bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role status and status-saving behaviour in world politics: the ASEAN case
Authors: He Kai , Feng Huiyun 
Published: February 2022

Abstract
Most research on status in international politics focuses on a state's ‘trait status’, defined by valued attributes that a state possesses, but ignores the importance of ‘role status’, which is constituted through state interactions and competent practices in world politics. By integrating prospect theory and role status scholarship, this article introduces a ‘status-saving’ argument to shed light on how states adopt risk-acceptant strategies to salvage the decline in their role status in world politics. We test the status-saving argument by examining the ASEAN states’ bold community-building efforts in the early 2000s, especially the adoption of the ASEAN Charter in 2007. We argue that both the economic and political conditions of ASEAN were far from mature enough to pursue such an institutionalization and legalization endeavour. The perceived decline of international role status after the 1998 Asian financial crisis, however, encouraged the ASEAN states to take this ‘great leap forward’ behaviour towards regional integration, which has placed ASEAN's long-term status and internal unity in a more risky and vulnerable position. We conclude that pursuing role status is another way for states, especially rising powers, to seek status in a deference hierarchy. Dominant powers should consider accommodating the pursuit of role status by rising powers and encourage ‘do-goodism’ in world politics.
Quasisteady models for weld temperatures in fused filament fabrication
Authors: Edwards D A 
Published: February 2022

Abstract
During fused filament fabrication (FFF), strands of hot extruded polymer are layered onto a cooler substrate. The bond strength between layers is related to the weld temperature at the polymer/substrate interface, and hence understanding temperature evolution is of keen interest. A series of increasingly sophisticated models is presented: a standard heat equation, an unsteady fin equation and a fin equation with a heat-loss jump condition. Each is analytically tractable and uses a quasisteady approximation for the temperature in the growing substrate. The jump condition introduces the complication of a non-self-adjoint problem, but fits the experimental data very well.
A6 MECHANISMS UNDERLYING GUT DYSFUNCTION FOLLOWING C. DIFFICILE INFECTION AND IMPLICATIONS FOR TREATMENT
Authors: Saqib Z , BAI X , De Palma G , Hynes A , Surette M , Bercik P , Collins S M 
Published: February 2022

Abstract

Background
Recent evidence suggests an increasing prevalence of gut dysfunction following C. difficile infection (CDI). The accompanying prolonged antibiotic (AB) exposure likely contributes to chronic gut dysfunction and our ability to induce gut dysfunction in germ free (GF) mice colonized with microbiota from a patient with severe slow transit post CDI (PCDI) supports this notion (10.1093/jcag/gwz047.117). Furthermore, we were able to restore gut function following fecal microbial transfer from healthy murine donors. Our studies have implicated a role for macrophages in the destruction of the Interstitial Cell of Cajal (ICC) network underlying slow colonic transit in the humanized mouse model. These findings prompted us to evaluate microbiota-directed therapy in normalising gut function in this model.

Aims
1)To investigate whether dietary psyllium rescues the development of slow colonic transit (SCT) through modulating host function via microbiota mediated immune mechanisms; and 2)To evaluate the mechanisms underlying the beneficial effects of psyllium

Methods
GF mice were colonized with either microbiota from the PCDI patient or healthy control (HC) for 3 weeks following which PCDI mice were treated with either a control diet or a 15% psyllium diet (PSY). Colonic motility was assessed before and after the diet intervention using the bead expulsion test. Stool samples were collected for microbial profiling, and short and branched-chain fatty acids (SCFA/BCFA) analysis. Colonic muscle layers encompassing myenteric plexus (MP) were collected for gene expression analysis and to evaluate activated macrophages and ICC degeneration using immunohistochemistry.

Results
Microbiota from a PCDI patient induced a SCT phenotype in GF mice (n=13) as compared to mice colonized with HC microbiota (p=0.0002). Psyllium rescued this SCT phenotype in mice (PCDI(n=7) vs.PSY(n=6):p=0.0014). The psyllium-induced rescue was accompanied by normalization of the ICC network and morphological alterations in infiltrating macrophages. This was supported by changes in immune-related gene expression in the MP including CD11b, NOS, Myd88, Mapk1 and NF-κB. Additionally, bacterial composition was different between PCDI and PSY group (p=0.003). SCFAs like acetic and propionic acid were increased, while BCFA like isobutyric and isovaleric acid were decreased following PSY treatment. These alterations in SCFA/BCFA were supported by fluctuations in specific bacteria like Butyricimonas, Phascolarctobacterium and Allistipes.

