, monetary, and labor market policies by uncovering substantial publication bias and unexpected determining factors in many bodies of literature—in particular those dominated by policy conclusions in the neoclassical tradition like minimum wages, central bank strategies, financial regulation and the relative effects of tax and spending policies.
Salvage debulking surgery and hyperthermic intrathoracic chemotherapy for massive recurrent mesothelioma in the mediastinum
Authors: Poon Shi Sum , Alberti Caterina , Nardini Marco , Migliore Marcello
Published: February 2022

Mediastinal malignant pleural mesothelioma with signs of tamponade is rare. Indication for reoperation for recurrent malignant pleural mesothelioma is a controversial but viable option in selected patients. We report a case of a 68-year-old man presenting with epithelioid malignant pleural mesothelioma who underwent a total of three debulking surgeries (pleurectomy/decortication) combined with hyperthermic intrathoracic chemotherapy. Five years after the first procedure, a third urgent operation was performed for recurrence of a large mediastinal mesothelioma causing acute symptoms of pericardial constriction and tamponade. The patient was alive for eight years since the first treatment and 36 months after the second reoperation.
Reduced cytotoxicity by mutation of lysine 590 of Pseudomonas exotoxin can be restored in an optimized, lysine-free immunotoxin
Authors: Ammon A , Mellenthin L , Emmerich C , Naschberger E , Stürzl M , Mackensen A , Müller F
Published: February 2022

Immunotoxins, which are fusion proteins of an antibody fragment and a fragment of a bacterial or a plant toxin, induce apoptosis in target cells by inhibition of protein synthesis. ADP-ribosylating toxins often have few lysine residues in their catalytic domain. As they are the target for ubiquitination, the low number of lysines possibly prevents ubiquitin-dependent degradation of the toxin in the cytosol. To reduce this potential degradation, we aimed to generate a lysine-free (noK), Pseudomonas exotoxin (PE)-based immunotoxin. The new generation 24 kDa PE, which lacks all but the furin-cleavage site of domain II, was mutated at lysine 590 (K590) and at K606 in a CD22-targeting immunotoxin and activity was determined against various B cell malignancies in vitro and in vivo. On average, K590 mutated to arginine (R) reduced cytotoxicity by 1.3-fold and K606R enhanced cytotoxicity by 1.3-fold compared to wild type (wt). Mutating K590 to histidine or deleting K590 did not prevent this loss in cytotoxicity. Neither stability nor internalization rate of K590R could explain reduced cytotoxicity. These results highlight the relevance of lysine 590 for PE intoxication. In line with in vitro results, the K606R mutant was more than 1.8-fold more active than the other variants in vivo suggesting that this single mutation may be beneficial when targeting CD22-positive malignancies. Finally, reduced cytotoxicity by K590R was compensated for by K606R and the resulting lysine-free variant achieved wt-like activity in vitro and in vivo. Thus, PE24-noK may represent a promising candidate for down-stream applications that would interfere with lysines.
Does the Pachytene Checkpoint, a Feature of Meiosis, Filter Out Mistakes in Double-Strand DNA Break Repair and as a side-Effect Strongly Promote Adaptive Speciation?
Authors: Foe Victoria E
Published: February 2022

Synopsis

This essay aims to explain two biological puzzles: why eukaryotic transcription units are composed of short segments of coding DNA interspersed with long stretches of non-coding (intron) DNA, and the near ubiquity of sexual reproduction. As is well known, alternative splicing of its coding sequences enables one transcription unit to produce multiple variants of each encoded protein. Additionally, padding transcription units with non-coding DNA (often many thousands of base pairs long) provides a readily evolvable way to set how soon in a cell cycle the various mRNAs will begin being expressed and the total amount of mRNA that each transcription unit can make during a cell cycle. This regulation complements control via the transcriptional promoter and facilitates the creation of complex eukaryotic cell types, tissues, and organisms. However, it also makes eukaryotes exceedingly vulnerable to double-strand DNA breaks, which end-joining break repair pathways can repair incorrectly. Transcription units cover such a large fraction of the genome that any mis-repair producing a reorganized chromosome has a high probability of destroying a gene. During meiosis, the synaptonemal complex aligns homologous chromosome pairs and the pachytene checkpoint detects, selectively arrests, and in many organisms actively destroys gamete-producing cells with chromosomes that cannot adequately synapse; this creates a filter favoring transmission to the next generation of chromosomes that retain the parental organization, while selectively culling those with interrupted transcription units. This same meiotic checkpoint, reacting to accidental chromosomal reorganizations inflicted by error-prone break repair, can, as a side effect, provide a mechanism for the formation of new species in sympatry. It has been a long-standing puzzle how something as seemingly maladaptive as hybrid sterility between such new species can arise. I suggest that this paradox is resolved by understanding the adaptive importance of the pachytene checkpoint, as outlined above.
Dietary supplementation with lysine (protein) stimulates mammary development in late pregnant gilts
Authors: Farmer Chantal , Palin Marie-France , Hovey Russell C , Falt Tara D , Huber Lee-Anne
Published: February 2022

