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We assessed depression, anxiety, and relevant cognitions in persons with mental retardation by administering modified versions of the Reynolds Child Depression Scale, the Beck Anxiety Inventory, the Automatic Thoughts Questionnaire, and the Cognitions Checklist to 46 persons with borderline to moderate mental retardation. Consistent with research with other groups, self-reports of depression and anxiety were highly correlated (r = .74) in these individuals, and cognitions were strong predictors of negative affect. Subscales measuring cognitions related to depression and anxiety were also highly related, limiting the 'cognitive-specificity' hypothesis. Hierarchical multiple regression analyses offered mixed support for cognitive-specificity. We discuss the implications of these findings for the cognitive and affective assessment of persons with intellectual limitations. [ABSTRACT FROM AUTHOR]

Background and study aims Reprocessing reusable endoscopes is challenging due to their non-sterilizable nature. Disinfection has been shown to have a significant risk of failure with serious consequences. Single-use endoscopes can eliminate contamination risk and reduce workflow delays caused by reprocessing. This study evaluated the clinical performance of single-use gastroscopes in patients undergoing esophagogastroduodenoscopy (EGD). Patients and methods In this case series, 60 patients underwent EGD using single-use gastroscopes, with 34 procedures in the endoscopy department and 26 in the intensive care unit. The primary outcome was successful completion of the intended EGD objective. Furthermore, certified endoscopists assessed device performance on a five-point Likert scale (ranging from 1-"much worse" to 5-"much better"), considering their experience with a reusable gastroscope. Results Successful completion of EGDs using only the single-use gastroscope was achieved in 58 of 60 cases (96.7%). In two cases, crossover to an ultra-slim endoscope was necessary to either reach the esophageal stenosis or to transverse the stenosis. Overall satisfaction was rated as comparable to reusable scopes in 51 of 56 cases (91.1%) and inferior in five cases (8.9%). The lower weight of the single-use gastroscope was rated as superior in 42 of 60 cases (70.0%). Drawbacks included reduced image quality (23 of 45 cases; 51.1%). Feedback included the absence of a freeze button, lens cleaning issues, and small image size. Conclusions Single-use gastroscopes exhibited a high EGD completion rate and effectiveness for various indications. Further research should focus on evaluating the implementation of single-use gastroscopes in a comprehensive context, considering clinical effectiveness, costs, and environmental impact., Competing Interests: Conflict of Interest KvdP, ADK, WJL and VP declare no conflict of interests for this article. PJFJ acted as consultant/lecturer for Boston Scientific. MCV has received research support from Boston Scientific, 3M and Pentax Medical. LA is a member of the advisory board of AMBU. MJB has received research support from Boston Scientific, Cook Medical, Pentax Medical, Mylan, ChiRoStim and acted as a consultant/lecturer for Boston Scientific, Cook Medical, Pentax Medical and AMBU., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Introduction: Treatment of primary biliary cholangitis (PBC) can improve the GLOBE score. We aimed to assess the association between changes in the GLOBE score (ΔGLOBE) and liver transplantation (LT)-free survival in patients with PBC who were treated with ursodeoxycholic acid (UDCA)., Methods: Among UDCA-treated patients within the Global PBC cohort, the association between ΔGLOBE (ΔGLOBE 0-1 : during the first year of UDCA, ΔGLOBE 1-2 : during the second year) and the risk of LT or death was assessed through Cox regression analyses., Results: Overall, 3,775 UDCA-treated patients were included; 3,424 (90.7%) were female, the median age was 54.0 (interquartile range [IQR] 45.9-62.4) years, and the median baseline GLOBE score was 0.25 (IQR -0.47 to 0.96). During a median follow-up of 7.2 (IQR 3.7-11.5) years, 730 patients reached the combined end point of LT or death. The median ΔGLOBE 0-1 was -0.27 (IQR -0.56 to 0.02). Cox regression analyses, adjusted for pretreatment GLOBE score and ΔGLOBE 0-12 , showed that ΔGLOBE was associated with LT or death (adjusted hazard ratio 2.28, 95% confidence interval 1.81-2.87, P < 0.001). The interaction between baseline GLOBE score and ΔGLOBE 0-1 was not statistically significant ( P = 0.296). The ΔGLOBE 1-2 was associated with LT or death (adjusted hazard ratio 2.19, 95% confidence interval 1.67-2.86, P < 0.001), independently from the baseline GLOBE score and the change in GLOBE score during the first year of UDCA., Discussion: UDCA-induced changes in the GLOBE score were significantly associated with LT-free survival in patients with PBC. While the relative risk reduction of LT or death was stable, the absolute risk reduction was heavily dependent on the baseline prognosis of the patient., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background and Aims: Patients with primary biliary cholangitis (PBC) and insufficient response to ursodeoxycholic acid (UDCA), currently assessed after 1 year, are candidates for second-line therapy. The aims of this study are to assess biochemical response pattern and determine the utility of alkaline phosphatase (ALP) at six months as a predictor of insufficient response., Methods: UDCA-treated patients in the GLOBAL PBC database with available liver biochemistries at one year were included. POISE criteria were used to assess response to treatment, defined as ALP <1.67 × upper limit of normal (ULN) and normal total bilirubin at one year. Various thresholds of ALP at six months were evaluated to predict insufficient response based on negative predictive value (NPV) and that with nearest to 90% NPV was selected., Results: For the study, 1362 patients were included, 1232 (90.5%) female, mean age of 54 years. The POISE criteria were met by 56.4% (n = 768) of patients at one year. The median ALP (IQR) of those who met POISE criteria compared to those who did not was 1.05 × ULN (0.82-1.33) vs. 2.37 × ULN (1.72-3.69) at six months (p < .001). Of 235 patients with serum ALP >1.9 × ULN at six months, 89% did not achieve POISE criteria (NPV) after one year of UDCA. Of those with insufficient response by POISE criteria at one year, 210 (67%) had an ALP >1.9 × ULN at six months and thus would have been identified early., Conclusions: We can identify patients for second-line therapy at six months using an ALP threshold of 1.9 × ULN, given that approximately 90% of these patients are non-responders according to POISE criteria., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: The are geographic variations in the incidence and prevalence of primary biliary cholangitis (PBC). The aim was to explore whether clinical outcomes of patients within Western Europe differ according to geographical region., Methods: Ursodeoxycholic acid-treated patients from European centers from the Global PBC database diagnosed from 1990 onwards were included. Patients with a time lag > 1 year from diagnosis to start of follow-up were excluded. Differences in baseline characteristics were studied according to North/South and East/West, whereas outcomes (transplant-free survival and decompensation) were studied with center latitude and longitude. Cox regression analyses were adjusted for age, sex, diagnosis year, biochemical markers, and cirrhosis as a time-dependent covariate., Results: One thousand eight hundred seventy-eight patients were included, and there were no geographical differences in age or sex, with a mean age of 54 years and 89% female patients. Those in North Europe were more often of a moderately advanced/advanced Rotterdam biochemical stage (28.4%) compared with South Europe (20.6%). Additionally, they exhibited higher median alkaline phosphatase (2.0 ×ULN vs. 1.4 ×ULN) and transaminases. In multivariable analysis, there was a significant interaction between center latitude and longitude for