bluuebunny/crossref_metadata_2025_split huggingface dataset:
A20 EARLY-LIFE FUNGAL COLONIZATION MEDIATES HOST METABOLISM AND WHITE ADIPOSE TISSUE INFLAMMATION IN MICE
Authors: Gutierrez M W , van Tilburg Bernardes E , Kalbfleisch K , Chleilat F , Arrieta M -C 
Published: March 2023

Abstract

Background
The gut microbiome has been linked to metabolic diseases including obesity, however the role of fungi (mycobiome) remains understudied. Recently, fungal taxa have been correlated with obesity in humans, though their causal contribution to obesity development, especially in the context of early life, is unknown. Obesity has been associated with metabolic inflammation, including alterations to the white adipose tissue (WAT) immune landscape, which has been shown to be influenced by the microbiome. Given the potent modulation of host immunity by the mycobiome, it is plausible that it also influences WAT inflammation.

Purpose
This research aimed to explore the role of early-life colonization by specific fungal taxa in obesity development and WAT inflammation.

Method
Gnotobiotic mice were colonized from birth with 12 mouse-derived bacteria (Oligo-MM12) alone or in combination with Candida albicans or Rhodotorula mucilaginosa. Mice were weaned onto a control or high-fat-high-sugar diet (HFHS) and evaluated at 12 weeks for metabolic and associated inflammatory outcomes.

Result(s)
C. albicans colonization reduced body weight in mice fed control diet, and induced resistance to weight and adiposity gain in mice fed HFHS. In contrast, R. mucilaginosa colonization was associated with increased adiposity in mice fed control diet, and elevated glycemia and LDL-cholesterol in mice fed HFHS. Fungal colonization had a broad impact on immune cells in white adipose tissue. C. albicans colonization was associated with increased adipose tissue inflammation with elevated Th1, Th17, ɣδT cells, ILC1, NK cells, cDC1 and neutrophils independently of diet. Additionally, vascular associated macrophages (VAM), CX3CR1+ macrophages and DCs, and ILC3 were elevated in mice fed control diet, while mice fed HFHS displayed elevated Th2, CD8+ T cells and eosinophils. In contrast, R. mucilaginosa colonized mice displayed decreased adipose tissue B cells and increased VAMs when fed control diet, and increased CX3CR1+ DCs when fed HFHS. Interestingly, C. albicans colonization was associated with increased relative expression of mPgc1⍺ in white adipose tissue of HFHS fed mice, indicative of enhanced mitochondrial biogenesis.

Conclusion(s)
Elevated adipose tissue inflammation with C. albicans colonization suggests dysfunction of energy storage and may explain the decreased body weight and resistance to diet-induced obesity, while the immune changes in R. mucilaginosa colonized mice may exacerbate obesity development. This work revealed that two common fungal colonizers have distinct and striking influences on obesity and metabolic inflammation and prompts for the inclusion of fungi in microbiome studies on host metabolism.

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CIHR, Other

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Cumming School of Medicine

Disclosure of Interest
None Declared
A27 DNA HYPOMETHYLATION INDUCED BY 5-AZA-CDR OR LOSS OF DNMT1 INHIBITS COLITIS-ASSOCIATED COLORECTAL CANCER
Authors: Larsen F , Good H , Shin A , Derouet M , Zhang L , Asfaha S 
Published: March 2023

Abstract

Background
Colorectal cancer is the second leading cause of cancer death in Canada. A major risk factor for the development of colorectal cancer is chronic inflammation leading to colitis-associated cancer (CAC). We previously described a CAC mouse model in which tumors arise from DCLK1+ tuft cells following loss of the tumor suppressor adenomatous polyposis coli (APC) and induction of colitis. Interestingly, both colitis and CAC display epigenetic changes that modulate gene expression. However, the impact of DNA methylation changes on colonic tumorigenesis is not known. Thus, we hypothesize that inhibition of DNA methylation in DCLK1+ tuft cells reduces colonic tumorigenesis.

Purpose
In this study, we aim to investigate the role of DNA methylation in CAC by inhibiting DNA methylation using genetic and pharmacologic means.

Method
Using a publicly available dataset (GSE75214) of gene expression data analyzed by microarray from colonic biopsies of patients with ulcerative colitis and Crohn’s Disease with active disease, we examined the expression of DNA methyltransferases (DNMTs). Expression of DNMTs in mice with colitis was additionally examined by RT-qPCR and global DNA methylation levels measured by 5-mC ELISA. In separate experiments, Dclk1-CreERT2/Apcf/f mice were crossed to DNMT1f/f mice to knock-out the DNA methyltransferase DNMT1 in DCLK1+ tuft cells. Dclk1/Apcf/f and Dclk1/Apcf/f/DNMT1f/f mice were then administered three doses of tamoxifen followed by 2.5% dextran sodium sulfate (DSS) for five days to induce colitis. Fourteen weeks later, we assessed colonic tumor number and size. In a separate cohort of Dclk1/Apcf/f mice, we induced colitis and treated the mice with six doses of the DNA de-methylating drug 5-AZA-2’-deoxycytidine (5-AZA) or vehicle, and assessed colonic tumor number. To examine DNA methylation changes, we then treated WT mice with 5-AZA and DSS and isolated intestinal epithelial cells. From the intestinal epithelial cell, we isolated DNA and ran the Infinium MouseMethylation BeadChip Array.

Result(s)
Patients with IBD were found to have increased expression of DNMT1 compared to healthy controls. Mice treated with DSS similarly had increased DNMT1 expression, as well as, global methylation levels compared to controls. Deletion of DNMT1 in DCLK1+ cells significantly inhibited the number and size of colonic tumors. Treatment of mice with 5-AZA decreased global and gene specific DNA methylation levels, and significantly reduced both the number of mice with tumors, and the average colonic tumor number and size per mouse.

Conclusion(s)
Our findings demonstrate that colitis in both patients and mice is associated with DNA methylation. Furthermore, DNA hypomethylation by 5-AZA treatment or loss of DNMT1 reduces CAC formation suggesting that altered DNA methylation plays a critical role in colonic tumorigenesis.

Disclosure of Interest
None Declared
A42 LIVE DONOR LIVER TRANSPLANTATION IN PRIMARY SCLEROSING CHOLANGITIS: AN INDICATOR OF AN ORGAN ALLOCATION SYSTEM NOT ADDRESSING PATIENT NEED
Authors: Zheng K , Onofrio F , Xu C , Chen S , Xu W , Vyas M , Bingham K , Patel K , Lilly L , Selzner N , Jaeckel E , Tsien C , Gulamhusein A , Hirschfield G M , Bhat M 
Published: March 2023

Abstract

Background
Liver transplantation is frequently lifesaving for people living with primary sclerosing cholangitis (PSC). However, patients are waitlisted for liver transplant (LT) according to the MELD-Na score, which may not accurately reflect the burden of living with PSC.

Purpose
We sought to describe and analyze the clinical trajectory for patients with PSC referred for LT, in a mixed deceased donor/live donor transplant programme.

Method
This was a retrospective cohort study from November 2012 to December 2019 including all patients with PSC referred for assessment at the University Health Network Liver Transplant Clinic. Patients who required multiorgan transplant or re-transplantation were excluded. Liver symptoms, hepatobiliary malignancy, MELD-Na progression, and death were abstracted from chart review. Competing Risk analysis was used for timing of LT, transplant type, and death.

Result(s)
Of 172 PSC patients assessed, 144 (84%) were listed, of whom 106/144 (74%) were transplanted. Mean age was 47.6 years and 66% were male. During follow-up through to 2021, 23/144 (16%) were removed from the waitlist due to infection, clinical deterioration, liver-related mortality or new cancer; 3 had clinical improvement. At the time of listing, 118/144 (81.95%) had a potential Living Donor (pLD) of whom 94 were transplanted: 64 live donor and 30 deceased donor. Patients with pLD had 79% lower mortality (p&lt;0.001), and higher rates of transplantation (80% vs 46%). Exception points were granted to 13/172 (7.5%) patients.

Conclusion(s)
In a high-volume North American liver transplant centre, most patients with PSC assessed for transplant were listed and subsequently transplanted. However, this was a consequence of patients engaging in live donor transplantation. Our findings support the concern from patients with PSC that MELD-Na allocation does not adequately address their needs.

