COVID-19 infection among international travellers: a prospective analysis.

OBJECTIVES: This report estimates the risk of COVID-19 importation and secondary transmission associated with a modified quarantine programme in Canada. DESIGN AND PARTICIPANTS: Prospective analysis of international asymptomatic travellers entering Alberta, Canada. INTERVENTIONS: All participants were required to receive a PCR COVID-19 test on arrival. If negative, participants could leave quarantine but were required to have a second test 6 or 7 days after arrival. If the arrival test was positive, participants were required to remain in quarantine for 14 days. MAIN OUTCOME MEASURES: Proportion and rate of participants testing positive for COVID-19; number of cases of secondary transmission. RESULTS: The analysis included 9535 international travellers entering Alberta by air (N=8398) or land (N=1137) that voluntarily enrolled in the Alberta Border Testing Pilot Programme (a subset of all travellers); most (83.1%) were Canadian citizens. Among the 9310 participants who received at least one test, 200 (21.5 per 1000, 95% CI 18.6 to 24.6) tested positive. Sixty-nine per cent (138/200) of positive tests were detected on arrival (14.8 per 1000 travellers, 95% CI 12.5 to 17.5). 62 cases (6.7 per 1000 travellers, 95% CI 5.1 to 8.5; 31.0% of positive cases) were identified among participants that had been released from quarantine following a negative test result on arrival. Of 192 participants who developed symptoms, 51 (26.6%) tested positive after arrival. Among participants with positive tests, four (2.0%) were hospitalised for COVID-19; none required critical care or died. Contact tracing among participants who tested positive identified 200 contacts; of 88 contacts tested, 22 were cases of secondary transmission (14 from those testing positive on arrival and 8 from those testing positive thereafter). SARS-CoV-2 B.1.1.7 lineage was not detected in any of the 200 positive cases. CONCLUSIONS: 21.5 per 1000 international travellers tested positive for COVID-19. Most (69%) tested positive on arrival and 31% tested positive during follow-up. These findings suggest the need for ongoing vigilance in travellers testing negative on arrival and highlight the value of follow-up testing and contact tracing to monitor and limit secondary transmission where possible.

Differential Effect of Genetic Burden on Disease Phenotypes in Crohn's Disease and Ulcerative Colitis in a Canadian Cohort.

BACKGROUND AND AIMS: Crohn's disease (CD) and ulcerative colitis (UC) demonstrate considerable phenotypic heterogeneity and course. Accurate predictors of disease behaviour are lacking. The contribution of genetics and specific polymorphisms is widely appreciated; however, their cumulative effect(s) upon disease behaviour remains poorly understood. Here, we investigate the relationship between genetic burden and disease phenotype in a Canadian inflammatory bowel disease (IBD) Cohort. METHODS: We retrospectively examined a cohort of CD and UC patients recruited from a single tertiary referral center genotyped using a Goldengate Illumina platform. A genetic risk score (GRS) incorporating strength of association (log odds ratio) and allele dose for 151 IBD-risk loci was calculated and evaluated for phenotypic associations. RESULTS: Among CD patients, higher GRS was associated with earlier onset of disease (regression coefficient -2.19, 95% confidence interval [CI] -3.77 to -0.61, P = 0.007), ileal disease (odds ratio [OR] 1.45), stricturing/penetrating disease (OR 1.72), perianal disease (OR 1.57) and bowel resection (OR 1.66). Higher GRS was associated with use of anti-tumor necrosis factor (TNF) (P < 0.05) but not immunomodulators. Interestingly, we could not demonstrate an association between higher GRS and family history of IBD (OR 1.27, P = 0.07). Onset of disease remained statistically significant for never smokers (P = 0.03) but not ever smokers (P = 0.13). For UC, having a higher GRS did not predict the age of diagnosis nor was it predictive of UC disease extent (P = 0.18), the need for surgery (P = 0.74), nor medication use (immunomodulators P = 0.53, anti-TNF P = 0.49). We could not demonstrate an association between increased GRS and having a family history of IBD in the UC group. CONCLUSIONS: Increasing genetic burden is associated with early age of diagnosis in CD and may be useful in predicting disease behaviour in CD but not UC.

Magnetic resonance imaging evidence of hippocampal structural changes in patients with primary biliary cholangitis.

INTRODUCTION: Behavioral symptoms are commonly reported by patients with primary biliary cholangitis (PBC). In other patient populations, symptoms are commonly associated with hippocampal volume reduction linked to neuroinflammation (inferred from regional iron deposition), as demonstrated by magnetic resonance imaging (MRI). We hypothesized that PBC patients would exhibit reduced volume and increased iron deposition of the hippocampus. METHODS: Seventeen female non-cirrhotic PBC patients and 17 age/gender-matched controls underwent 3-Tesla T1-weighted MRI and quantitative susceptibility mapping (QSM; an indicator of iron deposition). The hippocampus and its subfields were segmented from T1 images using Freesurfer, and susceptibility of the whole hippocampus was calculated from QSM images. Volume and susceptibility were compared between groups, and associations with PBC-40 score and disease indicators (years since diagnosis, Fibroscan value, alkaline phosphatase level, clinical response to ursodeoxycholic acid (UDCA)) were investigated. RESULTS: PBC patients exhibited significantly reduced hippocampal volume (p = 0.023) and increased susceptibility (p = 0.048). Subfield volumes were reduced for the subiculum, molecular layer, granule cell layer of the dentate gyrus and CA4 (p < 0.05). Fibroscan value was significantly correlated with PBC-40 (Spearman's rho = 0.499; p = 0.041) and disease duration (Spearman's rho = 0.568; p = 0.017). DISCUSSION: Our findings suggest hippocampal changes occur early in the disease course of PBC, similar in magnitude to those observed in major depressive disorder and neurodegenerative diseases. TRANSLATIONAL IMPACT: Clinical management of PBC could include early interventional strategies that promote hippocampal neurogenesis that may beneficially impact behavioral symptoms and improve quality of life.

Preoperative Ustekinumab Treatment Is Not Associated With Increased Postoperative Complications in Crohn's Disease: A Canadian Multi-Centre Observational Cohort Study.

BACKGROUND: Ustekinumab (UST), an anti-IL12/23 inhibitor is indicated for moderate-to-severe Crohn's disease (CD). However, it is unclear if patients treated with UST are at increased risk for postoperative complications. AIM: To evaluate the postoperative safety outcomes in UST-treated CD patients. METHODS: A multicentre cohort study of UST-treated CD patients at two tertiary care centres (University of Calgary, University of Alberta, Canada) undergoing abdominal surgery between 2009 and 2016 was performed. Postoperative outcomes were compared against a control cohort of anti-TNF-treated patients over the same time-period. The primary outcome was occurrence of postoperative complications up to six months postoperatively, stratified by timing (early <30 days vs. late complications ≥30 days). RESULTS: Twenty UST-treated patients and 40 anti-TNF-treated patients were included with a median preoperative treatment exposure of 6.5 months and 18 months, respectively (p=0.01). Bowel obstruction was the most common surgical indication in both cohorts. UST-treated patients were more likely to require an ostomy (70.0% vs. 12.5%, p<0.001) and be on combination therapy with either systemic corticosteroids or concurrent immunomodulators (azathioprine or methotrexate) (25.0% vs. 2.5%, p=0.01). Despite the increased concomitant use of immunosuppression in the UST-treated cohort, there were no significant differences in early or late postoperative wound infections (1/20 in UST-cohort, 2/40 in anti-TNF cohort, p=1.00), anastomotic leak (0/20 in UST-cohort, 3/40 in anti-TNF cohort, p=0.54), or postoperative ileus/obstruction (3/20 in UST-cohort, 4/40 in anti-TNF cohort, p=0.67). CONCLUSIONS: CD patients receiving preoperative UST did not experience an increase in postoperative complications, despite increased use of concurrent immunosuppression.