Conclusions
Our results provide evidence that chronic gut dysfunction following CDI and AB exposure is microbiota-driven. Furthermore, microbiota-directed therapy using psyllium could serve as a novel therapeutic strategy to normalize gut function via microbiota-mediated restoration of immune homeostasis in these patients.

Funding Agencies
W. Garfield Weston Foundation
A10 EARLY LIFE SENSITIZATION TO GLUTEN INDUCES SUSTAINED IMMUNOPATHOLOGY IN DR3-DQ2 MICE
Authors: Godbout J , Wulczynski M , Galipeau H J , Constante M , Ribeiro T , Sloboda D , Verdu E 
Published: February 2022

Abstract

Background
Celiac disease (CeD) is an autoimmune T-cell mediated enteropathy, triggered by gluten, a group of proteins found in wheat, barley, and rye. The defined role of gluten as a dietary trigger, necessary genes (HLA-DQ2 and/or DQ8), and tissue transglutaminase (TG2) as the autoantigen together, are unique features of CeD. Although CeD onset can occur at any age, first dietary introduction of gluten during infancy is a critical window of exposure, especially in infants homozygous for the HLA DQ2.5 allele. While adult sensitization studies have been recently performed in DR3-DQ2 mice, the consequences of early life gluten sensitization timing remain unexplored.

Aims
Our aim was to characterize gluten-immunopathology and CeD-specific serology in specific pathogen free (SPF) DR3-DQ2 transgenic mice sensitized to gluten, 1 week before weaning.

Methods
Seven-week-old SPF DR3-DQ2 transgenic mice, kept on a gluten-free diet (GFD), were paired for breeding. At post-natal day 3, pups were standardized to 4 per litter (n=2 male, n=2 female) to ensure equal nutrition across litters. At 14 days of age, pups were sensitized with pepsin-trypsin digested gliadin and cholera toxin (CT) three times in one week (n=15). At 21 days of age, pups were weaned and placed either on a gluten-containing diet (n=7), (equivalent of 20g/d of gluten in a human diet -high dose-) or an isocaloric GFD (n=8) until 10 weeks of age. Non-sensitized controls (n=7) received only CT and were kept on the GFD. At sacrifice, serum was collected for anti-TG2 and anti-gliadin antibodies (AGA). Jejunal tissue was collected for histological analysis using villus-to-crypt (V/C) ratios and CD3+ intraepithelial lymphocytes (IEL) counts.

Results
Gluten-sensitized mice placed on a gluten-containing diet post-weaning had lower V/C ratios and higher CD3+ IEL counts compared with controls (p&lt;0.01). Pre-weaning sensitized mice that were kept on a GFD post-weaning had sustained decreases in V/C ratios and higher CD3+ IEL counts (p&lt;0.01). Out of 15 sensitized mice, 7 developed positive anti-gliadin IgA (p=0.02) and 4 had positive anti-TG2 IgA antibodies (p=0.01) in intestinal contents, irrespective of gluten in the diet. None of the controls had detectable AGA or anti-TG2 antibodies.

Conclusions
Pre-weaning gluten sensitization of DR3-DQ2 mice induced prolonged gluten immunopathology that did not reverse after 5 weeks on a GFD. Our results indicate that young DR3-DQ2 mice are susceptible to gluten sensitization, with sustained immunopathology, suggesting a critical window of vulnerability in familial carriers of DQ2.5. This novel model will be useful to investigate environmental cofactors at the first time of gluten introduction to the diet.

Funding Agencies
CIHR
A28 RESPONSE RATE OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE (VEOIBD) PATIENTS TO ANTI-TNF TREATMENT IS HIGHER THAN PREVIOUSLY REPORTED, BUT HIGHER DOSING IS REQUIRED-A LARGE TERTIARY SINGLE CENTER EXPERIENCE
Authors: Eindor A , Meleady L , Jacobson K 
Published: February 2022

Abstract

Background
Very early onset inflammatory bowel disease (VEOIBD) patients are known to have special disease characteristics. Limited data is available regarding biologic use and long-term outcomes in VEOIBD patients.

Aims
We aimed to assess long-term outcomes and time to progression to biologic treatment in VEOIBD patients. Secondary aim was to determine Infliximab prescribing practice during the course of treatment.