decompensation (P < 0.001) and a trend for transplant-free survival, in which the Northwestern area demonstrated an increased risk for poor outcomes as compared to the reference (Paris)., Conclusion: We describe geographic variations in outcomes for patients across Europe from specialist centers in the Global PBC Study Group. Further study is important to explore the potential individual, environmental, and healthcare-related factors that may be contributors., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA-treated external controls., Methods: Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis., Results: During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10-0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12-0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03-1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09-1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21-0.85) including hepatic decompensation., Conclusions: Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: After 1 year of ursodeoxycholic acid (UDCA), patients with primary biliary cholangitis (PBC) may have a normal GLOBE score despite high alkaline phosphatase (ALP) levels., Aim: To assess the association between ALP and liver transplantation (LT)-free survival according to the GLOBE score METHODS: Among patients with a normal or elevated GLOBE score in the Global PBC cohort, the association between ALP after 1 year of UDCA and the risk of LT/death was assessed. The LT-free survival was compared with that of a matched general population., Results: After 1 year of UDCA, ALP was associated with the risk of LT/death (aHR 1.31, 95% CI 1.003-1.72, p = 0.048) among 2729 patients with a normal GLOBE score. The 10-year LT-free survival among these patients with an ALP >2.0 × ULN was 94.0% (95% CI 90.1-97.9) for those <50 years, and 82.6% (95% CI 76.5-88.7) for those ≥50 years, which was significantly lower (p = 0.040) and similar (p = 0.736) to that of the matched population, respectively. The 10-year LT-free survival in patients ≥50 years with normal GLOBE score and normal ALP (90.8%, 95% CI 87.7-93.9) was significantly higher (p = 0.022) than the matched population. Among 1045 patients with an elevated GLOBE score, ALP was associated with LT/death only in those <50 years (aHR 1.38, 95% CI 1.06-1.81, p = 0.016)., Conclusion: The LT-free survival of patients with PBC with a normal GLOBE score is optimal in case of normal ALP levels, also in relation to the general population. Despite their generally favourable prognosis, an elevated ALP level may still indicate a need for add-on therapy., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients., Objective: To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC., Methods: We included ursodeoxycholic acid-treated patients with PBC from the Global PBC Study Group. The performance of baseline and 1-year clinical markers with transplant-free survival was assessed to develop the 'ABA' tool using Age (A), Bilirubin (B), and Alkaline phosphatase (A). Added value of fibrosis estimation was assessed., Results: 'ABA' classification mapped three risk groups (n = 2226): low [Age > 50 years, bilirubin ≤ 1 × ULN, alkaline phosphatase (ALP) ≤ 3 × ULN], high (Age ≤ 50 years, bilirubin > 1 × ULN, ALP > 3 × ULN), and intermediate (other). Transplant-free survival at 10 years in the low-, intermediate-, and high-risk groups were 89, 77, and 59% at baseline and 86, 76, and 40% at 1 year, respectively. We propose that high-risk patients at baseline be directly triaged to enhanced (PBC-dedicated) care and the remaining be reassessed at 1 year. Modelling showed after 1 year 46% patients were proposed to enhanced care and 54% to standard care. The 'ABA' mapped pathways facilitated identification of patients at risk based on a young age, as compared to traditional liver biochemical stratification. In patients proposed to standard care, estimated fibrosis stage had ongoing prognostic value., Conclusion: Nonspecialist use of the 'ABA' risk tool could prioritize care journey choices for patients with PBC., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Gamma-glutamyltransferase (GGT) is a serum marker of cholestasis. We investigated whether serum level of GGT is a prognostic marker for patients with primary biliary cholangitis (PBC)., Methods: We analyzed data from patients with PBC from the Global PBC Study Group, comprising 14 centers in Europe and North America. We obtained measurements of serum GGT at baseline and time points after treatment. We used Cox model hazard ratios to evaluate the association between GGT and clinical outcomes, including liver transplantation and liver-related death., Results: Of the 2129 patients included in our analysis, 281 (13%) had a liver-related clinical endpoint. Mean age at diagnosis was 53 years and 91% of patients were female patients. We found a correlation between serum levels of GGT and alkaline phosphatase (ALP) (r = 0.71). Based on data collected at baseline and yearly for up to 5 years, higher serum levels of GGT were associated with lower hazard for transplant-free survival. Serum level of GGT at 12 months after treatment higher than 3.2-fold the upper limit of normal (ULN) identified patients who required liver transplantation or with liver-related death at 10 years with an area under the receiver operating characteristic curve of 0.70. The risk of liver transplantation or liver-related death in patients with serum level of GGT above 3.2-fold the ULN, despite level of ALP lower than 1.5-fold the ULN, was higher compared to patients with level of GGT lower than 3.2-fold the ULN and level of ALP lower than 1.5-fold the ULN (P < .05). Including information on level of GGT increased the prognostic value of the Globe score., Conclusions: Serum level of GGT can be used to identify patients with PBC at risk for liver transplantation or death, and increase the prognostic value of ALP measurement. Our findings support the use of GGT as primary clinical endpoint in clinical trials. In patients with low serum level of ALP, a high level of GGT identifies those who might require treatment of metabolic disorders or PBC treatment escalation., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Comparative data on scores that predict outcome in primary biliary cholangitis (PBC) are scarce. We aimed to assess and compare the prognostic value of the Mayo Risk Score (MRS, 1989 and 1994), UK-PBC score, and GLOBE score in a large international cohort of patients with PBC., Methods: Ursodeoxycholic acid-treated patients from 7 centers participating in the GLOBAL PBC Study Group were included. The discriminatory performance of the scores was assessed with concordance statistics at yearly intervals up to 5 years. Model for End-stage Liver Disease was included for comparison. Prediction accuracy was assessed by comparing predicted survival and actual survival in Kaplan-Meier analyses., Results: A total of 1,100 ursodeoxycholic acid-treated patients with PBC were included, with a mean (SD) age of 53.6 (12.0) years, of whom 1,003 (91%) were female. During a median follow-up of 7.6 (interquartile range 4.1-11.7) years, 42 patients underwent liver transplantation, and 127 patients died. At 1 year, the concordance statistic for Model for End-stage Liver Disease was 0.68 (95% confidence interval [CI] 0.64-0.72), 0.74 (95% CI 0.67-0.80) for the UK-PBC score, 0.76 (95% CI 0.72-0.81) for the MRS (1989 and 1994), and 0.80 (95% CI 0.76-0.84) for the GLOBE score. The GLOBE score showed superior discriminatory performance, but differences were not statistically different. For all scores, discriminatory performance increased in those with bilirubin >0.6 × ULN and advanced fibrosis estimated with Fibrosis-4. The predicted (median) minus observed 5-year transplant-free survival was +0.4% and +2.5% for the MRS (1989) and GLOBE score, respectively., Discussion: All prognostic scores developed for PBC (GLOBE, UK-PBC, and MRS) demonstrated comparable discriminating performance for liver transplantation or death as well as good prediction accuracy., (Copyright © 2021 by The American College of Gastroenterology.)