Primary Biliary Cholangitis Alters Functional Connections of the Brain's Deep Gray Matter.

OBJECTIVES: Fatigue, itch, depressed mood, and cognitive impairment significantly impact the quality of life of many patients with primary biliary cholangitis (PBC). Previous neuroimaging studies of non-hepatic diseases suggest that these symptoms are often associated with dysfunction of deep gray matter brain regions. We used resting-state functional magnetic resonance imaging (rsfMRI) to determine whether PBC patients exhibit altered functional connections of deep gray matter. METHODS: Twenty female non-cirrhotic PBC patients and 21 age/gender-matched controls underwent rsfMRI. Resting-state functional connectivity (rsFC) of deep gray matter brain structures (putamen, thalamus, amygdala, hippocampus) was compared between groups. Fatigue, itch, mood, cognitive performance, and clinical response to ursodeoxycholic acid (UDCA) were assessed, and their association with rsFC was determined. RESULTS: Relative to controls, PBC patients exhibited significantly increased rsFC between the putamen, thalamus, amygdala, and hippocampus, as well as with frontal and parietal regions. Reduced rsFC of the putamen and hippocampus with motor and sensory regions of the brain were also observed. Fatigue, itch, complete response to UDCA, and verbal working memory performance were also associated with altered rsFC of deep gray matter. These rsFC changes were independent of biochemical disease severity. CONCLUSIONS: PBC patients have objective evidence of altered rsFC of the brain's deep gray matter that is in part linked to fatigue severity, itch, response to UDCA therapy, and cognitive performance. These results may guide future approaches to define how PBC leads to altered brain connectivity and provide insight into novel targets for treating PBC-associated brain dysfunction and behavioral symptoms.

Validation of coding algorithms for the identification of patients hospitalized for alcoholic hepatitis using administrative data.

BACKGROUND: Epidemiologic studies of alcoholic hepatitis (AH) have been hindered by the lack of a validated International Classification of Disease (ICD) coding algorithm for use with administrative data. Our objective was to validate coding algorithms for AH using a hospitalization database. METHODS: The Hospital Discharge Abstract Database (DAD) was used to identify consecutive adults (≥18 years) hospitalized in the Calgary region with a diagnosis code for AH (ICD-10, K70.1) between 01/2008 and 08/2012. Medical records were reviewed to confirm the diagnosis of AH, defined as a history of heavy alcohol consumption, elevated AST and/or ALT (<300 U/L), serum bilirubin >34 µmol/L, and elevated INR. Subgroup analyses were performed according to the diagnosis field in which the code was recorded (primary vs. secondary) and AH severity. Algorithms that incorporated ICD-10 codes for cirrhosis and its complications were also examined. RESULTS: Of 228 potential AH cases, 122 patients had confirmed AH, corresponding to a positive predictive value (PPV) of 54% (95% CI 47-60%). PPV improved when AH was the primary versus a secondary diagnosis (67% vs. 21%; P < 0.001). Algorithms that included diagnosis codes for ascites (PPV 75%; 95% CI 63-86%), cirrhosis (PPV 60%; 47-73%), and gastrointestinal hemorrhage (PPV 62%; 51-73%) had improved performance, however, the prevalence of these diagnoses in confirmed AH cases was low (29-39%). CONCLUSIONS: In conclusion the low PPV of the diagnosis code for AH suggests that caution is necessary if this hospitalization database is used in large-scale epidemiologic studies of this condition.

Inclusion of Sarcopenia Within MELD (MELD-Sarcopenia) and the Prediction of Mortality in Patients With Cirrhosis.

