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Background: Chronic hepatitis B virus (HBV) remains a global concern, with current treatments achieving low rates of HBsAg seroclearance. VIR-2218 (elebsiran), a small interfering RNA agent against HBV transcripts, reduces HBsAg concentrations. We aimed to evaluate the safety and antiviral activity of VIR-2218 with and without pegylated interferon-alpha-2a treatment in participants with chronic HBV., Methods: This open-label, phase 2 study was conducted at 23 sites in six countries (New Zealand, Australia, Hong Kong, Thailand, South Korea, and Malaysia). Adults (aged 18-65 years) with chronic HBV infection without cirrhosis and with HBsAg more than 50 IU/mL and HBV DNA less than 90 IU/mL who were on continued nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) therapy for 2 months or longer were eligible. Participants were enrolled into one of six cohorts to receive VIR-2218 200 mg subcutaneously every 4 weeks, with or without 180 μg subcutaneous pegylated interferon-alfa-2a once per week. Cohort 1 received six doses of VIR-2218 (total 20 weeks); cohort 2 received six doses of VIR-2218 starting at day 1, plus 12 doses of pegylated interferon-alfa-2a starting at week 12 (total 24 weeks); cohort 3 received six doses of VIR-2218 and 24 doses of pegylated interferon-alfa-2a (total 24 weeks); cohort 4 received six doses of VIR-2218 and up to 48 doses of pegylated interferon-alfa-2a (total 48 weeks); cohort 5 received up to 13 doses of VIR-2218 and up to 44 doses of pegylated interferon-alfa-2a (total 48 weeks); and cohort 6 received three doses of VIR-2218 and 12 doses of pegylated interferon-alfa-2a (total 12 weeks). The primary endpoints were the incidence of adverse events and clinical assessments (including results of laboratory tests). Secondary endpoints were the mean maximum reduction of serum HBsAg at any timepoint; the proportion of participants with serum HBsAg seroclearance at any timepoint and for more than 6 months after the end of treatment; and the proportion of participants with anti-HBs seroconversion at any timepoint. For patients who were HBeAg-positive, we also assessed the proportion with HBeAg seroclearance or anti-HBe seroconversion at any timepoint. This study is registered with ClinicalTrials.gov, NCT03672188, and is ongoing., Findings: Between July 2, 2020, and Nov 2, 2021, 124 individuals were screened for eligibility, 84 of whom were enrolled (15 in cohort 1, 15 in cohort 2, 18 in cohort 3, 18 in cohort 4, 13 in cohort 5, and five in cohort 6). Participants were predominantly HBeAg-negative, Asian, and male (66 [79%] participants were male and 18 [21%] were female). Most treatment emergent adverse events were grades 1-2. Three (20%) participants in cohort 1, four (27%) in cohort 2, eight (44%) in cohort 3, seven (39%) in cohort 4, six (46%) in cohort 5, and two (40%) in cohort 6 reported treatment-emergent adverse events related to VIR-2218. 12 (80%) participants in cohort 2, 12 (67%) in cohort 3, 14 (78%) in cohort 4, 13 (100%) in cohort 5, and three (60%) in cohort 6 reported treatment-emergent adverse events related to pegylated interferon-alfa-2a. Two (13%) participants in cohort 1 had elevations in alanine aminotransferase, compared with 13 (87%) participants in cohort 2, 15 (83%) in cohort 3, 17 (94%) in cohort 4, 11 (85%) in cohort 5, and three (60%) in cohort 6. The mean maximum change from baseline at any timepoint in HBsAg concentration was -2·0 log 10 IU/mL (95% CI -2·1 to -1·8) in cohort 1, -2·2 log 10 IU/mL (-2·5 to -1·8) in cohort 2, -2·5 log 10 IU/mL (-2·8 to -2·1) in cohort 3, -2·4 log 10 IU/mL (-3·1 to -1·8) in cohort 4, -3·0 log 10 IU/mL (-3·7 to -2·3) in cohort 5, and -1·7 log 10 IU/mL (-2·1 to -1·4) in cohort 6. 11 participants (one in cohort 2, one in cohort 3, five in cohort 4, and four in cohort 5) receiving VIR-2218 plus pegylated interferon-alfa-2a had HBsAg seroclearance at any timepoint. Of these, ten (91%; one in cohort 2, five in cohort 4, and four in cohort 5) had anti-HBs seropositivity. Six participants (one in cohort 2, three in cohort 4, and two in cohort 5) had sustained HBsAg seroclearance through to 24 weeks after the end of treatment. No participants receiving VIR-2218 monotherapy (cohort 1) or VIR-2218 plus pegylated interferon-alfa-2a 12-week regimen (cohort 6) had HBsAg seroclearance. 12 (42%) of 26 participants (one of four in cohort 1, two of six in cohort 2, four of seven in cohort 3, four of six in cohort 4, and one of three in cohort 5) who were HBeAg positive at baseline had HBeAg seroclearance or anti-HBe seroconversion., Interpretation: The results of this phase 2 study support further development of VIR-2218 as a potential therapy for patients with chronic HBV infection. Additional clinical trials of VIR-2218 with and without pegylated interferon-alfa-2a in combination with an HBsAg-targeting monoclonal antibody are ongoing., Funding: Vir Biotechnology., Competing Interests: Declaration of interests M-FY is a consultant for AbbVie, Arbutus Biopharma, Bristol Myers Squibb, ClearB Therapeutics, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp & Dohme, Spring Bank Pharmaceuticals, Roche, and Vir Biotechnology, and has received grant support from Arrowhead Pharmaceuticals, Assembly Biosciences, Bristol Myers Squibb, Fujirebio Incorporation, Gilead Sciences, Merck Sharp & Dohme, Spring Bank Pharmaceuticals, and Sysmex Corporation. Y-SL has received grant support from Gilead Sciences, has received consultant fees from AbbVie, Assembly Biosciences, GlaxoSmithKline, Gilead Sciences, Janssen, Olix Pharmaceuticals, Roche, Vaccitech, and Vir Biotechnology, and has received honoraria from AbbVie, Gilead Sciences, and Vaccitech. JH has received grant support from Gilead Sciences and Roche, has received consultant fees from Roche and lecture fees from AbbVie Korea, Roche, Yuhan Korea, Oncolys, and Gilead, and is a member of an AstraZeneca steering committee. VT, SM, AA, ALC, SVG, and CH are employees of Vir Biotechnology. DC is a former employee of Vir Biotechnology. EG has served on scientific advisory boards for Gilead Sciences, ALIGOS, Janssen, Roche, and Assembly and has received unrestricted grant support from AbbVie. EG is an associate editor of the Journal of Hepatology and is a sponsored lecturer for the HCV Elimination Leaders Conference series for AbbVie. All other authors declare no competing interests., (© 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Aim: This post-marketing surveillance study evaluated the safety and effectiveness of lenvatinib as first-line treatment for unresectable hepatocellular carcinoma in Korea. Materials & methods: Adverse drug reactions (ADRs) and other safety and effectiveness end points were assessed in patients who initiated lenvatinib according to the approved label in republic of Korea. Results: Among 658 lenvatinib-treated patients, ADRs were reported in 57.8%; ADRs grade ≥3 in 13.5%. The most common grade ≥3 ADRs were asthenia (1.2%) and hepatic encephalopathy (1.2%). Physician-reported tumor responses (n = 511) were complete (1.0%) or partial (12.9%) response and stable (45.2%) or progressive disease (40.9%); objective response rates were higher with longer lenvatinib treatment duration ( p  < 0.001). Conclusion: Lenvatinib was generally well tolerated and effective in real-world clinical practice in Korea. Clinical trial registration: ClinicalTrials.gov NCT05225207.

An electron transport layer (ETL) for highly efficient perovskite solar cells (PSCs) should exhibit superior electrical transport properties and have its band levels aligned with interfacing layers to ensure efficient extraction of photo-generated carriers. Nitrogen-doped TiO 2 (TiO 2 :N) is considered a promising ETL because it offers higher electrical conductivity compared to conventional ETLs made from spray-pyrolyzed TiO 2 . However, the application of highly doped TiO 2 :N in PSCs is often limited by the misalignment of energy band levels with adjacent layers and reduced optical transparency. In this study, a novel approach is introduced to enhance the charge transport characteristics and accurately align the electronic band alignment of TiO 2 :N layer through nanoscale doping level grading, achieved through the pulsed laser deposition (PLD) technique. The TiO 2 :N ETL with a graded doping profile can combine characteristics of both highly doped and lightly doped phases on each side. Furthermore, a nanoscale doping gradation, employing an ultrathin sub-layer structure with graded doping levels, creates a smoothly cascading band-level alignment that bridges the adjacent layers, enhancing the transport of photo-generated carriers. Consequently, this method leads to a substantial increase in the power conversion efficiency (PCE), exceeding 22%, which represents a relative improvement of 11% compared to traditional spray-pyrolyzed TiO 2 -based PSCs., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Background: It is unclear whether direct-acting antivirals (DAAs) treatment improves the disease burden in hepatitis C virus (HCV) infection. This study aimed to investigate the effect of DAA treatment on the reduction of disease burden in patients with HCV infection using individual participant data., Methods: This nationwide multicentre retrospective cohort study recruited patients with HCV infection from 29 tertiary institutions in South Korea. The data collection was done from medical records in each institution. The study included the untreated patients and the DAAs-treated patients and excluded those with a history of interferon-based treatments. Disease burden was the primary outcome, as represented by disability-adjusted life years (DALYs). Improvement in fibrosis after DAA treatment was assessed using APRI, FIB-4 index, and liver stiffness (LS) as assessed by transient elastography. Clinical outcomes were hepatocellular carcinoma (HCC), decompensation, and mortality., Findings: Between January 1, 2007, and February 17, 2022, data from 11,725 patients with HCV infection, 8464 (72%) of whom were treated with DAAs, were analysed. DAA treatment significantly improved APRI- (median 0.64 [interquartile range (IQR), 0.35-1.31]-0.33 [0.23-0.52], p < 0.0001), FIB-4- (median 2.42 [IQR, 1.48-4.40]-1.93 [1.31-2.97], p < 0.0001), and liver LS-based fibrosis (median 7.4 [IQR, 5.3-12.3]-6.2 [4.6-10.2] kPa, p < 0.0001). During the median follow-up period of 27.5 months (IQR, 10.6-52.4), 469 patients died (4.0%), 586 (5.0%) developed HCC, and 580 (4.9%) developed decompensation. The APRI-based DALY estimate was significantly lower in the DAA group than in the untreated group (median 4.55 vs. 5.14 years, p < 0.0001), as was the FIB-4-based DALY estimate (median 5.43 [IQR, 3.00-6.44] vs. 5.79 [3.85-8.07] years, p < 0.0001). The differences between the untreated and DAA groups were greatest in patients aged 40-60 years. In multivariable analyses, the DAA group had a significantly reduced risk of HCC, decompensation, and mortality compared with the untreated group (hazard ratios: 0.41 [95% confidence interval (CI), 0.34-0.48], 0.31 [95% CI, 0.30-0.38], and 0.22 [95% CI, 0.17-0.27], respectively; p < 0.0001)., Interpretation: Our findings suggest that DAA treatment is associated with the improvement of liver-related outcomes and a reduction of liver fibrosis-based disease burden in patients with HCV infection. However, further studies using liver biopsy are needed to clarify the effect of DAA treatment on the reduction in the exact fibrosis-based disease burden beyond noninvasive tests., Funding: The Korea Disease Control and Prevention Agency., Competing Interests: All authors declare no financial or non-financial competing interests., (© 2024 The Authors. Published by Elsevier Ltd.)

Background/aims: Noninvasive methods have become increasingly critical in the diagnosis of fibrosis in chronic liver diseases. Herein, we compared the diagnostic performance of serum Mac2 binding protein glycosylation isomer (M2BPGi) and other serological panels for fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) and proposed an improved two-step diagnostic algorithm for advanced fibrosis., Methods: We enrolled 231 patients diagnosed with NAFLD who underwent a liver biopsy. We subsequently evaluated the diagnostic performance of serological panels, including serum M2BPGi, a fibrosis index based on four factors (FIB-4), aspartate aminotransferase-to-platelet ratio index (APRI), and NAFLD fibrosis score (NFS), in predicting the stage of liver fibrosis. We then constructed a two-step algorithm to better differentiate advanced fibrosis., Results: The areas under the receiver operating characteristic curves of serum M2BPGi, FIB-4, APRI, and NFS for advanced fibrosis (≥F3) were 0.823, 0.858, 0.779, and 0.827, respectively. To reduce the performance of unnecessary liver biopsy, we propose a two-step algorithm using FIB-4 as an initial diagnostic tool and serum M2BPGi (≥0.6) as an additional diagnostic method for patients classified as intermediate (23%). Using the proposed algorithm, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 0.812, 0.814, 0.814, 0.600, and 0.927, respectively., Conclusions: Serum M2BPGi is a simple and effective test for advanced fibrosis in patients with NAFLD. Application of the two-step algorithm based on FIB-4 and M2BPGi proposed here can improve diagnostic performance and reduce unnecessary tests, making diagnosis easily accessible, especially in primary medical centers.

A novel approach to producing high-color-purity blue-light-emitting diodes based on single-crystalline Ruddlesden-Popper perovskites (RPPs) is reported. The utilization of a pure bromide composition eliminates any possibility of halide segregation, which can otherwise lead to undesired shifts in the emission wavelength or irreversible degradation of the spectral line width. Phase-pure PEA 2 MAPb 2 Br 7 single crystals with a lateral size exceeding 1 cm 2 can be synthesized using the inverse temperature crystallization method. To prepare RPP layers with a thickness of less than 50 nm, we employ a thinning process of the initially thick bulk crystals, followed by a dry-transfer process to place them onto a hole transport layer and an indium-tin-oxide-coated glass substrate. By utilizing polydimethylsiloxane as a handling layer, deformations of the bulk RPP crystal and exfoliated RPP layer, as well as the formation of defects such as pinholes, can be effectively suppressed. Subsequent depositions of an electron transport layer and a metal contact complete the fabrication of electroluminescence (EL) devices. The EL devices utilizing the single-crystalline RPP demonstrate excellent spectral stability across a broad range of the applied bias voltage spanning from 4.5 to 10 V, exhibiting a significantly narrow line width of 14 nm at an emission wavelength of 440 nm that can potentially cover 99.3% of the Rec. 2020 color gamut. The sharp EL emission spectrum can be effectively preserved, avoiding any broadening of the line width, by suppressing Joule heating throughout the device operation, in addition to the intrinsic stability of single-crystalline RPPs.

Work-related musculoskeletal disorders represent a major occupational disability issue, and 53.4% of these disorders occur in the back or shoulders. Various types of passive shoulder exoskeletons have been introduced to support the weight of the upper arm and work tools during overhead work, thereby preventing injuries and improving the work environment. The general passive shoulder exoskeleton is constructed with rigid links and joints to implement shoulder rotation, but there exists a challenge to align with the flexible joint movements of the human shoulder. Also, a force-generating part using mechanical springs require additional mechanical components to generate torque similar to the shoulder joint, resulting in increased overall volume and inertia to the upper arm. In this study, we propose a new type of passive shoulder exoskeleton that uses magnetic spring joint and link chain. The redundant degrees of freedom in the link chains enables to follow the shoulder joint movement in the horizontal direction, and the magnetic spring joint generates torque without additional parts in a compact form. Conventional exoskeletons experience a loss in the assisting torque when the center of shoulder rotation changed during arm elevation. Our exoskeleton minimizes the torque loss by customizing the installation height and initial angle of the magnetic spring joint. The performances of the proposed exoskeleton were verified by an electromyographic evaluation of shoulder-related muscles in overhead work and box lifting task.

Background: Life-threatening bleeding following endoscopic variceal ligation (EVL) in patients with cirrhosis rarely can occur. The present study aimed to evaluate the performance of computed tomography (CT) in predicting the risk of early bleeding following EVL in cirrhotic patients., Methods: We retrospectively investigated 285 cirrhotic patients who had undergone EVL. EVL was performed for prophylaxis or acute variceal bleeding. The patients were classified into 2 groups: early bleeding (< 14 days after EVL) and non-early bleeding. We compared baseline characteristics including CT findings between the patient groups., Results: Among the 285 patients who underwent EVL treatment, 19 patients (6.7%) experienced early bleeding. On average, these bleeding occurred 9.3 ± 3.5 days after the EVL, with a range of 3 to 13 days. Patients who experience early bleeding had a higher six-week bleeding-related mortality rate compared to those in the non-early bleeding group (31.6% vs. 10.2%; p = 0.014). There was a correlation between the grade of esophageal varix observed during endoscopy and the diameter of esophageal varix observed on CT (p < 0.001). The diameter of esophageal varix on CT was identified as the only significant predictive factor for early bleeding (p = 0.005)., Conclusion: A larger esophageal varix diameter observed on CT is associated with an increased risk of early bleeding after EVL treatment. Early identification of this high-risk group can provide a change of treatment strategies to improve patient outcomes., (© 2023. The Author(s).)

Purpose: To evaluate the incidence, risk factors, and prognosis associated with peritoneal seeding after percutaneous radiofrequency ablation (RFA) for HCC, focusing on viable tumors after previous locoregional treatment, including TACE and RFA., Methods: Exactly 290 patients (mean age, 67.9 years ± 9.74; 223 men) with 383 HCCs (mean size, 15.9 mm ± 5.49) who underwent RFA between June 2012 and December 2019 were included in this retrospective study. Among them, 158 had history of previous treatment (mean number, 1.3 ± 1.8) with 109 viable HCCs. Cumulative seeding after RFA was estimated using the Kaplan-Meier method. Independent factors affecting seeding were investigated using multivariable Cox proportional hazards regression analysis., Results: Median follow-up was 1175 days (range: 28-4116). Seeding incidence was 4.1 (12/290) and 4.7% (17/383) per patient and tumor, respectively. The median time interval between RFA and detection of seeding was 785 days (range: 81-1961). Independent risk factors for seeding included subcapsular tumor location (hazard ratio [HR] 4.2; 95% confidence interval [CI] 1.4, 13.0; p = 0.012) and RFA for viable HCC after previous locoregional treatment (HR 4.5; 95% CI 1.7, 12.3; p = 0.003). Subgroup analysis for viable tumors, revealed no significant difference in cumulative seeding rates between the TACE and RFA groups (p = 0.078). Cumulative overall survival rates differed significantly between patients with and without seeding metastases (p < 0.001)., Conclusion: Peritoneal seeding after RFA is a rare, delayed complication. Subcapsular-located and viable HCC after previous locoregional treatment are potential risk factors for seeding. Seeding metastases could affect the prognosis of patients who cannot receive local therapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This study aimed to investigate the prevalence rate of hepatitis C virus (HCV) infection and identify the demographic, and sociological characteristics and changes in awareness of HCV infection by participating the study for North Korean defectors residing in South Korea., Methods: This study prospectively enrolled participants. Demographic, sociological and clinical data, and questionnaire surveys focused on awareness of HCV infection were collected., Results: In total, 211 North Korean defectors participated in this study from September 2020 until June 2021. There were 174 women (82.5%), and the overall mean age was 48.9 years (range, 20 to 80 years). Of these participants, 112 (53.1%) had immigrated to South Korea since 2011. The overall prevalence of anti-HCV antibody among North Korean defectors was 1.9%. Thirty participants (14.2%) had hepatitis B surface antigens. A huge lack of awareness regarding HCV infection has been observed among North Korean defectors., Conclusion: This is the first prospective study to investigate the prevalence rate of HCV infection among North Korean defectors residing in South Korea. As North Korean defectors are a vulnerable group concerning HCV infection, they may benefit from HCV screening policies and educational interventions for HCV infection., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Background/aims: Despite the availability of direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection in Korea, need remains for pangenotypic regimens that can be used in the presence of hepatic impairment, comorbidities, or prior treatment failure. We investigated the efficacy and safety of sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir for 12 weeks in HCV-infected Korean adults., Methods: This Phase 3b, multicenter, open-label study included 2 cohorts. In Cohort 1, participants with HCV genotype 1 or 2 and who were treatment-naive or treatment-experienced with interferon-based treatments, received sofosbuvir-velpatasvir 400/100 mg/day. In Cohort 2, HCV genotype 1 infected individuals who previously received an NS5A inhibitor-containing regimen ≥ 4 weeks received sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg/day. Decompensated cirrhosis was an exclusion criterion. The primary endpoint was SVR12, defined as HCV RNA < 15 IU/mL 12 weeks following treatment., Results: Of 53 participants receiving sofosbuvir-velpatasvir, 52 (98.1%) achieved SVR12. The single participant who did not achieve SVR12 experienced an asymptomatic Grade 3 ASL/ALT elevation on day 15 and discontinued treatment. The event resolved without intervention. All 33 participants (100%) treated with sofosbuvir-velpatasvir-voxilaprevir achieved SVR 12. Overall, sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir were safe and well tolerated. Three participants (5.6%) in Cohort 1 and 1 participant (3.0%) in Cohort 2 had serious adverse events, but none were considered treatment-related. No deaths or grade 4 laboratory abnormalities were reported., Conclusion: Treatment with sofosbuvir-velpatasvir or sofosbuvir-velpatasvir-voxilaprevir was safe and resulted in high SVR12 rates in Korean HCV patients.

Background: Hyperdynamic circulation in portal hypertension (PHT) depends on central neural activation. However, the initiating mechanism that signals PHT to the central neural cardiovascular-regulatory centers remains unclear. We aimed to test the hypothesis that oxidative stress in the gut initiates the signal that activates central cardiovascular nuclei in portal hypertensive rats., Methods: Two groups of rats were used. One had portal hypertension produced by partial portal vein ligation, while controls underwent sham operation. Hemodynamics including portal pressure, cardiac output, mean arterial pressure (MAP) and peripheral vascular resistance were measured. Activation of central cardiovascular nuclei was determined by immunohistochemical Fos expression in the paraventricular nucleus (PVN) of the hypothalamus. Myeloperoxidase activity, an oxidative stress marker, was measured in the jejunum. Hydrogen peroxide, the antioxidant N-acetyl-cysteine (NAC) or saline controls were administered for 12-14 days by gavage or osmotic minipumps placed in the peritoneal cavity., Results: Compared with controls, PHT rats showed increased cardiac output (54.2 ± 9.5 vs 33.6 ± 2.4 ml/min/100 g BW, p < 0.01), decreased MAP (96.2 ± 6.4 mmHg vs 103.2 ± 7.8, p < 0.01) and systemic vascular resistance (1.84 ± 0.28 vs 3.14 ± 0.19 mmHg/min/ml/100 g BW, p < 0.01). PHT rats had increased jejunal myeloperoxidase and PVN Fos expression. NAC treatment eliminated the hyperdynamic circulation, decreased jejunal myeloperoxidase and PVN Fos expression in PHT rats, but had no effect on sham controls. H 2 O 2 significantly increased PVN Fos expression and decreased MAP., Conclusion: These results indicate that in PHT, mesenteric oxidative stress is the initial signal that activates chemoreceptors and triggers hyperdynamic circulation by central neural cardiovascular-regulatory centers., (© 2023. Asian Pacific Association for the Study of the Liver.)

Background & Aims: Loss-of-function HSD17β13 mutations protect against the development of chronic liver disease. HSD17β13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17β13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH., Methods: The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17β13 mRNA and protein., Results: ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17β13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17β13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17β13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were -7.7% (25 mg), -39.3% (100 mg), and -42.3% (200 mg) (p <0.001 for pooled cohorts)., Conclusions: ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17β13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase., Gov Number: NCT04202354., Impacts and Implications: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17β13 expression and hence to phenocopy the protective effect seen in individuals with HSD17β13 loss-of-function. The reductions in HSD17β13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17β13, a drug target with substantial genetic validation, as an important modulator of human liver disease., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The bowel-cleansing efficacy and safety of 2 L polyethylene glycol (PEG) with ascorbic acid (2L PEG + Asc) has rarely been studied in the elderly population. In this randomized trial, we compared the bowel cleanliness, safety, and tolerability of 2L PEG + Asc with those of 4 L PEG in an elderly population aged 60-79., Methods: Study participants were randomized either to 2L PEG + Asc or 4L PEG. The primary endpoint was the success rate of bowel preparation, using the Boston Bowel Preparation Scale. Before colonoscopy, all participants were questioned about adverse events and tolerability regarding purgative ingestion., Results: A total of 347 individuals were enrolled (2L PEG + Asc, 174; 4L PEG, 173). Mean age in the 2L PEG + Asc and the 4L PEG was 69.3 ± 5.6 and 69.3 ± 5.0, respectively (P = 0.917). The rate for successful bowel cleansing was comparable between the 2L PEG + Asc (92%) and the 4L PEG (96%, P = 0.118). Total ingested liquid including purgative and water was lower in the 2L PEG + Asc group (2.9 L) than in the 4L PEG group (4.2 L, P < 0.001). The tolerability of purgative was superior in the 2L PEG + Asc (overall satisfaction, P < 0.001; willingness to reuse, P < 0.001). There were no serious adverse events during the trial., Conclusions: The bowel-cleansing efficacy of 2L PEG + Asc was comparable to that of 4L PEG. Tolerability was superior in the 2L PEG + Asc group. For older people, 2L PEG + Asc is an efficacious and safe bowel cleanser. (Clinical trial registration number: KCT0004123)., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alphaviruses are single stranded, positive sense RNA viruses that are often transmitted through mosquito vectors. With the increasing spread of mosquito populations throughout the world, these arboviruses represent a significant global health concern. Viruses such as Sindbis Virus (SINV), Chikungunya Virus (CHIKV) and Equine Encephalitis Viruses (EEV) are all alphaviruses. As viruses, these pathogens are dependent on the host cell environment for successful viral replication. It has been observed that viruses manipulate cellular metabolism and mitochondrial shape, activity, and dynamics to favor viral infection. This report looked to understand the metabolic changes present during Sindbis virus infection of hamster and human kidney cells. Cells were infected with increasing levels of SINV and at 24 hours post infection the mitochondria morphology was assessed with staining and mitochondrial activity was measured with a real-time Seahorse Bioanalyzer. The relative amount of mitochondrial staining intensity decreased with Sindbis virus infected cells. Both oxygen consumption rate and ATP production were decreased during SINV infection while non-mitochondrial respiration and extracellular acidification rate increased during infection. Collectively, the data indicates that SINV primarily utilizes non-mitochondrial metabolism to support viral infection within the first 24 hours. This understanding of viral preference for host cell metabolism may provide critical targets for antiviral therapies and help further define the nature of alphavirus infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rodriguez, Costlow, Sheedy, Yoon, Gabaldón and Steel.)

In the natural course of chronic hepatitis B, the immune tolerance phase is characterized by HBeAg positivity, very high levels of HBV DNA, and persistent normal alanine aminotransferase. The international guideline recommendation for patients in this phase is observation without antiviral treatment because of the low risk of disease progression and the lack of effective antiviral agents. However, recent retrospective studies have shown that progression to hepatic fibrosis and hepatocellular carcinoma may occur in patients who are in the immune tolerance phase. Despite the conceptual definition and clinical diagnostic criteria for this phase, it is difficult to accurately diagnose the true immune tolerance phase. Therefore, we should pay attention to the clinical evaluation and interpretation of the immune tolerance phase and understand the clinical situations in which antiviral treatments should be considered.

Cardiac dysfunction associated with cirrhosis in the absence of preexisting heart disease is a condition known as cirrhotic cardiomyopathy (CCM). Cardiac abnormalities consist of enlargement of cardiac chambers, attenuated systolic and diastolic contractile responses to stress stimuli, and repolarization changes. CCM may contribute to cardiovascular morbidity and mortality after liver transplantation and other major surgeries, and also to the pathogenesis of hepatorenal syndrome. The underlying mechanisms of CCM are poorly understood and as such medical therapy is an area of unmet medical need. The present review focuses on the pathogenic mechanisms responsible for development of CCM. The two major concurrent mechanistic pathways are the inflammatory phenotype due to portal hypertension, and protein/lipid synthetic/metabolic defects due to cirrhosis and liver insufficiency. The inflammatory phenotype arises from intestinal congestion due to portal hypertension, resulting in bacteria/endotoxin translocation into the systemic circulation. The cytokine storm associated with inflammation, particularly TNFα acting via NFκB depresses cardiac function. They also stimulate two evanescent gases, nitric oxide and carbon monoxide which produce cardiodepression by cGMP. Inflammation also stimulates the endocannabinoid CB-1 pathway. These systems inhibit the stimulatory beta-adrenergic contractile pathway. The liver insufficiency of cirrhosis is associated with defective synthesis or metabolism of several substances including proteins and lipids/lipoproteins. The protein defects including titin and collagen contribute to diastolic dysfunction. Other protein abnormalities such as a switch of myosin heavy chain isoforms result in systolic dysfunction. Lipid biochemical changes at the cardiac sarcolemmal plasma membrane result in increased cholesterol:phospholipid ratio and decreased membrane fluidity. Final common pathway changes involve abnormal cardiomyocyte intracellular ion kinetics, particularly calcium. In conclusion, cirrhotic cardiomyopathy is caused by two pathways of cellular and molecular dysfunction/damage due to hepatic insufficiency and portal hypertension., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Nguyen, Yoon and Lee.)

Background/aims: Galectin-3 plays a key pathogenic role in cardiac hypertrophy and heart failure. The present study aimed to investigate the effects of galectin-3 on cardiomyopathy - related factors and cardiac contractility in a rat model of cirrhotic cardiomyopathy., Methods: Rats were divided into two sets, one for a functional study, the other for cardiac contractile-related protein evaluation. There were four groups in each set: sham operated and sham plus N-acetyllactosamine (N-Lac, a galectin-3 inhibitor; 5 mg/kg); bile duct ligated (BDL) and BDL plus N-Lac. Four weeks after surgery, ventricular level of galectin-3, collagen I and III ratio, tumor necrosis factor alpha (TNFα), and brain natriuretic peptide (BNP) were measured either by Western blots or immunohistochemistry or enzyme-linked immunosorbent assay. Blood pressure was measured by polygraph recorder. Cardiomyocyte contractility was measured by inverted microscopy., Results: Galectin-3 and collagen I/III ratio were significantly increased in cirrhotic hearts. TNFα and BNP were significantly increased in BDL serum and heart compared with sham controls. Galectin-3 inhibitor significantly decreased galectin-3, TNFα, and BNP in cirrhotic hearts but not in sham controls. N-Lac also significantly improved the blood pressure, and systolic and diastolic cardiomyocyte contractility in cirrhotic rats but had no effect on sham controls., Conclusion: Increased galectin-3 in the cirrhotic heart significantly inhibited contractility via TNFα. Inhibition of galectin-3 decreased the cardiac content of TNFα and BNP and reversed the decreased blood pressure and depressed contractility in the cirrhotic heart. Galectin-3 appears to play a pathogenic role in cirrhotic cardiomyopathy.

Rationale: Most gastric varices at the fundus drain into the left renal vein via the gastrorenal shunt (80-85% of cases) or the inferior vena cava via the gastrocaval shunt (10-15%). Therefore, plug-assisted retrograde transvenous obliteration (PARTO) is usually performed via a gastrorenal shunt. Here, we report a case of gastric varix treated with PARTO via a gastrocaval shunt., Patient Concerns: A 46-year-old woman with hepatitis B virus and liver cirrhosis visited the emergency room in our hospital with the main symptom of hematemesis and hematochezia., Diagnoses: Endoscopy and computed tomography (CT) revealed a gastric varix and thrombotic-occluded transjugular intrahepatic portosystemic shunt (TIPS) stent., Interventions: The patient underwent PARTO via a gastrocaval shunt to manage gastric variceal bleeding after failed TIPS revision., Outcomes: On CT, the gastric varix completely disappeared. The patient did not experience any additional bleeding events., Lessons: PARTO via a gastrocaval shunt is safe and effective., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background/aims: Glecaprevir/pibrentasvir (G/P) is the first pan-genotypic direct-acting antiviral combination therapy approved in Korea. An integrated analysis of five phase II and III trials was conducted to evaluate the efficacy and safety of G/P in Korean patients with chronic hepatitis C virus (HCV) infection., Methods: The study analyzed pooled data on Korean patients with HCV infection enrolled in the ENDURANCE 1 and 2, SURVEYOR II part 4 and VOYAGE I and II trials, which evaluated the efficacy and safety of 8 or 12 weeks of G/P treatment. The patients were either treatment-naïve or had received sofosbuvir or interferon-based treatment. Efficacy was evaluated by assessing the rate of sustained virologic response at 12 weeks posttreatment (SVR12). Safety was evaluated by monitoring adverse events (AEs) and laboratory assessments., Results: The analysis included 265 patients; 179 (67.5%) were HCV treatment-naïve, and most patients were either subgenotype 1B (48.7%) or 2A (44.5%). In the intention-to-treat population, 262 patients (98.9%) achieved SVR12. Three patients did not achieve SVR12: one had virologic failure and two had non-virologic failures. Most AEs were grade 1/2; eight patients (3.0%) experienced at least one grade ≥3 AE. No serious AEs related to G/P treatment were reported, and grade ≥3 hepatic laboratory abnormalities were rare (0.8%)., Conclusions: G/P therapy was highly efficacious and well tolerated in Korean patients with HCV infection, with most patients achieving SVR12. The safety profile was comparable to that observed in a pooled analysis of a global pan-genotypic population of patients with HCV infection who received G/P.

Background and Aims: The influence of direct-acting antivirals (DAAs) on chronic hepatitis C (CHC)-related hepatocellular carcinoma (HCC) remains controversial. We investigated the effect of eradicating CHC using DAAs on treatment outcomes in patients with CHC-related HCC treated with transarterial chemoembolization (TACE)., Methods: This nationwide, multi-center, retrospective study recruited patients with CHC-related HCC treated with TACE as the first-line anti-cancer treatment, and who achieved a sustained virological response (SVR) using DAAs (DAA group) between 2006 and 2017. Patients achieving an SVR following interferon-based treatment (IFN group) and those without treatment (control group) were also recruited for comparison., Results: A total of 425 patients were eligible for the study. Of these, 356 (83.8%), 26 (6.1%), and 43 (10.1%) were allocated to the control, IFN, and DAA groups, respectively. A multivariate analysis showed that liver cirrhosis, segmental portal vein thrombosis, and larger maximal tumor size independently predicted an increased risk of progression (all p < 0.05), whereas, the DAA group (vs. IFN and control groups) independently predicted a reduced risk of progression (hazard ratio (HR) = 0.630, 95% confidence interval 0.411-0.966, p = 0.034). The cumulative incidence rate of HCC progression in the DAA group was significantly lower than that in the IFN and control groups (p = 0.033, log-rank test). In addition, the DAA group (vs. IFN and control groups) was independently associated with a reduced risk of mortality (p = 0.042)., Conclusions: DAA treatment provided significantly prolonged progression-free survival in patients with CHC-related HCC treated with TACE compared to that in patients administered IFN or no treatment.

Nonselective beta-adrenergic blocker (NSBB) therapy for the prevention of initial and recurrent gastrointestinal bleeding in cirrhotic patients with gastroesophageal varices has been used for the past four decades. NSBB therapy is considered the cornerstone of treatment for varices, and has become the standard of care. However, a 2010 study from the group that pioneered β-blocker therapy suggested a detrimental effect of NSBBs in decompensated cirrhosis, especially in patients with refractory ascites. Since then, numerous additional studies have incompletely resolved whether NSBBs are deleterious, although more recent evidence weighs against a harmful effect. The possibility of a "therapeutic window" has also been raised. We aimed to review the literature to analyze the pros and cons of using NSBBs in patients with cirrhosis, not only with respect to bleeding or mortality but also to other potential benefits and risks. β-blockers are highly effective in preventing first bleeding and recurrent bleeding. Furthermore, NSBBs improve congestion/ischemia of the gut mucosa, decrease intestinal permeability, and therefore indirectly alleviate systemic inflammation. β-blockers shorten the electrocardiographic prolonged QTc interval and may also decrease the incidence of hepatocellular carcinoma. On the other hand, the possibility of deleterious effects in cirrhosis has not been completely eliminated. NSBBs may be associated with an increased risk of portal vein thrombosis, although this could be correlational artifact. Overall, we conclude that β-blockers in cirrhosis are much more of a friend than enemy.

Background: The advancement of treatment with direct-acting antiviral (DAA) agents has improved the cure rate of hepatitis C virus (HCV) infection close to 100%. The aim of our study was to assess the real-world effectiveness and safety of DAA regimens for the treatment of patients with chronic HCV genotype 2., Methods: We retrospectively analyzed the clinical data of patients treated with sofosbuvir plus ribavirin (SOF + RBV) or glecaprevir/pibrentasvir (G/P) for chronic HCV genotype 2 infection at seven university hospitals in the Korean southeast region., Results: SOF + RBV therapy produced an 89% and 98.3% sustained virologic response 12 week (SVR12) after treatment completion in the full analysis set and per-protocol set, respectively, and the corresponding values for G/P therapy were 89.5% and 99.2%, respectively. The difference between the treatments was probably because 6.2% (59/953) of patients in the SOF + RBV group did not complete the treatment and 9.8% (14/143) in the G/P group did not test HCV RNA after treatment completion. Adverse events (A/Es) were reported in 59.7% (569/953) and 25.9% (37/143) of the SOF + RBV and G/P groups, respectively. In the SOF + RBV group, 12 (1.26%) patients discontinued treatment owing to A/Es, whereas no patients discontinued treatment because of A/Es in the G/P group., Conclusion: In both treatment groups, SVR was high when treatment was completed. However, there was a high dropout rate in the SOF + RBV group, and the dropout analysis showed that these were patients with liver cirrhosis (LC; 43/285, 15.1%), especially those with decompensated LC (12/32, 37.5%). Therefore, an early initiation of antiviral therapy is recommended for a successful outcome before liver function declines. Furthermore, patients with decompensated LC who are considered candidates for SOF + RBV treatment should be carefully monitored to ensure that their treatment is completed, especially those with low hemoglobin and high alanine transaminase., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Background: Regorafenib has shown promising results as a second-line therapy for patients with hepatocellular carcinoma (HCC) who progressed on sorafenib. Although there have been several data regarding the efficacy of sequential therapy with sorafenib and that of regorafenib in real-life, specific inflammation markers for predicting the prognosis have not been studied. This study aimed to investigate prognostic value of systemic inflammatory markers in patients with HCC who received sorafenib-regorafenib sequential therapy., Methods: We retrospectively analyzed medical data of patients who received regorafenib for the treatment of HCC after sorafenib failure. Progression free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier survival curves. Univariate and multivariate analyses were performed to analyze the factors associated with survival., Results: A total of 58 patients who received at least one dose of regroafenib and fulfilled the eligibility criteria, good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1) and preserved liver function (Child-Pugh-A), were included in the analysis. The median PFS was 3 months (95% confidence interval [CI] = 0.981-5.019) and the median OS was 8 months (95% CI = 5.761-10.239). Elevated systemic immune-inflammation index (SII ≥340) was independently associated with poor OS. In multivariate analysis, the SII (hazard ratio [HR] = 2.211, 95% CI = 1.089-4.489, P = 0.028) and alpha-fetoprotein (AFP) (HR = 2.750, 95% CI = 1.259-6.010, P = 0.011) were independent predictors of OS., Conclusion: Elevated SII is associated with poor OS in patients with HCC who received sequential therapy with sorafenib and regorafenib. In addition, when selecting a treatment strategy, the SII can be used in combination with the AFP level as a promising prognostic tool for HCC.

Background/aims: Glecaprevir/pibrentasvir (G/P) is a combination of direct-acting antiviral agents that is an approved treatment for chronic infections by all six hepatitis C virus (HCV) genotypes. However, there are limited data on the effect of G/P in Korean patients in actual real-world settings. We evaluated the real-life effectiveness and safety of G/P at a single institution in Korea., Methods: This retrospective, observational, cohort study used sustained virologic response at 12 weeks after treatment completion (SVR12) as the primary effectiveness endpoint. Safety and tolerability were also determined., Results: We examined 267 individuals who received G/P for chronic HCV infections. There were 148 females (55.4%), and the overall median age was 63.0 years (range, 25 to 87 years). Eighty-three patients (31.1%) had HCV genotype-1 and 182 (68.2%) had HCV-2. A total of 212 patients (79.4%) were HCV treatment-naïve, 200 (74.9%) received the 8-week treatment, 13 (4.9%) had received prior treatment for hepatocellular carcinoma, 37 (13.7%) had chronic kidney disease stage 3 or higher, and 10 (3.7%) were receiving dialysis. Intention to treat (ITT) analysis indicated that 256 (95.9%) achieved SVR12. A modified ITT analysis indicated that SVR12 was 97.7% (256/262). Six patients failed therapy because of posttreatment relapse. SVR12 was significantly lower in those who received prior sofosbuvir treatment (p=0.002) and those with detectable HCV RNA at week 4 (p=0.027). Seventy patients (26.2%) experienced one or more adverse events, and most of them were mild., Conclusions: These real-life data indicated that G/P treatment was highly effective and well tolerated, regardless of viral genotype or patient comorbidities.

Purpose of Review: Cirrhotic cardiomyopathy (CCM) is a well-recognized entity. When patients with CCM encounter challenges such as liver transplantation, overt cardiac dysfunction manifests, leading to morbidity and mortality. Although revised diagnostic criteria for CCM have recently been proposed, these still need to be validated., Recent Findings: Previous reviews have summarized the mechanisms of CCM, such as abnormalities of the β-adrenergic pathway, cardiac plasma membrane biophysical and biochemical properties, and electrophysiological changes. Cardiomyocyte apoptosis, inflammation, and oxidative stress also play important roles. The present review details further mechanisms of CCM, which include myosin heavy chain isoform shifts and abnormalities in cellular calcium transients. Additionally, we review recent studies on therapeutic strategies. Recent work underscores the importance of CCM in the natural history of the immediate and medium-term postoperative period after liver transplantation. Appropriate management strategies for CCM remain the area of greatest unmet need, requiring much further research., Summary: CCM is a clinically relevant syndrome affecting patients with cirrhosis, leading to increased morbidity and mortality. New diagnostic criteria have been recently proposed by an expert working group. The pathogenic mechanisms remain incompletely clarified and optimal management strategies need much further study., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aims: Several studies have shown that colorectal neoplasms (CRN) including colorectal cancer (CRC) may be prevalent in patients with gastric cancer. However, in most of these studies, colonoscopy to investigate the prevalence of CRN was performed prior to surgery. We aimed to investigate whether CRN was more prevalent in postgastrectomy gastric cancer patients than in healthy individuals., Methods: We reviewed the medical records of those patients within a cohort of gastric cancer patients with gastrectomy who underwent colonoscopy between 2016 and 2017. Controls age- and sex-matched with gastric cancer patients at a 2:1 ratio were identified among those who underwent colonoscopy at a health-promotion center. The frequencies of CRN, advanced CRN (ACRN), and CRC among patients with gastrectomy were compared with those in the control subjects. A total of 744 individuals (gastric cancer, 248; control, 496) were included., Results: The rates of CRN and ACRN in the gastric cancer group were higher than those in the healthy individuals (CRN, 47.6% vs. 34.7%, P< 0.001; ACRN, 16.9% vs. 10.9%, P= 0.020). The rate of CRC was comparable between the 2 groups (2.0% vs. 0.6%, P= 0.125). Multivariate analysis identified previous gastrectomy for gastric cancer and male sex as significant risk factors for (A)CRN., Conclusions: CRN and ACRN were more prevalent in patients who underwent surgery for gastric cancer than in the control group. Regular surveillance colonoscopy at appropriate intervals is indicated after gastrectomy.

Purpose: Alpha-fetoprotein (AFP) is a prognostic marker for hepatocellular carcinoma (HCC). We investigated the prognostic value of AFP levels in patients who achieved complete response (CR) to transarterial chemoembolization (TACE) for HCC., Materials and Methods: Between 2005 and 2018, 890 patients with HCC who achieved a CR to TACE were recruited. An AFP responder was defined as a patient who showed elevated levels of AFP (>10 ng/mL) during TACE, but showed normalization or a >50% reduction in AFP levels after achieving a CR., Results: Among the recruited patients, 569 (63.9%) with naïve HCC and 321 (36.1%) with recurrent HCC after complete resection were treated. Before TACE, 305 (34.3%) patients had multiple tumors, 219 (24.6%) had a maximal tumor size >3 cm, and 22 (2.5%) had portal vein tumor thrombosis. The median AFP level after achieving a CR was 6.36 ng/mL. After a CR, 473 (53.1%) patients experienced recurrence, and 417 (46.9%) died [median progression-free survival (PFS) and overall survival (OS) of 16.3 and 62.8 months, respectively]. High AFP levels at CR (>20 ng/mL) were independently associated with a shorter PFS [hazard ratio (HR)=1.403] and OS (HR=1.284), together with tumor multiplicity at TACE (HR=1.518 and 1.666, respectively). AFP non-responders at CR (76.2%, n=359 of 471) showed a shorter PFS (median 10.5 months vs. 15.5 months, HR=1.375) and OS (median 41.4 months vs. 61.8 months, HR=1.424) than AFP responders (all p =0.001)., Conclusion: High AFP levels and AFP non-responders were independently associated with poor outcomes after TACE. AFP holds clinical implications for detailed risk stratification upon achieving a CR after TACE., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2021.)

Nonsteroidal anti-inflammatory drugs (NSAID) are some of the most commonly prescribed medications in clinical practice. The long-term use of NSAIDs is one of the main causes of peptic ulcers and the increased risk of upper gastrointestinal tract complications, such as perforation and bleeding. Thus, the prevention of NSAID-induced peptic ulcers is an important clinical issue. Previous studies have evaluated various strategies for preventing ulcers in patients requiring prolonged NSAID use. The Korean clinical practice guidelines have been published recently based on the evidence of the currently available data. This review describes the strategies for the prevention of peptic ulcers due to NSAID. An assessment of the risk factors for peptic ulcers from NSAID is recommended to identify patients who should be considered for primary prophylaxis. The risk of NSAID-induced peptic ulcers can be reduced by the concomitant use of proton pump inhibitors (PPI), misoprostol, and histamine-2 receptor antagonists. Selective cyclooxygenase-2 inhibitors can be used with caution due to concerns regarding cardiovascular toxicity. Attempts should be made to use the lowest dose and shortest duration of the NSAID.

Background: Hand-foot skin reaction (HFSR) is the most common adverse event during sorafenib treatment in patients with hepatocellular carcinoma (HCC). In the present study, we aimed to investigate the role of urea cream in the prevention of HFSR or amelioration of HFSR severity., Patients and Methods: Patients with HCC were treated with either placebo cream or urea cream for 12 weeks concomitantly with sorafenib treatment. HFSR development, the Hand-Foot Skin Reaction and Quality of Life (HF-QoL) questionnaire score, and adverse events were assessed at 2, 4, 8 and 12 weeks., Results: Of the 288 patients, 247 patients, with 117 patients in the placebo control group and 130 patients in the urea cream group, were analysed. The urea cream group showed a trend towards a lower cumulative incidence of any-grade HFSR (log-rank, P = 0.247) and severe HFSR of grade II or higher (log-rank, P = 0.394) without statistical significance. In the incidence by time point, the incidence of severe HFSR of grade II or higher was significantly lower in the urea cream group than in the placebo control group at 2 weeks (13.8% versus 23.9%, P = 0.042). The urea cream group showed a significantly better HF-QoL questionnaire score than the placebo control group (11.8 versus 19.7, P = 0.014) at 12 weeks., Conclusions: Treatment with urea cream showed a lower incidence of severe sorafenib-induced HFSR at 2 weeks and reduced the tendency of HFSR development in HCC patients. Therefore, treatment with urea cream may be considered for prophylaxis or improvement of HFSR grade in HCC patients treated with sorafenib., Trial Registration: ClinicalTrials.gov (NCT03212625)., Competing Interests: Conflict of interest statement Ji Hoon Kim received funding from the Korea Liver Cancer Association and Hanmi Pharmacy. Other authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Since volar locking plates (VLPs) have the benefits of more stable fixation and fewer complications, VLP osteosynthesis is now the preferred osteosynthesis method in the operative management of distal radius fractures (DRF). Along with the increases in operative management of VLP, the character and frequency of complications have changed. Thus, this multicentre study aimed to identify the characteristics of patients with DRFs who were treated with VLP fixation, describe the complication types and rates related to the procedure, and compare the results with those found in the literature., Material and Methods: This retrospective multicentre study was conducted between January 2008 and December 2017. In total, data from 2225 patients over 17 years old who underwent VLP fixation for DRF were screened. Patients with closed reduction and pinning, external fixation, dorsal plate fixation, and screw-only fixation were excluded. Finally, 1955 wrists from 1921 patients (86.3%) were included. The following types of complications were investigated: (1) tendon injury, (2) nerve-related, (3) fixation- and instrument-related, (4) osteosynthesis-related, (5) infection, and (6) others., Results: The mean age of the patients was 60.3 ± 14.6 years with 587 males (30.6%). Distal ulnar fractures were found in 940 wrists (48.1%). The mean interval between fracture and surgery was 6.2 days, while the mean operative time was 68.3 ± 30.3 minutes. The following complications were found: (1) nine (0.46%) and 12 (0.61%) cases of flexor pollicis longus and complete extensor pollicis longus tears, respectively; (2) nine cases (0.46%) of palmar sensory median nerve branch damage, 15 cases (0.77%) of complex regional pain syndrome, and 36 cases (1.84%) of carpal tunnel syndrome; (3) five cases (0.26%) of fracture displacement even after plate fixation, six cases (0.31%) of screw breakage, 26 cases (1.33%) of radiocarpal joint screw penetration, and 511 cases (26.14%) of implant removal; (4) five cases (0.26%) of delayed union and three cases (0.15%) of non-union; (5) 83 (4.25%) and two (0.1%) cases of superficial and deep infection, respectively; and (6) two cases (0.1%) of compartment syndrome and three cases (0.15%) of radial artery damage., Conclusions: After 10 years of experience performing VLP fixation for DRFs in a multicentre setting, the results regarding complication types and rates support its use as a reasonable treatment option with low rates of complication.

Background: Hepatocellular carcinoma (HCC) is an inflammation-related cancer, where nonresolving inflammation contributes to its development and progression. Peripheral inflammatory cells have been shown to be associated with the prognosis of various types of cancer. The present study investigated the utility of pretreatment peripheral inflammatory cells in the prognosis of patients with HCC., Methods: We retrospectively analyzed data regarding peripheral inflammatory cell, and patient and tumor characteristics from patients with HCC who were diagnosed between November 2008 and March 2018. Baseline data, including peripheral inflammatory cell counts, were recorded before treatment. The relationships between overall survival (OS) and study variables were assessed., Results: A total of 1681 patients who were diagnosed with HCC were included. In univariate and multivariate analyses, individual neutrophil, lymphocyte and monocyte cell counts were found as independent indicators of poor OS. High neutrophil (≥3100 × 10 6 /L) and, monocyte (≥470 × 10 6 /L) counts and low lymphocyte counts (< 1640 × 10 6 /L) significantly associated with reduced OS (p < 0.05). Neutrophil and, monocyte cell counts rose and lymphocyte counts decreased in association with advancing the Barcelona Clinic Liver Cancer stage (P < 0.001)., Conclusions: Pretreatment peripheral neutrophils, lymphocytes, and monocytes are independently associated with outcomes of patients with HCC. These cells provides a noninvasive, low-cost, easy, and reproducible biomarker that can be used in routine clinical practice to predict the prognosis of patients with HCC.

Background and Aims: All published meta-analyses failed to demonstrate that preoperative transarterial chemoembolization improves the clinical outcomes of patients with resectable hepatocellular carcinoma. The present study aimed to investigate the utility of systemic inflammatory cells as a tumor biology marker predicting therapeutic benefit of neoadjuvant transarterial chemoembolization in patients with resectable hepatocellular carcinoma., Materials and Methods: We retrospectively investigated 441 hepatocellular carcinoma patients who underwent curative resection. Among 441 patients, 73 patients underwent preoperative transarterial chemoembolization, and 368 patients did not. We compared recurrence-free survival and overall survival between transarterial chemoembolization plus sequential resection group and resection only group. We analyzed whether pretreatment neutrophil-lymphocyte ratio demonstrates survival benefit in each groups., Results: No significant difference was observed in recurrence-free or overall survival between both groups. In the transarterial chemoembolization plus sequential resection group, the 5-year overall survival in patients with high neutrophil-lymphocyte ratio (≥1.6) was significantly lower than that in patients with low neutrophil-lymphocyte ratio (78.4% and 100%, P = 0.027). High neutrophil-lymphocyte ratio was associated with vascular invasion (P = 0.033)., Conclusion: Neutrophil-lymphocyte ratio can be considered as a predictive factor of long-term survival and used to identify patients with resectable hepatocellular carcinoma who benefit from neoadjuvant transarterial chemoembolization.

Purpose of Review: Cirrhotic cardiomyopathy is a syndrome of depressed cardiac function in patients with cirrhosis. We aimed to review the historical background, pathophysiology and pathogenesis, diagnostic definitions, clinical relevance, and management of this syndrome., Recent Findings: An inflammatory phenotype underlies the pathogenesis: gut bacterial translocation with endotoxemia stimulates cytokines and cardiodepressant factors, such as nitric oxide and endocannabinoids. Cardiomyocyte plasma membrane biochemical and biophysical changes also play a pathogenic role. These factors lead to impaired beta-adrenergic function. Proposed new echocardiographic criteria for the diagnosis of cirrhotic cardiomyopathy include systolic global longitudinal strain and indices of diastolic dysfunction. Cardiac dysfunction participates in the pathogenesis of hepatorenal syndrome and increased morbidity/mortality of cirrhotic patients to hemorrhage, infection, and surgery, including liver transplantation. There is no specific treatment, although β-adrenergic blockade and supportive management have been proposed, but it needs further study. Cirrhotic cardiomyopathy is a clinically relevant syndrome afflicting patients with established cirrhosis. Optimum management remains unclear, and further study is needed in this area.

Background and Aims: ARC-520, the first an RNA interference (RNAi) therapeutic, was designed to reduce all RNA transcripts derived from covalently closed circular DNA, leading to a reduction in viral antigens and hepatitis B virus (HBV) DNA., Approach and Results: We aimed to evaluate the depth of hepatitis B surface antigen (HBsAg) decline in response to multiple doses of ARC-520 compared to placebo (PBO) in two randomized, multicenter studies in nucleoside/nucleotide analogue reverse-transcriptase inhibitor (NUC)-experienced patients with hepatitis B early antigen (HBeAg)-negative (E-neg) or HBeAg-positive (E-pos) disease. A total of 58 E-neg and 32 E-pos patients were enrolled and received four monthly doses of PBO (n = 20 E-neg, 11 E-pos), 1 mg/kg ARC-520 (n = 17 E-neg, 10 E-pos), or 2 mg/kg ARC-520 (n = 21 E-neg, 11 E-pos) concomitantly with NUC. HBsAg change from baseline to 30 days after the last ARC-520 dose were compared to PBO. Both E-neg and E-pos high-dose groups significantly reduced HBsAg compared to PBO, with mean reductions of 0.38 and 0.54 log IU/mL, respectively. HBsAg reductions persisted for approximately 85 days and >85 days after the last dose in E-neg and E-pos patients, respectively. The low-dose groups did not reach statistical significance in either study. E-pos patients showed a dose-dependent reduction in HBeAg from baseline. Mean maximum reduction was 0.23 and 0.69 log Paul Ehrlich IUs/mL in the low-dose and high dose ARC-520 groups respectively. ARC-520 was well tolerated, with only two serious adverse events of pyrexia possibly related to study drug observed., Conclusions: ARC-520 was active in both E-neg and E-pos, NUC-experienced HBV patients; but absolute HBsAg reductions were moderate, possibly due to expression of HBsAg from integrated HBV DNA, indicating the need for RNAi therapeutics that can target viral transcripts regardless of origin., (© 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

Background: The Milan criteria (MC) used to select patients for liver transplantation among patients with hepatocellular carcinoma (HCC) do not include tumor biology. Furthermore, systemic inflammatory markers have been identified to predict tumor biology. The present study investigated prognostic value of systemic inflammatory markers, including neutrophil count, in predicting the prognosis of patients with HCC undergoing living donor liver transplantation (LDLT)., Methods: We retrospectively analyzed data regarding peripheral blood inflammatory markers, as well as patient and tumor characteristics of patients with HCC who underwent LDLT. Univariate and multivariate analyses were performed to analyze variables associated with survival., Results: A total of 103 patients with HCC who underwent LDLT were included. The 3- and 5-year recurrence-free survival (RFS) in patients with a high neutrophil count (>2,640/µL) were significantly lower than those in patients with a low neutrophil count (≤2,640/µL; 70.0% and 64.7% vs. 88.3% and 84.6%, respectively; P=0.02). Patients with a high neutrophil count also had lower 5-year overall survival (OS; 63.9% vs. 79.3%, P=0.03). In multivariate analysis, radiologic MC (hazard ratio [HR], 5.04; P=0.02) and neutrophil count (HR, 4.47; P=0.04) were independent factors predicting RFS. Among patients exceeding the MC, those with a high neutrophil count had significantly lower 5-year RFS than those with low neutrophil count (10% vs. 83%; P<0.01)., Conclusions: We demonstrated that high preoperative neutrophil count is associated with poor RFS and OS in patients with HCC undergoing LDLT., (© 2020 The Korean Society for Transplantation.)

Hepatitis B virus (HBV) suppression with nucleot(s)ide analogue therapy reduces the risk of hepatic decompensation and hepatocellular carcinoma (HCC) in patients with advanced liver disease. 1 In the present era of potent antiviral therapies, the prognostic significance of the serum HBV DNA level as a biological gradient has substantially diminished; the majority of treated patients achieve virologic suppression. 2,3 After control of viremia, a higher baseline fibrosis level is a useful predictor for disease progression. 4 Few "prospective" studies on the effects of antiviral agents, especially in chronic hepatitis B (CHB) patients with advanced liver disease, have been reported., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Although sorafenib is the first systemic therapy to show survival benefit for advanced hepatocellular carcinoma (HCC), its survival benefit is variable for HCC. Systemic inflammation may be associated with survival in HCC. We investigated the use of systemic inflammation markers, including neutrophil-to-lymphocyte ratio (NLR), in the prognosis of sorafenib-treated HCC patients., Patients and Methods: We retrospectively analyzed data of 82 patients with advanced HCC who received sorafenib as the first-line treatment. Data on pretreatment and post-treatment (2-3 months after initiating sorafenib therapy, first tumor response evaluation day) clinical, laboratory, and tumor characteristics were collected. Survival-related prognostic factors were analyzed., Results: Patients were mostly in the intermediate (12.2%) or advanced (87.8%) Barcelona Clinic Liver Cancer stages. Fifty-six (68.3%) patients had vascular invasion and 34 (41.5%) patients had extrahepatic disease. The median progression-free survival (PFS) and overall survival (OS) were 4.7 months [95% confidence interval (CI): 2.8-6.5 months] and 4.7 months (95% CI: 2.8-6.5 months). In multivariate analysis for OS, diarrhea (hazard ratio: 0.588; 95% CI: 0.348-0.993) and NLR decline (decreased compared with pretreatment) (hazard ratio: 0.479; 95% CI: 0.300-0.765) were independent factors of good OS. In the NLR decline group, the median PFS and OS were 7.1 and 7.3 months, respectively. In the NLR nondecline group, the median PFS and OS were 3.0 and 3.2 months, respectively. The difference in OS between the two groups was significant (P = 0.004)., Conclusion: A change in NLR after sorafenib therapy was associated with a better prognosis in patients with advanced HCC.

Background & Aims: There are no globally agreed upon treatment guidelines for patients with chronic hepatitis B virus (HBV) with multidrug resistance (MDR). We conducted a multicenter, prospective, real-world cohort study of effects of tenofovir disoproxyl fumarate (TDF) monotherapy and TDF-based combination therapy, as rescue therapy, in patients with multidrug-resistant chronic HBV infections., Methods: We recruited patients with chronic HBV infection with resistance to antivirals from 8 tertiary hospitals in Korea. Patients (n=423) received rescue therapy with TDF monotherapy (n=174) or TDF-based combination therapy (n=249). The median follow-up period was 180 weeks. A virologic response was defined as a serum HBV DNA level of <20 IU/mL., Results: Cumulative rates of virologic response did not differ significantly between the groups that received TDF monotherapy vs combination therapy at 48 weeks (71.7% vs 68.9%), 96 weeks (85.1% vs 84.2%), 144 weeks (92.1% vs 92.7%), 192 weeks (93.4% vs 95.7%), or 240 weeks (97.7% vs 97.2%). Serum levels of HBV DNA below 4.0 log 10 IU/mL (odds ratio, 2.478; 95% CI 1.959-3.135; P < .001) and the absence of mutations associated with resistance to adefovir (odds ratio, 1.570; 95% CI 1.279-1.926; P < .001) were associated with virologic response in patients with MDR. There was no significant difference of virologic response among patients of different ages, sex, patients with vs without cirrhosis, positivity for hepatitis B e antigen, or renal function (all P > .05)., Conclusion: In a multicenter, real-world cohort study, long-term use of TDF monotherapy showed non-inferior antiviral efficacy compared with that of TDF-based combination therapy in patients with MDR., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: Infected lateral malleolar bursitis occurring as a diabetic complication requires debridement and flap surgery because it cannot be treated by conservative methods. The most accessible flap is the reverse sural artery flap, which can be harvested as a fasciocutaneous flap or an adipofascial flap. The purpose of this study was to compare the two types of flap methods performed in patients with diabetic infected lateral malleolar bursitis., Methods: Twenty-nine cases of diabetic infected lateral malleolar bursitis treated with reverse sural artery flap between 2006 and 2017 were analyzed retrospectively. Fasciocutaneous flap methods were performed in 15 cases (group A), and adipofascial flap methods were performed in 14 cases (group B). Patients in the two groups did not differ in sex or age. The mean follow-up period was 16 months., Results: All flaps survived. Infection was controlled at a mean of 2.4 months in both groups. At final follow-up, infection recurred in one case of each group, which was treated with antibiotics. No case developed an ulcer in the flaps. The patients were able to ambulate in regular shoes. All but one of the patients (28 patients) expressed satisfaction with the aesthetic appearance following treatment. No case required a debulking operation., Conclusion: Both the fasciocutaneous and adipofascial methods for reverse sural artery flaps were shown to be viable options for the control of diabetic lateral infection. In addition, the two groups did not differ in terms of appearance or complication rate following treatment.

Background: Until now, various types of combined therapy with nucleotide analogs and pegylated interferon (Peg-INF) in patients with hepatitis B patients have been tried. However, studies regarding the benefits of de novo combination, late-add on, and sequential treatment are very limited. The objective of the current study was to identify the efficacy of sequential treatment of Peg-INF after short-term antiviral treatment., Methods: Between June 2010 and June 2015, hepatitis B e antigen (HBeAg)-positive patients (n = 162) received Peg-IFN for 48 weeks (mono-treatment group, n = 81) and entecavir (ETV) for 12 weeks with a 48-week course of Peg-IFN starting at week 5 of ETV therapy (sequential treatment group, n = 81). The primary endpoint was HBeAg seroconversion at the end of follow-up period after the 24-week treatment. The primary endpoint was analyzed using Chi-square test, Fisher's exact test, and regression analysis., Results: HBeAg seroconversion rate (18.2% vs. 18.2%, t = 0.03, P = 1.000) and seroclearance rate (19.7% vs. 19.7%, t = 0.03, P = 1.000) were same in both mono-treatment and sequential treatment groups. The rate of alanine aminotransferase (ALT) normalization (45.5% vs. 54.5%, t = 1.12, P = 0.296) and serum hepatitis B virus (HBV)-DNA <2000 U/L (28.8% vs. 28.8%, t = 0.10, P = 1.000) was not different in sequential and mono-treatment groups at 24 weeks of Peg-INF. Viral response rate (HBeAg seroconversion and serum HBV-DNA <2000 U/L) was not different in the two groups (12.1% vs. 16.7%, t = 1.83, P = 0.457). Baseline HBV-DNA level (7 log 10 U/ml vs. 7.5 log 10 U/ml, t = 1.70, P = 0.019) and hepatitis B surface antigen titer (3.6 log 10 U/ml vs. 4.0 log 10 U/ml, t = 2.19, P = 0.020) were lower and predictors of responder in mono-treatment and sequential treatment groups, respectively., Conclusions: The current study shows no differences in HBeAg seroconversion rate, ALT normalization, and HBV-DNA levels between mono-therapy and sequential therapy regimens., Trial Registration: ClinicalTrials.gov, NCT01220596; https://clinicaltrials.gov/ct2/show/NCT01220596?term=NCT01220596&rank=1., Competing Interests: There are no conflicts of interest

Background & Aims: Tenofovir alafenamide (TAF) is a new prodrug of tenofovir developed to treat patients with chronic hepatitis B virus (HBV) infection at a lower dose than tenofovir disoproxil fumarate (TDF) through more efficient delivery of tenofovir to hepatocytes. In 48-week results from two ongoing, double-blind, randomized phase III trials, TAF was non-inferior to TDF in efficacy with improved renal and bone safety. We report 96-week outcomes for both trials., Methods: In two international trials, patients with chronic HBV infection were randomized 2:1 to receive 25 mg TAF or 300 mg TDF in a double-blinded fashion. One study enrolled HBeAg-positive patients and the other HBeAg-negative patients. We assessed efficacy in each study, and safety in the pooled population., Results: At week 96, the differences in the rates of viral suppression were similar in HBeAg-positive patients receiving TAF and TDF (73% vs. 75%, respectively, adjusted difference -2.2% (95% CI -8.3 to 3.9%; p = 0.47), and in HBeAg-negative patients receiving TAF and TDF (90% vs. 91%, respectively, adjusted difference -0.6% (95% CI -7.0 to 5.8%; p = 0.84). In both studies the proportions of patients with alanine aminotransferase above the upper limit of normal at baseline, who had normal alanine aminotransferase at week 96 of treatment, were significantly higher in patients receiving TAF than in those receiving TDF. In the pooled safety population, patients receiving TAF had significantly smaller decreases in bone mineral density than those receiving TDF in the hip (mean % change -0.33% vs. -2.51%; p <0.001) and lumbar spine (mean % change -0.75% vs. -2.57%; p <0.001), as well as a significantly smaller median change in estimated glomerular filtration rate by Cockcroft-Gault method (-1.2 vs. -4.8 mg/dl; p <0.001)., Conclusion: In patients with HBV infection, TAF remained as effective as TDF, with continued improved renal and bone safety, two years after the initiation of treatment. Clinicaltrials.gov number: NCT01940471 and NCT01940341., Lay Summary: At week 96 of two ongoing studies comparing the efficacy and safety of tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B patients, TAF continues to be as effective as TDF with continued improved renal and bone safety. Registration: Clinicaltrials.gov number: NCT01940471 and NCT01940341., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aim: This multinational (Taiwan, South Korea, Russia) phase 3 study evaluated the all-oral, ribavirin-free, fixed-dose combination (DCV-TRIO) of daclatasvir (NS5A inhibitor) 30 mg, asunaprevir (NS3 inhibitor) 200 mg, and beclabuvir (NS5B inhibitor) 75 mg, in patients with chronic hepatitis C virus genotype-1 infection, with or without compensated cirrhosis., Methods: UNITY-4 (NCT02170727) was an open-label, two-cohort study in which 169 patients, treatment-naive (n = 138) or treatment-experienced (n = 31), received twice-daily DCV-TRIO for 12 weeks with 24 weeks of post-treatment follow-up. The primary efficacy end point was sustained virologic response at post-treatment week 12 (SVR12) in treatment-naive patients., Results: Eighty-eight (52%) patients were men, 81 (48%) Taiwanese, 78 (46%) Korean, and 10 (6%) Russian; 23 (14%) had compensated cirrhosis, and 52 (31%) were IL28B (rs1297860) non-CC genotype. Baseline resistance-associated NS5A polymorphisms (L31 and/or Y93) were detected in 25/165 (15%) patients with available genotype-1 sequencing data. SVR12 was achieved by 98.6% (136/138; 95% confidence interval: 94.9-99.8%) of treatment-naive and 100% (31/31; 95% confidence interval: 88.8-100%) of treatment-experienced patients. Both virologic failures were found to be infected with hepatitis C virus genotype-6g; 100% SVR12 was observed for genotype-1a (n = 8) and genotype-1b (n = 157). Two patients experienced serious adverse events. Eight (5%) patients experienced reversible grade 3/4 alanine aminotransferase or aspartate aminotransferase elevations, leading to discontinuation in four (2%); all achieved SVR12. There were no grade 3/4 total bilirubin increases and no deaths., Conclusions: Twelve weeks of DCV-TRIO was well tolerated and provided 100% SVR12 in treatment-naive and treatment-experienced patients with genotype-1 infection, with or without cirrhosis, including those with baseline NS5A-L31 or NS5A-Y93 resistance-associated substitutions., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)