Objective: The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC., Methods: The NNT was calculated based on the untreated LT-free survival and HR of UDCA with respect to LT or death as derived from inverse probability of treatment weighting-adjusted Cox proportional hazard analyses within the Global PBC Study Group database., Results: We included 3902 patients with a median follow-up of 7.8 (4.1-12.1) years. The overall HR of UDCA was 0.46 (95% CI 0.40 to 0.52) and the 5-year LT-free survival without UDCA was 81% (95% CI 79 to 82). The NNT to prevent one LT or death within 5 years (NNT 5y ) was 11 (95% CI 9 to 13). Although the HR of UDCA was similar for patients with and without cirrhosis (0.33 vs 0.31), the NNT 5y was 4 (95% CI 3 to 5) and 20 (95% CI 14 to 34), respectively. Among patients with low alkaline phosphatase (ALP) (≤2× the upper limit of normal (ULN)), intermediate ALP (2-4× ULN) and high ALP (>4× ULN), the NNT 5y to prevent one LT or death was 26 (95% CI 15 to 70), 11 (95% CI 8 to 17) and 5 (95% CI 4 to 8), respectively., Conclusion: The absolute clinical efficacy of UDCA with respect to LT or death varied with baseline prognostic characteristics, but was high throughout. These findings strongly emphasise the incentive to promptly initiate UDCA treatment in all patients with PBC and may improve patient compliance., Competing Interests: Competing interests: MHH reports a speaker fee from Zambon Nederland. WL reports consulting services for Intercept Pharmaceuticals. CC is a consultant for Intercept Pharmaceuticals France. DT reports consulting activities for Intercept Pharmaceuticals. HLAJ reports grants from and consulting work for AbbVie Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Innogenetics, Merck, Novartis, Roche, Intercept Pharmaceuticals and Janssen. KL reports that he is an unpaid advisor for Intercept Pharmaceuticals and Shire. PT receives institutional salary support from the NIHR Birmingham Liver Biomedical Research Centre. He received research grant funding from the Wellcome Trust, Guts UK, PSC Support and Intercept Pharmaceuticals. He also received advisory and consultancy fees from Intercept and Dr Falk Pharma, and speaker fees from Intercept, Dr Falk Pharma, Zambon and Perspectum Diagnostics. GH reports advisory services for Intercept Pharmaceuticals, Novartis and GlaxoSmithKline Pharmaceuticals. AP reports consulting services for Intercept Pharmaceuticals and Novartis Pharma. AF reports consulting activities for Intercept Pharmaceuticals. PI reports personal fees from Intercept and non-financial support from Bruschettini and Menarini Diagnostics. CYP has received grant support form Takeda, speaker’s fees from AbbVie, Takeda and Dr Falk Pharma, and served as a consultant for Takeda and Pliant. AM reports advisory services for Intercept Pharmaceuticals, AbbVie and Novartis, and research funding resources from the Canadian Institutes of Health Research, Canadian Liver Foundation, American Kennel Club, Intercept Pharmaceuticals, AbbVie and Gilead Sciences. KK reports personal fees from Gilead Sciences, Intercept Pharmaceuticals and Novartis, and grants from Gilead Sciences and Intercept Pharmaceuticals. BEH reports grants from Intercept Pharmaceuticals and Zambon Nederland, and consulting work for Intercept Pharmaceuticals and Novartis. HvB is a consultant for Intercept Pharma Benelux and received unrestricted research grants from Intercept Pharmaceuticals and from Zambon Nederland. AJvdM reports speaker's fees from MSD, Gilead Sciences, AbbVie Pharmaceuticals and Zambon Nederland, received an unrestricted grant from Gilead Sciences, and reports travel expenses covered by Dr Falk Pharma., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Introduction: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined., Methods: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated., Results: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN., Discussion: Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.

Background & Aims: Patients usually receive a diagnosis of primary biliary cholangitis (PBC) at an early stage, based on biochemical analyses. We investigated the proportion of patients who progress to moderate or advanced PBC and factors associated with progression and patient survival., Methods: We obtained data from 1615 patients (mean age, 55.4 y) with early stage PBC (based on their normal levels of albumin and bilirubin), collected at the time of initial evaluation or treatment, from the Global PBC Study Group database (comprising patients at 19 liver centers in North American and European countries). We collected data from health care evaluations on progression to moderate PBC (abnormal level of bilirubin or albumin) or advanced-stage PBC (abnormal level of both). The median follow-up time was 7.9 years. The composite end point was decompensation, hepatocellular carcinoma, liver transplantation, or death., Results: Of the 1615 patients identified with early stage PBC, 904 developed moderate PBC and 201 developed advanced disease over the study period. The proportions of patients who transitioned to moderate PBC at 1, 3, and 5 years were 12.9%, 30.2%, and 45.8%. The proportions of these patients who then transitioned to advanced PBC at 1, 3, and 5 years later were 3.4%, 12.5%, and 16.0%, respectively. During the follow-up period, 236 patients had a clinical event. The proportions of patients with moderate PBC and event-free survival were 97.9%, 95.1%, and 91.5% at 1, 3, and 5 years, respectively, and the proportions of patients with advanced PBC and event-free survival were 90.6%, 71.2%, and 58.3% at 1, 3, and 5 years later, respectively. Variables associated with transition from early to moderate PBC included baseline levels of bilirubin, albumin, and alkaline phosphatase; aspartate to alanine aminotransferase ratio; platelet count; and treatment with ursodeoxycholic acid. Transitions from early to moderate PBC and from moderate to advanced PBC were associated with higher probabilities of a clinical event (time-dependent hazard ratios, 3.0; 95% CI, 2.0-4.5; and 4.6; 95% CI, 3.5-6.2)., Conclusions: Approximately half of patients with early stage PBC progress to a more severe stage within 5 years. Progression is associated with an increased risk of a clinical event, so surveillance is important for patients with early stage PBC., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Recently the Amsterdam-Oxford model (AOM) was introduced as a prognostic model to assess the risk of death and/or liver transplantation (LT) in primary sclerosing cholangitis (PSC). We aimed to validate and assess the utility of the AOM., Methods: Clinical and laboratory data were collected from the time of PSC diagnosis until the last visit or time of LT or death. The AOM was calculated at yearly intervals following PSC diagnosis. Discriminatory performance was assessed by calculation of the C-statistic and prediction accuracy by comparing the predicted survival with the observed survival in Kaplan-Meier estimates. A grid search was performed to identify the most discriminatory AOM threshold., Results: A total of 534 patients with PSC and a mean (SD) age of 39.2 (13.1) years were included. The diagnosis was large duct PSC in 466 (87%), PSC with features of autoimmune hepatitis in 52 (10%) and small-duct PSC in 16 (3%). During the median (IQR) follow-up of 7.8 (4.0-12.6) years, 167 patients underwent LT and 65 died. The median LT-free survival was 13.2 (11.8-14.7) years. The C-statistic of the AOM ranged from 0.67 at baseline to 0.75 at 5 years of follow-up. The difference between the predicted and observed survival ranged from -1.6% at 1 year to + 3.9% at 5 years of follow-up. Patients that developed AOM scores >2.0 were at significant risk of LT or death (time-dependent hazard ratio 4.09; 95% CI 2.99-5.61)., Conclusions: In this large cohort of patients with PSC, the AOM showed an adequate discriminative performance and good prediction accuracy at PSC diagnosis and during follow-up. This study further validates the AOM as a valuable risk stratification tool in PSC and extends its utility., Lay Summary: In our study we assessed whether the Amsterdam-Oxford model (AOM) is able to correctly estimate the risk of liver transplantation or death in patients with primary sclerosing cholangitis (PSC). This model uses 7 objective and readily available variables to estimate prognosis for individual patients at the time of PSC diagnosis. The AOM may aid in patient counselling and timing of diagnostic procedures or therapeutic interventions for complications of liver disease. We confirm that the model works well at PSC diagnosis, but also when the AOM is recalculated at different timepoints during follow-up, greatly improving the applicability of the model in clinical practice and for individual patients., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Fibrosis stage predicts prognosis in patients with chronic liver disease independent of aetiology, although its precise role in risk stratification in patients with primary biliary cholangitis (PBC) remains undefined., Aim: To assess the utility of baseline fibrosis stage in predicting long-term outcomes in the context of biochemical risk stratification METHODS: In a large and globally representative cohort of patients with PBC, liver biopsies performed from 1980 to 2014 were evaluated. The predictive ability of histologic fibrosis stage in addition to treatment response at 1 year (Toronto/Paris-II criteria), as well as non-invasive markers of fibrosis (AST/ALT ratio [AAR], AST to platelet ratio index [APRI], FIB-4), for transplant-free survival was assessed with Cox proportional-hazards models., Results: There were 1828 patients with baseline liver biopsy. Advanced histologic fibrosis (stage 3/4) was an independent predictor of survival in addition to non-invasive measures of fibrosis with the hazard ratios ranging from 1.59 to 2.73 (P < .001). Patients with advanced histologic fibrosis stage had worse survival despite biochemical treatment response, with a 10-year survival of 76.0%-86.6% compared to 94.5%-95.1% depending on the treatment response criteria used. Poor correlations were observed between non-invasive measures of fibrosis and histologic fibrosis stage., Conclusion: Assessment of fibrosis stage grants prognostic value beyond biochemical treatment response at 1 year. This highlights the need to incorporate fibrosis stage in individual risk stratification in patients with PBC, partly to identify those that may derive benefit from novel therapies., (© 2019 John Wiley & Sons Ltd.)

