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BACKGROUND AND AIM Besifovir dipivoxil maleate (BSV) was reported to have comparable antiviral efficacy and superior renal and bone safety to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. The present study aims to evaluate changes of liver histology and intrahepatic covalently closed circular DNA (cccDNA) levels by BSV treatment in comparison with TDF therapy. METHODS This is a subset study of the phase 3 trial comparing BSV with TDF. Among them, only CHB patients willing to participate in a histologic evaluation study were enrolled. Liver histologic examination and intrahepatic cccDNA quantification were performed. RESULTS A total of 46 CHB patients received liver biopsies (BSV, n = 29; TDF, n = 17). After 48 weeks of treatment, virological response rate was comparable between the groups (P = 0.707). Follow-up liver biopsies showed that necroinflammation was significantly improved in the both groups. However, the histological response rate defined as the proportion of subjects whose modified histologic activity index score decreased by ≥ 2 without deterioration in fibrosis was higher in the BSV group than in the TDF group (77.8% vs 36.4%, P = 0.048). The proportion of subjects with Ishak fibrosis score 3 or more decreased from 77.7% to 55.5% in the BSV and that decreased from 72.7% to 45.4% in the TDF group. The intrahepatic cccDNA significantly decreased from baseline after 48 weeks of BSV or TDF treatment (P

Purpose: To assess patient radiation doses during diagnostic and therapeutic neurointerventional procedures from multiple centers and propose dose reference level (RL).Materials and Methods: Consecutive neurointerventional procedures, performed in 22 hospitals from December 2020 to June 2021, were retrospectively studied. We collected data from a sample of 429 diagnostic and 731 therapeutic procedures. Parameters including dose-area product (DAP), cumulative air kerma (CAK), fluoroscopic time (FT), and total number of image frames (NI) were obtained. RL were calculated as the 3rd quartiles of the distribution.Results: Analysis of 1160 procedures from 22 hospitals confirmed the large variability in patient dose for similar procedures. RLs in terms of DAP, CAK, FT, and NI were 101.6 Gy·cm2, 711.3 mGy, 13.3 minutes, and 637 frames for cerebral angiography, 199.9 Gy·cm2, 3,458.7 mGy, 57.3 minutes, and 1,000 frames for aneurysm coiling, 225.1 Gy·cm2, 1,590 mGy, 44.7 minutes, and 800 frames for stroke thrombolysis, 412.3 Gy·cm2, 4,447.8 mGy, 99.3 minutes, and 1,621.3 frames for arteriovenous malformation (AVM) embolization, respectively. For all procedures, the results were comparable to most of those already published. Statistical analysis showed male and presence of procedural complications were significant factors in aneurysmal coiling. Male, number of passages, and procedural combined technique were significant factors in stroke thrombolysis. In AVM embolization, a significantly higher radiation dose was found in the definitive endovascular cure group.Conclusion: Various RLs introduced in this study promote the optimization of patient doses in diagnostic and therapeutic interventional neuroradiology procedures. Proposed 3rd quartile DAP (Gy·cm2) values were 101.6 for diagnostic cerebral angiography, 199.9 for aneurysm coiling, 225.1 for stroke thrombolysis, and 412.3 for AVM embolization. Continual evolution of practices and technologies requires regular updates of RLs.

Liver-gut communication is vital in fatty liver diseases, and gut microbes are the key regulators in maintaining liver homeostasis. Chronic alcohol abuse and persistent overnutrition create dysbiosis in gut ecology, which can contribute to fatty liver disease. In this review, we discuss the gut microbial compositional changes that occur in alcoholic and nonalcoholic fatty liver diseases and how this gut microbial dysbiosis and its metabolic products are involved in fatty liver disease pathophysiology. We also summarize the new approaches related to gut microbes that might help in the diagnosis and treatment of fatty liver disease.