The goal of this project was to determine if standardized ileal digestible (SID) lysine provided at 40% above estimated requirements, with the concomitant increase in protein intake, from days 90 to 110 of gestation would stimulate mammary development in gilts. From day 90 of gestation, Yorkshire × Landrace gilts were fed 2.65 kg of either a conventional diet (CTL, control, n = 19) providing 18.6 g/d of SID Lys or a diet providing 26.0 g/d of SID Lys via additional soybean meal (HILYS, n = 19). Both diets were isoenergetic. Jugular blood samples obtained on days 90 and 110 of gestation were used to measure concentrations of insulin-like growth factor-1 (IGF-1), metabolites, and amino acids (AA). Gilts were necropsied on day 110 ± 1 of gestation to obtain mammary glands for compositional analyses, immunohistochemistry, and analysis of mRNA abundance for AA transporters and markers of cell proliferation and differentiation. The HILYS gilts gained more body weight (P < 0.01) during the experimental period compared with CTL gilts, and had greater fetal weights (1.29 vs. 1.21 ± 0.03 kg, P < 0.05). There was no difference in circulating IGF-1, glucose, or albumin (P > 0.10) between HILYS and CTL gilts on day 110 of gestation, whereas concentrations of urea and free fatty acids were greater (P < 0.01), and those of Trp and Ala were lower (P < 0.05), in HILYS than CTL gilts. The provision of lysine at 40% above estimated requirements increased total mammary parenchymal mass by 44%, as well as total parenchymal fat, protein, DNA, and RNA (P < 0.01). The mRNA abundance of ACACA was greater (P < 0.05) in HILYS than CTL gilts, while only the AA transporter SLC6A14 tended (P < 0.10) to be greater. Results demonstrate that providing dietary Lys above current National Research Council recommendations in late gestation increases mammary development in gilts. Results also indicate that Lys may have been limiting for protein retention. These data suggest that the use of a two-phase feeding strategy during gestation, whereby dietary Lys is increased from day 90, could benefit potential sow milk yield in the subsequent lactation.
A9 SIALIC ACID METABOLISM PLAYS A KEY ROLE IN INTESTINAL FITNESS AND VIRULENCE OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN
Authors: Liang Q , Allaire J M , Yu H , Crowley S M , Han X , Vallance B
Published: February 2022

Background

The gastrointestinal (GI) mucus barrier acts as an important interface between the host and luminal gut microbes, beyond its role in limiting direct contact between noxious luminal agents and the underlying intestinal epithelium. Mucus is comprised of highly glycosylated mucin proteins, modified by O-glycan side chains, formed by five sugar monomers, including sialic acid. Sialic acid frequently occupies the terminal position of O-glycans and can be cleaved by microbial sialidases. We hypothesize that upon entering their hosts, enteric pathogens, such as the attaching and effacing (A/E) family (EHEC, EPEC and Citrobacter rodentium) metabolically adapt to their intestinal environment, and express key virulence factors by sensing and metabolizing mucin sugars, such as sialic acid.

Aims

Investigate the role of sialic acid in regulating the fitness and virulence strategies of the A/E pathogen C. rodentium within the GI environment.

Methods

C57Bl/6 mice were orally infected with either wildtype (WT) or mutant strains of C. rodentium to study bacterial pathogenicity in vivo. Sialic acid was localized in mouse colonic tissue sections through lectin staining, and quantified in mouse feces and mucus scrapings using a commercial kit. Protein secretion by C. rodentium, in the presence or absence of sialic acid was analyzed by SDS-PAGE and mass spectrometry. Intestinal epithelial cell lines were infected with enteropathogenic E. coli (EPEC) or C. rodentium to examine bacterial adherence.

Results

Sialic acid was expressed widely in the GI tracts of mice, primarily in the colonic mucus layer and by intestinal goblet cells. Both EPEC and C. rodentium were found to take up and metabolize sialic acid through the transporter NanT. A C. rodentium strain deficient in sialic acid uptake ( ΔnanT) was dramatically impaired in colonizing the intestines of mice and was rapidly cleared. Sialic acid also impacted C. rodentium’s virulence by inducing the secretion of two key virulence factors, which significantly enhanced the pathogen’s adhesion to intestinal epithelial cells. Moreover, sialic acid increased C. rodentium’s ability to degrade mucus, due to the increased production of these two secreted virulence factors.

Conclusions

We demonstrate that sialic acid, a mucin-derived sugar, is an essential nutrient for A/E pathogens to thrive and expand within their host’s intestines. Moreover, sialic acid enhances pathogen virulence by inducing secretion of two important virulence factors, which increase adhesion to the epithelium and promote the degradation of mucus.

Funding Agencies

CCC, CIHRCH.I.L.D. Fdn
A19 PROTEOMICS FOR PREDICTING NECROTIZING ENTEROCOLITIS IN THE PREMATURE NEONATE
Authors: Shajari E , Gagné D , Thibault M , Tremblay É , Gryspan D , Ferretti E , Bertelle V , Beaulieu J
Published: February 2022

Background

Necrotizing enterocolitis (NEC) represents a major challenge in neonatal intensive care units (NICU). The search for indicators that could be used to predict the development of NEC, which would provide more time to apply targeted interventions in the NICU before the appearance of the symptoms is required.

Aims

The aim of the present work was to investigate the potential of fecal proteomics signatures for NEC prediction

Methods

In the present study, stools from 132 very low birth weight infants (less than 1500 g and born younger than 30 weeks) were collected daily in the context of a multi-center prospective study. Seven of the infants received a stage 3 NEC diagnosis. Stools collected up to 10 days before diagnosis were included and each NEC was matched with 2 non-NEC controls. These samples had been used to evaluate various biomarkers by ELISA in a previous study, which revealed that lipocalin-2 and calprotectin used in conjunction can allow the prediction of half of very low birth weight infants 7 days before their NEC diagnosis (Thibault et al., Ped Res 2021). Herein, we explore a proteomics approach to investigate whether this predictability can be improved. The same stool samples were thus prepared and processed for liquid chromatography-tandem mass spectrometer analysis (TripleTOF 5600) coupled with SWATH acquisition software.

Results

Data were analyzed by Skyline using the peptide transition list of a spectral library leading to the identification of 1374 proteins with a minimum of two peptides. From these, 192 proteins (1061 peptides) were detected at strong levels in a majority of the samples while 37 of them (2–4 peptides/protein, 102 peptides) were found to display significantly altered levels between NEC and non-NEC samples (17 up; 20 down) based on statistical analyzes and displaying an AUC ≥ 0.7 (ROC curve). Interestingly, both sets of peptides for the NEC samples were significantly different from controls for all three tested periods (group 1: -10 to -7, group 2: -6 to -3, and group 3: -2 to +1 days before diagnosis) using One-way ANOVA Dunnett’s multiple comparison test, p < 0.001. Furthermore, analyzing the data for each infant confirmed the usefulness of the peptide signature for predicting NEC development in 6 of the 7 available cases one week in advance of the diagnosis.

Conclusions

Taken together, these results indicate that stool proteomics represents a promising potential approach for predicting NEC in very low-weight infants.

Funding Agencies

CIHR
A20 INTESTINAL SMOOTH MUSCLE AND FIBROSTENOSIS: TARGETING NR4A1 TO MODULATE PROLIFERATIVE SIGNALLING
Authors: Lee J , Szczepanski H E , Flannigan K L , Hirota S A
Published: February 2022

Background

Fibrostenotic Crohn’s Disease (CD), presenting with intestinal fibrosis and stricture formation, has a substantial impact on patient quality of life. Given our poor understanding of its etiology, we lack viable preventative and therapeutic methods. While much focus has been on the fibrotic component, recent studies have implicated the role of intestinal smooth muscle cell (SMC) hyperplasia/hypertrophy in stricture formation. These data suggest targeting SMC proliferation may provide benefit for fibrostenotic CD patients. NR4A1 (nuclear receptor subfamily 4 group A member 1) is an orphan nuclear receptor that has shown to regulate inflammation in experimental models of colitis and dampen SMC proliferation and fibrotic signalling in intestinal and non-intestinal systems. Thus, we sought to characterize the role of NR4A1 in regulating proliferative signalling in intestinal SMCs to determine whether it could be a therapeutic target for fibrostenotic CD.

Aims

To determine how NR4A1 regulates intestinal SMC proliferative responses to mitogenic signalling.

Methods

Primary intestinal SMCs were isolated from the colonic tissue of Nr4a1+/+ and Nr4a1-/- mice. A commercially available human colonic SMC line was also used. EdU incorporation assays were used to quantify the relative proliferation of Nr4a1+/+ and Nr4a1-/- SMCs in their basal or stimulated state (with platelet-derived growth factor (PDGF)-BB). In addition, NR4A1 was activated using selective agonists, cytosporone-B (Csn-B) and 6-mercaptopurine (6-MP). Differences in PDGF-BB-induced intracellular signalling was determined using western blotting of phosphorylated proteins after stimulation. Quantification of PDGF receptor transcript expression in Nr4a1+/+ and Nr4a1-/- SMCs was done using qPCR. Finally, immunofluorescence was used to determine the localization of NR4A1 when stimulated with Csn-B, 6-MP, and/or PDGF-BB.

Results

The proliferation assays showed that Nr4a1-/- SMCs exhibit greater proliferation at baseline and when stimulated with PDGF-BB, compared to Nr4a1+/+ SMCs. However, this was not associated with any differences in the intracellular signalling directly downstream of PDGF receptor activation. Specifically, there were no differences in the intensity and temporal characteristics of Akt- and Erk1/2-phosphorylation between Nr4a1+/+ and Nr4a1-/- SMCs. Interestingly, Nr4a1-/- SMCs had less expression of Pdgfrb, the gene encoding PDGF receptor beta, when compared to Nr4a1+/+ SMCs. However, no changes in receptor expression were observed when SMCs were stimulated with Csn-B and 6-MP.

Conclusions

We show that NR4A1 regulates basal and PDGF-BB-induced SMC proliferation, without directly altering the intracellular signalling cascades induced by receptor activation. Our data supports NR4A1 as a target to control the aberrant SMC proliferation that contributes to fibrostenosis.

Funding Agencies

CIHR
A22 IMPACT OF COVID-19 PANDEMIC ON FOREIGN BODY INGESTION IN CHILDREN AND ADOLESCENTS: A CROSS-SECTIONAL STUDY
Authors: Zhao Y , Dehbidi Assadzadeh L , Gallant A , Gorenko-Lévêque S , Chekkal A , Djoukam Mbuko B , Pierre N , Dirks M , Groleau V , Lapointe A , Ngwanou D , Piché N , Deslandres C , Gravel J , Jantchou P
Published: February 2022

Background

Foreign Body Ingestions (FBI), sometimes associated with severe complications, are a common reason for emergency unit visits in children. In Quebec, since March 2020, the restrictions in response to the COVID-19 pandemic have increased the time children spend at home. We hypothesized that this could contribute to a rise in FBI incidence and severity.

Aims

The primary objective of our study was to evaluate the incidence as well as the clinical presentation of FBI cases seen at CHU Sainte-Justine Children’s Hospital in Montreal (CHUSJ) during the COVID-19 pandemic as compared to the two previous years. Our secondary objectives were to estimate the rate of severe FBI (involving hospitalisations and/or complications) and to evaluate the nature of the foreign bodies that were ingested.

Methods

All children referred to or who presented at CHUSJ for FBI between March 2018 and February 2020 (pre-pandemic) as well as between March 2020 and February 2021 (pandemic) were included (n=690). Cases of food impaction were excluded (n=78). Incidence of FBI was calculated by dividing the number of FBI cases by the total number of emergency department visits per period. Differences between the two groups were analyzed by Student T test or Chi-square test.

Results

Between March 2018 and February 2021, 612 patients (median age 3.5 years (1.6–5.9); 54% male) were eligible. The mean monthly number of FBI cases (min-max) in 2020–2021 was 18.6 (9–28), significantly higher than the year 2018 [16.6 (8–22)] and the year 2019 [15.5 (9–24)]; p=0.04. The incidence rate of FBI doubled during the pandemic as compared to the prepandemic group: respectively 57.5/10,000 emergency department visits and 23.2/10,000 visits (p=0.002). Almost one fourth of the cohort was hospitalized. The hospitalization rate (>1 day) was similar between the 2 periods: 8.8% before the pandemic and 7.1% during the pandemic. Digestive endoscopy was performed in 21.5% of cases, a rate similar before and during the pandemic. A total of 3.3% of the children developed complications related to FBI. This rate remained stable between the two periods. The most frequently ingested objects were coins (25.0%), toys (10.8%), button batteries (10.6%), magnets (6.2%), and jewellery (6.2%). There was no significant difference in the nature of FB ingested between the 2 periods although the number of magnet ingestions increased during the pandemic (18 per year vs 10 per year).

Conclusions

The incidence of FBI increased significantly during the pandemic in comparison with the two previous years. The high hospitalization and complications rates, although stable during the pandemic, underline the significant impact of pediatric FBI.

Funding Agencies

None
A32 DEVELOPMENT AND VALIDATION OF THE TORONTO UPPER GASTROINTESTINAL CLEANING SCORE
Authors: Seleq S , Khan R , Gimpaya N , Vargas J I , Amin S , Bilal M , Bollipo S , Charabaty A , de-Madaria E , Hashim A , Kral J , Pawlak K M , Sandhu D S , Lui R N , Sanchez-Luna S , Siau K , Mosko J , Grover S
Published: February 2022

Background

High quality esophagogastroduodenoscopy (EGD) depends on the ability to appropriately visualize upper gastrointestinal (GI) mucosa pathology. Evaluation can be limited by the presence of mucus, foam, bubbles and solid materials. Currently, there is no standardized method to assess mucosal visualization for use in clinical or research settings.

Aims

To develop and establish the content validity of the Toronto Upper Gastrointestinal Cleaning Score (TUGCS) and evaluate its interrater reliability.

Methods

An international panel of endoscopy experts rated potential items and their associated anchors for importance as indicators of adequacy of mucosal visualization during EGD. The survey utilized a Likert scale (1 (strongly disagree) to 5 (strongly agree)). The Delphi process was repeated until consensus was reached. Consensus was defined priori as ≥80% of experts in a given round scoring ≥4 on all survey items. To assess content validity, 48 EGD procedures were evaluated in real-time by two endoscopist reviewers using the TUGCS at a single institution. The interrater agreement between assessments was calculated for TUGCS total scores using intraclass correlation coefficient, one-way random effects model (ICC 1,1).

Results

Fourteen experts agreed to be part of the Delphi panel. An anatomical framework representing the upper GI mucosa and anchors for each mucosal portion representing various levels of visibility was generated through systematic review. Three survey rounds, with response rates of 100%, 100% and 71% respectively, achieved consensus. The final TUGCS includes four anatomical areas (fundus, body, antrum, duodenum) and mucosal visualization anchors ranging from 0 to 3 (Figure 1). TUGCS was used to assess foregut cleaning in 48 procedures (Table 1). The mean TUGCS for staff and trainee were 8.1 (±2.4) and 8.1 (±2.6), respectively. The ICC was 0.78 (95% confidence interval 0.62–0.88) indicating good reliability.

Conclusions

We developed and generated content validity evidence for the TUGCS through rigorous Delphi methodology, reflective of practice across different centres. Planned as future research is a video survey distributed to endoscopists internationally to further validate the TUGCS to create a tool that may be used to judge mucosal visualization for EGD in research and clinical settings.

Funding Agencies

None
A38 EVALUATING GLYCOCAGED DEXAMETHASONE IN SHIP-DEFICIENT MICE
Authors: Luzentales-Simpson M , Jung H , Menzies S , Ma W , Wang C , Brumer H , Sly L M
Published: February 2022

Background

Corticosteroids systemically reduce immune system activity thereby limiting inflammation in the GI tract. Corticosteroid use is limited by deleterious systemic effects including immunosuppression and adverse effects on growth and development (Giles et al., 2018). The metabolism of dietary polysaccharides, such as plant cell wall xyloglucan, by gut symbionts has been demonstrated to be mediated by niche members of the human gut microbiota (Larsbrink et al., 2014). By caging corticosteroids like dexamethasone (DEX) with xyloglucans to be released by microbiota at the site of disease, there is potential to increase efficacy and limit adverse effects.