Background & Aims: Primary biliary cholangitis (PBC) predominantly affects middle-aged women; there are few data on disease phenotypes and outcomes of PBC in men and younger patients. We investigated whether differences in sex and/or age at the start of ursodeoxycholic acid (UDCA) treatment are associated with response to therapy, based on biochemical markers, or differences in transplant-free survival., Methods: We performed a longitudinal retrospective study of 4355 adults in the Global PBC Study cohort, collected from 17 centers across Europe and North America. Patients received a diagnosis of PBC from 1961 through 2014. We evaluated the effects of sex and age on response to UDCA treatment (based on GLOBE score) and transplant-free survival using logistic regression and Cox regression analyses, respectively., Results: Male patients were older at the start of treatment (58.3±12.1 years vs 54.3±11.6 years for women; P<.0001) and had higher levels of bilirubin and lower circulating platelet counts (P<.0001). Younger patients (45 years or younger) had increased serum levels of transaminases than older patients (older than 45 years). Patients older than 45 years at time of treatment initiation had increased odds of a biochemical response to UDCA therapy, based on GLOBE score, compared to younger patients. The greatest odds of response to UDCA were observed in patients older than 65 years (odds ratio compared to younger patients 45 years or younger, 5.48; 95% CI, 3.92-7.67; P<.0001). Risk of liver transplant or death (compared to a general population matched for age, sex, and birth year) decreased significantly with advancing age: hazard ratio for patients 35 years or younger, 14.59 (95% CI, 9.66-22.02) vs hazard ratio for patients older than 65 years, 1.39 (95% CI, 1.23-1.57) (P<.0001). On multivariable analysis, sex was not independently associated with response or transplant-free survival., Conclusion: In longitudinal analysis of 4355 adults in the Global PBC Study, we associated patient age, but not sex, with response to UDCA treatment and transplant-free survival. Younger age at time of treatment initiation is associated with increased risk of treatment failure, liver transplant, and death., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC., Methods: This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW)., Results: In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1-12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1-81.2) among UDCA-treated patients and 60.7% (95% CI 58.2-63.4) among untreated patients (p <0.001). UDCA was associated with a statistically significant reduced risk of LT or death (hazard ratio 0.46, 95% CI 0.40-0.52; p <0.001). The hazard ratio remained statistically significant in all stages of disease. Patients classified as inadequate biochemical responders after 1 year of UDCA had a lower risk of LT or death than patients who were not treated (adjusted hazard ratio 0.56; 95% CI 0.45-0.69; p <0.001)., Conclusion: The use of UDCA improves LT-free survival among patients with PBC, regardless of the disease stage and the observed biochemical response. These findings support UDCA as the current universal standard of care in PBC., Lay Summary: In this international multicenter study of 3,902 patients with primary biliary cholangitis, we found that treatment with ursodeoxycholic acid is associated with prolonged liver transplant-free survival. This association was significant, irrespective of sex, age, or disease stage. The survival benefit remained statistically significant in patients with an incomplete biochemical response to ursodeoxycholic acid therapy., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Changes over time in the presenting features and clinical course of patients with primary biliary cholangitis are poorly described. We sought to describe temporal trends in patient and disease characteristics over a 44-year period across a large international primary biliary cholangitis cohort of 4,805 patients diagnosed between 1970 and 2014, from 17 centers across Europe and North America. Patients were divided into five cohorts according to their year of diagnosis: 1970-1979 (n = 143), 1980-1989 (n = 858), 1990-1999 (n = 1,754), 2000-2009 (n = 1,815), and ≥2010 (n = 235). Age at diagnosis, disease stage, response to ursodeoxycholic acid, and clinical outcomes were compared. Mean age at diagnosis increased incrementally by 2-3 years per decade from 46.9 ± 10.1 years in the 1970s to 57.0 ± 12.1 years from 2010 onward (P < 0.001). The female to male ratio (9:1) and antimitochondrial antibody positivity (90%) were not significantly variable. The proportion of patients presenting with mild biochemical disease (according to Rotterdam staging) increased from 41.3% in the 1970s to 72.2% in the 1990s (P < 0.001) and remained relatively stable thereafter. Patients with a mild histological stage at diagnosis increased from 60.4% (1970-1989) to 76.5% (1990-2014) (P < 0.001). Correspondingly, response to ursodeoxycholic acid according to Paris-I criteria increased; 51.7% in the 1970s and 70.5% in the 1990s (P < 0.001). Recent decades were also characterized by lower decompensation rates (18.5% in the 1970s to 5.8% in the 2000s, P < 0.001) and higher 10-year transplant-free survival (48.4%, 68.7%, 79.7%, and 80.1% for each respective cohort; P < 0.001)., Conclusion: In recent decades, a pattern of primary biliary cholangitis presentation consistent with an older age at diagnosis alongside reduced disease severity has been noted; the observed trends may be explained by an increase in routine testing of liver function and/or a changing environmental trigger. (Hepatology 2018;67:1920-1930)., (© 2017 by the American Association for the Study of Liver Diseases.)

The GLOBAL Primary Biliary Cholangitis (PBC) Study Group and United Kingdom-PBC (UK-PBC) Consortium have demonstrated that dichotomous response criteria are not as accurate as continuous equations at predicting mortality or liver transplantation in PBC. The aim of this analysis was to assess the clinical utility of the GLOBE and UK-PBC risk scores using data from POISE, a phase 3 trial investigating obeticholic acid (OCA) in patients with PBC. Data (N = 216) at baseline and month 12 were used to calculate the GLOBE and UK-PBC risk scores to assess the projected change in risk with OCA versus placebo. Additionally, the benefit of OCA was assessed in patients not meeting the POISE primary endpoint. Both the GLOBE and UK-PBC risk scores predicted a significant reduction in long-term risk of death and liver transplantation after OCA treatment ( P < 0.0001). The differences in the relative risk reduction from baseline in the 10-year event risk after 1 year for OCA 10 mg versus placebo was 26% (GLOBE) and 37% (UK-PBC). The scores also predicted a significantly decreased risk in patients treated with OCA who did not meet POISE response criteria after 1 year of treatment compared to an increased risk with placebo ( P < 0.0001). Conclusion: This analysis demonstrates the use of the GLOBE and UK-PBC risk scores to assess risk reduction of a cohort treated with OCA. While validation of this risk reduction in studies with clinical outcomes is needed, this study highlights the potential use of these scores in individualizing risk prediction in PBC both in clinical practice and therapeutic trials. ( Hepatology Communications 2018;2:683-692).

Inflammation is a crucial defense mechanism that protects the body from the devastating effects of invading pathogens. However, an unrestrained inflammatory reaction may result in systemic manifestations with dire consequences to the host. The extent of activation of the inflammatory response is tightly regulated through immunological and neural pathways. Previously, we demonstrated that cholinergic stimulation confers enhanced protection in experimental animals orally infected with virulent Salmonella enterica serovar Typhimurium. In this study, we investigated the mechanism by which this enhanced protection takes place. Cholinergic stimulation was induced by a 3-week pretreatment with paraoxon, a highly specific acetylcholinesterase (AChE) inhibitor. This treatment enhanced host survival following oral-route infection and this correlated with significantly reduced bacterial load in systemic target organs. Enhanced protection was not due to increased gut motility or rapid bacterial clearance from the gastrointestinal tract. Moreover, protection against bacterial infection was not evident when the animals were infected systemically, suggesting that acetylcholine-mediated protective effect was mostly confined to the gut mucosal tissue. In vivo imaging demonstrated a more localized infection and delay in bacterial dissemination into systemic organs in mice pretreated with paraoxon. Morphological analysis of the small intestine (ileum) showed that AChE inhibition induced the degranulation of goblet cells and Paneth cells, two specialized secretory cells involved in innate immunity. Our findings demonstrate a crucial pathway between neural and immune systems that acts at the mucosal interface to protect the host against oral pathogens.

Objectives: In this era of near universal ursodeoxycholic acid (UDCA) treatment for primary biliary cholangitis (PBC), progression to cirrhosis still occurs in an important proportion of patients. The aim of this study was to describe the incidence of cirrhosis-associated complications in patients with PBC and assess risk factors and impact on survival., Methods: Cohorts of UDCA-treated patients from 16 European and North-American liver centers were included. We used Cox proportional hazards assumptions and Kaplan-Meier estimates., Results: During 8.1 years' median follow-up, 278 of 3,224 patients developed ascites, variceal bleeding, and/or encephalopathy (incidence rate of 9.7 cases/1,000 patient years). The overall cumulative incidence was 9.1% after 10 years of follow-up, but decreased over time to 5.8% after the year 2000. Earlier calendar year of diagnosis (P<0.001), high aspartate aminotransferase to platelets ratio index (APRI; P<0.001) and biochemical non-response (P<0.001) were independently associated with future complications. Patients with both biochemical non-response and an APRI >0.54 after 12 months of UDCA had a 10-year complication rate of 37.4%, as compared to 3.2% in biochemical responders with an APRI ≤0.54. The 10-year transplantation-free survival after a complication was 9% (time-dependent hazard ratio 21.5; 20.1-22.8). Prognosis after variceal bleeding has improved over time., Conclusions: In this large international cohort, up to 15% of UDCA-treated PBC patients developed major non-neoplastic, cirrhosis-associated hepatic complications within 15 years, but cumulative incidence has decreased over time. Biochemical non-response to UDCA and APRI were independent risk factors for these complications. Subsequent long-term outcome after complications is generally poor, but has improved over the past decades.

Background: The fibrous structure of the myometrium has previously been characterised at high resolutions in small tissue samples (< 100 mm3) and at low resolutions (∼500 μm per voxel edge) in whole-organ reconstructions. However, no high-resolution visualisation of the myometrium at the organ level has previously been attained., Methods and Results: We have developed a technique to reconstruct the whole myometrium from serial histological slides, at a resolution of approximately 50 μm per voxel edge. Reconstructions of samples taken from human and rat uteri are presented here, along with histological verification of the reconstructions and detailed investigation of the fibrous structure of these uteri, using a range of tools specifically developed for this analysis. These reconstruction techniques enable the high-resolution rendering of global structure previously observed at lower resolution. Moreover, structures observed previously in small portions of the myometrium can be observed in the context of the whole organ. The reconstructions are in direct correspondence with the original histological slides, which allows the inspection of the anatomical context of any features identified in the three-dimensional reconstructions., Conclusions and Significance: The methods presented here have been used to generate a faithful representation of myometrial smooth muscle at a resolution of ∼50 μm per voxel edge. Characterisation of the smooth muscle structure of the myometrium by means of this technique revealed a detailed view of previously identified global structures in addition to a global view of the microarchitecture. A suite of visualisation tools allows researchers to interrogate the histological microarchitecture. These methods will be applicable to other smooth muscle tissues to analyse fibrous microarchitecture.

Background: Criteria assessing biochemical response to ursodeoxycholic acid (UDCA) are established risk stratification tools in primary biliary cholangitis (PBC). We aimed to evaluate to what extent liver tests influenced patient management during a three decade period, and whether this changed over time., Methods: 851 Dutch PBC patients diagnosed between 1988 and 2012 were reviewed to assess patient management in relation to liver test results during UDCA treatment. To do so, biochemical response at one year was analysed retrospectively according to Paris-1 criteria., Results: Response was assessable for 687/851 (81%) patients; 157/687 non-responders. During a follow-up of 8.8 years (IQR 4.8-13.9), 141 died and 30 underwent liver transplantation. Transplant-free survival of non-responders (60%) was significantly worse compared with responders (87%) (p < 0.0001). Management was modified in 46/157 (29%) non-responders. The most frequent change observed, noted in 26/46 patients, was an increase in UDCA dosage. Subsequently, 9/26 (35%) non-responders became responders within the next two years. Steroid treatment was started in one patient; 19 patients were referred to a tertiary centre. No trend towards more frequent changes in management over time was observed (p = 0.10)., Conclusion: Changes in medical management occurred in a minority of non-responders. This can largely be explained by the lack of accepted response criteria and of established second-line treatments for PBC. Nevertheless, the observation that response-guided management did not increase over time suggests that awareness of the concept of biochemical response requires further attention,particularly since new treatment options for PBC will soon become available.

Objective: Hepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (PBC); however, predictive tools remain ill-defined. Our objective was to identify candidate risk factors for HCC development in patients with PBC., Design: Risk factor analysis was performed in over 15 centres from North America and Europe spanning >40 years observation period using Cox proportional hazards assumptions, logistic regression, and Kaplan-Meier estimates., Results: Of 4565 patients with PBC 123 developed HCC, yielding an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p<0.0001), and on univariate analysis factors at PBC diagnosis associated with future HCC development were male sex (unadjusted HR 2.91, p<0.0001), elevated serum aspartate transaminase (HR 1.24, p<0.0001), advanced disease (HR 2.72, p=0.022), thrombocytopenia (HR 1.65, p<0.0001), and hepatic decompensation (HR 9.89, p<0.0001). As such, non-treatment with ursodeoxycholic acid itself was not associated with cancer development; however, 12-month stratification by biochemical non-response (Paris-I criteria) associated significantly with future risk of HCC (HR 4.52, p<0.0001; IR 6.6 vs 1.4, p<0.0001). Non-response predicted future risk in patients with early stage disease (IR 4.7 vs 1.2, p=0.005), advanced disease (HR 2.79, p=0.02; IR 11.2 vs 4.4, p=0.033), and when restricting the analysis to only male patients (HR 4.44, p<0.001; IR 18.2 vs 5.4, p<0.001). On multivariable analysis biochemical non-response remained the most significant factor predictive of future HCC risk (adjusted HR 3.44, p<0.0001)., Conclusions: This uniquely powered, internationally representative cohort robustly demonstrates that 12-month biochemical non-response is associated with increased future risk of developing HCC in PBC. Such risk stratification is relevant to patient care and development of new therapies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The pregnant uterus is a smooth muscle organ whose pattern of contraction is dictated by the propagation of electrical impulses. Such electrical activity may originate from one or more pacemakers, but the location of these sites has not yet been determined. To detect the location of the pacemaker in the gravid uterus, two approaches were used: 1) determine the site from where the contraction started using isolated uteri from the pregnant guinea pig, and videotape their contractions; and 2) record, in isolated uteri from pregnant term rats, with 240 extracellular electrodes simultaneously, and determine where the electrical bursts started. In both the contractile and electrophysiological experiments, there was not a single, specific pacemaker area. However, most contractions (guinea pig 87%) and bursts (rat 76%) started close to the mesometrial border (mean 2.7 ± 4.0 mm SD in guinea pigs and 1.3 ± 1.4 mm in rats). In addition, in the rat, most sites of initiations were located closer to the ovarial end of the horn (mean distance from the ovarial end 6.0 ± 6.2 mm SD), whereas such an orientation was not seen in the guinea pig. In both guinea pig and rat uteri at term, there is not one specific pacemaker area. Rather, contractile and electrical activity may arise from any site, with the majority starting close to the mesometrial border. Furthermore, in the rat, most activities started at the ovarial end of the horn. This may suggest a slightly different pattern of contraction in both species., (Copyright © 2015 the American Physiological Society.)

Background: Ethanol ingestion causes a variety of gastrointestinal disturbances including motility alterations. Slow wave propagation coordinates gastrointestinal motility, and abnormal slow wave activity is thought to contribute to motility disorders. To date, however, little is known about the effect of acute ethanol on motility disturbances associated with slow wave activity., Aim: To investigate the effect of ethanol on small intestine slow wave activity., Methods: Segments (3-5 cm long) were isolated from the rat duodenum, jejunum, and ileum and mounted in an organ bath superfused with a normal Tyrode solution or with 1, 3, or 5% ethanol containing Tyrode. The electrical activities were recorded using an array of 121 extracellular electrodes, and motility recordings were performed using a digital video camera., Results: The frequency and amplitude of slow wave activity were not altered at 1, 3, or 5% ethanol concentrations, but a significant drop in velocity was found at 3 and 5% ethanol. Furthermore, inexcitable areas appeared in a dose-dependent manner. Slow wave was sometimes also seen to propagate in a circular fashion, thereby describing a reentrant loop. Finally, in all duodenal, jejunal, and ileal segments, ethanol inhibited contractions and became fully quiescent at 3-5%., Conclusions: These studies for the first time demonstrate that ethanol significantly inhibits slow wave and spike activity in a dose-dependent manner and could also initiate reentrant activities. Intestinal contractions were also inhibited in a dose-dependent manner. In conclusion, ethanol inhibits both slow wave activity and motor activity to cause ethanol-induced intestinal disturbances.

Background & Aims: Approaches to risk stratification for patients with primary biliary cirrhosis (PBC) are limited, single-center based, and often dichotomous. We aimed to develop and validate a better model for determining prognoses of patients with PBC., Methods: We performed an international, multicenter meta-analysis of 4119 patients with PBC treated with ursodeoxycholic acid at liver centers in 8 European and North American countries. Patients were randomly assigned to derivation (n = 2488 [60%]) and validation cohorts (n = 1631 [40%]). A risk score (GLOBE score) to predict transplantation-free survival was developed and validated with univariate and multivariable Cox regression analyses using clinical and biochemical variables obtained after 1 year of ursodeoxycholic acid therapy. Risk score outcomes were compared with the survival of age-, sex-, and calendar time-matched members of the general population. The prognostic ability of the GLOBE score was evaluated alongside those of the Barcelona, Paris-1, Rotterdam, Toronto, and Paris-2 criteria., Results: Age (hazard ratio = 1.05; 95% confidence interval [CI]: 1.04-1.06; P < .0001); levels of bilirubin (hazard ratio = 2.56; 95% CI: 2.22-2.95; P < .0001), albumin (hazard ratio = 0.10; 95% CI: 0.05-0.24; P < .0001), and alkaline phosphatase (hazard ratio = 1.40; 95% CI: 1.18-1.67; P = .0002); and platelet count (hazard ratio/10 units decrease = 0.97; 95% CI: 0.96-0.99; P < .0001) were all independently associated with death or liver transplantation (C-statistic derivation, 0.81; 95% CI: 0.79-0.83, and validation cohort, 0.82; 95% CI: 0.79-0.84). Patients with risk scores >0.30 had significantly shorter times of transplant-free survival than matched healthy individuals (P < .0001). The GLOBE score identified patients who would survive for 5 years and 10 years (responders) with positive predictive values of 98% and 88%, respectively. Up to 22% and 21% of events and nonevents, respectively, 10 years after initiation of treatment were correctly reclassified in comparison with earlier proposed criteria. In subgroups of patients aged <45, 45-52, 52-58, 58-66, and ≥66 years, age-specific GLOBE-score thresholds beyond which survival significantly deviated from matched healthy individuals were -0.52, 0.01, 0.60, 1.01 and 1.69, respectively. Transplant-free survival could still be accurately calculated by the GLOBE score with laboratory values collected at 2-5 years after treatment., Conclusions: We developed and validated scoring system (the GLOBE score) to predict transplant-free survival of ursodeoxycholic acid-treated patients with PBC. This score might be used to select strategies for treatment and care., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The propagation of the slow wave in the stomach and its role in inducing sweeping peristaltic contractions toward the pylorus, essential for a proper digestion and emptying, have been studied for many years. Irregularities in the timing or in the pattern of propagation of the slow wave have been known to induce various gastric malfunctions and, recently, several types of gastric dysrhythmias have been described which could lead to gastric contraction abnormalities. In this study, Du et al. have analyzed the disturbances caused by a simple transmural incision in a human stomach, performed to obtain a biopsy of the muscle, on the propagation pattern of the slow wave. In addition, they show that such an incision may by itself also induce new types of gastric dysrhythmias. These results are important in demonstrating that the function of the stomach can easily be disturbed by such procedures. This mini-review describes several ways in which inhomogeneities in propagation may affect the conduction pattern of the slow wave, including the genesis of several dysrhythmias, and what is currently known about their impact on gastric contraction and digestion., (© 2015 John Wiley & Sons Ltd.)

As in other muscular organs, small intestinal motility is determined to a large degree by the electrical activities that occur in the smooth muscle layers of the small intestine. In recent decades, the interstitial cells of Cajal, located in the myenteric plexus, have been shown to be responsible for the generation and propagation of the electrical impulse: the slow wave. It was also known that the slow waves as such do not cause contraction, but that the action potentials ('spikes') that are generated by the slow waves are responsible for the contractions. Recording from large number of extracellular electrodes simultaneously is one method to determine origin and pattern of propagation of these electrical signals. This review reports the characteristics of slow wave propagation through the intestinal tube, the occurrence of propagation blocks along its length, which explains the well-known decrease in frequency, and the specific propagation pattern of the spikes that follow the slow waves. But the value of high-resolution mapping is highest in discovering and analysing mechanisms of arrhythmias in the gut. Most recently, circus movements (also called 're-entries') have been described in the small intestine in several species. Moreover, several types of re-entries have now been described, some similar to what may occur in the heart, such as functional re-entries, but others more unique to the small intestine, such as circumferential re-entry. These findings seem to suggest the possibilities of hitherto unknown pathologies that may be present in the small intestine., (© 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cholangitis (PBC), as it can delay histological progression, improve long-term outcome and is extremely safe and well tolerated. However, UDCA is not always sufficient and the prognosis of patients inadequately responding to treatment is worse compared with the general population. Reliable identification of so-called non-responders is of key importance, not only for selecting patients who could benefit from additional, second-line therapy, but also for identifying those individuals who are at low risk of developing end-stage disease and in whom UDCA mono-therapy can be safely continued. Several laboratory surrogate endpoints for the long-term response to UDCA have been proposed, including the Barcelona, Paris, Toronto and Rotterdam criteria. All these criteria have limitations and the superiority of one over the other has not been firmly established., Key Messages: Recently the Global PBC Study Group developed a new prognostic tool by studying a large, representative and multinational cohort of 4,119 UDCA-treated patients. In a random sample of 2,488 cases, a risk score--the GLOBE score--was developed, predictive of transplantation-free survival. This risk score comprises age, and bilirubin, albumin, alkaline phosphatase and platelet count obtained after 1 year therapy, and has a performance (C statistic 0.81, 95% CI 0.79-0.83) that is markedly better than that of previously proposed response criteria. Comparable performance was found in an independent validation cohort of 1,631 cases (C statistic 0.82, 95% CI 0.79-0.84). A web app will allow the easy use of the score in clinical practice., (© 2015 S. Karger AG, Basel.)

Aim: To evaluate and characterize motility patterns from small intestinal gut segments depending on different perfusion media and pressures., Methods: Experiments were carried out in a custom designed perfusion chamber system to validate and standardise the perfusion technique used. The perfusion chamber was built with a transparent front wall allowing for optical motility recordings and a custom made fastener to hold the intestinal segments. Experiments with different perfusion and storage media combined with different luminal pressures were carried out to evaluate the effects on rat small intestine motility. Software tools which enable the visualization and characterization of intestinal motility in response to different stimuli were used to evaluate the videotaped experiments. The data collected was presented in so called heatmaps thus providing a concise overview of form and strength of contractility patterns. Furthermore, the effect of different storage media on tissue quality was evaluated. Haematoxylin-Eosin stainings were used to compare tissue quality depending on storage and perfusion mode., Results: Intestinal motility is characterized by different repetitive motility patterns, depending on the actual situation of the gut. Different motility patterns could be recorded and characterized depending on the perfusion pressure and media used. We were able to describe at least three different repetitive patterns of intestinal motility in vitro. Patterns with an oral, anal and oro-anal propagation direction could be recorded. Each type of pattern finalized its movement with or without a subsequent distension of the wavefront. Motility patterns could clearly be distinguished in heatmap diagrams. Furthermore undirected motility could be observed. The quantity of the different patterns varies and is highly dependent on the perfusion medium used. Tissue preservation varies depending on the perfusion medium utilized, therefore media with a simple composition as Tyrode solution can only be recommended for short time experiments. The more complex media, MEM-HEPES medium and especially AQIX(®) RS-I tissue preservation reagent preserved the tissue much better during perfusion., Conclusion: Perfusion media have to be carefully chosen considering type and duration of the experiments. If excellent tissue quality is required, complex media are favorable. Perfusion pressure is also of great importance due to the fact that a minimum amount of luminal pressure seems to be necessary to trigger intestinal contractions.

Background & Aims: Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points., Methods: We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death)., Results: Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤ 2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels >2.0 times the ULN (P < .0001). Absolute levels of alkaline phosphatase 1 year after study enrollment predicted patient outcomes better than percentage change in level. One year after study enrollment, a bilirubin level 1.0 times the ULN best predicted patient transplant-free survival (C statistic, 0.79). Of patients with bilirubin levels ≤ 1.0 times the ULN, 86% survived for 10 years after study enrollment compared with 41% of those with levels >1.0 times the ULN (P < .0001). Combining levels of alkaline phosphatase and bilirubin increased the ability to predict patient survival times. We confirmed the predictive value of alkaline phosphatase and bilirubin levels in multiple subgroups, such as patients who had not received treatment with ursodeoxycholic acid, and at different time points after study enrollment., Conclusions: Levels of alkaline phosphatase and bilirubin can predict outcomes (liver transplantation or death) of patients with PBC and might be used as surrogate end points in therapy trials., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Gastric arrhythmia continues to be of uncertain diagnostic and therapeutic significance. However, recent progress has been substantial, with technical advances, theoretical insights and experimental discoveries offering new translational opportunities. The discoveries that interstitial cells of Cajal (ICC) generate slow waves and that ICC defects are associated with dysmotility have reinvigorated gastric arrhythmia research. Increasing evidence now suggests that ICC depletion and damage, network disruption and channelopathies may lead to aberrant slow wave initiation and conduction. Histological and high-resolution (HR) electrical mapping studies have now redefined the human 'gastric conduction system', providing an improved baseline for arrhythmia research. The application of HR mapping to arrhythmia has also generated important new insights into the spatiotemporal dynamics of arrhythmia onset and maintenance, resulting in the emergence of new provisional classification schemes. Meanwhile, the strong associations between gastric functional disorders and electrogastrography (EGG) abnormalities (e.g. in gastroparesis, unexplained nausea and vomiting and functional dyspepsia) continue to motivate deeper inquiries into the nature and causes of gastrointestinal arrhythmias. In future, technical progress in EGG methods, new HR mapping devices and software, wireless slow wave acquisition systems and improved gastric pacing devices may achieve validated applications in clinical practice. Neurohormonal factors in arrhythmogenesis also continue to be elucidated and a deepening understanding of these mechanisms may open opportunities for drug design for treating arrhythmias. However, for all translational goals, it remains to be seen whether arrhythmia can be corrected in a way that meaningfully improves organ function and symptoms in patients., (© 2014 Wiley Publishing Asia Pty Ltd.)

Aim: To test a hypothesis attributing arrhythmia in Brugada Syndrome to right ventricular (RV) outflow tract (RVOT) conduction abnormalities arising from Nav 1.5 insufficiency and fibrotic change., Methods: Arrhythmic properties of Langendorff-perfused Scn5a+/- and wild-type mouse hearts were correlated with ventricular effective refractory periods (VERPs), multi-electrode array (MEA) measurements of action potential (AP) conduction velocities and dispersions in conduction direction (CD), Nav 1.5 expression levels, and fibrotic change, as measured at the RVOT and RV. Two-way anova was used to test for both independent and interacting effects of anatomical region and genotype on these parameters., Results: Scn5a+/- hearts showed greater arrhythmic frequencies during programmed electrical stimulation at the RVOT but not the RV. The Scn5a+/- genotype caused an independent increase of VERP regardless of whether the recording site was the RVOT or RV. Effective AP conduction velocities (CV†s), derived from fitting regression planes to arrays of observed local activation times were reduced in Scn5a+/- hearts and at the RVOT independently. AP conduction velocity magnitudes derived by averaging MEA results from local vector analyses, CV*, were reduced by the Scn5a+/- genotype alone. In contrast, dispersions in conduction direction, were greater in the RVOT than the RV, when the atrioventricular node was used as the pacing site. The observed reductions in Nav 1.5 expression were attributable to Scn5a+/-, whereas increased levels of fibrosis were associated with the RVOT., Conclusions: The Scn5a+/- RVOT recapitulates clinical findings of increased arrhythmogenicity through reduced CV† reflecting reduced CV* attributable to reduced Nav 1.5 expression and increased CD attributable to fibrosis., (© 2014 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

There is little knowledge about macroscopic electrical propagation in the wall of the urinary bladder. Recording simultaneously from a large number of extracellular electrodes is one technology that could be used to study the patterns of macroscopic electrical propagations. The urinary bladders from 14 guinea pigs were isolated and placed in an organ bath. A 16 × 4-electrode array was positioned at various sites on the serosal bladder surface, and recordings were performed at different intravesical volumes. In four experiments, carbachol (CCH; 10(-6) M), nifedipine (10 mM), or tetrodotoxin (TTX; 10(-6) M) was added to the superfusing fluid. After the experiments, the extracellular signals were analyzed and propagation maps were constructed. Electrical waves were detected at all sites on the bladder surface and propagated for a limited distance before terminating spontaneously. The majority of waves (>90%) propagated in the axial direction (i.e., from dome to base or vice versa). An increase in vesicle volume significantly decreased the conduction velocity (from 4.9 ± 1.5 to 2.7 ± 0.7 cm/s; P < 0.05). CCH increased, nifedipine decreased, while TTX had little effect on electrical activities. In addition, a new electrical phenomenon, termed a "patch," was discovered whereby a simultaneous electrical deflection was detected across an area of the bladder surface. Two types of electrical activities were detected on the bladder surface: 1) electrical waves propagating preferentially in the axial direction and 2) electrical patches. The propagating electrical waves could form the basis for local spontaneous contractions in the bladder during the filling phase., (Copyright © 2014 the American Physiological Society.)

Primary biliary cirrhosis (PBC) is a slowly progressive autoimmune liver disease that may ultimately result in liver failure and premature death. Predicting outcome is of key importance in clinical management and an essential requirement for patients counselling and timing of diagnostic and therapeutic interventions. The following factors are associated with progressive disease and worse outcome: young age at diagnosis, male gender, histological presence of cirrhosis, accelerated marked uctopenia in relation to the amount of fibrosis, high serum bilirubin, low serum albumin levels, high serum alkaline phosphatase levels, esophageal varices, hepatocellular carcinoma (HCC) and lack of biochemical response to ursodeoxycholic acid (UDCA). The prognostic significance of symptoms at diagnosis is uncertain. UDCA therapy and liver transplantation have a significant beneficial effect on the outcome of the disease. The Mayo risk score in PBC can be used for estimating individual prognosis. The Newcastle Varices in PBC Score may be a useful clinical tool to predict the risk for development of esophageal varices. Male gender, cirrhosis and non-response to UDCA therapy in particular, are risk factors for development of HCC.

In contrast to the current state of knowledge of cardiac and of gastrointestinal electrophysiology, our current knowledge of the physiology of the uterus during pregnancy is still very rudimentary. Despite seminal work performed in the past decades, there are still significant areas that we know little about. In this review, some of these areas are explored. For example, although many studies have tried to find the site of the uterus pacemaker, such a site has not yet been found and its mechanism and location remain, to date, a mystery. Similarly, there is much confusion as to the mechanism of propagation of the electrical impulse. Although the existence of gap junctions, connecting neighboring myometrial cells to each other, have been known since 1977, alternative or additional mechanisms are being suggested such as the potential existence of a network of interstitial cells, similar to the one that is functioning in the gut, or the involvement of stretch receptors to synchronize activity and contraction. In recent years, high-resolution studies have been introduced enabling detailed analysis of the location and spatial patterns of propagation. This work is being developed at the in-vitro level in isolated tissues, in the whole organ and in several animal species. Most recently, a surge in new technology enabling high fidelity and high resolution recording from the human uterus through the abdominal wall are being explored which could ultimately lead to new diagnostic tools and a clearer understanding of the physiology of pregnancies and (premature) labor.