Methods
We retrospectively reviewed IBD patients diagnosed under 6 years of age, between January 2005 and December 2019, from the British Columbia (BC) Pediatric IBD database. Demographic data, disease characteristics, symptoms at diagnosis, disease location and severity were documented. Data on biologic treatment at initiation and during follow up including type of biologic, dosing and response were collected. Kaplan Meier curves were used to assess the number of years to progression to biologic treatment and the parameters influencing commencement. Infliximab dosing and intervals were recorded for all patients treated with Infliximab during induction, after one year and at last follow up.

Results
89 patients with VEOIBD were diagnosed during the study period. Median age at diagnosis was 3.8 years (IQR 2.6–5.1), 45.3% had Crohn’s disease (CD) and 62.8% were males. Median duration of follow up was 6.39 years (IQR 3.71–10.55). Biologic treatment was started on 39.5% of patients and 7.1% underwent surgery. In patients with CD, the addition of perianal fistulizing disease or stricturing disease was associated with more rapid progression to biologic treatment (p=0.024, p=0.038, respectively). In patients with UC, disease severity (p=0.017) was associated with early initiation of a biologic. The median Infliximab dose at one year was 10 mg/kg (IQR 7.5–11) with median dose interval of 4 weeks (IQR 4–6). At the time of the last follow up, 18 patients (72%) maintained treated with Infliximab and had a median dose of 9 mg/kg per dose (IQR 8.1–10) and a median dose interval of 4.5 weeks (IQR 4–6). Clinical remission was reported in 61.8% of patients on their first biologic agent at the last follow up.

Conclusions
Factors influencing earlier progression to biologics were disease severity and disease behaviour. The response rate was higher than previously reported and might be due to higher Infliximab dosing with shorter infusion intervals than standard dosing.

Funding Agencies
None
A36 NON-PSYCHOTROPIC PHYTOCANNABINOIDS ATTENUATE VISCERAL HYPERSENSITIVITY IN DEXTRAN SULFATE SODIUM (DSS)-INDUCED COLITIS
Authors: Svendsen K , Defaye M , Sharkey K A , Altier C 
Published: February 2022

Abstract

Background
The inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are complex chronic diseases that affect an increasing proportion of the population. Abdominal pain is a major clinical symptom, but current treatments are limited and a source of frustration for patients, many of whom seek alternatives such as cannabis. Cannabis contains many compounds with therapeutic potential that do not have the prohibitive psychotropic effects of tetrahydrocannabinol. These non-psychotropic cannabinoids (npCBs) have a variety of effects including analgesia and anti-inflammatory actions and show potentiating effects when administered in combination. The range of actions of these compounds potentially allows for their development as novel therapeutics for treatment of pain in IBD.

Aims
To investigate the analgesic effects of cannabichromene (CBC), cannabidiol (CBD), cannabidivarin (CBDV), and cannabigerol (CBG), individually and in combination, in the treatment of colitis-evoked visceral hypersensitivity.

Methods
The analgesic effects of the npCBs were investigated in an acute dextran sodium sulfate model of colitis. Abdominal pain was quantified by electromyographic recordings of the reflexive contraction of the external oblique muscles in response to colorectal distension. Activation of the spinal cord was assessed using immunohistochemistry for the neuronal activity marker c-Fos in neurons of the spinal dorsal horn.

Results
CBD reduced pain responses in the functional assay and spinal cord c-Fos activity in a dose-dependent manner. A single intraperitoneal injection of 10 mg/kg, 30 minutes prior to application of the noxious stimulus, reduced pain responses to the level of non-DSS treated control animals. CBDV, and CBG were found to be ineffective in either assay at doses of 1, 5, and 10 mg/kg.

Conclusions
These results suggest CBD may be a promising therapeutic agent in the treatment of colitis–induced visceral hypersensitivity with rapid translational value due to the legalization of cannabis and rapidly growing cannabis industry in Canada. Additionally, CBDV, CBC, and CBG will be further investigated for their analgesic effects and any potentiating effects from administration of multiple npCBs examined.

Funding Agencies
Alberta Innovates
A44 PGC1-α INHIBITION WORSENS DSS-INDUCED COLITIS IN MICE
Authors: Oliveira Ponce J P , Lopes F 
Published: February 2022

Abstract

Background
Inflammatory bowel diseases (IBD) represent a wide range of gastrointestinal diseases that are characterized by chronic inflammation of the gastrointestinal tract (GIT). Affecting more than 6 million individuals globally, the most prevalent forms of IBD are Ulcerative colitis (UC), characterized by inflammation and ulceration of the colon and rectum, and Crohn’s disease (CD), characterized by inflammation of several areas of the GIT. Due to the morbidity and occasionally mortality arising from IBD, as well as its increasing global prevalence, the search for novel treatments and cures for IBD presents great importance. Loss of immune tolerance significantly contributes to the inflammatory patterns observed in IBD patients. Dendritic Cells (DCs), key antigen-presenting cells, are important mediators of tolerance in the gut when polarized to tolerogenic DCs (tolDCs). The phenotype of tolDCs has been shown to directly depend on their intracellular metabolism, mostly by adopting mitochondrial oxidative phosphorylation. Peroxisome proliferator-activated receptor-gamma coactivator (PGC)1-α is a transcription coactivator that plays a crucial role in mediating cellular energy metabolism. Evidence shows that activation of PGC1-α stimulates mitochondrial biogenesis and promotes oxidative metabolism in a variety of biological processes.

Aims
The aim of this project was to evaluate whether activation or inhibition of PGC1-α impacts inflammatory response in DSS-induced colitic in mice. We hypothesize that the PGC1-α pharmacological activator ZLN005 would ameliorate colitis as a result of tolDC polarization. On other hand, the PGC1-α pharmacological inhibitor SR18292 would increase inflammatory responses and decrease tolerance.

Methods
C57/b6 mice received DSS in drinking water for 5 days, followed by 3 days of tap water. Mice were treated with vehicle, ZLN005 (10 mg/kg), or SR18292 treatment (25 mg/kg) for the 3 days of drinking tap water. Under necropsy, colitis was assessed by disease activity score (DAS), colon length, weight change, myeloperoxidase (MPO) activity assay, histopathology score, and cytokines by ELISA. Intestinal tolerance was accessed by evaluating T cells polarization to Treg, TH1, TH2, or TH17 by qPCR of the transcription factors Foxp3 (Treg), Tbx21 (TH1), Gata3 (TH2), and Rorγt (TH17) expressed in the colon.

Results
Our results demonstrated that ZLN005 did not alter the inflammatory response induced by DSS, gauged by MPO assay, DAS, and histopathology, suggesting that ZLN005 was ineffective in polarizing tolDCs. However, we observed a worsening of inflammatory conditions with treatment with SR18292 with a decrease in IL-10 levels and increased MPO values, potentially stemming from the loss of tolDCs and intestinal tolerance.

Conclusions
PGC1-α inhibition worsens inflammatory response in DSS-induced colitis potentially by inhibiting tolDC polarization and loss of intestinal tolerance.

Funding Agencies
None
A45 INFLIXIMAB IN COMBINATION WITH AN IMMUNOMODULATOR IS ASSOCIATED WITH AN ATTENUATED ANTIBODY RESPONSE TO BNT162B2 SARS-COV-2 VACCINE IN PEDIATRIC INFLAMMATORY BOWEL DISEASE PATIENTS
Authors: Lawrence S , Shire Z , Reicherz F , Lavoie P , Jacobson K 
Published: February 2022

Abstract

Background
Adult data have shown that Infliximab (IFX) impairs the antibody response to a single dose of the mRNA-BNT162b2 SARS-CoV-2 vaccine in patients with inflammatory bowel disease (IBD). The true impact of IFX on SARS-CoV-2 vaccine efficacy in pediatric IBD (PIBD) patients is unknown.

Aims
To evaluate the humoral immune response to the BNT162b2 SARS-CoV-2 in PIBD patients treated with anti-tumor necrosis factor (TNF) therapy.

Methods
PIBD patients treated with anti-TNF therapy either alone or in combination with an immunomodulator, who received at least one dose of the BNT162b2 SARS-CoV-2 vaccine, were prospectively enrolled from 1st June 2021 at BC Children’s Hospital. Serum antibody levels for [spike (S) protein and receptor-binding domain (RBD)] were determined at baseline and 28 days after their first and second vaccine doses. Antibody responses were assessed using multiplex serology IgG assay against four SARS-CoV-2 antigens: S-protein, RBD, N-terminal domain (NTD) and N-protein using the SARS-CoV-2 Panel 2 (Meso Scale Diagnostics).

