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Background and Aims: The benefit of rapid on-site evaluation (ROSE) on the diagnostic accuracy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) has never been evaluated in a randomized study. This trial aimed to test the hypothesis that in solid pancreatic lesions (SPLs), diagnostic accuracy of EUS-FNB without ROSE was not inferior to that of EUS-FNB with ROSE., Methods: A noninferiority study (noninferiority margin, 5%) was conducted at 14 centers in 8 countries. Patients with SPLs requiring tissue sampling were randomly assigned (1:1) to undergo EUS-FNB with or without ROSE using new-generation FNB needles. The touch-imprint cytology technique was used to perform ROSE. The primary endpoint was diagnostic accuracy, and secondary endpoints were safety, tissue core procurement, specimen quality, and sampling procedural time., Results: Eight hundred patients were randomized over an 18-month period, and 771 were analyzed (385 with ROSE and 386 without). Comparable diagnostic accuracies were obtained in both arms (96.4% with ROSE and 97.4% without ROSE, P = .396). Noninferiority of EUS-FNB without ROSE was confirmed with an absolute risk difference of 1.0% (1-sided 90% confidence interval, -1.1% to 3.1%; noninferiority P < .001). Safety and sample quality of histologic specimens were similar in both groups. A significantly higher tissue core rate was obtained by EUS-FNB without ROSE (70.7% vs. 78.0%, P = .021), with a significantly shorter mean sampling procedural time (17.9 ± 8.8 vs 11.7 ± 6.0 minutes, P < .0001)., Conclusions: EUS-FNB demonstrated high diagnostic accuracy in evaluating SPLs independently on execution of ROSE. When new-generation FNB needles are used, ROSE should not be routinely recommended. (ClinicalTrial.gov number NCT03322592.)., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Benign biliary strictures (BBS) are complications of chronic pancreatitis (CP). Endotherapy using multiple plastic stents (MPS) or a fully covered self-expanding metal stent (FCSEMS) are acceptable treatment options for biliary obstructive symptoms in these patients., Methods: Patients with symptomatic CP-associated BBS enrolled in a multicenter randomized noninferiority trial comparing 12-month treatment with MPS vs FCSEMS. Primary outcome was stricture resolution status at 24 months, defined as absence of restenting and 24-month serum alkaline phosphatase not exceeding twice the level at stenting completion. Secondary outcomes included crossover rate, numbers of endoscopic retrograde cholangiopancreatography (ERCPs) and stents, and stent- or procedure-related serious adverse events., Results: Eighty-four patients were randomized to MPS and 80 to FCSEMS. Baseline technical success was 97.6% for MPS and 98.6% for FCSEMS. Eleven patients crossed over from MPS to FCSEMS, and 10 from FCSEMS to MPS. For MPS vs FCSEMS, respectively, stricture resolution status at 24 months was 77.1% (54/70) vs 75.8% (47/62) (P = .008 for noninferiority intention-to-treat analysis), mean number of ERCPs was 3.9 ± 1.3 vs 2.6 ± 1.3 (P < .001, intention-to-treat), and mean number of stents placed was 7.0 ± 4.4 vs 1.3 ± .6 (P < .001, as-treated). Serious adverse events occurred in 16 (19.0%) MPS and 19 (23.8%) FCSEMS patients (P = .568), including cholangitis/fever/jaundice (9 vs 7 patients respectively), abdominal pain (5 vs 5), cholecystitis (1 vs 3) and post-ERCP pancreatitis (0 vs 2). No stent- or procedure-related deaths occurred., Conclusions: Endotherapy of CP-associated BBS has similar efficacy and safety for 12-month treatment using MPS compared with a single FCSEMS, with FCSEMS requiring fewer ERCPs over 2 years. (ClinicalTrials.gov, Number: NCT01543256.)., (Copyright © 2021. Published by Elsevier Inc.)

Background and Study Aims: The international consensus Fukuoka guideline (Fukuoka ICG), The European evidence-based guideline on pancreatic cystic neoplasms (European EBG) and the American Gastroenterological Association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts (AGA IG) are 3 frequently cited guidelines for the risk stratification of neoplastic pancreatic cysts. The aim of this study was to assess the accuracy of detecting malignant cysts by strictly applying these guidelines retrospectively to a cohort of surgically resected pancreatic cysts., Patients and Methods: 72 resected cysts were included in the analysis. Invasive carcinoma, high grade dysplasia and neuro-endocrine tumour were considered as "malignant cysts" for the purpose of the study., Results: 32% of the resected cysts were malignant. The analysis showed that the Fukuoka ICG, European EBG and AGA IG had a sensitivity of 66,8%, 95,5%, 80%; a specificity of 26,8%, 11,3%, 43,8%; a positive predictive value of 31,8%, 35%, 47,1% and a negative predicted value of 61,1%, 83,3%, 77,8% respectively. The missed malignancy rate was respectively 11,3%, 1,5%, 7,7% and surgical overtreatment was respectively 48,4%, 59,1%, 34,6%., Conclusion: In this retrospective analysis, the European EBG had the lowest rate of missed malignancy at the expense of a high number of "unnecessary" resections. The Fukuoka ICG had the highest number of missed malignancy. The AGA IG showed the lowest rate of unnecessary surgery at the cost of a high number of missed malignancy. There is need to develop better biomarkers to predict the risk of malignancy., Competing Interests: The authors declare that they have no conflict of interest, (© Acta Gastro-Enterologica Belgica.)