Mice deficient in Src homology 2 domain-containing inositol polyphosphate 5’-phosphatase (SHIP-/-) develop spontaneous CD-like ileal inflammation (Ngoh et al., 2016). We have used SHIP-/- mice to compare the efficacy of DEX versus caged DEX to reduce intestinal inflammation.

Aims

Caged DEX will reduce CD-like ileal inflammation in SHIP-/- mice at a lower dose than uncaged DEX because it is released and acts at the site of inflammation.

To assess this hypothesis we propose 3 aims:

Measure decaging activity along the GI tract of SHIP-/- mice ex vivo

Determine the minimum effective dose of DEX required to reduce ileal inflammation in SHIP-/- mice

Determine if equimolar and lower concentrations of caged DEX can reduce ileal inflammation in SHIP-/- mice

Methods

Intestinal contents and feces were harvested from SHIP-/- mice. Decaging activity was measured ex vivo, using caged resorufin (a fluorescent reporter).

SHIP-/- mice were orally gavaged with dexamethasone (or vehicle), or the molar equivalent of caged dexamethasone from 6–8 weeks of age. At 8 weeks of age, gross and histopathology were assessed and IL-1β concentrations were measured in full-thickness tissue homogenates.

Results

SHIP-/- mice demonstrated decaging activity in the cecal, colon, and fecal contents assayed. DEX treatment (3 or 1 mg/kg) of SHIP-/- mice eliminated CD-like gross pathology and histopathology, and reduced IL-1β concentrations in full-thickness ileal tissue homogenates from SHIP-/- mice compared to untreated or vehicle-treated mice. DEX did not have any harmful effects on the intestines of SHIP+/+ mice. 1 or 0.3 mg/kg molar equivalent of caged DEX (3-fold lower concentrations) eliminated CD-like gross pathology in SHIP-/- mice compared to treatment with vehicle control. Additionally, the mean IL-1β concentration in tissue homogenates of mice treated with the molar equivalent of 1 mg/kg caged DEX was reduced

Conclusions

SHIP-/- mice express decaging activity are effectively treated by DEX, and caged DEX shows similar efficacy at reducing SHIP-/- ileal pathology at lower concentrations than uncaged DEX. In future experiments, we will examine caged DEX at a lower concentration, and in 2nd mouse model of intestinal inflammation.

Funding Agencies

GlycoNet
A40 IDENTIFYING NOVEL ROLES FOR TLR2 SIGNALING IN THE INTESTINAL EPITHELIUM USING ORGANOIDS
Authors: Chen Y , Allaire J M , Han X , Yang H , Crowley S M , Vallance B
Published: February 2022

Background

Inflammatory bowel disease (IBD) is thought to result from an imbalance between protective and damaging immune responses to the resident microbiota and other luminal antigens. Increasing evidence suggests that toll-like-receptor (TLR)-mediated innate immune dysfunction contributes to the pathogenesis of IBD. Among the receptors in the TLR family, TLR2 and its signalling pathway appears to play an important protective role in the gastrointestinal (GI) tract. Notably, our group previously discovered that Tlr2 expression by nonhematopoietic cells played an important protective role in the Citrobacter rodentium model of infectious colitis.

Aims

To determine if intestinal epithelial cells (IECs) control Tlr2 dependent tissue protective responses, we sought to characterize the role of Tlr2 signalling in intestinal organoids. In addition, to better define the role of Tlr2 during C. rodentium infection, we developed a novel in vitro model of C. rodentium infection using organoid-derived monolayers.

Methods

Organoids were derived from the colonic tissue of wild type (C57BL/6J) and Tlr2 deficient (-/-) mice and then stimulated with Tlr2 agonists, and their responses were evaluated by qPCR, ELISA, Western blot and immunostaining. In addition, 2D monolayers were grown from organoids, and infected with C. rodentium to explore whether Tlr2 signaling regulates other protective IEC functions such as barrier proteins and cell death in response to noxious stimuli.

Results

Stimulation of WT, but not Tlr2-/- mouse orgnaoids led to increased transcription of chemokine and cytokine genes Ccl20, Mcp-1, Cxcl1 and Tnf-α. This was accompanied by increased protein secretion through a NF-κB and p38 MAP kinase dependent mechanism. Interestingly, organoids derived from the distal colon displayed stronger Tlr2 responses than organoids from the proximal colon. During C. rodentium infection of monolayers, Tlr2 signaling had no effect on the distribution of tight junction proteins such as ZO-1 or Claudin3, however, Tlr2 did regulate levels of IEC apoptosis upon C. rodentium infection.

Conclusions

Our study demonstrates that colonic organoids express functional Tlr2, which upon stimulation, leads to pro-inflammatory responses as well as control over cell death. Our novel C. rodentium infection model enables us to further study the role of IEC in promoting host defense during bacterial infection. Futher work will examine how interactions with Tlr2 dependent cytokines (ie. IL-6, IL-22) impact IEC responses to C. rodentium.

Funding Agencies

CCC, CIHRCH.I.L.D
A54 DIETARY COMPONENTS ARE ASSOCIATED WITH FECAL CALPROTECTIN IN ULCERATIVE COLITIS
Authors: Chiu E , Taylor L , Ingram R , Panaccione R , Ghosh S , Ramay H , McCoy K , Reimer R , Raman M
Published: February 2022

Background

Ulcerative colitis (UC) is thought to arise from dysregulated immune responses due to intestinal dysbiosis and altered epithelial barrier function. Dietary components may affect the gut microbiome and contribute to either inflammation or its resolution. The relationship between diet and disease activity in UC warrants further investigation.

Aims

This prospective cohort study explored the relationship between dietary components, and markers of disease activity: fecal calprotectin (FCP) and partial Mayo score (PMS) in patients with UC.

Methods

40 participants were recruited from University of Calgary IBD clinics. Study staff obtained two 24-hour diet recalls using the validated automated self administered (ASA)-24 and captured PMS at baseline (T1) and follow-up at week 12 (T2). FCP samples were collected at T1 and T2. Diet variables included adjusted macro/micronutrients (n=44), food groups (n=36) and the validated Canadian healthy eating index-2009 (CHEI) where higher scores reflect healthier intake. CHEI captures intake of dark green and orange foods (DGO) and moderation scoring (MOD) of saturated fats (SF), sodium and added sugars. Higher CHEI scores result from increased intake of DGO and lower intake of SF, sodium and added sugars (higher MOD score). Associations with outcome variables were examined at T1 and T2 individually and across both timepoints (BT). Mixed effect logistic regression models identified relationships between dietary variables, FCP and PMS. Models were adjusted for age, sex, BMI, medications, probiotics, and for repeated measures in both timepoint analyses.

Results

A positive association was identified between FCP as a continuous variable and SF (T1:Coef=0.22, p_adj=0.02) and a negative association identified between FCP with citrus/melon/berries (BT:Coef=-1.01, p_adj =0.04), total sugars (BT:Coef=-0.06, p_adj=0.025) and HEI (BT:Coef=-0.13, p_adj =0.06 and T1 coef=-0.18, p_adj =7.0 e-5). FCP increased as SF (-0.30,p_adj=0.01), DGO (-0.60, p_adj=0.02), and MOD (-0.21, p_adj=0.02) scores decreased. The presence of inflammation (as a binary variable, FCP >250) was negatively associated with higher fiber intake (BT: Odds Ratio (OR)= 0.016, CI(0.001,0.40) p_adj=0.08). For PMS as a continuous variable, HEI had a negative association with PMS (T2: -0.05, p_adj=0.06). With PMS as a discrete score (remission=PMS<2) there was no significant association with any diet components.

Conclusions

This study suggests that a healthier diet, both in overall pattern and specific dietary components, was associated with lower FCP and PMS. Our findings related to SF, citrus/melons/berries, and DGO parallel the IOIBD dietary guidelines. Future research should explore through controlled intervention studies whether modifying dietary patterns and components independently reduces disease activity.

Funding Agencies

Crohn’s and Colitis Foundation
A67 ABC, EASY AS 123, SIMPLE AS GLUTEN-FREE? KNOWLEDGE AND ADHERENCE IN ADOLESCENTS WITH CELIAC DISEASE
Authors: Pohoreski K , Gidrewicz D
Published: February 2022

Background

Research shows that adolescents with celiac disease (CeD) are at great risk for non-adherence to the gluten-free diet (GFD), and that knowledge of the GFD may play a role in adherence.

Aims

The primary objective of this study was to examine the relationship between patient knowledge and adherence to the GFD in a local population of adolescents with CeD. Secondary objectives were to identify information sources used to learn about the GFD, and compare adolescent and parent knowledge of the GFD.

Methods

Adolescents with CeD (12–17 years) were recruited at pediatric gastroenterology clinics in Calgary, Alberta. Preliminary data was collected October 2020 to August 2021. Both the adolescent and a parent were asked to complete a 5 minute online survey received via email. Survey measures included a validated adherence scale (Biagi score) and a unique knowledge assessment (GFD-Q), adapted from a previously published questionnaire. GFD-Q scores were categorized as “sufficient knowledge” based on correctly identifying 3/3 gluten-containing foods, at least 4/7 of gluten-free foods, and at least 4/7 foods that may contain gluten. Respondents submitted demographic and clinical information, as well as reviewed information sources used to learn about the GFD.

Results

Initial data were reviewed for 25 participant pairs (adolescent with respective parent), with a planned sample size of 40 participant pairs. Most adolescents (96%) reported adherence to the GFD (Biagi score of 3 or 4). Eleven (44%) adolescents had sufficient knowledge of the GFD. About 90% of adolescents correctly identified which foods to question, however, 20% did not correctly identify a gluten-containing food (namely malt), and 36% did not identify most gluten-free foods (such as maltodextrin and balsamic vinegar). Parents scored higher on the GFD-Q with 17/25 (68%) demonstrating sufficient knowledge. Interestingly, of the 11 adolescents with sufficient knowledge, 10/11 (91%) respective parents also had sufficient knowledge. Most adolescents and parents identified the gastroenterologist, another individual with CeD, and Google as helpful information sources. Adolescents also indicated their parents were a helpful information source.

Conclusions

While the study is still enrolling to reach sample size, we acknowledge that most adolescents in our study report being adherent to the GFD. However, their reported knowledge is variable, especially in knowing which foods are safe to eat. Thus, education should also focus as much on which foods to avoid, as well as safe foods to consume. Parent knowledge of the GFD may have a role in adolescent knowledge. At study completion, descriptive statistics will be used to examine participant characteristics and identify trends to assist in the development of future health education for adolescents with CeD.

Funding Agencies

Canadian Celiac Association - James A.Campbell Research Fund
A80 CANADIAN NEUROGASTROENTEROLOGY NETWORK (CNN) SURVEY ON PH/MOTILITY TESTING IN CANADA
Authors: Reed D E , Beyak M J , Rodrigues D , Vanner S , Paterson W G
Published: February 2022

Background

Anecdotal reports suggest that access to pH/motility testing is problematic in Canada, but to date there is little data documenting this.

Aims

To assess the volume and accessibility of motility lab testing in Canada.

Methods

The CNN developed a questionnaire directed at the scope, volume and accessibility of pH/motility testing in Canadian labs. Fifty-three labs were identified using lists provided by companies that supply pH/motility recording equipment in Canada. Of these, 12 labs were excluded (10 had incorrect or absent contact information, 1 had recently closed and 1 had just opened). Questionnaires were sent in early 2020 to the remaining 41 labs, and respondents were asked to use data from their last fiscal year pre-pandemic.

Results

26 completed questionnaires were returned (i.e., 63% response rate, but representing ~ 51% of active labs): 23 adult units (7 community, 15 academic and 1 private) and 3 academic pediatric units. Of the adult units, 6 performed studies in children <12 yrs old. All 3 pediatric units provided both esophageal and anorectal high-resolution manometry (HRM) and pH/Impedance recording, with wait times of < 3 months. All 23 adult labs provided esophageal HRM, but just 50% performed anorectal manometry and only 3 anorectal manometry with biofeedback. Ambulatory pH/Impedance was performed in all but 1 adult unit. 15 of 23 adult centres reported access to colon transit studies and only one performed colonic manometry. No units performed antroduodenal manometry. Five units offered Bravo wireless pH recording and 4 performed ENDOFLIP. In adult units, the median number of procedures per year were as follows: esophageal HRMs - 278 (range: 50–1140); pH/impedance - 225 (range: 40–634); anorectal manometry - 90 (range: 10–450). Corresponding median wait times in months were as follows: esophageal HRM - 4 (range: 0.5–14); pH/Impedance - 4.5 (range: 0.5–14); anorectal manometry - 4.6 (range: 2–9). Only 6 of the 23 adult units met recommended wait time targets of <2 months. Testing was performed by a nurse in ~ 80% of centres, while testing was done by technicians in 2 units and physicians in 3 units. 8 units accepted referrals from primary care physicians, whereas the remainder only accepted specialist referrals. 50% screened referrals for appropriateness and restricted access accordingly.

Conclusions

The scope of motility and pH testing across Canada is variable, with lower GI testing lacking in many regions. Wait times vary significantly across labs and the majority of centres exceed recommended limits of 2 months. The reasons underlying the identified limitations to pH/motility testing access warrant further study.

Funding Agencies

None
A84 SECURE ELECTRONIC DOCUMENT SIGNING UPTAKE IN BIOLOGIC PRESCRIBING FOR IMMUNE MEDIATED DISEASES
Authors: Sharma S , Jones J , Stewart M
Published: February 2022

Background

The COVID-19 pandemic drastically impacted workflows in gastroenterology practice. Physicians managing immune-mediated diseases (IMDs) must complete special authorization (SA) and prescription renewal (Rx) forms for patients on biologic therapy. This adds significant administrative burden potentially leading to delays in therapy initiation and care continuity. Historically, document completion has largely been paper-based, with forms faxed between patient support programs (PSPs) and physician offices. Disruption of normal office processes during the pandemic necessitated the movement of existing paper-based workflows online. The use of secure electronic document signing (SEDS) platforms has allowed physicians to receive and complete documents digitally.

Aims

To evaluate the impact of SEDS-based biologic documentation on clinical practice. Objectives were 1) to determine if the use of SEDS platforms increased timeliness of document returns compared to traditional workflows 2) assess whether SEDS usage is acceptable and sustainable and 3) assess MD satisfaction with SEDS platforms.

Methods

This was a retrospective audit of SEDS and paper-based biologic document workflows from a single PSP (Abbvie Care). Outcomes of interest were the number of documents completed monthly using SEDS, new monthly users, and the number of active monthly users between April 1, 2020-March 31, 2021. Time (days) to SEDS completion (vs. paper process) was determined by reviewing timepoint data for SA and Rx documents from May 2019-January 2020 (‘pre- SEDS’) and for SEDS documents from May 2020-January 2021(‘SEDS’). The return time (RT) was defined as the time between date sent to a physician’s office by the PSP to the date returned to the PSP. Documents in the pre-SEDS cohort with a RT exceeding 30 days were excluded

Results

In totality, 5573 SA and Rx documents were completed by 383 physicians using the SEDS platform from April 2020-March 2021. A mean of 14.6 (sd 21.8) documents were signed per physician. The number of monthly electronic documents processed increased from 104 in April 2020 to 800 in March 2021. Active monthly users increased from 24 in April 2020 to 213 in March 2021 (31 new users monthly). A total of 19,387 paper documents were processed during the ‘pre-SEDS’ period and 3,317 electronic documents processed in the ‘SEDS’ period. The mean RT in the ‘pre-SEDS’ period was 8.03 days (Sd 8.2) and the ‘SEDS’ period was 1.11 days (sd 2.6).

Conclusions

This data demonstrates acceptability, appropriateness, and improved processing efficiency of a SEDS platform improving timeliness of patient care. Next steps in this research include surveying physicians to understand the work-flow impact of SEDS, functionality, long-term sustainability, satisfaction and impacts on disease related outcomes.

Funding Agencies

None
A88 UNDERSTANDING NURSE PERCEPTIONS OF CARING FOR PATIENTS WITH ALCOHOL USE DISORDER: A CROSS-SECTIONAL STUDY
Authors: Hyde A , Johnson E , Bray C , Meier T , Carbonneau M , Spiers J , Tandon P
Published: February 2022

Background

Alcohol Use Disorder (AUD), the problematic consumption of alcohol, affects 107 million people worldwide. AUD increases morbidity and mortality and has a substantial impact on daily functioning including quality of life, relationships and employment. AUD is particularly detrimental in patients who already have liver damage like cirrhosis. The management of AUD includes screening, brief intervention and referral to treatment for psychological and pharmacotherapy based treatment. People with AUD have frequent interactions with the healthcare system. These interactions represent opportunities to engage patients with therapy. As front-line workers who have maximal contact with patients, nurses practicing in acute care are in an ideal position to initiate AUD related discussion with patients. Prior to the design of an educational intervention to increase nursing engagement with AUD screening and brief intervention, there is a need to understand baseline knowledge, attitudes and perceptions in this group.

Aims

The aim of the present study was to explore the knowledge, attitudes and perceptions of nurses caring for patients with cirrhosis and AUD.

Methods

We conducted a cross-sectional survey using the Survey of Attitudes and Perceptions (SAP). The SAP is derived from a validated tool to assess attitudes and perceptions towards patients with AUD. Anonymous surveys were distributed on inpatient medicine units across 5 geographic zones in Alberta between September 2019-March 2020. Data were analyzed using descriptive and inferential statistics.

Results

A total of 93 nurses from 7 inpatient medicine units across Alberta participated in the study. The majority of participants were Registered Nurses (74.9%), who practiced in an urban setting (69%), and had worked in their role for an average of 9.9 years. Few (22.6%) participants reported any prior structured education on caring for patients with AUD, with the majority reporting limited knowledge of alcohol and effects of alcohol consumption. Though most reported that caring for patients with AUD was part of their professional role, only 15.7% felt motivated to work with this group of patients. Responses to individual questions or sub-domains of the survey did not significantly differ by length or time in professional role, or practice setting.

Conclusions

Our results indicate that nurses have limited knowledge on caring for patients with AUD. Given the importance of AUD in the development and progression of cirrhosis as well as the frequency of hospitalizations for patients with cirrhosis, increasing nurse knowledge of AUD is crucial to improving the quality of care for these patients. The results of this study will be used to inform the development of an educational intervention to increase nursing knowledge of caring for patients with cirrhosis and AUD.

Funding Agencies

Alberta Innovates
A92 EDUCATIONAL INTERVENTIONS TO IMPROVE ERGONOMIC PERFORMANCE IN GASTROINTESTINAL ENDOSCOPY: A SYSTEMATIC REVIEW
Authors: Bansal R , Scaffidi M , Gimpaya N , Fecso A , Khan R , Li J , Torabi N , Shergill A , Grover S
Published: February 2022

Background

Physicians in procedural specialties, such as gastrointestinal endoscopy, are at a high risk of musculoskeletal injuries (MSPI) which can affect physician wellness and productivity. Training in ergonomic principles for endoscopy may help reduce and prevent the incidence of MSPI.

Aims

The aim of this systematic review was to identify educational interventions using ergonomic strategies that target the reduction of MSPI and/or pain from GI endoscopy.

Methods

We conducted a systematic search following PRESS guidelines in MEDLINE, EMBASE, PsycINFO, Web of Science, Scopus, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews for articles published from inception to December 16, 2020. Studies were included if they investigated educational interventions aimed at changing knowledge and/or behaviours related to ergonomics in gastrointestinal endoscopy. After screening and full-text review, we extracted data on the study design, participants, type of training and assessment of primary outcomes. We evaluated study quality with the Medical Education Research Study Quality Instrument (MERSQI). A qualitative synthesis of the data was conducted.

Results

Of the initial 575 records identified in the search, 5 met inclusion criteria for qualitative synthesis. We found that most studies (n=4, 90%) were single armed interventional studies that were conducted in simulated and/or clinical settings. The most common types of intervention were didactic sessions and/or videos (n=4, 80%). Other interventions included individualized feedback (n=2, 40%), checklists (n=2, 40%), and simulated training (n=1, 20%). Two (40%) studies used both standardized assessment studies and formal statistical analyses to assess primary outcomes. All included studies reported a benefit of their interventions on their respective dimensions assessed for ergonomics. The mean MERSQI score was 9.7.

Conclusions

There is emerging literature demonstrating the effectiveness of interventions to improve ergonomic performance in gastrointestinal endoscopy, which is likely to reduce MSPI among endoscopists. Further higher quality research in this field is required to make robust recommendations.

Study flow diagram

Funding Agencies

None