Results
Forty-two PIBD patients received a single dose of BNT162b2 (median age 14.5yrs (IQR 14–16); 43% female; 79% crohn’s disease, 21%, ulcerative colitis). Of those on IFX monotherapy (43%), both S-protein and RBD antibody concentrations 28 days post BNT162b2 were comparable to healthy adult controls (n=20, median age: 36yrs (IQR 29–40); 65% female) who had received one dose of BNT162b2 (p = 0.07) [Figure 1]. In PIBD patients on IFX in combination with either azathioprine or methotrexate (57%) both S-protein and RBD antibody concentrations were significantly lower than controls after 1 dose of BNT162b2 (p = 0.0003) [Figure 1].
In the PIBD cohort (n=27) who received 2 doses of BNT162b2 vaccine (median age 14yrs (IQR 14–16);41% female;63% crohn’s disease, 37% ulcerative colitis; median interval between doses 56 days (IQR 22–105)), there was no difference in antibody response after 2 doses compared to healthy adult controls (n=14, median age: 44 years (IQR 36–51); 29% female) whether they were on IFX monotherapy (41%) or in combination with an immunomodulator (59%) [Figure 1].

Conclusions
We provide evidence of an attenuated antibody response in PIBD patients on IFX in combination with an immunomodulator after a single dose of BNT162b2. However, our data show a robust antibody response in PIBD patients, despite their infliximab treatment, after two doses of BNT162b2 vaccine. Our results are consistent with adult IBD data and highlight the importance of administering the second vaccine dose to achieve protection in this vulnerable patient population. Long-term follow-up to assess longevity of vaccine protection is warranted.

Funding Agencies
None
A51 ROLE OF GUT MICROBIOTA IN THE EPISODIC NATURE OF SYMPTOMS IN IRRITABLE BOWEL SYNDROME
Authors: Mohan V , Pinto-Sanchez M I , Nardelli A , Borojevic R , De Palma G , Collins S M , Bercik P 
Published: February 2022

Abstract

Background
Irritable bowel syndrome (IBS) is a complex functional gastrointestinal disorder with likely heterogenous pathophysiology, multiple symptoms, and comorbidities. Growing evidence shows that the gut microbiota composition and function are altered in IBS patients. However, identifying the critical drivers of clinical expression remains challenging due to the episodic occurrence of IBS symptoms, the inherent variability in composition of gut microbiota across individuals, and high sensitivity of gut microbiota to dietary and environmental cues.

Aims
To identify whether changes in gut microbiota composition accompany or, predict the occurrence of symptoms.

Methods
28 IBS patients (IBS-D n=20, IBS-C n=8) and 10 healthy controls (HC) were followed longitudinally for 25 weeks, collecting stool samples, and recording their symptoms weekly. Stool microbiota profiles were assessed by 16S rRNA gene sequencing using Illumina platform. The sequences were preprocessed, filtered, and annotated using DADA2 and phyloseq pipelines; statistical analyses were performed using FactomineR and microbiomeanalyst packages in R. Statistical significance was set at p&lt;0.05.

Results
Multifactorial analysis of clinical data classified 950 samples in 6 clusters. Distribution of samples among the clusters was based on Bristol stool scale defining symptomatic periods (scores &lt;3 and &gt;4 indicating abnormal stool) and asymptomatic periods (scores 3 or 4), with several gut and mood symptoms varying significantly between the two categories. IBS-D patients, but not IBS-C patients presented with changes in symptoms severity, such as pain, diarrhea, constipation, and anxiety during the symptomatic periods. Depression scores were, however, higher in IBS-C compared to IBS-D patients. In contrast, immune makers such as fecal b-defensin-2 and calprotectin were higher during asymptomatic periods in IBS-D, but not in IBS-C patients. Bacterial diversity profiles differed among IBS patients (IBS-D and IBS-C) and HC, namely Shannon index and Bray-Curtis distance, but they did not change significantly between the symptomatic and asymptomatic periods within each subtype. Despite this, several bacterial taxa unique to each cluster were identified using linear mixed models.

Conclusions
Our results demonstrate the need to study patterns of co-occurrence of IBS symptoms and their severity during symptomatic and asymptomatic periods to better understand the role of identified bacterial taxa in the symptom generation. Identifying their temporal changes and cross-feeding patterns in individual patients will shed light on the underlying mechanistic role of gut microbiota in IBS, which might be otherwise obscured by group generalizations.

Funding Agencies
CIHR