tbuckley/cabot-search huggingface dataset:
Association of Closed-Loop Brain Stimulation Neurophysiological Features With Seizure Control Among Patients With Focal Epilepsy
Authors: Vasileios Kokkinos, Nathaniel D. Sisterson, Thomas A. Wozny, R. Mark Richardson
Journal: JAMA Neurology (2019)

A bidirectional brain-computer interface that performs neurostimulation has been shown to improve seizure control in patients with refractory epilepsy, but the therapeutic mechanism is unknown.To investigate whether electrographic effects of responsive neurostimulation (RNS), identified in electrocorticographic (ECOG) recordings from the device, are associated with patient outcomes.Retrospective review of ECOG recordings and accompanying clinical meta-data from 11 consecutive patients with focal epilepsy who were implanted with a neurostimulation system between January 28, 2015, and June 6, 2017, with 22 to 112 weeks of follow-up. Recorded ECOG data were obtained from the manufacturer; additional system-generated meta-data, including recording and detection settings, were collected directly from the manufacturer's management system using an in-house, custom-built platform. Electrographic seizure patterns were identified in RNS recordings and evaluated in the time-frequency domain, which was locked to the onset of the seizure pattern.Patterns of electrophysiological modulation were identified and then classified according to their latency of onset in relation to triggered stimulation events. Seizure control after RNS implantation was assessed by 3 main variables: mean frequency of seizure occurrence, estimated mean severity of seizures, and mean duration of seizures. Overall seizure outcomes were evaluated by the extended Personal Impact of Epilepsy Scale questionnaires, a patient-reported outcome measure of 3 domains (seizure characteristics, medication adverse effects, and quality of life), with a range of possible scores from 0 to 300 in which lower scores indicate worse status, and the Engel scale, which comprises 4 classes (I-IV) in which lower numbers indicate greater improvement.Electrocorticographic data from 11 patients (8 female; mean [range] age, 35 [19-65] years; mean [range] duration of epilepsy, 19 [5-37] years) were analyzed. Two main categories of electrophysiological signatures of stimulation-induced modulation of the seizure network were discovered: direct and indirect effects. Direct effects included ictal inhibition and early frequency modulation but were not associated with improved clinical outcomes (odds ratio [OR], 0.67; 95% CI, 0.06-7.35; P > .99). Only indirect effects-those occurring remote from triggered stimulation-were associated with improved clinical outcomes (OR, infinity; 95% CI, -infinity to infinity; P = .02). These indirect effects included spontaneous ictal inhibition, frequency modulation, fragmentation, and ictal duration modulation.These findings suggest that RNS effectiveness may be explained by long-term, stimulation-induced modulation of seizure network activity rather than by direct effects on each detected seizure.
Cancer Goes Undiagnosed in Almost Half the World’s Children
Authors: M.J. Friedrich
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Real-world treatment patterns for metastatic non-small cell lung cancer at IRST Italy
Authors: M. Altini, I. Massa, W. Balzi, N. Gentili, F. Foca, V. Danesi, S. Manunta, M.A. Burgio, P. Cravero, F. Ejzykowicz, S. Chandwani, A. Delmonte
Journal: Annals of Oncology (2019)

Background: This study sought to describe treatment patterns in terms of real world first-line (1L) and second-line (2L) treatment of metastatic non-small cell lung cancer (NSCLC) prior to the availability of Immunotherapies (IOs) in Italy. Methods: Metastatic NSCLC pts who initiated anti-cancer systemic treatment at IRST from Jan 2014 to Jun 2017 were included in this retrospective analysis based on electronic health records database, including information on demographics, clinical, tumor, molecular characteristics and treatment(s) administered. Results: In total, 440 pts for 1L and 152 for 2L were analyzed. Median age was 69.5 and 65.9 yrs for the 1L and 2L, respectively.Table176PPts characteristics1L n = 440 n(%)2L1 n = 152 n(%)DemographicsAge ≤ 65 yrs > 65 yrs156 (35.5) 284 (64.5)68 (44.7) 84 (55.3)Gender F M166 (37.7) 274 (62.3)56 (36.8) 96 (63.2)Smoking status Never Former Current Unk38 (8.6) 200 (45.5) 119 (27.0) 83 (18.9)15 (9.9) 80 (52.6) 43 (28.3) 14 (9.2)ClinicalECOG 0-1 >2 Unknown345 (78.4) 71 (16.1) 24 (5.5)133 (87.5) 13 (8.6) 6 (3.9)Stage at primary diagnosis IA-IIIB IV Unk104 (23.7) 335 (76.1) 1 (0.2)39 (25.7) 112 (73.7) 1 (0.7)Histology Squamous Non Squamous Other Unk69 (15.7) 338 (76.8) 26 (5.9) 7 (1.6)20 (13.2) 124 (81.6) 8 (5.3) -MolecularEGFR2 Wild-type Translocated Unk279 (76.6) 51 (14.0) 34 (9.3)113 (85.6) 15 (11.4) 4 (3.0)ALK2 Wild-type Translocated Unk232 (63.7) 21 (5.8) 111 (30.5)107 (81.1) 11 (8.3) 14 (10.6)TreatmentDouble Agent Combination Pemetrexed + Platinum3Platinum = cisplatin or carboplatin Gemcitabine + Platinum3Platinum = cisplatin or carboplatin Paclitaxel+ Carboplatin 3Platinum = cisplatin or carboplatin Other doublets Single Agent Chemotherapy Gemcitabine Vinorelbine Docetaxel Targeted therapy Immunotherapy Clinical trials251 (57.0) 132 (30.0) 108 (24.6) 9 (2.0) 2 (0.4) 106 (24.1) 58 (54.7) 44 (41.5) 4 (3.8) 43 (9.8) 1 (0.2) 39 (8.9)27 (17.8) 19 (12.5) 6 (3.9) 1 (0.7) 1 (0.7) 44 (28.9) 8 (18.2) 17 (38.6) 19 (43.2) 41 (27.0) 9 (5.9) 31 (20.4)1 Pts in the 2L group were also included in 1L group.2 EGFR and ALK status are reported for pts with non-squamous and other histology (n = 364 for 1L, n = 132 for 2L)3 Platinum = cisplatin or carboplatin Open table in a new tab 1 Pts in the 2L group were also included in 1L group. 2 EGFR and ALK status are reported for pts with non-squamous and other histology (n = 364 for 1L, n = 132 for 2L) Conclusions: In this real world population prior IOs approval in Italy, treatments were largely in line with NSCLC treatment guidelines. As expected, the most frequent type of regimen in 1L setting was platinum doublet and in 2L was single agent chemo. Legal entity responsible for the study: Merck & Co., Inc. Funding: Merck & Co., Inc. Disclosure: F. Ejzykowicz, S. Chandwani: Employee, shareholder: Merck & Co, Inc. All other authors have declared no conflicts of interest.
Cancer Hospital Network Affiliation and Complex Cancer Surgery—What Is in a Name?
Authors: Lesly A. Dossett
Journal: JAMA Network Open (2019)

Jessica R. Hoag, PhD; Benjamin J. Resio, MD; Andres F. Monsalve, MD; Alexander S. Chiu, MD; Lawrence B. Brown, MHS; Jeph Herrin, PhD; Justin D. Blasberg, MD; Anthony W. Kim, MD; Daniel J. Boffa, MD
Complement Membrane Attack Complexes Assemble NLRP3 Inflammasomes Triggering IL-1 Activation of IFN-γ–Primed Human Endothelium
Authors: Catherine B. Xie, Lingfeng Qin, Guangxin Li, Caodi Fang, Nancy C. Kirkiles-Smith, George Tellides, Jordan S. Pober, Dan Jane-wit
Journal: Circulation Research (2019)

Rationale: Complement activation contributes to multiple immune-mediated pathologies. In late allograft failure, donor-specific antibody deposits complement membrane attack complexes (MAC) on graft endothelial cells (ECs), substantially increasing their immunogenicity without causing lysis. Internalized MAC stabilize NIK (NF-κB [nuclear factor kappa-light-chain-enhancer of activated B cells]–inducing kinase) protein on Rab5+MAC+ endosomes, activating noncanonical NF-κB signaling. However, the link to increased immunogenicity is unclear. Objective: To identify mechanisms by which alloantibody and internalized MAC activate ECs to enhance their ability to increase T-cell responses. Methods and Results: In human EC cultures, internalized MAC also causes NLRP3 (NOD-like receptor family pyrin domain containing 3) translocation from endoplasmic reticulum to Rab5+MAC+NIK+ endosomes followed by endosomal NIK-dependent inflammasome assembly. Cytosolic NIK, stabilized by LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells), does not trigger inflammasome assembly, and ATP-triggered inflammasome assembly does not require NIK. IFN-γ (interferon-γ) primes EC responsiveness to MAC by increasing NLRP3, pro-caspase 1, and gasdermin D expression. NIK-activated noncanonical NF-κB signaling induces pro-IL (interleukin)-1β expression. Inflammasome processed pro-IL-1β, and gasdermin D results in IL-1β secretion that increases EC immunogenicity through IL-1 receptor signaling. Activation of human ECs lining human coronary artery grafts in immunodeficient mouse hosts by alloantibody and complement similarly depends on assembly of an NLRP3 inflammasome. Finally, in renal allograft biopsies showing chronic rejection, caspase-1 is activated in C4d + ECs of interstitial microvessels, supporting the relevance of the cell culture findings. Conclusions: In response to antibody-mediated complement activation, IFN-γ-primed human ECs internalize MAC, triggering both endosomal-associated NIK-dependent NLRP3 inflammasome assembly and IL-1 synthesis, resulting in autocrine/paracrine IL-1β-mediated increases in EC immunogenicity. Similar responses may underlie other complement-mediated pathologies.
Selecting optimal patient candidates to assess the clinical utility of patient-derived xenograft (PDX) models in advanced solid tumors.
Authors: Cathie T. Chung, Lawrence D. Piro, Daniel Lieber, Melani P. Shaum, Peter D. Boasberg, Ani Sarkis Balmanoukian, Omid Hamid, Basmina Parmakhtiar, Amanda Katz, Angela M. Davies, Jordan Rubinson, Silvana Martino
Journal: Journal of Clinical Oncology (2015)

e22186 Background: Management of patients with advanced cancer remains a challenge due to inability to predict response to current therapies. Identifying tools to optimize drug selection for individual patients would be of significant clinical benefit. One strategy is utilizing patient-derived xenografts (PDXs). Growing evidence demonstrates that PDXs recapitulate the patient's tumor histopathologically and genetically (Weroha 2014, Zhang 2013). Additionally, it has been demonstrated that drug response in PDX models correlate with clinical response and can be utilized to guide personalized treatments (Stebbing, 2014). We report on a pilot initiative to utilize PDX models to personalize therapy. Methods: Patients with solid tumors were consented to provide tumor tissue for development of a PDX model to guide their personal therapy. Fresh tumor specimens were obtained and engrafted into immunodeficient mice to establish PDX models. Successfully engrafted PDX models were expanded and cohorts of mice were assigned for drug sensitivity testing. Treating physicians identified drugs to be tested. Results: To date, a total of 32 tumors have been implanted including breast, NSCLC, colorectal, ovarian, sarcoma, and others. Of these, 13 tumors were procured from surgeries, 17 from biopsies, and 2 from ascites. So far, 12 PDX models have successfully engrafted (8 from surgeries, 4 from biopsies), 11 have been discontinued due to no growth and the remaining tumors are being monitored for growth. The median time to drug study was 91.6 days. Eight patients have proceeded with drug sensitivity testing. Drug panels ranged from 2-8 test arms including standard and nonstandard therapies. Three patients died prior to drug testing and one prior to receiving drug. PDX and clinical correlation data will be presented. Conclusions: Personalized PDX models assessing drug activity have the potential to translate into clinical application and a platform for therapeutic decision making. Practical implications for incorporating the use of PDX models such as patient selection, timing of model development, drug selection and use of data from PDX drug testing will be reported.
Expression and clinical significance of PD-L1, B7-H3, B7-H4 and TILs in human small cell lung Cancer (SCLC)
Authors: Daniel Carvajal-Hausdorf, Mehmet Altan, Vamsidhar Velcheti, Scott N. Gettinger, Roy S. Herbst, David L. Rimm, Kurt A. Schalper
Journal: Journal for ImmunoTherapy of Cancer (2019)

Small cell lung cancer (SCLC) accounts for 10-15% of all lung malignancies and its prognosis is dismal. Although early studies have shown promising clinical activity of immune checkpoint blockers, the immune composition and expression of potentially actionable immunostimulatory targets in this malignancy are poorly understood.Using multiplexed quantitative immunofluorescence (QIF), we measured the levels of 3 different B7 family ligands PD-L1, B7-H3, B7-H4 and major tumor infiltrating lymphocyte (TIL) subsets in 90 SCLC samples represented in tissue microarray format. Associations between the marker levels, clinicopathological variables and survival were studied.PD-L1 protein was detected in 7.3%, B7-H3 in 64.9% and B7-H4 in 2.6% of SCLC cases. The markers showed limited co-expression and were not associated with the level of TILs, age, gender and stage. Elevated B7-H4 was associated with shorter 5-year overall survival. The levels of CD3+, CD8+ and CD20+ TILs and the ratio of total/effector T-cells were significantly lower in SCLC than in non-small cell lung cancer. High levels of CD3+, but not CD8+ or CD20+ TILs were significantly associated with longer survival.Taken together, our study indicate variable expression and clinical role of B7-family ligands in SCLC with predominant expression of the candidate target B7-H3 and the presence of a limited cytotoxic anti-tumor immune response. These results support the evaluation of B7-H3 blockers and/or pro-inflammatory therapies in SCLC.
THU-405-Complications of chronic hepatitis B: Prevalence and disparities in a US health system cohort 2006-2016
Authors: Mei Lu, Yueren Zhou, Jia Li, Loralee B Rupp, Joseph A. Boscarino, Yihe G Daida, Mark A Schmidt, Sheri Trudeau, Stuart C Gordon
Journal: Journal of Hepatology (2019)
PTH-022 Hyperamylasaemia post antegrade double balloon enteroscopy – does indomethacin make a difference?
Authors: Stefania Chetcuti Zammit, Suneil A Raju, Hey-Long Ching, David S Sanders, Reena Sidhu
Journal: Endoscopy (2018)

<h3>Introduction</h3> High amylase does not always signify acute pancreatitis and it can occur due to focal areas of ischaemia in the pancreas due to mechanical stress during double balloon enteroscopy (DBE). The use of rectal NSAIDs to prevent post DBE pancreatitis has never been explored unlike in ERCP where patients receiving rectal NSAIDs have a lower incidence of pancreatitis. <h3>Methods</h3> Patients who received rectal indomethacin (100 mg) 30 min prior to antegrade DBE were compared to a control group who did not receive indomethacin before the above protocol was implemented. Serum amylase and CRP 3 hours before and after DBE were compared. <h3>Results</h3> 240 patients (56 indomethacin, 184 controls; 50% males; mean age 58.5±SD14.0) were included. <h3>Indications included</h3> IDA (37.5%), obscure overt gastrointestinal bleeding (17.1%), suspected crohn's disease and strictures (17.9%), complication of coeliac disease (1.3%), small bowel (SB) tumours/polyps (17.9%), others (8.3%). Patients had a median of 13.0±SD13.0 passes, 65.0±SD25.0 min, 170±SD52.0 cm of SB examined. 36.3% underwent a therapeutic procedure during DBE: APC/adrenaline/clips (27.5%), foreign body removal (0.4%), polypectomy (8.3%). Only 4 (1.67%; 2 females) patients developed pancreatitis, all prior to implementation of indomethacin into the local protocol. They had a median age of 47.0±SD3.20 years, 11±SD29.4 passes, 90±SD52.0 min, 150 cm ±SD64.2 cm of SB examined and median hospital stay of 14±SD3.70 days. 3 had polypectomies. 2 episodes occurred in the same patient. All had evidence of pancreatitis on CT scan. None of the patients received indomethacin before DBE. Mean amylase (51.6±SD22.7 vs 143.0±SD143.9 IU/L p=0.0001) and CRP (13.0±SD46.1 vs 17.3±SD81.7 mg/L p=0.0001) after the procedure were significantly higher than before the procedure. Females had a significantly higher amylase than males post procedure (155.2 vs 130.7 IU/L p=0.017). Mean amylase 3 hours after DBE was significantly lower in patients who received indomethacin (114 vs 152) (p=0.044). 83.9% had a rise in amylase in the indomethacin group compared to 92.2% controls.(p=0.064). Whilst there was no correlation between post-procedure amylase (p=0.552), CRP (p=0.058) and duration of the procedure, there was a significant association between amylase post procedure and length of SB examined.(Spearman's rho 0.186; p=0.005) <h3>Conclusions</h3> This study identifies a role for rectal indomethacin in patients undergoing antegrade DBE. We have demonstrated that rectal indomethacin reduces amylase post DBE and no patients given indomethacin experienced pancreatitis. Larger studies are required to assess if this also transforms into lowering risk or severity of pancreatitis.
RNA helicase DDX3 is a novel therapeutic target for Ewing sarcoma.
Authors: David Mark Loeb, Breelyn A. Wilky, Catherine Kim, Gregory McCarty, Lauren R DeVine, Robert N Cole, Venu Raman
Journal: Journal of Clinical Oncology (2015)

10026 Background: There is growing interest in RNA and DNA helicases as therapeutic targets in a variety of sarcomas. We investigated the expression and function of RNA helicase DDX3 in Ewing sarcoma and have begun to explore the effect of a novel DDX3 inhibitor, RK-33. Methods: We determined DDX3 expression in Ewing sarcoma cell lines, xenografts, and tissue microarrays by quantitative RT-PCR, western blotting, immunohistochemistry and quantitative proteomics using isobaric mass tags (tandem mass tags, TMTs). Stable DDX3-knockdown cell lines were created and evaluated. Proliferation, clonogenic activity in soft agar, sphere formation, and growth in immunodeficient mice were assayed. The effect of RK-33 on Ewing sarcoma was evaluated in cell lines and xenografts. Results: RNA helicase mRNA and protein are expressed at high level in Ewing sarcoma cell lines and patient-derived xenografts, and immunohistochemical staining is seen in 22 of 25 biopsy samples. Knockdown of DDX3 impairs proliferation, soft agar clonogenic activity, and sarcosphere formation and increases radiation sensitivity by slowing DNA damage repair in Ewing sarcoma cell lines, and impairs tumor growth in xenografts. Proteomic analysis implicates DDX3 in the translation of proteins important for numerous cellular pathways, including DNA damage repair and resistance to apoptosis. The DDX3 inhibitor, RK-33, is cytotoxic to Ewing sarcoma cell lines in vitro, including to chemotherapy-resistant Ewing sarcoma stem cells, and increases radiation sensitivity, and knockdown of DDX3 inhibits cytotoxicity. RK-33 also impairs the growth of a DDX3-positive Ewing sarcoma xenograft. Conclusions: Our data implicate DDX3 in Ewing sarcoma tumorigenesis. In light of data implicating other helicases in the pathogenesis of Ewing sarcoma and osteosarcoma, this work supports the idea that this enzymatic family plays a key role in the development of sarcomas in general, and that helicase inhibitors might be an important new class of therapeutics. In fact, we found that a novel DDX3 inhibitor, RK-33, shows strong therapeutic promise, either as a direct cytotoxic agent or as a radiation sensitizing agent.
Comprehensive three-dimensional analysis (CUBIC-kidney) visualizes abnormal renal sympathetic nerves after ischemia/reperfusion injury
Authors: Sho Hasegawa, Etsuo A. Susaki, Tetsuhiro Tanaka, Hirotaka Komaba, Takehiko Wada, Masafumi Fukagawa, Hiroki R. Ueda, Masaomi Nangaku
Journal: Kidney International (2019)
First Experience With 177Lu-PSMA-617 Therapy for Advanced Prostate Cancer in the Netherlands
Authors: Ludwike van Kalmthout, Arthur Braat, Marnix Lam, Rachel van Leeuwaarde, Gerard Krijger, Tessa Ververs, Niven Mehra, Adriaan Bins, Jarmo Hunting, Bart de Keizer
Journal: Clinical Nuclear Medicine (2019)

The present study summarizes the first experience with Lu-PSMA-617 (Lu-PSMA) treatment in metastatic castration-resistant prostate cancer (PCa) in our institution.This was an analysis of the first 30 consecutive patients who underwent Lu-PSMA therapy. Biochemical response was defined as prostate-specific antigen decrease of 50% or greater. Clinical toxicity was based on standardized physician's report, and biochemical and hematological toxicity was graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) criteria. Clinical response was objectified in terms of severity of pain and usage of analgesics after separate treatment cycles.Thirty patients with advanced PCa received therapy cycles with 6 GBq Lu-PSMA (median, 4; range, 1-6). After the first cycle, usage of analgesics decreased in 45% of the patients. During treatment, maximum prostate-specific antigen decrease was 50% or greater and 90% or greater in 57% and 24% of the patients, respectively. Despite CTCAE grades III and IV anemia occurring in 2 patients (7%), all other newly originated biochemical toxicity was limited to maximum CTCAE grades I and II. Grade II xerostomia occurred in 17% of the patients. During a median follow-up length of 13.7 months (range, 9.8-32.3 months), median overall survival from start of the first therapy cycle was 11.3 months (range, 1.4-32.3 months).These results confirm the favorable safety and efficacy profile of Lu-PSMA, even up to 6 treatment cycles. Therefore, Lu-PSMA seems a promising therapeutic strategy for metastatic castration-resistant PCa patients. However, randomized controlled trials are warranted to obtain robust data.
Annals Story Slam - Saving Karma
Authors: James K. Schmitt
Journal: Annals of Internal Medicine (2019)

Web Exclusives7 May 2019Annals Story Slam - Saving KarmaFREEJames K. Schmitt, MDJames K. Schmitt, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W19-0008 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Saving Karma "Saving Karma," by Dr. James K. Schmitt (Duration 3:53)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: This article was published at Annals.org on 12 April 2019. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 7 May 2019Volume 170, Issue 9Page: SS1 ePublished: 12 April 2019 Issue Published: 7 May 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.Loading ...
PS-048-Definition of aneuploidy profiles and their impact on tumour progression and immune features in hepatocellular carcinoma
Authors: Roger Esteban-Fabró, Laia Bassaganyas, Sara Torrecilla, Agrin Moeini, Sebastià Franch-Expósito, Maria Vila-Casadesús, Ferran Nadeu, Laia Cabellos, Daniela Sia, Itziar Salaverria, Roser Pinyol, Jordi Camps, Vincenzo Mazzaferro, Josep M. Llovet
Journal: Journal of Hepatology (2019)