Infections, due to a dysfunctional immune response, pose a great risk to patients with decompensated cirrhosis and herald the beginning of the terminal phase of this disease. Infections typically result from breaches in innate immune barriers and inadequate clearance by immune cells. This leads to bacterial and bacterial product translocation to the systemic circulation, which is already primed by ongoing hepatic inflammation in patients with cirrhosis, who are particularly prone to developing organ failure in the presence of an infection. Early identification of bacterial infection, along with the prompt use of appropriate antibiotics, have reduced the mortality associated with certain infections in patients with decompensated cirrhosis. Judicious use of antibiotic therapy remains imperative given the emergence of multidrug-resistant infections in the cirrhotic population. Important research over the last few years has identified molecular targets on immune cells that may enhance their function, and theoretically prevent infections. Clinical trials are ongoing to delineate the beneficial effects of targeted molecules from their off-target effects. Herein, we review the mechanisms that predispose patients with cirrhosis to bacterial infections, the clinical implications of infections and potential targets for the prevention or treatment of infections in this vulnerable population., Competing Interests: Conflict of interest The authors do not report any conflict of interest in relation to the content of this article. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The increasing rate of liver transplantation (LT) for nonalcoholic fatty liver disease (NAFLD) raises concerns on cardiovascular morbidity and mortality after LT in these patients., Methods: We collected variables regarding the presence of metabolic risk factors, NAFLD recurrence, cardiovascular morbidity, and overall survival at time of listing and after LT of 112 patients with NAFLD and a control group of 120 patients with hepatitis C (HCV)., Results: Metabolic syndrome and cardiovascular morbidity component rates (24.1% vs 12.5%) at the time of LT listing were higher in patients with NAFLD compared with patients with HCV (for all, P < .0390). Median follow-up after LT was 5.6 years in patients with NAFLD vs 13.5 years in patients with HCV (P = .0009). There was no difference in 6-weeks postoperative mortality (1.7% vs 2.5%) (P =1.0000). Metabolic syndrome components after LT were more frequent in patients with NAFLD than in patients with HCV (for all, P < .0008). The incidence of NAFLD 5 years after LT was higher in patients transplanted for NAFLD compared with HCV (43.5% vs 4.2%) (P < .0001). Patients with recurrent NAFLD more often had myocardial infarction compared with those without recurrence (8.3% vs 0%) (P = .0313). Five years after LT, cardiovascular morbidity was more frequent in the NAFLD group than in the HCV group (12.8% vs 9.3%) (P = .0256), whereas no difference in overall survival was observed., Conclusion: LT for NAFLD is associated with satisfactory 5-year outcomes; however, our data underscore the need for close monitoring and aggressive management of cardiovascular risk factors in these patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Neuregulin 4 (Nrg4), a novel adipokine enriched in brown adipose tissue has been observed to negatively regulate de novo hepatic lipogenesis and limit nonalcoholic fatty liver disease (NAFLD) progression to nonalcoholic steatohepatitis (NASH) in rodents. However, the role of Nrg4 in human NAFLD remains unclear to date. We analysed Nrg4 plasma levels and its association with liver disease severity together with the transcriptional profile of the Nrg4 pathway in liver and visceral adipose tissue (VAT) of NAFLD patients., Methods: Plasma Nrg4 levels were measured in 65 NAFLD patients and 43 healthy controls (HC). Hepatic steatosis and fibrosis were diagnosed and quantified with chemical shift MRI and transient elastography respectively. Furthermore, blood lipid levels, HOMA-IR and systemic pro-inflammatory cytokines (TNF-α, IL-6 and IFN-γ) were analysed. Microarray analyses to assess differences in the Nrg4 and its receptor family ErbB pathway in liver and VAT from an independent patient group with biopsy proven NAFL (simple steatosis) (n = 4), NASH (n = 5) and normal liver (n = 6) were performed., Results: Plasma Nrg4 levels were not significantly different between NAFLD patients and HC (p = 0.622). Furthermore, plasma Nrg4 levels did not correlate with the hepatic fat fraction (r = -0.028, p = 0.829) and were not significantly different between NAFLD patients with or without hepatic fibrosis (p = 0.087). Finally, the expression profile of 82 genes related to the Nrg4-ErbB pathway in liver and VAT was not significantly different between NAFL, NASH or obese controls., Conclusion: Our study does not support a role for Nrg4 in the pathophysiology of human NAFLD., Competing Interests: The authors have declared that no competing interests exist.

Background: Donor hepatectomy and liver implantation time reduce long-term graft and patient survival after liver transplantation. It is not known whether these surgical times influence early outcomes after liver transplantation., Methods: This single-center study evaluated the effect of donor hepatectomy and implantation time on the risk of nonanastomotic biliary strictures (NAS) occurring within 1 year and of early allograft dysfunction (EAD) after deceased-donor solitary liver transplantation, adjusting for other donors, recipient, and surgical factors., Results: Of 917 transplants performed between January 2000 and December 2016, 106 (11.56%) developed NAS and 247 (27%) developed EAD. Donor hepatectomy time (median 35 min, IQR: 26-46) was an independent risk factor of NAS [adjusted hazard ratio, 1.19; 95% CI, 1.04-1.35; P = 0.01]. Implantation time (median 80 min, IQR: 69-95) was independently associated with EAD [adjusted odds ratio (OR), 1.15; 95% CI,1.07-1.23; P < 0.0001). The risk of EAD was increased by anastomosis time of both portal vein (adjusted OR, 1.26; 95% CI, 1.12-14.42; P = 0.0001) and hepatic artery (adjusted OR, 1.13; 95% CI, 1.04-1.22; P = 0.005). The magnitude of these effects was similar in donation after circulatory death liver grafts., Conclusions: Donor hepatectomy and implantation time negatively affect short-term outcomes., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Giraffes are an important tourist attraction, and human presence to wildlife is increasing. This has an impact on an animal's behavior and its endocrine correlates. Studies on other species show alterations in movement patterns, vigilance, and stress-related hormone levels in the presence of humans. Limited information is available on how anthropogenic activities alter giraffe's behavior, social structure, and related endocrine parameters. The purpose of this study was to obtain insight into anthropogenic influences on giraffe's behavior and adrenal activity. We used GPS devices mounted onto giraffes to compare the distance walked in the presence or absence of human observers. We also conducted behavioral observations to assess their vigilance and collected fecal samples to analyze their fecal glucocorticoid metabolite (fGCM) concentrations. Giraffes walked significantly further distances in the presence of humans, but the cumulative time that observers were present decreased the hourly distance walked with an observer present, suggesting that the giraffes were becoming habituated. The number of observers present significantly increased the percentage of time spent on observing an observer as well as the number of unhabituated individuals present in the herd. The percentage of time spent observing a human observer did not decrease with the increase of habituation. Last, fGCM concentrations increased with human presence but decreased when individuals became habituated to human presence. More research is needed to understand the effect of anthropogenic influences in different scenarios (e.g., tourism, vehicles, hunting, etc.).

Competing Interests: M. Bronswijk received travel grants from Prion Medical, Taewoong, and Takeda. S. van der Merwe holds the Cook Chair in Interventional Endoscopy, the Boston Chair in Therapeutic EUS, as well as consultancy agreements with Pentax and Olympus.The other authors declare no competing interests regarding this specific paper.

Background: Although evidence suggests frequent gastrointestinal (GI) involvement during coronavirus disease 2019 (COVID-19), endoscopic findings are scarcely reported., Aims: We aimed at registering endoscopic abnormalities and potentially associated risk factors among patients with COVID-19., Methods: All consecutive patients with COVID-19 undergoing endoscopy in 16 institutions from high-prevalence regions were enrolled. Mann-Whitney U, χ 2 or Fisher's exact test were used to compare patients with major abnormalities to those with negative procedures, and multivariate logistic regression to identify independent predictors., Results: Between February and May 2020, during the first pandemic outbreak with severely restricted endoscopy activity, 114 endoscopies on 106 patients with COVID-19 were performed in 16 institutions (men=70.8%, median age=68 (58-74); 33% admitted in intensive care unit; 44.4% reporting GI symptoms). 66.7% endoscopies were urgent, mainly for overt GI bleeding. 52 (45.6%) patients had major abnormalities, whereas 13 bled from previous conditions. The most prevalent upper GI abnormalities were ulcers (25.3%), erosive/ulcerative gastro-duodenopathy (16.1%) and petechial/haemorrhagic gastropathy (9.2%). Among lower GI endoscopies, 33.3% showed an ischaemic-like colitis.Receiver operating curve analysis identified D-dimers >1850 ng/mL as predicting major abnormalities. Only D-dimers >1850 ng/mL (OR=12.12 (1.69-86.87)) and presence of GI symptoms (OR=6.17 (1.13-33.67)) were independently associated with major abnormalities at multivariate analysis., Conclusion: In this highly selected cohort of hospitalised patients with COVID-19 requiring endoscopy, almost half showed acute mucosal injuries and more than one-third of lower GI endoscopies had features of ischaemic colitis. Among the hospitalisation-related and patient-related variables evaluated in this study, D-dimers above 1850 ng/mL was the most useful at predicting major mucosal abnormalities at endoscopy., Trial Registration Number: ClinicalTrial.gov (ID: NCT04318366)., Competing Interests: Competing interests: GV received travel grants from Mylan and Alfasigma. GC is a consultant for Mylan. IB is consultant for Apollo Endosurgery, Cook Medical and Boston Scientific; board member for Endo Tools; research grant recipient from Apollo Endosurgery; had food and beverage compensation from Apollo Endosurgery, Cook Medical, Boston Scientific and Endo Tools. LR is a consultant for Cancer Prevention Pharmaceuticals; has received research grants from SLA Pharma AG and Takeda and receives funds from the Italian Association for Cancer Research (IG21723). MB received travel grants from Takeda, Taewoong Medical and Prion Medical. KWO has received lecture fees from Olympus, Medtronic and Mylan. He has received a research grant from Medtronic. LP received advisory board fees from Janssen and Takeda; presentation fees from AbbVie and Ferring; and personal fees from AbbVie, Ferring, Norgine and Takeda. SWVdM holds the Cook chair in interventional endoscopy and holds consultancy agreements with Boston Scientific, Cook, Pentax and Olympus. ES has received lecture or consultancy fees from Medtronic, Reckitt Benckiser, Takeda, Merck & Co, Bristol Myers Squibb, AbbVie, Amgen, Novartis, Fresenius Kabi, Sandoz, Sofar, Malesci, Janssen, Grifols, Aurora Pharma, Innovamedica, Johnson & Johnson, SILA, Unifarco, Alfasigma, Shire, EG Stada Group. MK has done consulting work for Boston Scientific, Interscope Med and AbbVie. He has received research grants from Boston Scientific, Emcision, Conmed, Pinnacle, Cook, Gore, Merit and Olympus. PR is supported by Clinical Mandate from Belgian Foundation against Cancer (Stichting tegen Kanker) and receives speaking and consultancy fees from MSD Belgium. GC is consultant for and had food and beverage compensation from Cook Medical, Boston Scientific and Olympus., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The unprecedented situation caused by the coronavirus disease 2019 (COVID-19) pandemic has profoundly affected endoscopic practice in regard to access, volume, and workflow. We aimed to assess the potential changes in the technical outcomes of endoscopic retrograde cholangiopancreatography (ERCP) procedures carried out in patients with confirmed SARS-CoV-2 infection., Methods: We conducted an international, multicenter, retrospective, matched case-control study of ERCP procedures carried out in patients with confirmed COVID-19. The main outcome was technical success of the procedure as assessed by the endoscopist, and the secondary outcome was the development of procedure-related adverse events. Each case was matched in a 1:4 ratio with controls extracted from each center's database in order to identify relevant changes in outcome measures compared with the pre-pandemic era., Results: Eighteen procedures performed in 16 COVID-19 patients [14 men, 65 years (9-82)] and 67 controls were included in the final analysis. Technical success was achieved in 14/18 COVID-19 cases, which was significantly lower as compared with the control group (14/18 versus 64/67, p  = 0.034), with an endoscopic reintervention required in 9/18 cases. However, the rate of procedure-related adverse events was low in both groups (1/18 versus 10/67, p  = 0.44). On multivariable analysis, COVID-19 status remained the only risk factor for technical failure of the procedure [odds ratio of 19.9 (95% confidence interval 1.4-269.0)]., Conclusions: The COVID-19 pandemic has affected the volume and practice of ERCP, resulting in lower technical success rates without significantly impacting patient safety. Prioritizing cases and following recommendations on safety measures can ensure good outcome with minimal risk in dedicated centers., Competing Interests: Conflict of interest statement: Michiel Bronswijk received travel grants from Taewoong, Takeda, and Prion Medical. Schalk van der Merwe holds the Cook chair in interventional endoscopy and holds consultancy agreements with Cook, Pentax and Olympus. Professor Guido Costamagna is a consultant for Cook Medical, Boston Scientific, and Olympus. Ivo Boškoski is a consultant for Apollo Endosurgery, Cook Medical, and Boston Scientific; board member for Endo Tools; research grant recipient from Apollo Endosurgery. Also, he has received food and beverage compensation from Apollo Endosurgery, Cook Medical, Boston Scientific, and Endo Tools. The other authors report no conflict of interest., (© The Author(s), 2020.)

Background and study aims  Endoscopic ultrasound-guided intrahepatic biliary drainage (EUS-IBD) struggles to find a place in management algorithms, especially compared to percutaneous drainage (PTBD). In the setting of hilar stenoses or postsurgical anatomy data are even more limited. Patients and methods  All consecutive EUS-IBDs performed in our tertiary referral center between 2012 - 2019 were retrospectively evaluated. Rendez-vous (RVs), antegrade stenting (AS) and hepatico-gastrostomies (HGs) were compared. The predefined subgroup of EUS-IBD patients with proximal stenosis/surgically-altered anatomy was matched 1:1 with PTBD performed for the same indications. Efficacy, safety and events during follow-up were compared. Results  One hundred four EUS-IBDs were included (malignancies = 87.7 %). These consisted of 16 RVs, 43 ASs and 45 HGs. Technical and clinical success rates were 89.4 % and 96.2 %, respectively. Any-degree, severe and fatal adverse events (AEs) occurred in 23.3 %, 2.9 %, and 0.9 % respectively. Benign indications were more common among RVs while proximal stenoses, surgically-altered anatomy, and disconnected left ductal system among HGs. Procedures were shorter with HGs performed with specifically designed stents (25 vs . 48 minutes, P  = 0.004) and there was also a trend toward less dysfunction with those stents (6.7 % vs . 30 %, P  = 0.09) compared with previous approaches. Among patients with proximal stenosis/surgically-altered anatomy, EUS-IBD vs. PTBD showed higher rates of clinical success (97.4 % vs. 79.5 %, P  = 0.01), reduced post-procedural pain (17.8 % vs. 44.4 %, p = 0.004), shorter median hospital stay (7.5 vs 11.5 days, P  = 0.01), lower rates of stent dysfunction (15.8 % vs. 42.9 %, P  = 0.01), and the mean number of reinterventions was lower (0.4 vs. 2.8, P  < 0.0001). Conclusions  EUS-IBD has high technical and clinical success with an acceptable safety profile. HGs show comparable outcomes, which are likely to further improve with dedicated tools. For proximal strictures and surgically-altered anatomy, EUS-IBD seems superior to PTBD., Competing Interests: Competing interests Dr. van der Merwe holds the Cook chair in Interventional endoscopy and holds consultancy agreements with Cook, Pentax and Olympus. Dr. Laleman co-chairs the Boston Scientific Chair in Therapeutic Biliopancreatic Endoscopy with Dr. van der Merwe and has consultancy agreements with Boston Scientific and Cook. Dr. Van Malenstein holds a consultancy agreement with Boston Scientific, (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

The potential of microporous zeolites FAU and BEA, and mesoporous MCM-41, for prolonged release of atenolol in drug delivery systems was investigated both experimentally, using drug release studies, and theoretically using classical molecular dynamics simulations. Remarkably, zero-order release of atenolol was achieved from FAU (SiO 2 :Al 2 O 3  = 80:1) into phosphate buffer for 24 h followed by prolonged release for at least another 48 h. Experimental data also demonstrate the ability for all of the drug-zeolite combinations investigated to achieve prolonged release of atenolol, with the release rates determined by the combination of framework topology, aluminium content and drug release study media. Molecular dynamics simulations give an insight into the reasons for the different release rates observed for FAU and BEA. The results of this work emphasise the need for sophisticated models in order to explain subtle differences in release, such as those observed at different SiO 2 :Al 2 O 3 ratios., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Purpose: To prospectively evaluate the feasibility of solid gold marker placement in oesophageal cancer patients and to quantify inter-fractional and intra-fractional (baseline shift) marker motion during radiation treatment. Radiotherapy target margins and matching strategies were investigated., Materials/methods: Thirty-four markers were implanted by echo-endoscopy in 10 patients. Patients received a planning 4D CT, daily pre-treatment cone-beam CT (CBCT) and a post-treatment CBCT for at least five fractions. For fractions with both pre- and post-treatment CBCT, marker displacement between planning CT and pre-treatment CBCT (inter-fractional) and between pre-treatment and post-treatment CBCT (intra-fractional; only for fractions without rotational treatment couch correction) were calculated in left-right (LR), cranio-caudal (CC) and anterior-posterior (AP) direction after bony-anatomy and soft-tissue matching. Systematic/random setup errors were estimated; treatment margins were calculated., Results: No serious adverse events occurred. Twenty-three (67.6%) markers were visible during radiotherapy (n = 3 middle oesophagus, n = 16 distal oesophagus, n = 4 proximal stomach). Margins for inter-fractional displacement after bony-anatomy match depended on the localisation of the primary tumour and were 11.2 mm (LR), 16.4 mm (CC) and 8.2 mm (AP) for distal markers. Soft-tissue matching reduced the CC margin for these markers (16.4 mm to 10.5 mm). The mean intra-fractional shift of 12 distal markers was 0.4 mm (LR), 2.3 mm (CC) and 0.7 mm (AP). Inclusion of this shift resulted in treatment margins for distal markers of 12.8 mm (LR), 17.3 mm (CC) and 10.4 mm (AP) after bony-anatomy matching and 12.4 mm (LR), 11.4 mm (CC) and 9.7 mm (AP) after soft-tissue matching., Conclusion: This study demonstrated that the implantation of gold markers was safe, albeit less stable compared to other marker types. Inter-fractional motion was largest cranio-caudally for markers in the distal oesophagus, which was reduced after soft-tissue compared to bony-anatomy matching. The impact of intra-fractional baseline shifts on margin calculation was rather small., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Cirrhosis is a multisystemic disease wherein inflammatory responses originating from advanced liver disease and its sequelae affect distant compartments. Patients with cirrhosis are susceptible to bacterial infections, which may precipitate acute decompensation and acute-on-chronic liver failure, both of which are associated with high short-term mortality. Innate immune cells are an essential first line of defence against pathogens. Activation of liver macrophages (Kupffer cells) and resident mastocytes generate proinflammatory and vaso-permeating mediators that induce accumulation of neutrophils, lymphocytes, eosinophils and monocytes in the liver, and promote tissue damage. During cirrhosis progression, damage- and pathogen-associated molecular patterns activate immune cells and promote development of systemic inflammatory responses which may involve different tissues and compartments. The antibacterial function of circulating neutrophils and monocytes is gradually and severely impaired as cirrhosis worsens, contributing to disease progression. The mechanisms underlying impaired antimicrobial responses are complex and incompletely understood. This review focuses on the continuous and distinct perturbations arising in innate immune cells during cirrhosis, including their impact on disease progression, as well as reviewing potential therapeutic targets., Competing Interests: Conflict of interest The authors do not report any conflict of interest in relation to the content of this article. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Competing Interests: None