OBJECTIVES: Limitations of the Model for End-Stage Liver Disease (MELD) score include its failure to assess the nutritional and functional status of cirrhotic patients. Our objectives were to evaluate the impact of sarcopenia in cirrhosis and whether the inclusion of muscularity assessment within MELD could improve the prediction of mortality in patients with cirrhosis. METHODS: We included 669 cirrhotic patients who were consecutively evaluated for liver transplantation. Skeletal muscle index at the third lumbar vertebra (L3 SMI) was measured by computed tomography, and sarcopenia was defined using previously published gender and body mass index-specific cutoffs. Using Cox proportional hazards regression, a novel MELD-sarcopenia score was derived. RESULTS: Sarcopenia was present in 298 patients (45%); sarcopenic patients had shorter median survival than non-sarcopenic patients (20±3 vs. 95±24 months, P<0.001). By Cox regression analysis adjusted for age, gender, and hepatocellular carcinoma, both MELD (hazard ratio (HR) 1.08, 95% confidence interval (CI) 1.06-1.10, P<0.001), and the L3 SMI (HR 0.97, 95% CI 0.96-0.99, P<0.001) were associated with mortality. Overall, the c-statistics for 3-month mortality were 0.82 (95% CI 0.78-0.87) for MELD and 0.85 (95% CI 0.81-0.88) for MELD-sarcopenia (P=0.1). Corresponding figures for 1-year mortality were 0.73 (95% CI 0.69-0.77) and 0.77 (95% CI 0.73-0.80), respectively (P=0.03). The c-statistics for 3-month mortality in patients with MELD<15 (0.85 vs. 0.69, P=0.02) and refractory ascites (0.74 vs. 0.71, P=0.01) were significantly higher for MELD-sarcopenia compared with MELD. CONCLUSIONS: Modification of MELD to include sarcopenia is associated with improved prediction of mortality in patients with cirrhosis, primarily in patients with low MELD scores. External validation of this prognostic index in larger cohorts of cirrhotic patients is warranted.

Risk factors for mortality in patients with alcoholic hepatitis and assessment of prognostic models: A population-based study.

BACKGROUND: Severe alcoholic hepatitis (AH) is associated with a substantial risk for short-term mortality. OBJECTIVES: To identify prognostic factors and validate well-known prognostic models in a Canadian population of patients hospitalized for AH. METHODS: In the present retrospective study, patients hospitalized for AH in Calgary, Alberta, between January 2008 and August 2012 were included. Stepwise logistic regression models identified independent risk factors for 90-day mortality, and the discrimination of prognostic models (Model for End-stage Liver Disease [MELD] and Maddrey discriminant function [DF]) were examined using areas under the ROC curves. RESULTS: A total of 122 patients with AH were hospitalized during the study period; the median age was 49 years (interquartile range [IQR] 42 to 55 years) and 60% were men. Median MELD score and Maddrey DF on admission were 21 (IQR 18 to 24) and 45 (IQR 26 to 62), respectively. Seventy-three percent of patients received corticosteroids and/or pentoxifylline, and the 90-day mortality was 17%. Independent predictors of mortality included older age, female sex, international normalized ratio, MELD score and Maddrey DF (all P<0.05). For discrimination of 90-day mortality, the areas under the ROC curves of the prognostic models (MELD 0.64; Maddrey DF 0.68) were similar (P>0.05). At optimal cut-offs of ≥22 for MELD score and ≥37 for Maddrey DF, both models excluded death with high certainty (negative predictive values 90% and 96%, respectively). CONCLUSIONS: In patients hospitalized for AH, well-known prognostic models can be used to predict 90-day mortality, particularly to identify patients with a low risk for death.

Liver stiffness by transient elastography predicts liver-related complications and mortality in patients with chronic liver disease.

BACKGROUND: Liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is a validated method for noninvasively staging liver fibrosis. Most hepatic complications occur in patients with advanced fibrosis. Our objective was to determine the ability of LSM by TE to predict hepatic complications and mortality in a large cohort of patients with chronic liver disease. METHODS: In consecutive adults who underwent LSM by TE between July 2008 and June 2011, we used Cox regression to determine the independent association between liver stiffness and death or hepatic complications (decompensation, hepatocellular carcinoma, and liver transplantation). The performance of LSM to predict complications was determined using the c-statistic. RESULTS: Among 2,052 patients (median age 51 years, 65% with hepatitis B or C), 87 patients (4.2%) died or developed a hepatic complication during a median follow-up period of 15.6 months (interquartile range, 11.0-23.5 months). Patients with complications had higher median liver stiffness than those without complications (13.5 vs. 6.0 kPa; P<0.00005). The 2-year incidence rates of death or hepatic complications were 2.6%, 9%, 19%, and 34% in patients with liver stiffness <10, 10-19.9, 20-39.9, and ≥40 kPa, respectively (P<0.00005). After adjustment for potential confounders, liver stiffness by TE was an independent predictor of complications (hazard ratio [HR] 1.05 per kPa; 95% confidence interval [CI] 1.03-1.06). The c-statistic of liver-stiffness for predicting complications was 0.80 (95% CI 0.75-0.85). A liver stiffness below 20 kPa effectively excluded complications (specificity 93%, negative predictive value 97%); however, the positive predictive value of higher results was sub-optimal (20%). CONCLUSIONS: Liver stiffness by TE accurately predicts the risk of death or hepatic complications in patients with chronic liver disease. TE may facilitate the estimation of prognosis and guide management of these patients.

The feasibility and reliability of transient elastography using Fibroscan®: a practice audit of 2335 examinations.

BACKGROUND: Liver stiffness measurement (LSM) using transient elastography is widely used in the management of patients with chronic liver disease. OBJECTIVES: To examine the feasibility and reliability of LSM, and to identify patient and operator characteristics predictive of poorly reliable results. METHODS: The present retrospective study investigated the frequency and determinants of poorly reliable LSM (interquartile range [IQR]/median LSM [IQR/M] >30% with median liver stiffness ≥7.1 kPa) using the FibroScan (Echosens, France) over a three-year period. Two experienced operators performed all LSMs. Multiple logistic regression analyses examined potential predictors of poorly reliable LSMs including age, sex, liver disease, the operator, operator experience (<500 versus ≥500 scans), FibroScan probe (M versus XL), comorbidities and liver stiffness. In a subset of patients, medical records were reviewed to identify obesity (body mass index ≥30 kg/m2). RESULTS: Between July 2008 and June 2011, 2335 patients with liver disease underwent LSM (86% using the M probe). LSM failure (no valid measurements) occurred in 1.6% (n=37) and was more common using the XL than the M probe (3.4% versus 1.3%; P=0.01). Excluding LSM failures, poorly reliable LSMs were observed in 4.9% (n=113) of patients. Independent predictors of poorly reliable LSM included older age (OR 1.03 [95% CI 1.01 to 1.05]), chronic pulmonary disease (OR 1.58 [95% CI 1.05 to 2.37), coagulopathy (OR 2.22 [95% CI 1.31 to 3.76) and higher liver stiffness (OR per kPa 1.03 [95% CI 1.02 to 1.05]), including presumed cirrhosis (stiffness ≥12.5 kPa; OR 5.24 [95% CI 3.49 to 7.89]). Sex, diabetes, the underlying liver disease and FibroScan probe were not significant. Although reliability varied according to operator (P<0.0005), operator experience was not significant. In a subanalysis including 434 patients with body mass index data, obesity influenced the rate of poorly reliable results (OR 2.93 [95% CI 0.95 to 9.05]; P=0.06). CONCLUSIONS: FibroScan failure and poorly reliable LSM are uncommon. The most important determinants of poorly reliable results are older age, obesity, higher liver stiffness and the operator, the latter emphasizing the need for adequate training.