Acute-on-chronic liver failure (ACLF) is a rapidly progressive illness with high short-term mortality. Timely liver transplant (LT) may improve survival. We evaluated various indices for assessment of the severity of liver failure and their application for eligibility and timing of living donor LT (LDLT). Altogether 1021 patients were analyzed for the severity and organ failure at admission to determine transplant eligibility and 28 day survival with or without transplant. The ACLF cohort [mean age 44 ± 12.2 years, males 81%) was of sick patients; 55% willing for LT at admission, though 63% of them were ineligible due to sepsis or organ failure. On day 4, recovery in sepsis and/or organ failure led to an improvement in transplant eligibility from 37% at baseline to 63.7%. Delay in LT up to 7 days led to a higher incidence of multiorgan failure (p

OBJECTIVE Hyperattenuation on CT scanning performed immediately after endovascular treatment (EVT) is known to be associated with the final infarct. As flat-panel CT (FPCT) scanning is readily accessible within their angiography suite, the authors evaluated the ability of the extent of hyperattenuation on FPCT to predict clinical outcomes after EVT. METHODS Patients with successful recanalization (modified Thrombolysis in Cerebral Infarction grade 2b or 3) were reviewed retrospectively. The extent of hyperattenuation was assessed by the Alberta Stroke Program Early CT Score on FPCT (FPCT-ASPECTS). FPCT-ASPECTS findings were compared according to functional outcome and malignant infarction. The predictive power of the FPCT-ASPECTS with initial CT images before EVT (CT-ASPECTS) and follow-up diffusion-weighted images (MR-ASPECTS) was also compared. RESULTS A total of 235 patients were included. All patients were treated with mechanical thrombectomy, and 45.5% of the patients received intravenous tissue plasminogen activator. The mean (± SD) time from stroke onset to recanalization was 383 ± 290 minutes. The FPCT-ASPECTS was significantly different between patients with a favorable outcome and those without (mean 9.3 ± 0.9 vs 6.7 ± 2.6) and between patients with malignant infarction and those without (3.4 ± 2.9 vs 8.8 ± 1.4). The FPCT-ASPECTS was an independent factor for a favorable outcome (adjusted OR 3.28, 95% CI 2.12–5.01) and malignant infarction (adjusted OR 0.42, 95% CI 0.31–0.57). The area under the curve (AUC) of the FPCT-ASPECTS for a favorable outcome (0.862, cutoff ≥ 8) was significantly greater than that of the CT-ASPECTS (0.637) (p < 0.001) and comparable to that of the MR-ASPECTS (0.853) (p = 0.983). For malignant infarction, the FPCT-ASPECTS was also more predictive than the CT-ASPECTS (AUC 0.906 vs 0.552; p = 0.001) with a cutoff of ≤ 5. CONCLUSIONS The FPCT-ASPECTS was highly predictive of clinical outcomes in patients with successful recanalization. FPCT could be a practical method to immediately predict clinical outcomes and thereby aid in acute management after EVT.

Rationale Very early stage blood pressure (BP) levels may affect outcome in stroke patients who have successfully undergone recanalization following intra-arterial treatment, but the optimal target of BP management remains uncertain. Aim We hypothesized that the clinical outcome after intensive BP-lowering is superior to conventional BP control after successful recanalization by intra-arterial treatment. Sample-size estimates We aim to randomize 668 patients (334 per arm), 1:1. Methods and design We initiated a multicenter, prospective, randomized, open-label trial with a blinded end-point assessment (PROBE) design. After successful recanalization (thrombolysis in cerebral infarction score ≥ 2 b), patients with elevated systolic BP level, defined as the mean of two readings ≥ 140 mmHg, will be randomly assigned to the intensive BP-lowering (systolic BP Study outcomes The primary efficacy outcomes are from dichotomized analysis of modified Rankin Scale (mRS) scores at three months (mRS scores: 0–2 vs. 3–6). The primary safety outcomes are symptomatic intracerebral hemorrhage and death within three months. Discussion The OPTIMAL-BP trial will provide evidence for the effectiveness of active BP control to achieve systolic BP Clinical trial registration ClinicalTrials.gov Identifier: NCT04205305.

We evaluated the dynamics of hepatic encephalopathy (HE) and ammonia estimation in acute-on-chronic liver failure (ACLF) patients due to a paucity of evidence. ACLF patients recruited from the APASL-ACLF Research Consortium (AARC) were followed up till 30 days, death or transplantation, whichever earlier. Clinical details, including dynamic grades of HE and laboratory data, including ammonia levels, were serially noted. Of the 3009 ACLF patients, 1315 (43.7%) had HE at presentation; grades I–II in 981 (74.6%) and grades III–IV in 334 (25.4%) patients. The independent predictors of HE at baseline were higher age, systemic inflammatory response, elevated ammonia levels, serum protein, sepsis and MELD score (p

Multiple predictive models of mortality exist for acute-on-chronic liver failure (ACLF) patients that often create confusion during decision-making. We studied the natural history and evaluated the performance of prognostic models in ACLF patients.Prospectively collected data of ACLF patients from APASL-ACLF Research Consortium (AARC) was analyzed for 30-day outcomes. The models evaluated at days 0, 4, and 7 of presentation for 30-day mortality were: AARC (model and score), CLIF-C (ACLF score, and OF score), NACSELD-ACLF (model and binary), SOFA, APACHE-II, MELD, MELD-Lactate, and CTP. Evaluation parameters were discrimination (c-indices), calibration [accuracy, sensitivity, specificity, and positive/negative predictive values (PPV/NPV)], Akaike/Bayesian Information Criteria (AIC/BIC), Nagelkerke-RThirty-day survival of the cohort (n = 2864) was 64.9% and was lowest for final-AARC-grade-III (32.8%) ACLF. Performance parameters of all models were best at day 7 than at day 4 or day 0 (p 0.05 for C-indices of all models except NACSELD-ACLF). On comparison, day-7 AARC model had the numerically highest c-index 0.872, best accuracy 84.0%, PPV 87.8%, RAPASL-ACLF is often a progressive disease, and models assessed up to day 7 of presentation reliably predict 30-day mortality. Day-7 AARC model is a statistically robust tool for classifying risk of death and accurately predicting 30-day outcomes with relatively lower prediction errors. Day-7 AARC score 12 may be used as a futility criterion in APASL-ACLF patients.

Background and Purpose: Patients with acute stroke are often accompanied by comorbidities, such as active cancer. However, adequate treatment guidelines are not available for these patients. The purpose of this study was to evaluate the association between cancer and the outcomes of reperfusion therapy in patients with stroke. Methods: We compared treatment outcomes in patients who underwent reperfusion therapy, using a nationwide reperfusion therapy registry. We divided the patients into 3 groups according to cancer activity: active cancer, nonactive cancer, and without a history of cancer. We investigated reperfusion processes, 24-hour neurological improvement, adverse events, 3-month functional outcome, and 6-month survival and related factors after reperfusion therapy. Results: Among 1338 patients who underwent reperfusion therapy, 62 patients (4.6%) had active cancer, 78 patients (5.8%) had nonactive cancer, and 1198 patients (89.5%) had no history of cancer. Of the enrolled patients, 969 patients received intravenous thrombolysis and 685 patients underwent endovascular treatment (316 patients received combined therapy). Patients with active cancer had more comorbidities and experienced more severe strokes; however, they showed similar 24-hour neurological improvement and adverse events, including cerebral hemorrhage, compared with the other groups. Although the functional outcome at 3 months was poorer than the other groups, 36.4% of patients with active cancer showed functional independence. Additionally, 52.9% of the patients with determined stroke etiology showed functional independence despite active cancer. During the 6-month follow-up, 46.6% of patients with active cancer died, and active cancer was independently associated with poor survival (hazard ratio, 3.973 [95% CI, 2.528–6.245]). Conclusions: In patients with active cancer, reperfusion therapy showed similar adverse events and short-term outcomes to that of other groups. While long-term prognosis was worse in the active cancer group than the nonactive cancer groups, not negligible number of patients had good functional outcomes, especially those with determined stroke mechanisms.

Background and Purpose We aimed to develop a model predicting early recanalization after intravenous tissue plasminogen activator (t-PA) treatment in large-vessel occlusion.Methods Using data from two different multicenter prospective cohorts, we determined the factors associated with early recanalization immediately after t-PA in stroke patients with large-vessel occlusion, and developed and validated a prediction model for early recanalization. Clot volume was semiautomatically measured on thin-section computed tomography using software, and the degree of collaterals was determined using the Tan score. Follow-up angiographic studies were performed immediately after t-PA treatment to assess early recanalization.Results Early recanalization, assessed 61.0±44.7 minutes after t-PA bolus, was achieved in 15.5% (15/97) in the derivation cohort and in 10.5% (8/76) in the validation cohort. Clot volume (odds ratio [OR], 0.979; 95% confidence interval [CI], 0.961 to 0.997; P=0.020) and good collaterals (OR, 6.129; 95% CI, 1.592 to 23.594; P=0.008) were significant factors associated with early recanalization. The area under the curve (AUC) of the model including clot volume was 0.819 (95% CI, 0.720 to 0.917) and 0.842 (95% CI, 0.746 to 0.938) in the derivation and validation cohorts, respectively. The AUC improved when good collaterals were added (derivation cohort: AUC, 0.876; 95% CI, 0.802 to 0.950; P=0.164; validation cohort: AUC, 0.949; 95% CI, 0.886 to 1.000; P=0.036). The integrated discrimination improvement also showed significantly improved prediction (0.097; 95% CI, 0.009 to 0.185; P=0.032).Conclusions The model using clot volume and collaterals predicted early recanalization after intravenous t-PA and had a high performance. This model may aid in determining the recanalization treatment strategy in stroke patients with large-vessel occlusion.

Esophageal Squamous Cell Carcinoma (ESCC) is the predominant type of Esophageal Cancer (EC), accounting for nearly 88% of EC incidents worldwide. Importantly, it is also a life-threatening cancer for patients diagnosed in advanced stages, with only a 20% 5-year survival rate due to a limited number of actionable targets and therapeutic options. Increasing evidence has shown that inter-tumor and intra-tumor heterogeneity are widely distributed across ESCC tumor tissues. In our work, multi-omics data from ESCC cell lines, tumor tissue, normal tissue and Patient-Derived Xenograft (PDX) tissues were analyzed to investigate the heterogeneity among ESCC samples at the DNA, RNA, and protein level. We identified enrichment of ECM-receptor interaction and Focal adhesion pathways from the subset of protein-coding genes with non-silent mutations in ESCC patients. We also found that TP53, TTN, KMT2D, CSMD3, DNAH5, MUC16 and DST are the most frequently mutated genes in ESCC patient samples. Out of the identified genes, TP53 is the most frequently mutated, with 84 distinct non-silent mutation variants. We observed that p.R248Q, p.R175G/H, and p.R273C/H are the most common TP53 mutation variants. The diversity of TP53 mutations reveal its importance in ESCC progression and may also provide promising targets for precision therapeutics. Additionally, we identified the Olfactory transduction as the top signaling pathway, enriched from genes uniquely expressed in The Cancer Genome Atlas (TCGA)-ESCC patient tumor tissues, which may provide implications for the exact roles of the corresponding genes in ESCC. Cyclic nucleotide-gated channel subunit beta 1(CNGB1), a gene belonging to the Olfactory transduction pathway, was found exclusively overexpressed in ESCC. Expression of CNGB1 could serve as a marker, indicating potential diagnostic or therapeutic value. Finally, we investigated heterogeneity in the context of the ESCC PDX model, which is an emerging tool used to predict drug response and recapitulate tumor behavior in vivo. We observed trans-species heterogeneity in as high as 75% of the identified proteins, indicating that the ambiguity of proteins should be addressed by specific strategies to avoid drawing false conclusions. The identification and characterization of gene mutation and expression heterogeneity across different ESCC datasets, including various novel TP53 mutations, ECM-receptor interaction, Focal adhesion, and Olfactory transduction pathways (CNGB1), provide researchers with evidence and implications for accurate research and precision therapeutic development.

We investigated the effect of non-selective β-blockers (NSBB) in real-world situations and whether low-dose NSBB is beneficial compared to maximally tolerated doses. We performed a retrospective study of 740 patients with cirrhosis requiring prophylactic treatment of esophageal varices: 473 primary prophylaxis (PP: NSBB = 349, non-NSBB = 124) and 267 secondary prophylaxis (SP: NSBB = 200, non-NSBB = 67). The NSBB group was divided into low-dose (≤ 80 mg/day) and high-dose (> 80 mg/day). In the PP group, NSBB treatment reduced mortality and showed the most pronounced effect in patients with moderate/severe ascites (hazard ratio [HR], 0.46; p

Background/aims Besifovir dipivoxil maleate (BSV), an acyclic nucleotide phosphonate, shows potent antiviral activity against hepatitis B virus (HBV). Our previous 48-week trial revealed that BSV has comparable antiviral efficacy to tenofovir disoproxil fumarate (TDF) and better safety profiles in terms of improved renal and bone safety. This extension study evaluated the prolonged efficacy and safety of BSV in treatment-naive chronic hepatitis B patients. Methods Patients continued to participate in an open-label BSV study after an initial 48-week double-blind comparison of BSV and TDF treatment. The antiviral efficacy and drug safety was evaluated up to 192 weeks in two groups: patients continuing BSV treatment (BSV-BSV) and patients switching from TDF to BSV after 48 weeks (TDF-BSV). Results Among 197 patients receiving randomized treatments, 170 (86%) entered the open-label phase and 152 (77%) entered the 192-week extension study. Virological response rates over 192 weeks were 92.50% and 93.06% in the BSV-BSV and TDF-BSV groups, respectively (p = 0.90). Hepatitis B envelop antigen seroconversion and alanine aminotransferase normalization rates were similar between the groups (p = 0.75 and p = 0.36, respectively). There were no drug-resistant mutations to BSV. Bone mineral density and renal function were well preserved in the BSV-BSV group, whereas these initially worsened then recovered after switching therapy in the TDF-BSV group. Conclusions BSV maintained potent antiviral efficacy after 192 weeks and showed no evidence of drug resistance. BSV was safe, well tolerated, and effective in patients who switched from TDF to BSV. Trial Registration Number: NCT01937806 (Date: September 10, 2013).

Glutamyl-prolyl-tRNA synthetase (EPRS/GluRS) is primarily part of the multi-synthetase complex that may play a key role in cancer development. However, the biological function, molecular mechanism, and inhibitor of EPRS have not been investigated in gastric cancer (GC). Immunohistochemistry was performed to detect the expression of EPRS in human gastric tumor tissues. Knocking down of EPRS, cell-derived xenograft mouse model, and patient-derived xenograft mouse model was used to identify the biological function of EPRS. Immunoprecipitation was applied to elucidate the interaction between EPRS and SCYL2. Computer docking model and multiple in vitro and in vivo experiments were conducted to discover EPRS inhibitors. Here, we report that EPRS is frequently overexpressed in GC tissues compared to that adjacent controls and its overexpression predicts poor prognosis in GC patients. Functionally, high expression of EPRS positively co-relates with GC development both in vitro and in vivo. Mechanistically, EPRS directly binds with SCYL2 to enhance the activation of WNT/GSK-3β/β-catenin signaling pathway and the accumulation of β-catenin in the nuclear, leading to GC cell proliferation and tumor growth. Moreover, we identified that xanthoangelol (XA) and 4-hydroxyderricin (4-HD) can directly bind to EPRS to block WNT/GSK-3β/β-catenin signaling pathway. More importantly, XA and 4-HD restrain gastric cancer patient-derived xenograft tumor growth and Helicobacter pylori combined with alcohol-induced atrophic gastritis and gastric tumorigenesis. These findings unveil a promising strategy for GC prevention and therapy by targeting EPRS-mediated WNT/GSK-3β/β-catenin cascades. Moreover, XA and 4-HD may be effective reagents used for GC prevention and therapy.

BACKGROUND AND PURPOSE: The efficacy of mechanical thrombectomy methods may differ depending on the characteristics of the occlusion. The purpose of this study was to compare the recanalization efficacy and treatment outcome of a stent retriever versus contact aspiration in patients with acute basilar artery occlusion according to the angiographic characteristics of the occlusion. MATERIALS AND METHODS: One hundred sixty-one patients with acute basilar artery occlusion who underwent mechanical thrombectomy were retrospectively analyzed. A stent retriever was compared with contact aspiration thrombectomy according to the clot meniscus sign, defined as a meniscoid/tram-track-like sidewall contrast opacification of the thrombus. A propensity score matching analysis was performed. Clinical/angiographic characteristics and treatment and clinical outcomes were compared. RESULTS: Overall, a stent retriever (n = 118) and contact aspiration (n = 43) did not show significant differences in the successful recanalization (82.2% versus 86.0%) and good clinical outcome rates (32.2% versus 39.5%). In patients with the positive meniscus sign, contact aspiration was associated with shorter procedural time (44 versus 26 minutes, P = .018), a lower number of passes (2 versus 1, P = .041), a higher complete recanalization rate (58.8% versus 85.7%, P = .021), and a higher rate of first-pass effect (27.9% versus 53.6%, P = .031) compared with a stent retriever. After propensity score matching, contact aspiration was associated with higher complete recanalization rates (59.3% versus 85.7%, P = .033). No significant differences in the outcomes were noted between a stent retriever and contact aspiration in patients negative for the meniscus sign. CONCLUSIONS: The efficacy of the mechanical thrombectomy techniques may differ according to the angiographic characteristics of occlusion in patients with basilar artery occlusion. Contact aspiration may be more effective in terms of recanalization compared with a stent retriever in patients with the clot meniscus sign.

Background & Aims: Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. Methods: This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. Results: A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p

Anwulignan is a monomer compound derived from Schisandra sphenanthera lignans. It has been reported to possess a spectrum of pharmacological activities, including anti‐bacterial, anti‐inflammatory, anticancer and hepatoprotective properties. However, its anticancer capacity and molecular mechanism(s) against non‐small cell lung cancer (NSCLC) have not been fully elucidated. Anwulignan significantly inhibited cell growth and increased G1‐phase cell cycle arrest in NSCLC cells. Anwulignan strongly attenuates the JAK1/STAT3 signalling pathway by directly targeting JAK1 protein kinase activity in vitro. The anticancer activity by Anwulignan is dependent upon the JAK1 protein expression. Remarkably, Anwulignan strongly inhibited tumour growth in vivo. In conclusion, Anwulignan is a novel JAK1 inhibitor that may have therapeutic implications for NSCLC management.

BACKGROUND Metabolic risk factors may impact the severity and outcome of alcoholic liver disease. The present study evaluated this effect in patients with alcohol-associated acute-on-chronic liver failure (ACLF). METHODOLOGY One thousand two hundred and sixteen prospectively enrolled patients with ACLF (males 98%, mean age 42.5 ± 9.4 years, mean CTP, MELD and AARC scores of 12 ± 1.4, 29.7 ± 7 and 9.8 ± 2 respectively) from the Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC) database were analysed retrospectively. Patients with or without metabolic risk factors were compared for severity (CTP, MELD, AARC scores) and day 30 and 90 mortality. Information on overweight/obesity, type 2 diabetes mellitus (T2DM), hypertension and dyslipidaemia were available in 1028 (85%), 1019 (84%), 1017 (84%) and 965 (79%) patients respectively. RESULTS Overall, 392 (32%) patients died at day 30 and 528 (43%) at day 90. Overweight/obesity, T2DM, hypertension and dyslipidaemia were present in 154 (15%), 142 (14%), 66 (7%) and 141 (15%) patients, respectively, with no risk factors in 809 (67%) patients. Patients with overweight/obesity had higher MELD scores (30.6 ± 7.1 vs 29.2 ± 6.9, P = .007) and those with dyslipidaemia had higher AARC scores (10.4 ± 1.2 vs 9.8 ± 2, P = .014). Overweight/obesity was associated with increased day 30 mortality (HR 1.54, 95% CI 1.06-2.24, P = .023). None of other metabolic risk factors, alone or in combination, had any impact on disease severity or mortality. On multivariate analysis, overweight or obesity was significantly associated with 30-day mortality (aHR 1.91, 95% CI 1.41-2.59, P

OBJECTIVE Clinical outcomes of patients who undergo transarterial chemoembolization (TACE) for single small hepatocellular carcinoma (HCC) are not consistent, and may differ based on certain imaging findings. This retrospective study was aimed at determining the efficacy of pre-TACE CT or MR imaging findings in predicting survival outcomes in patients with small HCC upon being treated with TACE. Besides, the study proposed to build a risk prediction model for these patients. MATERIALS AND METHODS Altogether, 750 patients with functionally good hepatic reserve who received TACE as the first-line treatment for single small HCC between 2004 and 2014 were included in the study. These patients were randomly assigned into training (n = 525) and validation (n = 225) sets. RESULTS According to the results of a multivariable Cox analysis, three pre-TACE imaging findings (tumor margin, tumor location, enhancement pattern) and two clinical factors (age, serum albumin level) were selected and scored to create predictive models for overall, local tumor progression (LTP)-free, and progression-free survival in the training set. The median overall survival time in the validation set were 137.5 months, 76.1 months, and 44.0 months for low-, intermediate-, and high-risk groups, respectively (p < 0.001). Time-dependent receiver operating characteristic curves of the predictive models for overall, LTP-free, and progression-free survival applied to the validation cohort showed acceptable areas under the curve values (0.734, 0.802, and 0.775 for overall survival; 0.738, 0.789, and 0.791 for LTP-free survival; and 0.671, 0.733, and 0.694 for progression-free survival at 3, 5, and 10 years, respectively). CONCLUSION Pre-TACE CT or MR imaging findings could predict survival outcomes in patients with small HCC upon treatment with TACE. Our predictive models including three imaging predictors could be helpful in prognostication, identification, and selection of suitable candidates for TACE in patients with single small HCC.

Background: Korea Red Ginseng (KRG) has been used as remedies with hepato-protective effects in liver-related condition. Microbiota related gut-liver axis plays key roles in the pathogenesis of chronic liver disease. We evaluated the effect of KRG on gut-liver axis in patients with nonalcoholic statohepatitis by the modulation of gut-microbiota. Methods: A total of 94 patients (KRG: 45 and placebo: 49) were prospectively randomized to receive KRG (2,000 mg/day, ginsenoside Rg1+Rb1+Rg3 4.5mg/g) or placebo during 30 days. Liver function test, cytokeraton 18, and fatigue score were measured. Gut microbiota was analyzed by MiSeq systems based on 16S rRNA genes. Results: In KRG group, the mean levels (before vs. after) of aspartate aminotransferase (53 ± 19 vs. 45 ± 23 IU/L), alanine aminotransferase (75 ± 40 vs. 64 ± 39 IU/L) and fatigue score (33 ± 13 vs. 26 ± 13) were improved (p

INTRODUCTION: Chronic hepatitis B (CHB) remains a major worldwide public health concern. Besifovir dipivoxil maleate (BSV) is a new promising treatment for CHB. However, long-term efficacy and safety have not yet been evaluated. Therefore, the goal of the study is to determine the antiviral efficacy and safety of BSV treatment over a 144-week duration (BSV-BSV) in comparison with those of a sequential treatment with tenofovir disoproxil fumarate (TDF) followed by a 96-week duration BSV administration (TDF-BSV). METHODS: After 48 weeks of a double-blind comparison between BSV and TDF treatments, patients continued the open-label BSV study. We evaluated antiviral efficacy and drug safety up to 144 weeks for BSV-BSV and TDF-BSV groups. The primary endpoint was a virological response (hepatitis B virus DNA < 69 IU/mL). RESULTS: Among the 197 patients enrolled, 170 and 158 patients entered the second-year and third-year open-label phase extensional study, respectively, whereas 153 patients completed the 144-week follow-up. The virological response rate over the 144-week period was 87.7% and 92.1% in BSV-BSV and TDF-BSV groups, respectively (P = 0.36). The rates of ALT normalization and HBeAg seroconversion were similar between the groups. No drug-resistant mutations to BSV were noted. Bone mineral density and renal function were well preserved in the BSV-BSV group and were significantly improved after switching therapy in TDF-BSV patients. DISCUSSION: This extensional study of a phase 3 trial (NCT01937806) suggests that BSV treatment is efficacious and safe for long-term use in treatment-naïve and TDF-experienced patients with CHB.

Background and Aim Data on the trends in the prevalence of chronic liver disease (CLD) in Korea are scarce. This study aimed to evaluate whether the CLD prevalence changed between 1998–2001 and 2016–2017. Methods Data were extracted from the Korea National Health and Nutrition Examination Survey (1998–2001 to 2016–2017; n=25,893). Non-alcoholic fatty liver disease (NAFLD) was defined as a hepatic steatosis index >36 in the absence of any other evidence of CLD. The definition of alcohol-related liver disease (ALD) was excessive alcohol consumption (≥210 g/week for men and ≥140 g/week for women) and an ALD/NAFLD index >0. Results The prevalence of NAFLD increased from 18.6% (95% confidence interval [CI], 17.8–19.5%) in 1998–2001 to 21.5% (95% CI, 20.6–22.6%) in 2016–2017. During the same time period, increases were observed in the prevalence of obesity (27.0 vs. 35.1%), central obesity (29.4 vs. 36.0%), diabetes (7.5 vs. 10.6%), and excessive drinking (7.3 vs. 10.5%). ALD prevalence also increased from 3.8% (95% CI, 3.4–4.2%) to 7.0% (95% CI, 6.4–7.6%). In contrast, chronic hepatitis B decreased from 5.1% (95% CI, 4.6–5.5%) to 3.4% (95% CI, 3.0–3.8%). The prevalence of chronic hepatitis C was approximately 0.3% in 2016–2017. Conclusions The prevalence of NAFLD and ALD increase among Korean adults. Our results suggest potential targets for interventions to reduce the future burden of CLD.

Background/Aims Enzymatic analysis of aspartate/alanine aminotransferase (AST/ALT) does not exactly represent the progression of liver fibrosis or inflammation. Immunoassay for AST (cytoplasmic [c] AST/mitochondrial [m] AST) and ALT (ALT1/ALT2) has been suggested as one alternatives for enzymatic analysis. The objective of this study was to evaluate the efficacy of immunoassay in predicting liver fibrosis and inflammation. Methods A total of 219 patients with chronic hepatitis B (CHB) who underwent hepatic venous pressure gradient (HVPG) and liver biopsy before antiviral therapy were recruited. Serum samples were prepared from blood during HVPG. Results of biochemical parameters including enzymatic AST/ALT and immunological assays of cAST, mAST, ALT1, and ALT2 through sandwich enzyme-linked immunosorbent assay (ELISA) immunoassay with fluorescence labeled monoclonal antibodies were compared with the results of METAVIR stage of live fibrosis and the Knodell grade of inflammation. Results METAVIR fibrosis stages were as follows: F0, six (3%); F1, 52 (24%); F2, 88 (40%); F3, 45 (20%); and F4, 28 patients (13%). Mean levels of AST and ALT were 121 ± 157 and 210 ± 279 IU/L, respectively. Mean HVPG score of all patients was 4.7 ± 2.5 mmHg. According to the stage of liver fibrosis, HVPG score (p < 0.001, r = 0.439) and ALT1 level (p < 0.001, r = 0.283) were significantly increased in all samples from patients with CHB. ALT (p < 0.001, r = 0.310), ALT1 (p < 0.001, r = 0.369), and AST (p < 0.001, r = 0.374) levels were positively correlated with Knodell grade of inflammation. Conclusions ALT1 measurement by utilizing sandwich ELISA immunoassay can be useful method for predicting inf lammation grade and fibrosis stage in patients with CHB.

Targeting the gut-liver axis by modulating the gut-microbiome can be a promising therapeutic approach in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the effects of single species and a combination of Lactobacillus and Pediococcus in NAFLD mice model. Six-week male C57BL/6J mice were divided into 9 groups (n = 10/group; normal, Western diet, and 7 Western diet-strains [10(9) CFU/g, 8 weeks]). The strains used were L. bulgaricus, L. casei, L. helveticus, P. pentosaceus KID7, and three combinations (1: L. casei+L. helveticus, 2: L. casei+L. helveticus+P. pentosaceus KID7, and 3: L. casei+L. helveticus+L. bulgaricus). Liver/Body weight ratio, serum and stool analysis, liver pathology, and metagenomics by 16S rRNA-sequencing were examined. In the liver/body ratio, L. bulgaricus (5.1 ± 0.5), L. helveticus (5.2 ± 0.4), P. pentosaceus KID7 (5.5 ± 0.5), and combination1 and 2 (4.2 ± 0.6 and 4.8 ± 0.7) showed significant reductions compared with Western (6.2 ± 0.6)(p < 0.001). In terms of cholesterol and steatosis/inflammation/NAFLD activity, all groups except for L. casei were associated with an improvement (p < .05). The elevated level of tumor necrosis factor-α/interleukin-1β (pg/ml) in Western (65.8 ± 7.9/163.8 ± 12.2) was found to be significantly reduced in L. bulgaricus (24.2 ± 1.0/58.9 ± 15.3), L. casei (35.6 ± 2.1/62.9 ± 6.0), L. helveticus (43.4 ± 3.2/53.6 ± 7.5), and P. pentosaceus KID7 (22.9 ± 3.4/59.7 ± 12.2)(p < 0.01). Cytokines were improved in the combination groups. In metagenomics, each strains revealed a different composition and elevated Firmicutes/Bacteroidetes ratio in the western (47.1) was decreased in L. bulgaricus (14.5), L. helveticus (3.0), and P. pentosaceus KID7 (13.3). L. bulgaricus, L. casei, L. helveticus, and P. pentosaceus KID7 supplementation can improve NAFLD-progression by modulating gut-microbiome and inflammatory pathway.

Recent advances in endovascular thrombectomy have enabled the histopathologic analysis of fresh thrombi in patients with acute stroke. Histologic analysis has shown that the thrombus composition is very heterogeneous between patients. However, the distribution pattern of each thrombus component often differs between patients with cardiac thrombi and those with arterial thrombi, and the efficacy of endovascular thrombectomy is different according to the thrombus composition. Furthermore, the thrombus age is related to the efficacy of reperfusion therapy. Recent studies have shown that neutrophils and neutrophil extracellular traps contribute to thrombus formation and resistance to reperfusion therapy. Histologic features of thrombi in patients with stroke may provide some clues to stroke etiology, which is helpful for determining the strategy of stroke prevention. Research on thrombus may also be helpful for improving reperfusion therapy, including the development of new thrombolytic agents.

(1) Background: To analyze changes in treatment patterns for advanced retinoblastoma over time and differences in globe salvage rates, (2) Methods: Retrospective, observational case-control study of 97 eyes of 91 patients with advanced retinoblastoma (Group D and E)., (3) