bluuebunny/crossref_metadata_2025 huggingface dataset:
A199 UTILIZATION OF MUCUS-DERIVED O-GLYCAN SUGARS BY THE PATHOGEN C. RODENTIUM FACILITATE ITS COLONIZATION OF THE MURINE GUT
Authors: Mslati M , Yu H , Ma C , Vallance B
Published: February 2022

Background

The ability of enteric pathogens to colonize and expand within the mammalian gastrointestinal (GI) tract is determined by several factors, including the ability to find and acquire nutrients. The thick mucus layer that lines the inner surface of the large intestine is rich in sugars that can serve as nutrient sources for several members of the microbiota. Whether these sugars can also be used by invading bacterial pathogens to colonize the GI tract is still unclear, in particular for the family of attaching and effacing (A/E) bacterial pathogens, including the human diarrheal pathogens EHEC and EPEC.

Aims

To investigate the ability of the murine A/E pathogen Citrobacter rodentium to use mucin-derived sugars as a nutrient source, and the importance of these sugars in the virulence of C. rodentium during in-vivo infection.

Methods

To identify which sugar(s) are required for C. rodentium to colonize and grow in the murine GI tract, we generated mutants lacking single or multiple genes involved in the uptake and catabolism of mucin-derived O-glycan sugars. This was followed by in-vitro growth assays in minimal media supplemented with mucin sugars to investigate the growth properties of C. rodentium and the generated mutants on mucin sugars.

Results

We determined that C. rodentium was able to use three mucin O-glycan sugars: sialic acid, galactose, and N-acetylglucosamine (GlcNAc) as both carbon and nitrogen sources for in-vitro growth. C. rodentium exhibited the maximal growth rate and density on GlcNAc, followed by sialic acid, and finally galactose. A mutant C. rodentium strain carrying a deletion in the nagA gene was unable to grow on both GlcNAc and sialic acid, confirming that the breakdown pathways for these two sugars merge and are processed by shared suite of enzymes. As for galactose, combined deletions in the genes mglB and galP were required to abolish growth on this sugar. Notably, a mutant strain carrying simultaneous deletions in nagA, mglB, and galP was unable to grow on all three mucin sugars, as well as on purified mucin.

Conclusions

Our results demonstrate that intestinal mucin sugars serve as potential nutrient sources for C. rodentium and that C. rodentium can catabolize three of these sugars. Future work will examine whether these sugar pathways contribute to C. rodentium colonization of the murine GI tract.

Funding Agencies

CCC, CIHRCH.I.L.D. Fdn
A203 INCIDENCE AND PREDICTORS OF NON-HEPATIC CANCERS IN ALCOHOL RELATED LIVER DISEASE IN THE WALDO COHORT
Authors: Hindi Z , Brahmania M , Arab J , Shi N , Rajoriya N , Aithal G , Allison M , Hagström H , Likhitsup A , McCune A , Masson S , Parker R
Published: February 2022

Background

Alcohol-related liver disease (ArLD) accounts for 48% of cirrhosis-related deaths in the world. Alcohol is a known contributor to hepatocellular carcinoma (HCC) and non-hepatic cancers (NHC).

Aims

We aimed to describe the incidence and predictors of NHC in patients with histologically characterized ArLD.

Methods

Data came from an international, multicenter retrospective cohort study of patients with histologically characterized ArLD. We excluded all patients with clinical, biochemical, or histologic evidence of liver disease due to another etiology noted either at diagnosis or during follow-up. The primary outcome was incidence of the first of NHC. To identify risk factors of NHC, baseline characteristics of patients with and without NHC were compared. Outcomes were presented as unadjusted and adjusted hazard ratios (HR) based on COX analysis. All statistical analysis was done in R using the ‘cmprsk’ package.

Results

A total of 633 patients with histologically characterized ArLD were included. The mean age was 51 years, 64% of patients were male and 58% had cirrhosis on biopsy. We found that 69 patients with ArLD (11%) developed NHC during a median follow-up of 8.8 years. The most common NHC was lung cancer (19%). Other cancers are shown in Figure 2. Patients who developed NHC were older (55 vs. 50 years old; p<0.0001) compared to those without NHC. BMI, current or past smoking status, peak alcohol use, absence of cirrhosis and histological findings did not differ between groups. On multivariable analysis, past smoking status (HR 5.70, p=0.002) and current smoking status (HR 4.95; p = 0.003) were associated with higher rates of NHC.

Conclusions

In this large multicenter cohort study, we found ArLD is associated with an increased incidence of NHCs, primarily lung cancer. Past and current smoking are risk factors associated with an increased risk of NHC in ArLD.

Funding Agencies

None
A205 IS REPEAT ERCP REQUIRED AFTER INITIAL ENDOSCOPIC MANAGEMENT OF POST-SURGICAL BILE LEAKS? MULTI-CENTER VALIDATION OF THE CALGARY BILE LEAK RULE
Authors: Xiao Y , Salim M , Meng Z , Khan U , Kohansal A R , Forbes N , Heitman S , James P D
Published: February 2022

Background

The Calgary Bile Leak Rule was developed to identify patients in whom biliary stent removal via gastroscopy could be safely performed in lieu of ERCP for post-surgical bile leaks.

Aims

This study aimed to evaluate a Modified Calgary Bile Leak Rule (MCBLR) for a cohort of patients who underwent laparoscopic cholecystectomy complicated by bile leak.