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives., (© 2019 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Background: Instead of choosing one endoscopic ultrasound (EUS) needle over the other, some advocate the use of fine-needle aspiration (FNA) and fine-needle biopsy (FNB) consecutively. We explored the yield of combined use of 20 G FNB and 25 G FNA needles in patients with a suspicious solid gastrointestinal lesion., Methods: Patients from the ASPRO study who were sampled with both needles during the same procedure were included. The incremental yield of dual sampling compared with the yield of single needle use on the diagnostic accuracy for malignancy was assessed for both dual sampling approaches - FNA followed by FNB, and vice versa., Results: 73 patients were included. There were 39 (53 %) pancreatic lesions, 18 (25 %) submucosal masses, and 16 (22 %) lymph nodes. FNA was used first in 24 patients (33 %) and FNB was used first in 49 (67 %). Generally, FNB was performed after FNA to collect tissue for ancillary testing (75 %), whereas FNA was used after FNB to allow for on-site pathological assessment (76 %). Diagnostic accuracy for malignancy of single needle use increased from 78 % to 92 % with dual sampling ( P  = 0.002). FNA followed by FNB improved the diagnostic accuracy for malignancy ( P  = 0.03), whereas FNB followed by FNA did not ( P  = 0.13)., Conclusion: Dual sampling only improved diagnostic accuracy when 25 G FNA was followed by 20 G FNB and not vice versa. As the diagnostic benefit of the 20 G FNB over the 25 G FNA needle has recently been proven, sampling with the FNB needle seems a logical first choice., Competing Interests: Dr. van Riet was a consultant for Cook Medical Devices during the UEGW in 2016. Dr. Bruno is a consultant and lectures for Cook Medical and Boston Scientific., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Aim: A recently carried out randomized controlled trial showed the benefit of a novel 20-G fine-needle biopsy (FNB) over a 25-G fine-needle aspiration (FNA) needle. The current study evaluated the reproducibility of these findings among expert academic and non-academic pathologists., Methods: This study was a side-study of the ASPRO (ASpiration versus PROcore) study. Five centers retrieved 74 (59%) consecutive FNB and 51 (41%) FNA samples from the ASPRO study according to randomization; 64 (51%) pancreatic and 61 (49%) lymph node specimens. Samples were re-reviewed by five expert academic and five non-academic pathologists and rated in terms of sample quality and diagnosis. Ratings were compared between needles, expert academic and non-academic pathologists, target lesions, and cytology versus histological specimens., Results: Besides a higher diagnostic accuracy, FNB also provided for a better agreement on diagnosing malignancy (ĸ = 0.59 vs ĸ = 0.76, P < 0.001) and classification according to Bethesda (ĸ = 0.45 vs ĸ = 0.61, P < 0.001). This equally applied for expert academic and non-academic pathologists and for pancreatic and lymph node specimens. Sample quality was also rated higher for FNB, but agreement ranged from poor (ĸ = 0.04) to fair (ĸ = 0.55). Histology provided better agreement than cytology, but only when a core specimen was obtained with FNB (P = 0.004 vs P = 0.432)., Conclusion: This study shows that the 20-G FNB outperforms the 25-G FNA needle in terms of diagnostic agreement, independent of the background and experience of the pathologist. This endorses use of the 20-G FNB needle in both expert and lower volume EUS centers., (© 2019 The Authors. Digestive Endoscopy published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that could lead to serious health problems including liver failure, cancer, or death. The term NAFLD includes a spectrum of disease states with histological features ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). A key aspect within this research field is the identification of pathogenic factors that trigger inflammation, thus fueling the transition from nonalcoholic fatty liver to NASH. These inflammatory triggers may originate from within the liver as a result of innate immune cell activation and/or hepatocyte injury. Additionally, they may originate from other sites such as adipose tissue or the intestinal tract. In the current review, the authors will primarily focus on events within adipose tissue which may be of importance in triggering the disease progression. They specifically focus on the role of adipose tissue macrophages during NAFLD pathogenesis and how microenvironmental factors may shape their metabolic profile. They further dissect how redirecting the macrophage's metabolic profile alters their immunological functions. Finally, they discuss the opportunities and challenges of targeting macrophages to interfere in disease progression., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objectives: Portal vein aneurysm is an unusual vascular dilatation of the portal vein. The etiology, diagnosis and management are ill-defined., Methods: A case of a portal vein aneurysm complicated with complete thrombosis is presented with a literature review providing an overview of the etiology, clinical presentation and management., Results: Portal venous aneurysms represent approximately 3% of all venous aneurysms with a reported prevalence of 0.06%. The reported incidence is on the rise with increasing use of modern imaging techniques in clinical practice. Usually, portal vein aneurysms are incidental findings and patients are asymptomatic. They can be congenital or acquired and portal hypertension represents the most frequent cause of the acquired version. Various complications such as biliary tract compression, portal vein thrombosis, and rupture can occur. Treatment options are conservative management or surgery. Surgical treatment is currently reserved for symptomatic patients with severe abdominal pain, symptoms of pressure effect or with expanding aneurysms, and/or complications such as thrombosis or rupture., Conclusion: Conservative management seems the best option in the majority of patients. A multidisciplinary approach discussing the best option on a case-by-case base in light of their individual underlying risk and symptoms is advised.

Background: Older donors and recipients are increasingly considered for liver transplantation. Both donor and recipient age have a negative impact on outcomes. Large registry analyses show that older donors are frequently matched to older recipients. Whether age-related risks accumulate in a synergic negative effect on outcomes because of donor-recipient age matching is poorly understood., Methods: We investigated the impact of donor-recipient age interaction on patient and death-censored graft survival in multivariate Cox regressions in 849 transplants (January 2000 to December 2015)., Results: Donors 70 years or older did not affect long-term patient or graft survival. Recipient age independently increased the risk of death (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.02-1.05, P < 0.0001), but donor-recipient age interaction was noninfluential. The negative impact of recipient age on patient survival was significant as early as 6 months after transplantation (HR, 1.06; 95% CI, 1.03-1.09; P = 0.00008). The adjusted risk of death was significant for patients aged 60 to 69 years (HR, 1.995; 95% CI, 1.40-2.85; P < 0.0001) and 70 years or older (HR, 2.001; 95% CI, 1.10-2.66; P = 0.04). In contrast, the risk of graft loss was not influenced by recipient age (HR, 1.02; 95% CI, 0.996-1.04; P = 0.11) or age interaction., Conclusions: Older livers can be safely used in older recipients without jeopardizing graft and patient survival if other risk factors are minimized., Competing Interests: The authors declare no conflicts of interest.

Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca 2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H 1 R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca 2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H 1 R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H 1 R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H 1 R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H 1 R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H 1 R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H 1 R antagonism in IBS.