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CIHR, Other

Please indicate your source of funding;
This study was supported by PSC Partners Canada, Canadian Institutes of Health Research (CIHR), Toronto General and Western Hospital Foundation.

Disclosure of Interest
None Declared
A46 ENTEROBACTERIACEAE ENRICHMENT IN THE GUT MICROBIOME OF CRITICALLY ILL PATIENTS PROMOTES IMMUNE DYSFUNCTION AND SUSCEPTIBILITY TO NOSOCOMIAL INFECTIONS
Authors: Schlechte J M , Zucoloto A Z , Yu I -L , Doig C J , Dunbar M J , McCoy K D , McDonald B 
Published: March 2023

Abstract
NOT PUBLISHED AT AUTHOR’S REQUEST

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CIHR, Other

Please indicate your source of funding;
Government of Alberta

Disclosure of Interest
None Declared
A56 DEVELOPMENT OF A PROGNOSTIC SURVIVAL MODEL FOR PATIENTS DIAGNOSED WITH PANCREATIC CANCER IN ONTARIO
Authors: James P , Gayowsky A , Salim M , Seow H , Sutradhar R , Tanuseputro P , Coburn N , Hallet J , Hsu A , Mahar A , Webber C 
Published: March 2023

Abstract

Background
Pancreatic adenocarcinoma (PAC) is a deadly disease with an overall 5-year survival of less than 8%. The current literature on patient outcomes are limited by small samples sizes and patients enrolled in clinical trials. There are no prognostic tools for patients with pancreatic cancer.

Purpose
To develop a prognostic survival model for patients with pancreatic cancer

Method
All patients with a diagnosis of pancreatic cancer cancer from January 2007 to December 2020 were identified through the Ontario Cancer Registry. The primary outcome was survival. The cohort was used to develop a multivariable cox proportional hazards regression model with baseline characteristics under a backward stepwise variable selection process to predict the risk of mortality. Covariates included patient age, sex, tumour location, cancer stage, treatment types, distance to a cancer centre, hospitalizations, comorbidities, access to family physician, and symptoms as captured using the Edmonton Symptom Assessment System datasets.

Result(s)
There was a total of 17,450 pancreatic cancer patients in the cohort, 48% of which were female and the mean age was 72 years. 44% of patients presented with a tumor in the head of the pancreas. Among those with stage data (44%), 24% were stage IV at diagnosis. Mean survival was approximately 0.7 years. Approximately 60% were hospitalized in the 3 months prior to diagnosis. Almost all patients had a family doctor rostered (95%). In multivariate analysis, key predictors of survival assessed at the time of diagnosis were age, sex, tumour location in the pancreas, stage at diagnosis, pain, appetite functional status and treatment choice (all p&lt;0.001). Using these variables, we created a prediction model that can estimate one-year probability of death with high discrimination (area under the curve = 0.82, c-statistic 0.76).

Conclusion(s)
Our model accurately predicts one-year pancreatic cancer survival risk using clinical symptom and performance status data. The model has the potential to be a useful prognostic tool that can be completed by patients and their caregivers in support of patient-centered care.

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CIHR

Disclosure of Interest
None Declared
A62 IDENTIFICATION OF SPECIFIC COLONIC DEEP MUSCLE LAYER MACROPHAGES SUBSETS BY THE CD64 (FCΓRI) MARKER
Authors: Nishihara Y , Zarwa S , Bai X , De Palma G , Collins S , Bercik P 
Published: March 2023

Abstract

Background
Although intestinal muscle layer macrophages have been suggested to play an important role in the colonic transit by interacting with the myenteric plexus neurons, they have not been fully characterized. CD64 (FcγRI) is one of the most generally used markers for intestinal macrophages, but several studies suggested existence of a subpopulation of macrophages that lack CD64. In addition, the muscle layer macrophage subsets currently identified are considered to be same in the small intestine and colon, although this has not been formally tested.

Purpose
In this study, we aim to identify and characterize the subsets of muscle layer macrophages by CD64 marker. We hypothesize that colon specific CD64-macrophages have a different role from CD64+ conventional macrophages.