Methods

This retrospective cohort study included patients who underwent ERCP for management of laparoscopic cholecystectomy-induced bile leaks between 2005 and 2017. The primary outcome was defined as the absence of persisting bile leak or other pathology on follow-up ERCP. The MCBLR includes a) normal post-surgical serum alkaline phosphatase, b) small or absent leak with no other biliary pathology on initial ERCP, and c) time between initial and follow-up ERCP was 4–8 weeks. Test performance of the prediction rule was analyzed by calculating sensitivity, specificity, positive predictive value and negative predictive value.

Results

124 cases met inclusion criteria, of which 116 (94%) of bile leak cases had no leak identified during the follow-up ERCP. 8 (6.4%) had a persisting bile leak on follow-up ERCP. Bivariate analysis found no factors significantly associated with the primary outcome. The MCBLR demonstrated a sensitivity of 100% (95% CI 63% - 100%), a specificity of 35% (95% CI 26% - 44%), a positive predictive value of 10% (95% CI 4% - 18%), and a negative predictive value of 100.0% (91% to 100%).

Conclusions

The MCBLR demonstrated high sensitivity and negative predictive value for determining the need for repeat ERCP following endoscopic management of laparoscopic cholecystectomy-induced bile leaks.

Funding Agencies

None
A208 ASSESSING FEASIBILITY AND ACCEPTABILITY OF AN ONLINE MIND-BODY WELLNESS PROGRAM FOR PRIMARY BILIARY CHOLANGITIS
Authors: Watt M , Hyde A , Wright G M , Vander Well S , Spence J C , Mason A , McLeod M , Johnson E
Published: February 2022

Background

Persons with primary biliary cholangitis (PBC) experience significantly higher rates of fatigue, stress, anxiety, depression, and impaired health related quality of life (HRQOL) as compared to the general population. While online wellness programming has been shown to be effective in decreasing fatigue and improving mental wellness in a variety of chronic disease populations, limited data is available for PBC.

Aims

This pilot study aimed to assess the hypothesis that a 12-week, online, mind-body wellness program would be feasible (assessed through adherence and retention) and acceptable in people with PBC. We also aimed to explore indicators of impact on measures of wellbeing.

Methods

Persons with PBC were recruited across Alberta and British Columbia in January 2021. The program included a 20–30 minute video containing low intensity mindful movement, meditation, and breathwork (goal 2–3 times/week) as well as a weekly behaviour change tip, PBC tip from a physician, and PBC nutrition tip. The online programming was accompanied by brief (10-minute) once weekly phone check-ins from a member of the study team, and optional once monthly zoom group sessions hosted by the Canadian PBC Society. Satisfaction and adherence were assessed at the end of the study using a survey. The pre-post exploratory efficacy assessment included: fatigue (Modified Fatigue Impact Scale), perceived stress (Perceived Stress Scale), anxiety and depression (Hospital Anxiety and Depression Scale), and HRQOL (PBC-40). Using a qualitative descriptive approach, we conducted semi-structured interviews at the end of the study to explore experiences with the intervention, and gather feedback for improvement.

Results

Participants (N = 32) completed baseline surveys and 29 (91%) were retained to end-of-study. Twenty-five (86%) adhered to the program goal of carrying out the mind-body practice at least 2–3 days per week. Comparing baseline to end-of-study, significant reductions were observed in fatigue (13%, p=0.004), anxiety (30%, p=0.005), and depression (28%, p=0.022), and significant improvements were observed in the PBC-40 itch (22%, 0.043), fatigue (13%, 0.005), cognitive (17%, 0.006), and emotional (18%, 0.001) domains. Eleven individuals participated in qualitative interviews, reporting an increase in energy, a more positive outlook, and increased knowledge of PBC. Feedback supported acceptability (satisfaction score of 90%), with fatigue cited as the primary barrier to increased program participation.

Conclusions

These findings suggest that a 12-week online mind-body intervention is feasible and acceptable to persons with PBC and has promising impact on efficacy. Recognizing the limitations of a single-arm study with a small sample size, a future RCT will be designed using this feedback.

Funding Agencies

MITACS Accelerate, Canadian PBC Society
A210 HEPATOLITHIASIS IS A FREQUENT AND PROGNOSTIC FINDING IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS
Authors: Jubran B , Ismail M , Stein M , Little D H , Hansen B , Gulamhusein A , Hirschfield G
Published: February 2022

Aims

Intrahepatic biliary stones (hepatolithiasis) are not well characterised in patients with primary sclerosing cholangitis (PSC).

Methods

Chart reviews were conducted on 302 patients with a histologic or radiographic diagnosis of PSC followed at the Toronto Centre for Liver Disease. Radiographic data were collected for patients between the years 2008–2018. Depending on frequency of testing, magnetic resonance imaging (MRI) and ultrasound (US) data was reviewed every 3–5 years. We assessed factors associated with hepatolithiasis based on sex, race, age and phenotype of PSC and inflammatory bowel disease (IBD). Qualitative radiographic findings on image report review, episodes of cholangitis, endoscopic retrograde cholangiopancreatography (ERCP) and occurrence of cholangiocarcinoma (CCA), death and transplant were documented. Data are reported with median and IQR and analysed using χ 2 and Mann-Whitney U tests.

Results

302 patients were reviewed. The median time to follow-up, defined as from date of diagnosis to last clinic visit or to transplantation date, was 98 months (IQR = 87). The mean age at diagnosis was 38 (SD = 15.1) years; 54% of patients were male. A total of 224 patients had IBD (74%). Of the 302 patients, 80 patients (26%) had evidence of hepatolithiasis on US or MRI. Patients with hepatolithiasis were more likely to be younger (37.4 vs 39.1, p = 0.025), male (65% vs. 50%, p = 0.021), and have large duct disease (99% vs. 88%, p = 0.004). Imaging report review revealed patients with hepatolithiasis were more likely to have intrahepatic biliary thickening (76% vs. 45%, p < 0.001), extrahepatic biliary thickening (69% vs. 50%, p = 0.003), focal biliary dilation (96% vs. 78%, p < 0.001) and disease characterised by more reported strictures on qualitative imaging report review (89% vs 69%, p < 0.001). Concomitant presence of cholelithiasis was greater in the hepatolithiasis vs. the non-hepatolithiasis group (45% vs. 19%, p < 0.001). There was no significant difference in the prevalence of hepatic or portal venous thrombosis in both groups. Patients with hepatolithiasis more likely have experienced acute ascending cholangitis (50% vs. 20%, p < 0.001) and need for ERCP (50% vs. 35%, p = 0.020). CCA was numerically higher in the hepatolithiasis group (8.75% vs. 4%, p = 0.1). Patients with hepatolithiasis received transplant more frequently (26.3% vs 12.2%, p < 0.001) with no significant difference in mortality.

Conclusions

Hepatolithiasis is common in PSC and associated with an increased clinical and radiologic disease burden.

Funding Agencies

None
A212 LIVER TRANSPLANTATION FOR PRIMARY SCLEROSING CHOLANGITIS (PSC): EXPERIENCE FROM THE LAST THREE DECADES
Authors: Zhu J , Lim D R , James L J , Yoshida E M , Peltekian K M
Published: February 2022

Background

In liver transplantation (LT) for PSC, pre-transplant colectomy may lower the risk of PSC recurrence (rPSC), and well-controlled or lack of IBD may protect against rPSC, however, these findings are not consistent across all studies. It is unknown whether recipient/donor sex plays a role in rPSC.

Aims

To study factors associated with PSC recurrence in the post-transplant population.

Methods

This is a retrospective study on adults who received an LT for PSC in Halifax NS from 1985 to 2020. Graft and patient outcomes are analyzed by logistic regression models.

Results

A total of 92 patients underwent deceased donor LT for PSC with a mean follow-up time of 9.2 yrs (SD 7.1). Fifty-three remain active in the program, 2 were lost to follow up and 37 died. The mean age at transplant was 43 (SD13, range 18.9–67.8). Seven patients had a second transplant. The five- and 10-year patient survival rate of the entire cohort was 78.7% and 66% respectively. In the active cohort, the prevalence of rPSC was 23.5% (12/51). Retransplantation for rPSC occurred in 8.3% (1/12). The prevalence of IBD was 82.4% (42/51), consisted of ulcerative pancolitis (64.7%, 33/51), ulcerative proctitis (3.9%), left-sided UC (2%) and Crohn’s disease (9.8%). Males are much more likely than females to undergo a colectomy at any time (OR 5.5, 95% CI 1.07–28.22, p 0.041). Refractory IBD was the predominant indication for a colectomy (10/16), followed by dysplasia or colon cancer (6/16). In the post-transplant period, 69% had stable IBD without therapy escalation, 11.9% were escalated to a biologic, 19% underwent a colectomy for active IBD symptoms. Pre-transplant colectomy negatively predicted rPSC, in this subgroup 0% (0/6) developed rPSC. Neither recipient sex (OR 1.14, 95% CI 0.26–5.0, p 0.86) or recipient age predicted the likelihood of rPSC. There was no association between donor sex on rPSC (OR 1.25, 95% CI 0.30–5.27, p 0.76). A trend towards increased rPSC was observed in male donors to female recipients versus female-to-female transplants (OR 6, 95% CI 0.33–107.42, p 0.224). Overall, having a post-transplant colectomy, subtotal or total, irrespective of timing, did not significantly impact rPSC (OR 0.389, 95% CI 0.09–1.66, p 0.20). Diagnosis of IBD was not associated with an increased risk of rPSC (OR 1.21, p 0.83).

Conclusions

Several factors were associated with rPSC after liver transplant in patients with PSC and IBD, pre-transplant colectomy was found to be protective, male donor to female recipient was a potential risk factor. It is important to study these factors in multi-centered cohorts to understand the pathogenesis of PSC. Pre-transplant total colectomy may be beneficial for several reasons, reducing rPSC, controlling IBD activities, and lowering dysplasia and colon cancer rates in the post-transplant population.

Funding Agencies

None
A213 ERCP-RELATED ADVERSE EVENTS IN PRIMARY SCLEROSING CHOLANGITIS: A SYSTEMATIC REVIEW & META-ANALYSIS
Authors: Natt N , Michael F , Michael H , Dubois S , Al Mazrou’i A
Published: February 2022

Background

Endoscopic retrograde cholangiopancreatography (ERCP) is a valuable diagnostic and therapeutic tool in primary sclerosing cholangitis (PSC). Although the complications of ERCP are well known in the general population, there is conflicting data regarding complications in patients with PSC. Factors that predict ERCP-related adverse events in PSC are also unclear.

Aims

To conduct a systematic review and meta-analyses to 1. compare ERCP-related adverse events in patients with and without PSC and 2. determine risk factors associated with ERCP-related adverse events in PSC.

Methods

A systematic search was conducted in Embase, PubMed and CENTRAL for studies published from January 1, 2000 to May 12, 2021. Eligible studies included adults with PSC undergoing ERCP and reported at least one ERCP-related adverse event (bleeding, perforation, pancreatitis, cholangitis) or risk factor associated with complications. Raw event rates for adverse events and risk factors were used to calculate odds ratios (ORs) which were then pooled using random-effects models.

Results

Four studies contributed to the first meta-analysis. There was a significant three-fold increase in the 30-day odds of cholangitis in PSC compared to those without PSC (4.3% vs. 2.0%; OR 3.26, 95% CI 1.08–9.90; p=0.037; I2=73.0%) (Figure 1). However, there were no significant differences in 30-day pancreatitis (4.2% vs. 3.4%; OR 0.89, 95% CI 0.26–3.07; p=0.851; I2=87.9%), bleeding (0.3% vs. 1.1%; OR 0.36, 95% CI 0.06–2.21; p=0.272; I2=50.3%), or perforation (0.7% vs. 0.5%; OR 1.19, 95% CI 0.40–3.51; p=0.752; I2=28.5%).

In a second meta-analysis, risk factors contributing to post-ERCP pancreatitis (PEP) in PSC were pooled from five studies. While female sex was not associated with PEP, accidental passage of wire into the pancreatic duct (OR 7.44, 95% CI 3.33–16.65; p<0.001; I2=65.0%) and biliary sphincterotomy (OR 4.80, 95% CI 1.92–12.03; p=0.001; I2=73.1%) were associated with higher PEP odds.

Conclusions

In the context of limited comparative data and study heterogeneity, PSC patients have higher odds of post-ERCP cholangitis despite the majority receiving antibiotics. Odds of bleeding, pancreatitis, and perforation were similar between groups. Accidental wire passage and biliary sphincterotomy increased odds of PEP, which helps identify higher-risk groups. Future studies should elucidate ERCP-related risks in PSC and guide preventive strategies.

Figure 1: 30-Day ERCP Complications

Funding Agencies

None
A215 CAUSE-SPECIFIC MORTALITY IN PATIENTS WITH CIRRHOSIS: A POPULATION-BASED COHORT STUDY
Authors: Wang P , Djerboua M , Flemming J
Published: February 2022

Background

Cirrhosis is a major global health concern with increasing mortality secondary to cirrhosis and chronic liver diseases observed both in the United States and Canada. However, population-level causes of death among patients with cirrhosis in North America have not been reported.

Aims

The aim of this study was to describe cause-specific mortality in patients with cirrhosis stratified by cirrhosis etiology.

Methods

Retrospective cohort study using linked administrative healthcare data from Ontario, Canada. Adult patients with cirrhosis 2000/01/01-2017/12/31 were identified and etiology of liver disease was assigned as hepatitis C (HCV), hepatitis B (HBV), alcohol-associated liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), or autoimmune liver disease (AI)/other using validated algorithms for cirrhosis (sensitivity [sn] 99%, specificity [sp] 79%) and cirrhosis etiology (sn 75%-97%, sp 95%-100%). Patients were followed until death, liver transplant, or end of study. The primary outcome of cause of death was defined based on the top 10 causes of death reported by Statistics Canada; however, hepatocellular carcinoma and cholangiocarcinoma were included in liver-related deaths as opposed to malignant neoplasms. The proportion of deaths by each cause was described, stratified by cirrhosis etiology. The cumulative incidence of death with liver transplant and hepatocellular carcinoma as competing risks were calculated at 1, 5 and 10 years.

Results

202,022 patients with cirrhosis were identified (60% male sex, median age 56 years [IQR 46–67], 52% NAFLD, 26% ALD, 11% HCV, 5% HBV, 6% AI/Other). Overall, 81,428 (40%) patients died after a median follow-up of 5 years (IQR 2–12) and 3,024 (2%) patients received liver transplant. The overall leading cause of death was liver-related (32%) but varied substantially by cirrhosis etiology. Liver-related deaths were highest among those with viral hepatitis (HBV 56%, HCV 52%), and lowest in NAFLD (20%). In NAFLD cirrhosis, the most common causes of death were non-hepatic malignancy (26%), followed by a composite of cardiovascular disease, cerebrovascular disease, or diabetes (22%).

Conclusions

Although the overall leading cause of death in patients with cirrhosis is liver-related, the most common causes of mortality in patients with NAFLD cirrhosis is non-hepatic malignancy, cerebrovascular disease, and diabetes. This supports the involvement of multidisciplinary teams and healthcare providers for patients with NAFLD cirrhosis to optimize appropriate cancer screening and management of co-morbid cardiovascular and metabolic conditions.

Funding Agencies

None
A220 THE IMPACT OF DIABETES AND AGE ON PERFORMANCE OF NON-INVASIVE SERUM-BASED TESTS FOR PREDICTION OF ADVANCED FIBROSIS IN BIOPSY-PROVEN NAFLD
Authors: Kosick H M , Shengir M , Adeyi O , Sebastiani G , Patel K
Published: February 2022

Background

Non-alcoholic fatty liver disease (NAFLD) is now a leading cause of end-stage liver disease. Advanced stage F3-4 fibrosis predicts liver-related mortality in NAFLD patients. Simple non-invasive serum-based tests (NIT) for F3-4 are limited by indeterminate scores, necessitating secondary tests or liver biopsy. Diagnostic NIT cut-offs may vary in NAFLD patients with diabetes mellitus (DM) and the elderly. Identifying appropriate thresholds in populations in which these tests can be applied will reduce indeterminates and facilitate their broader use.

Aims

The aim of this study was to assess the impact of DM status and age on the performance of NIT for prediction of advanced fibrosis in patients with biopsy-proven NAFLD.

Methods

Patients presenting to two Canadian tertiary care centers between 2010–2018 for liver biopsy to diagnose NAFLD were included in this study. NIT including NFS, FIB4, BARD, AST-to-platelet ratio index (APRI), and AST to ALT ratio (AST/ALT) were calculated for each patient using validated cut-offs.

Results

457 patients were included in this study. Mean age was 48.8±12.9 years, 56% male, mean BMI 32.3 ± 6.7kg/m2, 69% with DM, and F3-4 prevalence 48%. Indeterminate rates for NIT were generally higher for older patients, with or without DM (27–49% and 37–52%, vs. 33–42% and 20–37%, respectively). FIB-4 and NFS both had high specificity >0.9 in DM patients <60 years (Table 1). There were no differences in AUROC for individual NITs between patients with and without DM, and those < 60 vs. ≥ 60, nor between individual NIT within these groups.

Conclusions

DM status and age, ≥ 60 vs. < 60, do not appear to have a significant impact on diagnostic performance of serum-based NIT in our cohort. Older patients had higher indeterminate results and reduced specificity, but T2DM status and age did not appear to have an impact on rate of misclassified patients. Serum-based NIT thresholds need to be optimized for older patients to reduce indeterminates and improve specificity.

Funding Agencies

None
A221 CONGENITAL PORTOSYSTEMIC SHUNTS: FROM PRENATAL DIAGNOSIS TO LONG- TERM POSTNATAL OUTCOME
Authors: Steg Saban O , Weissbach T , Achiron R , Pekar Zlotin M , Haberman Y , Kassif E , Weiss B
Published: February 2022

Background

Congenital portosystemic shunts (CPSS) are rare vascular malformations that result in blood bypassing the liver and re-entering the systemic circulation unfiltered. The outcomes of CPSS diagnosed prenatally are unknown. Previously published data is related to patients diagnosed after symptom appearance, including hepatic encephalopathy, liver tumors and portal hypertension.

Aims

To describe a cohort of prenatally diagnosed children with CPSS and report on the natural history and outcomes.

Methods

The study was conducted between 2006 and 2019. Prenatal diagnosis was performed during routine prenatal ultrasound. Patients were followed by the pediatric gastroenterologists’ unit.

Results

32 patients were identified; 28 patients with intrahepatic shunts and four patients with extrahepatic shunts. During follow up, Failure to Thrive (FTT) was observed in three of the patients with one shunt (16.7%), and five of the patients with two shunts or more (55.6%). The difference is significant (p- value=0.037). 24 patients with intrahepatic shunts had their shunts closed spontaneously. Median time for closure of the shunt was seven months (IQR 2–14 months, range 0–35 months). No predicting factor was detected for closure of the shunt before the age of one year. All extrahepatic shunts required surgical closure.

Conclusions

Congenital intrahepatic shunts usually close spontaneously and do not need intervention. All patients in our prenatally diagnosed cohort survived with limited to no sequelae.

Funding Agencies

None
A222 BILIARY ATRESIA IN BRITISH COLUMBIA: THE ROLE OF REFERRAL AGE AND DIAGNOSITIC EVALUATION ON OUTCOME
Authors: Smyth M , Baird R , Schreiber R
Published: February 2022

Background

Biliary atresia (BA), a newborn liver disease, is the leading cause of cirrhosis and liver-related death in children and the most common indication for pediatric liver transplantation (LT). The current standard of BA care is sequential surgery with an initial Kasai hepatoportoenterostomy (KP), followed by LT for those who progress to liver failure. Survival with native liver (SNL) correlates to infant age at KP with best outcome at early KP at <30 days of age. Novel screening tests and diagnostic algorithms have been proposed, however the variability of clinical presentation and lack of a diagnostic test challenge early diagnosis and timely KP.

Aims

To assess age at BA presentation and subsequent investigations to the timing of KP and outcome.

Methods

A retrospective study of all BA cases referred to BC Children’s Hospital January 1, 2000-December 31, 2018. Data collection included age at referral, clinical presentation, laboratory and imaging studies, age at KP and LT. SNL and overall survival rates were determined. Descriptive statistics and data analyses using SSPS were applied.

Results

In this 19-year study, there were 48 cases (58% female) of BA in BC (1:17,000 live births). KP was performed in 41 patients and 7 had primary LT. Following the initial KP, 23 cases had LT. Median age at presentation decreased from 55 to 42 days after introduction of the BC BA stool card screening program in 2014. The Median (IQR) age at KP was 62 days (48–87). Median delay from the age at first encounter to the KP was 10 days (4–21); early referral (youngest 3rd of cohort) had a mean delay to KP of 25 days (15–40) compared with the late group (oldest 3rd of cohort) with median delay to KP of 5 days (1–8). There were 2.4 and 1.4 investigations/patient before undergoing KP in the youngest and oldest age at presentation cohorts. HIDA scan was done in 41% and 19% of the youngest and oldest presentation cohorts respectively. Median LT age was 9.6 months (8-13months). Median age at KP for patients who received LT was 77 days (53–92), compared to 52 days (41–79) in those without LT (p=0.08). All KPs were completed by 7 surgeons, each completing 1- 10 KPs. Overall patient survival and SNL were 98% and 37.5%.

Conclusions

In this cohort, SNL rates were below SNL rates in other national studies. SNL rates were higher in patients who underwent KP at a younger age, and early findings from a provincial screening program show a shift in age at presentation, potentially owing in part to increased community awareness of BA. A diagnostic algorithm that accounts for age at presentation is needed achieve timely KP.

Funding Agencies

None
A224 COVID-19 INFECTION IN LIVER TRANSPLANT RECIPIENTS: CLINICAL FEATURES, HOSPITALIZATION, AND MORTALITY FROM A CANADIAN MULTICENTRE COHORT
Authors: Smith M K , Chow J , Huang R , Omar M , Ebadi M , Wong P , Huard G , Yoshida E M , Peretz D , Brahmania M , Montano-Loza A J , Bhanji R
Published: February 2022

Background

The COVID-19 pandemic has brought significant challenges to clinicians caring for liver transplant (LT) recipients. Researchers have sought to better understand the risk and clinical outcomes of LT recipients infected with COVID-19 globally, however, there is a paucity of data from within Canada.

Aims

Our multi-center study aims to examine the characteristics and clinical outcomes of LT patients with COVID-19 in Canada.

Methods

We identified a retrospective cohort of adult LT recipients with RT-PCR confirmed COVID-19 from 7 Canadian tertiary care centers between March 2020 and June 2021. Demographic and clinical data were compiled by clinicians within those centers. We identified liver enzyme profile at the time of COVID-19 infection, immunosuppression type and post-infection adjustments, rate of hospitalization, ICU admission, mechanical ventilation, and death.

Results

A total of 49 patients with a history of LT and COVID-19 infection were identified. Twenty nine patients (59%) were male, the median time from LT was 66 months (1, 128) and the median age at COVID-19 infection was 59 years (52, 65). At COVID-19 diagnosis, the median ALT was 37 U/L (21, 41), AST U/L was 34 (20, 37), ALP U/L was 156 (88, 156), Total Bilirubin was 11 umol/L (7, 14), and INR was 1.1 (1.0, 1.1). The majority of patients (92%) were on tacrolimus monotherapy or a combination of tacrolimus and mycophenolate mofetil (MMF); median tacrolimus level at COVID-19 diagnosis was 5.3 ug/L (4.0, 8.1). Immunosuppression was modified in 8 (16%) patients post-infection; either the tacrolimus dose was reduced or MMF was held. One patient developed acute cellular rejection which recovered after re-initiation of the prior regimen. Eighteen patients (37%) required hospitalization, 6 (12%) were treated with dexamethasone, and 3 (6%) required ICU admission and mechanical ventilation. Four patients (8%) died due to complications of COVID-19. On univariate analysis, neither age, sex, co-morbidities nor duration post-transplant were associated with risk of hospitalization.

Conclusions

In our national retrospective study, approximately 40% of patients required hospitalization with a mortality rate of < 10%. Previous studies have shown proximity to LT as an independent factor for mortality with COVID-19; the median time from LT for our patients was 5 years, which may explain the lower mortality rate. Of note, the median tacrolimus levels were much lower in comparison to the target of 8–10 ug/L used in the first year post-transplant. As the landscape of COVID-19 changes with vaccination, evolving treatments, and increasing rates of variant transmission, additional studies are required to continue identifying trends in clinical outcomes.

Funding Agencies

None
A227 THE EFFECTIVENESS OF PEG 3350 COMPARED TO LACTULOSE FOR THE TREATMENT OF ACUTE HEPATIC ENCEPHALOPATHY IN ADULT CIRRHOTIC PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Afzaal T , Karvellas C J , Dionne J
Published: February 2022

Background

Cirrhosis is the leading cause of liver-related death globally. Hepatic encephalopathy (HE) leads to significant morbidity and mortality. Lactulose is the current gold standard treatment for HE; it eliminates nitrogenous waste from the gut. Polyethylene glycol 3350–electrolyte solution (PEG) is a safe, common and effective purgative with recent studies suggesting its efficacy resulting in faster resolution of HE and shorter hospital length of stay.

Aims

To assess the efficacy and safety of PEG 3350 compared to lactulose in adult cirrhotic patients 18 years of age and older with overt hepatic encephalopathy on patient important outcomes including: improvement of hepatic encephalopathy, hospital length of stay and mortality.

Methods

We reviewed databases MEDLINE, EMBASE, OVID, CINAHL, Cochrane Database, PubMed, Trip database, the grey literature, and clinicaltrials.gov from inception to December 2020: PROSPERO CRD42021257641. Search strategy was developed in conjunction with medical librarian. Randomized controlled trials (RCTs), either published or non-published, were included in the review. Continuous data was analyzed using mean difference with random-effects model. Dichotomous data was analyzed using the Mantel-Haenszel method using random-effects model. Statistical effect-size heterogeneity was assessed using Chi2 test and quantifying the relative proportion of variation using I2 statistic. The overall certainty of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations system (GRADE).

Results

From the 68 studies, 16 were assessed for full text review from which 5 studies were included in the meta-analysis representing a total of 351 patients. The primary outcome of mean change in Hepatic Encephalopathy Scoring Algorithm (HESA) at 24-hours from baseline demonstrated an improvement in the PEG group compared to lactulose group [Mean difference (MD)= 0.60, 95% CI (0.20, 1.01)]. In comparison to lactulose, PEG also demonstrated a shorter hospital length of stay [MD = -1.00, 95% CI (-1.99, -0.01)], shorter time to HE resolution [MD= -1.49, 95% CI (-1.81, -1.16)] and showed a mortality benefit [RR=0.35, 95% CI (0.13 to 0.92)]. There was no significant difference between change in ammonia levels at 24 hours [MD= -25.80, 95% CI (-95.39, 43.78)].

Conclusions

PEG leads to a faster improvement and resolution of HE when compared to the current standard of care, lactulose.

Funding Agencies

None
A229 GUT MICROBIOTA PROFILES, DIET AND SHORT-CHAIN FATTY ACIDS AS PREDICTORS OF GENERALIZED ANXIETY DISORDER
Authors: Rabbia V , De Palma G , Lu J , Verdu E , Armstrong H , Collins S M , Anglin R , Surette M , Bercik P
Published: February 2022

Background

Generalized anxiety disorder (GAD) is a debilitating chronic condition with a lifetime prevalence of 4–7% worldwide. Both diet and gut microbiota have been previously associated with anxiety.

Aims

To investigate whether bacterial taxa and/or nutrients associate with GAD, and whether they differ from those of healthy controls (HC).

Methods

Patients with GAD (n=82) and matched HC (n=97) were assessed by validated questionnaires for anxiety (DASS-21), gastrointestinal (GI) symptoms (Rome III, Short-Form Leeds Dyspepsia), and dietary profiles by the Dietary Questionnaire for Epidemiological Studies. We quantified several blood and stool biomarkers, including inflammatory and neuroactive metabolites, as well as short-chain fatty acids. Stool microbiota profiles were assessed by16S rRNA gene sequencing through Illumina. The data was then analyzed following the pipelines of dada2 and by multiple factor analysis (MFA), mean comparisons, correlation, LEfSe and XGBoost using R software (v.1.2.1335). Multiple comparison results were corrected allowing 5% of FDR.

Results

Using MFA to analyze all variables, we identified 3 clusters: one mainly composed of HC (n=99, 91% HC, GI symptoms in 25% of subjects), a second mixed cluster (n=30, 80% GAD, GI symptoms in 80%) and a third cluster mainly composed of GAD patients (n=50, 98% GAD, GI symptoms in 86%). When focusing only on the HCs of cluster 1 (n=90) and GADs of cluster 3 (n=49), we found higher GI symptoms, body mass index, serum C-reactive protein and stool calprotectin levels (adj. p=1.3x10-9, 0.001, 0.017 and 0.017, respectively) and lower concentrations of propionate, butyrate and acetate in GAD compared to HC. GADs also reported overall lower caloric intake (kJ/day; adj. p=1.7x10-4) in the food frequency questionnaire. Fibre (g/day) was the macronutrient most negatively associated with anxiety scores (R=-0.44; adj. p=4.2x10-5). Bacteroides was the only bacterial taxon significantly associated with GAD, as well as with anxiety scores (R=0.31, adj. p=0.003). Interestingly, Bacteroides/fiber ratio was strongly correlated to anxiety scores (R=0.58, adj. p=2.7x10-09). Furthermore, demographic, biomarkers and bacterial taxa data were predictive of the patients’ disease state with 92.8% accuracy. The features that aid the model to predict disease state were Bacteroides/fiber ratio, GI symptoms and stool acetate levels.

Conclusions

Our results suggest that most GAD patients differ in dietary and microbiota profiles from HCs, and that the Bacteroides/fiber ratio, stool acetate and GI symptoms might be good predictors of disease state. Furthermore, these data strongly support the role of microbiota-gut-brain axis in genesis of psychiatric diseases, and they will inform mechanistic studies in gnotobiotic mouse models.

Funding Agencies

NIH
A237 VIRULENCE POTENTIAL OF BACTERIA ISOLATED FROM NON-INFLAMED COLON IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES
Authors: Arjomand Fard N , Bording-Jorgensen M , Webb J , Veniamin S , Perry T , Wine E
Published: February 2022

Background

As inflammation can impact microbes, our lab has focused on non-inflamed bowel sections of patients with inflammatory bowel diseases (IBD) and found bacterial alterations in the terminal ileum. We are also interested in the appendix given the involvement of the peri-appendicular region and effects of appendectomy in ulcerative colitis.

Aims

In this study, we aimed to identify and evaluate microbes from the appendix and non-inflamed regions of the colon in IBD patients. We hypothesized that microbes originating from the non-inflamed sections of the colon or appendix are more invasive and could trigger inflammation in IBD patients.

Methods

16S DNA Sanger sequencing was performed on bacteria, aerobically and anaerobically cultured from tissues of the appendix, peri-appendicular region, cecum, and ascending colon, collected from the resected colons of 5 pediatric IBD patients. The invasive capacity of the identified bacteria was evaluated by gentamicin protection assays on Caco-2 intestinal epithelial cells in vitro. Presence of select invasive or adhesive genes in the bacteria was assessed by PCR.

Results

Escherichia coli was the most frequently cultured species in the aerobic cultures; additional aerobic species included Enterococcus and Klebsiella. Bifidobacterium and Erysipelatoclostridium were identified among the anaerobic cultures. Gentamicin protection assays indicated that Klebsiella isolated from the peri-appendicular region was significantly more invasive (mean ~3000 CFU/ml) than HB101 (~1000 CFU/ml; non-invasive control; P<0.05). Enterococcus avium and Enterococcus faecalis were also more invasive than HB101 in the peri-appendicular region (~10000 CFU/ml) and cecum (~4000 CFU/ml; P<0.05), respectively. E. coli isolated from the appendix showed a higher invasive potential (~3000 CFU/ml) than E. coli isolated from other sections. Additionally, PCR showed that E. coli obtained from different sections, except the ascending colon of one the patients, had the fimH gene while the other types of bacteria did not. None of the isolated bacteria had Hemolysin ( hlyA) or attaching and effacing ( eaeA) genes.

Conclusions

Bacteria, especially E. coli, from non-inflamed bowel in IBD (including the appendix) appear to have increased invasive potential. This suggests that the microenvironment in these regions could be altered, resulting in increased invasion of bacteria or the gut harboring more invasive microbial populations in IBD patients. As a result, inflammation could be triggered or exacerbated through this reservoir of pathobionts.

Funding Agencies

CIHR
A240 OPIOID-INDUCED HYPEREXCITABILITY IN DRG NEURONS IS MEDIATED BY DOR-DEPENDENT ENDOCYTOSIS
Authors: Jaramillo Polanco J , Lopez Lopez C , Lomax A E , Reed D E , Vanner S
Published: February 2022

Background

Opioids are effective for the treatment of abdominal pain but are also associated with tolerance, and increased dosing leads to severe side effects. We previously showed that prolonged exposure to high doses of opioids evoked paradoxical hyperexcitability of colonic afferent nerves that was mediated by δ-opioid receptor (DOR) signaling. Recent studies suggest that DOR-dependent analgesia is mediated not only by G proteins but also via receptor endocytosis and downstream signaling, but it is unclear what intracellular signaling mechanisms are underlying opioid-induced hyperexcitability.

Aims

To examine the mechanisms underlying DOR-mediated hyperexcitability of dorsal root ganglia (DRG) neurons.

Methods

We assessed the excitability of DRG neurons isolated from C57BL/6 mice by measuring the rheobase (minimal current to elicit an action potential, i.e. lower rheobase=increased excitability) using perforated patch-clamp recordings. Dissociated neurons were exposed to a high concentration (10 µM) of the μ-opioid receptor agonist DAMGO, the DOR agonist DADLE, or the weakly internalizing DOR agonist ARM390 overnight. To examine the role of receptor endocytosis and intracellular receptor activation underlying the excitatory effect by opioids, DRG neurons exposed to DAMGO or DADLE were preincubated with the membrane-permeable opioid receptor antagonist naloxone or the endocytosis inhibitor Pitstop2. To further understand the mechanisms involved in the hyperexcitability evoked by opioid re-exposure, following overnight incubation with high concentrations of DAMGO or DADLE, neurons were washed for 1 hr and treated either with the PKA inhibitor H89 or the PKC inhibitor GFX before re-exposure to DAMGO or DADLE at a low concentration (10 nM).

Results

Neurons exposed to 10 µM DAMGO or DADLE were hyperexcitable (rheobase decreased 25 % and 26 % compared to controls respectively; p≤0.05, 2-way ANOVA). Naloxone and Pitstop2 blocked the increased excitability of DRG neurons induced by overnight incubations with either DAMGO or DADLE. In contrast to the hyperexcitability induced by DAMGO and DADLE, overnight incubation with 10 µM ARM390 decreased excitability (rheobase increased 31%, p≤0.05, unpaired t-test). The hyperexcitability induced by DAMGO and DADLE was reversed after a 1 hr washout but acute reapplication of a low concentration of DAMGO or DADLE (10nM) now evoked hyperexcitability (rheobase decreased 34 and 35 % respectively, p≤0.05, 2-way ANOVA). This effect was prevented by inhibiting PKC but not PKA.

Conclusions

Our data suggest that the DOR-dependent hyperexcitability evoked by prolonged exposure to high concentrations of opioids is dependent on receptor endocytosis and downstream PKC signaling. Targeting these pathways could mitigate the hyperexcitability of pain signaling neurons caused by high doses of opioids.

Funding Agencies

CCC
A252 DO GLIM CRITERIA FOR DIAGNOSING MALNUTRITION AGREE WITH SGA IN HOSPITALIZED PATIENTS RECEIVING TPN?
Authors: Vantomme E , Sulymka B , Stevens M , Duerksen D
Published: February 2022

Background

The Global Leadership Initiative on Malnutrition (GLIM) proposed a new two-step model for diagnosing malnutrition in 2019. A combination of two etiologic and three phenotypic criteria are used to assess malnutrition. The Subjective Global Assessment (SGA) is the most well validated assessment tool for diagnosing malnutrition in hospitalized patients. Evaluation of the performance of GLIM criteria in comparison to SGA is necessary before implementing this new diagnostic tool in practice.

Aims

To compare GLIM criteria to SGA in assessing malnutrition severity in hospitalized patients requiring parenteral nutrition (PN).

Methods

This is a retrospective analysis of a prospectively collected database of malnourished hospitalized adult patients requiring PN admitted between March 2020 and March 2021 to an academic hospital in Winnipeg, Canada. 172 cases were evaluated. GLIM malnutrition screening was considered positive if one etiologic (high CRP or low food intake) and one phenotypic (weight loss or low BMI) criteria were identified. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated and expressed with a Wilson 95% confidence interval.

Results

The prevalence of malnutrition using SGA B or C criteria was 82.3% (CI 73.8, 85.5). Using GLIM criteria, the prevalence of malnutrition was 33.7% (27.1, 41.1). The prevalence of severe malnutrition using SGA C was 32.6% (26.0, 40.0) and using GLIM criteria the prevalence was 19.2% (14.0, 25.7). Using any combination of GLIM criteria versus SGA B or C combined, the PPV was 100% (90.4, 100) and the specificity was 100% (89.9, 100); NPV was 30.0% (22.0, 38.5) and the sensitivity was 42.0% (34.1, 50.4). Using any combination of GLIM criteria versus only SGA C patients, PPV decreased to 72.4% (59.8, 82.3) and specificity was 86.2% (78.8, 91.3); NPV increased to 87.7% (80.4, 92.5) and sensitivity was 75.0% (62.3, 84.5). Comparing severely malnourished patients by GLIM criteria to only SGA C patients, PPV was 97% (84.7, 99.5) and specificity was 99.1% (95.3, 100). NPV was 82.7% (75.6, 88.1) and sensitivity was 57.1% (44.1, 69.2).

Conclusions

Using SGA as the gold standard for diagnosing malnutrition in hospitalized patients requiring PN, GLIM criteria had a very high PPV but unacceptably low NPV in diagnosing malnutrition. The NPV improved when GLIM criteria was compared only to severely malnourished patients by SGA. Importantly, in comparing severely malnourished patients by GLIM and SGA criteria, the sensitivity was also unacceptably low. Based on these results, GLIM criteria are most useful in confirming the diagnosis of malnutrition or severe malnutrition; a negative result should not reassure clinicians that severe malnutrition is absent. Further studies evaluating GLIM criteria are needed before it replaces SGA as a decision making tool.

Funding Agencies

None