Background and Aims: Several studies have compared EUS-guided FNA with fine-needle biopsy (FNB), but none have proven superiority. We performed a multicenter randomized controlled trial to compare the performance of a commonly used 25-gauge FNA needle with a newly designed 20-gauge FNB needle., Methods: Consecutive patients with a solid lesion were randomized in this international multicenter study between a 25-gauge FNA (EchoTip Ultra) or a 20-gauge FNB needle (ProCore). The primary endpoint was diagnostic accuracy for malignancy and the Bethesda classification (non-diagnostic, benign, atypical, malignant). Technical success, safety, and sample quality were also assessed. Multivariable and supplementary analyses were performed to adjust for confounders., Results: A total of 608 patients were allocated to FNA (n = 306) or FNB (n = 302); 312 pancreatic lesions (51%), 147 lymph nodes (24%), and 149 other lesions (25%). Technical success rate was 100% for the 25-gauge FNA and 99% for the 20-gauge FNB needle (P = .043), with no differences in adverse events. The 20-gauge FNB needle outperformed 25-gauge FNA in terms of histologic yield (77% vs 44%, P < .001), accuracy for malignancy (87% vs 78%, P = .002) and Bethesda classification (82% vs 72%, P = .002). This was robust when corrected for indication, lesion size, number of passes, and presence of an on-site pathologist (odds ratio, 3.53; 95% confidence interval, 1.55-8.56; P = .004), and did not differ among centers (P = .836)., Conclusion: The 20-gauge FNB needle outperformed the 25-gauge FNA needle in terms of histologic yield and diagnostic accuracy. This benefit was irrespective of the indication and was consistent among participating centers, supporting the general applicability of our findings. (Clinical trial registration number: NCT02167074.)., (Copyright © 2019 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Dominant strictures occur in approximately 50% of patients with primary sclerosing cholangitis (PSC). Short-term stents have been reported to produce longer resolution of dominant strictures than single-balloon dilatation. We performed a prospective study to compare the efficacy and safety of balloon dilatation vs short-term stents in patients with non-end-stage PSC., Methods: We performed an open-label trial of patients with PSC undergoing therapeutic endoscopic retrograde cholangiopancreatography (ERCP) at 9 tertiary-care centers in Europe, from July 2011 through April 2016. Patients found to have a dominant stricture during ERCP were randomly assigned to groups that underwent balloon dilatation (n = 31) or stent placement for a maximum of 2 weeks (n = 34); patients were followed for 24 months. The primary outcome was the cumulative recurrence-free patency of the primary dominant strictures., Results: Study recruitment was terminated after a planned interim analysis because of futility and differences in treatment-related serious adverse events (SAEs) between groups. The cumulative recurrence-free rate did not differ significantly between groups (0.34 for the stent group and 0.30 for the balloon dilatation group at 24 months; P = 1.0). Most patients in both groups had reductions in symptoms at 3 months after the procedure. There were 17 treatment-related SAEs: post-ERCP pancreatitis in 9 patients and bacterial cholangitis in 4 patients. SAEs occurred in 15 patients in the stent group (45%) and in only 2 patients in the balloon dilatation group (6.7%) (odds ratio, 11.7; 95% confidence interval, 2.4-57.2; P = .001)., Conclusions: In a multicenter randomized trial of patients with PSC and a dominant stricture, short-term stents were not superior to balloon dilatation and were associated with a significantly higher occurrence of treatment-related SAEs. Balloon dilatation should be the initial treatment of choice for dominant strictures in patients with PSC. This may be particularly relevant to patients with an intact papilla. ClinicalTrials.gov no. NCT01398917., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

ACLF is a specific, but complex and multifactorial form of acute decompensation of cirrhosis and is characterized by an extraordinary dynamic natural course, rapidly evolving organ failure, and high short-term mortality. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic inflammatory response that drives organ failure and mortality. Later in its course, immuno-exhaustion/immunoparalysis prevails predisposing the patient to secondary infectious events and reescalation in end-organ dysfunction and mortality. The management of patients with ACLF is still poorly defined. However, as its pathophysiology is gradually being unravelled, potential therapeutic targets emerge that warrant further study such as restoring or substituting albumin via plasma exchange or via albumin dialysis and evaluating usefulness of TLR4 antagonists, modulators of gut dysbiosis (pre- or probiotics), and FXR-agonists.

Background: Achieving weight loss is the cornerstone of the treatment of the metabolic consequences of obesity, in particular of glucose intolerance., Objective: To determine whether improvement in glucose control depends on dietary macronutrient composition of the diet at identical weight loss., Materials and Methods: Twenty-two weeks old diet-induced obese C57BL/6 mice lost weight through caloric restriction on normal chow (R-NC) or high fat diet (R-HF). Control mice were fed normal chow (LEAN) or high fat diet (OBESE) ad libitum. Body weight and composition were assessed after 8 weeks of dietary intervention. Glucose homeostasis was evaluated by intraperitoneal glucose tolerance tests (IPGTT). Epididymal white adipose (eWAT) and hepatic tissues were analyzed by immunohistochemistry and RT-qPCR., Results: By 30 weeks of age, the body weight of the mice on R-NC (31.6±1.7g, mean±SEM) and R-HF (32.3±0.9g) was similar to LEAN mice (31.9±1.4g), while OBESE mice weighed 51.7±2.4g. Glucose tolerance in R-NC was better than in LEAN mice (69% AUC IPGTT, P 0.0168) whereas R-HF mice remained significantly less glucose tolerant (125% AUC IPGTT, P 0.0279 vs LEAN), despite identical weight loss. The eWAT pads and adipocyte size were similar in LEAN and R-NC mice, while the eWAT pad size of R-HF was 180% of R-NC (P < 0.0001) and the average adipocyte size of R-HF mice was 134% of R-NC fed mice (P 0.0285). No LEAN or R-NC mice had hepatic steatosis, in contrast to 28.6% of R-HF mice. Compared to OBESE mice, inflammatory markers were lower in eWAT and liver tissue of R-NC, but not in R-HF mice. Measures of visceral adiposity correlated well with glucose tolerance parameters., Conclusions: In mice, caloric restriction on a normal chow diet improved glucose tolerance significantly more when identical weight loss was achieved on a high fat diet., Competing Interests: The authors have declared that no competing interests exist.