Method
The muscle layers of small intestine (ileum) and colon were separated from SPF mice and cells from each muscle layer were analyzed by flow cytometry and fluorescent staining. The muscle layer macrophages were gated withCD45+, F4/80+, CD11b+ and Ly6c-, and analyzed with CD64 and MHCⅡmarkers by flow cytometry. In additional experiments, fluorescent staining with CD64 and F4/80 was assessed in whole-mount tissue of the separated muscle layer.

Result(s)
Within the macrophage population from the colon muscle layer, we found not only CD64+ cells, a conventional marker of macrophage, but also CD64- cell population (CD45+, F4/80+, CD11b+, Ly6c-). However, in the small intestine, this CD64- cell population was barely detectable. In addition, colonic CD64+ cells had mostly high expression of MHCⅡ marker, while CD64- cells had low expression of MHCⅡ. A similar pattern was found when we examined intestinal and colonic tissues by immunofluorescent staining.

Conclusion(s)
We identified a colon-specific CD64- subset of macrophage in muscle layer. Additional experiments are needed to characterize their immunomodulatory properties.

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None

Disclosure of Interest
None Declared
CLIINICAL PRACTICE
A94 EXPLORING THE SOCIOECONOMIC BURDEN OF PEDIATRIC INFLAMMATORY BOWEL DISEASE: A SURVEY OF FAMILIES AND PEDIATRIC PROVIDERS
Authors: Desai T , Yaskina M , Carroll M 
Published: March 2023

Abstract

Background
Rates of pediatric inflammatory bowel disease (IBD) have been increasing significantly over recent decades, contributing to the rising chronic disease burden across pediatrics. Currently, there is very limited literature exploring the financial burden on families of children with IBD. In fact, there is only one Canadian study in this area despite Canada having one of the highest rates of pediatric IBD in the world.

Purpose
The goal of this study is to better understand the socioeconomic burden of pediatric IBD at our institution and compare institutional practices across the country.

Method
The study took place at a large, tertiary care pediatric centre in Edmonton, Alberta, Canada between October 2022 and January 2023. Two separate electronic surveys were developed and distributed to all families of children with IBD at our institution (N= ~400) and pediatric IBD providers across the country (N= ~45) respectively. Surveys explored demographic information, financial impacts of IBD diagnosis and perceptions around pediatric IBD care and financial support.

Result(s)
Interim results (N=3) indicate dietary therapy costs, missed time off work and school and time off for IBD treatment as considerable burdens on families. Across the country, initial provider data (N=6) suggests significant variability in clinical practice, allied health support and financial support for families. There is overwhelming agreement among providers that the socioeconomic burdens on families is significant. Further data and regression analysis is ongoing.

Conclusion(s)
This is the first study in Canada to directly explore the socioeconomic burden on families of children with IBD. Results indicate good correlation between provider awareness and the increased financial burden on families but also considerable variation in practice across the country. Data suggest further research and advocacy is required to better support patients, however various quality improvement opportunities exist both locally and beyond.

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None

Disclosure of Interest
None Declared
A100 CAVERNOUS TRANSFORMATION OF THE PORTAL VEIN IN A PEDIATRIC PATIENT WITH GOLDENHAR SYNDROME: A CASE REPORT
Authors: Diaz F , Briglia F 
Published: March 2023

Abstract

Background
Goldenhar syndrome is a rare congenital condition thought to arise from the first and second branchial arches and typically asymmetrically affects the eyes, ears, and spine. Portal vein thrombosis/cavernous transformation is one of the main causes of portal hypertension in children. It is often associated with risk factors such as catheterization of the umbilical vein in the neonatal period, omphalitis, intra-abdominal infections in the neonatal period and prothrombotic conditions. This is a challenging clinical scenario as it leads to portal hypertension and variceal bleed with no chronic liver disease stigmata and liver function is essentially normal. While previous European literature from the early-2000s reported associated portal vein anomalies in Goldenhar syndrome, we are not aware of any recent and/or Canadian pediatric cases.

Purpose
We report a Canadian case of cavernous transformation of the portal vein with resulting gastrointestinal bleeding in a child with Goldenhar syndrome.

Method
Case report

Result(s)
A pediatric patient with a postnatal suspicion of Goldenhar syndrome, with confirmation by 6 months of age, presented with an acute 3-day history of melena, on the context of a recent viral illness and ibuprofen use. Laboratory testing showed a normocytic anemia (Hb 68) with a normal INR (1.1). The rest of the workup was unremarkable. There was no history of catheterization of the umbilical vein on the neonatal period nor other hematological complications. To assess for potential duplication cyst as differential diagnosis, a computerized tomography of the chest, abdomen and pelvis was ordered and revealed suspected cavernous transformation of the portal vein with suspected varices near the gastroesophageal junction and within the abdomen, and hepatomegaly with spleen size at the upper limit of normal. Octreotide was started after the CT results. A gastroscopy was done 24h after presentation and found portal hypertensive gastropathy and esophageal varices (2 Grade II and 1 Grade I). Sclerotherapy was performed. Post-gastroscopy ultrasound supported earlier radiographic findings of cavernous portal vein transformation and hepatosplenomegaly. Moreover, the ultrasound noted normal flow direction in the portal and hepatic veins. The patient has not re-presented for further episodes of gastrointestinal bleeding.

Conclusion(s)
This case report supports the previously reported association between Goldenhar syndrome and portal venous anomalies. Early consideration may lead to prompt diagnosis and management of the potentially life-threatening complications of portal hypertension in this population.

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None

Disclosure of Interest
None Declared
A111 CLINICAL AND PATHOLOGICAL OUTCOMES BETWEEN WATER EXCHANGE AND AIR INSUFFLATION USING NON-SEDATED EXTENDED FLEXIBLE SIGMOIDOSCOPY FOR AVERAGE RISK COLORECTAL CANCER SCREENING: PRELIMINARY FINDINGS FROM A RANDOMIZED CONTROL TRIAL
Authors: Aulakh A , Parker B , Sullivan B , Recsky M , Oliveira C , Richardson W , Hirschkorn P , Perini R , Bak A 
Published: March 2023

Abstract

Background
Colorectal cancer (CRC) is Canada's third most common cancer type and represents approximately 11% of all cancer deaths. While sedated colonoscopy or flexible sigmoidoscopy (FS) continues to be considered for CRC screening, these modalities have limitations and risks. Another unevaluated screening modality, known as an extended FS (EFS), attempts to capitalize on the benefits of a FS while minimizing the risks involved with a sedated colonoscopy. EFS provides a scope-based examination up to the splenic flexure and then attempts to examine beyond, often to the point of the caecum. Providing the option for EFS may produce improvements in the patient experience and performance, which may improve the feasibility of using scope-based screening more broadly in screening programs.

Purpose
To determine the extent non-sedated EFS using the water exchange method (WE) is associated with a complete colon examination compared to the traditional air insufflation (AI) method using CO2 in an average-risk screening population.

Method
This randomized control trial included 90 non-sedated participants, screened by trained general surgery and gastroenterology clinicians at Kelowna General Hospital, British Columbia, Canada, using two different scope insufflation techniques, WE and AI. The primary outcome of interest was the cecal intubation rates (CIR), while secondary outcomes included the adenoma detection rate (ADR) and reported pain scores. Other metrics, such as patient satisfaction rates, sessile serrated adenoma detection rates (SSADR), and serrated lesion detection rates (SLDR) were also recorded.

Result(s)
The demographic characteristics between the WE and AI groups were statistically similar, with the mean age of participants being 58 and 57, respectively. During the study period, four endoscopists performed the EFS. There were higher initial satisfaction rates in the WE group vs the AI (95% vs 77%, satisfaction of ≥ 9/10 p = 0.028). CIR and ADR were similar between the WE and AI group (CIR = 93% vs 91%, p = 0.710), (ADR = 40% vs 34%, p = 0.660). The SSADR and SLDR were also similar between the WE and AI group (SSADR = 21% vs 14%, p = 0.408), (SLDR = 42% vs 36%, p = 0.528).

Conclusion(s)
EFS without sedation using either technique exceeds quality benchmarks recommended for sedated screening colonoscopy while maintaining adequate patient safety and comfort. The WE method optimizes a patient's overall experience making a strategy of average risk colorectal cancer screening with non-sedated WE EFS feasible.

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CAG, Other

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Kelowna General Hospital, Interior Health

Disclosure of Interest
None Declared