Currently, nucleos(t)ide analogs (NAs) in monotherapy are favored as prophylaxis against hepatitis B recurrence after liver transplantation. However, in patients at risk of renal failure, renal safety of NAs is of concern. We investigated the safety and efficacy of subcutaneous (SC) hepatitis B immunoglobulins (HBIG) in monotherapy. This is a single-arm prospective trial in patients transplanted >1 year. We included 43 Caucasian patients. The majority was treated with calcineurin inhibitors, and several patients had other risk factors for renal impairment as well: diabetes mellitus (n = 10/43), arterial hypertension (n = 11/43), and hyperlipidemia (=10/43). At inclusion, 42% (n = 18) had chronic kidney disease ≥ grade 3a. All patients were switched from IV HBIG with or without NAs to SC HBIG without NAs. After one year, the targeted titer was lowered to ≥150 IU/l in patients with low risk of recurrence. Mean follow-up time was 36 ± 5 months. None of the patients had a relapse of HBsAg or HBV DNA. The treatment was well tolerated, safe and the renal function remained unchanged both in patients with (n = 18) or without (n = 25) renal impairment at baseline. The mean HBsAb titer could be decreased from 343 ± 163 to 199 ± 81 IU/l in the low-risk group (n = 17) and 218 ± 71 IU/l in the high-risk group (n = 26). In 86% (n = 37) doses, reductions were possible, which significantly lowered the cost of treatment. SC HBIG without NAs had a 100% success rate in the long-term prevention of HBsAg and HBV DNA reappearance, without deterioration of renal function., (© 2018 Steunstichting ESOT.)

Little is known about nonsurgical risk factors for hepatic artery thrombosis (HAT) after liver transplantation (LT). We determined risk factors for HAT occurring within 90 days post-LT and analysed the effect of HAT on graft and patient survival. Donor and recipient demographics, surgery-related data and outcome in transplants complicated by thrombosis (HAT+) and their matched controls (HAT-) were compared. Risk factors were assessed by univariate logistic regression. Median (IQR) is given. A total of 25 HAT occurred among 1035 adult LT (1/1997-12/2014) and 50 controls were manually matched. Donor and recipient demographics were similar. Pre-LT trans-catheter arterial chemo-embolization (TACE) was more frequent in HAT+ (HAT+ 20% vs. HAT- 4%, P = 0.037). HAT+ had longer implantation [HAT+ 88 min (76-108) vs. HAT- 77 min (66-93), P = 0.028] and surgery times [HAT+ 6.25 h (5.18-7.47) vs. HAT- 5.25 h (4.33-6.5), P = 0.001]. Early graft dysfunction and sepsis were more frequent in HAT+ and hospitalization longer. TACE had the greatest odds ratio in unadjusted analysis (OR: 6, 95% CI: 1.07-33.53, P = 0.03). All but seven grafts were lost after HAT (HAT+ 72% vs. HAT- 36%, P = 0.003); however, patient survival was unaffected (HAT+ 79.8% vs. HAT- 76%, P = 0.75). LT candidates undergoing TACE are at risk of developing HAT early after transplant., (© 2017 Steunstichting ESOT.)

Background and study aims  Biliary stenting of unresectable malignant bile duct obstruction is generally accepted as the standard of care but it can be hampered by tumor ingrowth and stent dysfunction. We aimed to test the feasibility, safety, and biliary patency rate of a new endoscopically applied intraductal radiofrequency ablation (RFA) device. Patients and methods  Eighteen patients with inoperable malignant biliary obstruction underwent endoscopic retrograde cholangiopancreatography (ERCP)-directed RFA and stenting. Results  Between December 2014 and November 2015, 18 patients underwent RFA to the intended region, with no complications within 3 months of the procedure. Bilirubin levels post-RFA and stenting decreased significantly (7.8 ± 1 mg/dL to 1.7 ± 0.4 mg/dL; P  < 0.001). At 90 and 180 days post-intervention, biliary patency was maintained in 80 % and 69 % of patients still alive at that time, respectively. The median overall stent patency was 110 days (range 16 - 374), with a median patient survival of 227 days (range 16 - 374). Conclusion  Intraductal RFA using a new device in patients with inoperable biliopancreatic cancer complicated by jaundice appeared feasible and safe with acceptable biliary patency. Randomized trials with prolonged follow-up are warranted.ClinTrials.gov: NCT02468076., Competing Interests: Competing interests: None, (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The crime rate in South Africa is extraordinarily high. The problem of crime is further complicated when a person, who suffers from a mental illness, becomes involved in a crime. Furthermore, the forensic evaluation of a person suspected of having a mental illness involved in alleged criminal behaviour can be challenging. However, a dearth of information exists in South African literature regarding the link between crime and mental illness., Aim: To determine the percentage of alleged offenders, referred to the Free State Psychiatric Complex (FSPC) for observation, found accountable and not accountable, and to compare the biographical, diagnosis and offence profiles of these two groups. The analysis of differences can contribute to a better understanding of the complex process of forensic assessments., Setting: Forensic Observation Ward, FSPC, Bloemfontein., Methods: In this comparative, retrospective study, all 505 trial-awaiting alleged offenders (observati) referred from 2009 to 2012 for a 30-day observation period, according to Sections 77 and/or 78 of the Criminal Procedures Act, were included. Results were summarised as frequencies and percentages, and means or percentiles. Significant differences between the groups were determined by sample t -tests or chi-squared tests., Results: Observati found not accountable were in the majority (64.5%). Significant differences were found regarding marital and employment status, substance abuse, type of offence and diagnoses between the two groups. Almost all of the observati found to be not accountable were diagnosed with mental illness at the time of the assessment, whereas most observati found to be accountable for their actions at the time of the alleged offence were not found to be mentally ill. Observati found not accountable were significantly more likely to be diagnosed with schizophrenia, intellectual disability and substance-induced psychotic disorder, and committed mostly assault, murder and vandalism. Observati found accountable committed mostly rape, murder and theft., Conclusion: The majority of observati were found not accountable, with significant differences found between the two groups regarding demographic characteristics, type of diagnosis and offences committed. The identified differences can be used to assist in establishing criteria for the appropriate referral of alleged offenders by courts. Unnecessary referrals have a serious financial impact on the Department of Health. Furthermore, the high incidence of substance abuse among persons referred to the FSPC highlights the need for more substance rehabilitation centres in the Free State Province., Competing Interests: The authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article.

Purpose: To retrospectively analyse long-term patency and overall survival of cirrhotic patients treated with TIPSS using e-PTFE-covered stents. Additionally, prognostic factors for better patency and survival were analysed., Materials and Methods: Two hundred and eighty-five consecutive cirrhotic patients with severe portal hypertension-related symptoms were included. Follow-up, including clinical assessment and duplex ultrasound, was analysed up to end of study, patient's death, liver transplantation or TIPSS-reduction. Patency rates and overall survival were estimated by the Kaplan-Meier method; potential differences in outcome between subgroups were calculated using the Pepe and Mori test., Results: The 1-, 2- and 5-year primary patencies were 91.5 %, 89.2 % and 86.2 %, respectively, with no new shunt dysfunctions after 5 years' follow-up. TIPSS revision was performed more often in ascites patients (P = 0.02). The 1-, 4- and 10-year survival rates were 69.2 %, 52.1 % and 30.7 %, respectively. Survival was higher in Child-Pugh class A-B (P = 0.04), in the recurrent bleeding group (P = 0.008) and in patients with underlying alcoholic cirrhosis (P = 0.01)., Conclusion: Long term, primary patency of e-PTFE-covered TIPSS stents remains very high (>80 %); shunt revision was required more frequently in ascites patients. Overall survival was better in Child-Pugh A-B patients with recurrent variceal bleeding and alcoholic liver cirrhosis., Keypoints: • Long-term primary patency rate of e-PTFE-covered TIPSS stents remains very high. • No new shunt dysfunction was found after 5 years of follow-up. • Shunt revision was required more frequently in ascites patients. • Four and 10 years' overall survival was 50 and 30 %, respectively.

Background and Study Aim: Indeterminate biliary strictures and difficult bile duct stones remain clinically arduous and challenging situations. We aimed to evaluate the utility of the single-operator cholangioscopy (SOC)-system SpyGlass in both conditions in a single-center biliopancreatic interventional unit and in perspective of available aggregated literature., Methods: Usefulness of SOC was assessed for the above-mentioned indications by means of the combination of successful procedural completion, clinical success and incidence of procedure-related adverse events in our own prospective cohort from 3/2010 to 7/2014 and all available literature till 6/2015., Results: Our single-center cohort constituted of 84 patients undergoing SpyGlass either for indeterminate strictures (n = 45) or difficult stones (n = 39). In addition, a comprehensive literature review yielded 851 patients (from 15 series) for either stenosis (n = 646, 75.9 %) and difficult stones (n = 205, 24.1 %). In our series, overall procedural success amounted to 85.7 % (with 88.9 % for stenosis or 82.1 % for stones) compared to 90.7, 91.5 and 88.3 % in overall literature, respectively. Sensitivity, specificity and accuracy for visual diagnosis in our cohort added up to 83.3, 82.9 and 82.9 % compared to 90.8, 90.9 and 90.8 % in the pooled analysis. Respective figures for SOC-directed biopsies totaled 85.7, 100 and 95.7 % in our cohort and 72.4, 100 and 84 % overall. Overall procedure-related complications varied between 9.4 and 21.4 %., Conclusions: The SOC-platform SpyGlass can be considered useful in the context of indeterminate biliary strictures and difficult-to-remove biliary stones. In both, SpyGlass-assisted intervention is associated with high procedural success and alters clinical outcome compared to conventional approaches with an acceptable safety profile.

Background: Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment. However, histological evidence of its efficacy is limited and its impact on hepatic pathways involved in NASH is underreported. The efficacy of the angiotensin receptor type 1 blocker losartan is controversial because of varying results in a few animal and human studies. We evaluated the effect of dietary intervention versus losartan on NASH and associated systemic metabolic features in a representative mouse model., Methods: Male C57BL/6 J mice with high fat-high sucrose diet (HF-HSD) induced NASH, obesity, insulin resistance and hypercholesterolemia were subjected to dietary intervention (switch from HF-HSD to normal chow diet (NCD)) (n = 9), continuation HF-HSD together with losartan (30 mg/kg/day) (n = 9) or continuation HF-HSD only (n = 9) for 8 weeks. 9 mice received NCD during the entire experiment (20 weeks). We assessed the systemic metabolic effects and performed a detailed hepatic histological and molecular profiling. A P-value of < 0.05, using the group with continuation of HF-HSD only as control, was considered as statistically significant., Results: Dietary intervention normalized obesity, insulin resistance, and hypercholesterolemia (for all P < 0.001), and remarkably, completely reversed all histological features of pre-existent NASH (for all P < 0.001), including fibrosis measured by quantification of collagen proportional area (P < 0.01). At the hepatic molecular level, dietary intervention targeted fibrogenesis with a normalization of collagen type I alpha 1, transforming growth factor β1, tissue inhibitor of metalloproteinase 1 mRNA levels (for all P < 0.01), lipid metabolism with a normalization of fatty acid translocase/CD36, fatty acid transport protein 5, fatty acid synthase mRNA levels (P < 0.05) and markers related to mitochondrial function with a normalization of hepatic ATP content (P < 0.05) together with sirtuin1 and uncoupling protein 2 mRNA levels (for both P < 0.001). Dietary intervention abolished p62 accumulation (P < 0.01), suggesting a restoration of autophagic flux. Losartan did not significantly affect obesity, insulin resistance, hypercholesterolemia or any histological NASH feature., Conclusions: Dietary intervention, and not losartan, completely restores the metabolic phenotype in a representative mouse model with pre-existent NASH, obesity, insulin resistance and hypercholesterolemia.

Systemic lipopolysaccharide (LPS) is implicated in increasing mortality in patients with alcoholic hepatitis but the underlying mechanisms are not well characterised. The objective of this study was to characterise neutrophil function, LPS and cytokine concentrations within the splanchnic circulation of alcoholic cirrhotic patients undergoing TIPSS insertion for variceal haemorrhage and correlate this with outcome. 26 patients with alcoholic cirrhosis and variceal haemorrhage were studied prior to and 1-hour after TIPSS insertion. Neutrophil function, LPS and cytokine concentrations were determined in arterial, hepatic venous (HV) and portal venous blood (PV). Significantly higher LPS concentrations and neutrophil reactive oxidant species (ROS) production were observed in PV vs HV blood. Cross-incubation of HV plasma with PV neutrophils resulted in reduced ROS production. Insertion of TIPSS was associated with a significant increase in arterial LPS concentrations and deterioration in neutrophil phagocytosis. Number of organ failures and arterial IL-6 concentrations at presentation were associated with increased mortality. The portal circulation has a distinct immunological milieu characterised by a pathological neutrophil phenotype and an anti-inflammatory cytokine profile associated with heightened LPS levels. TIPSS insertion renders this neutrophil functional defect systemic, associated with an increase in arterial LPS and a susceptibility to sepsis., Competing Interests: Rajiv Jalan has served on the Scientific Advisory Board for Conatus Pharma. He has received lecture fees from Gambro and has an on-going research collaboration with Gambro, Grifols and is the Principal Investigator of an Industry sponsored study (Sequana Medical). He is also inventor for the drug, L-ornithine phenyl acetate (OCR-002) which UCL has licensed to Ocera Therapeutics. He is also the founder of UCL spin-out company Yaqrit ltd. and Cyberliver ltd.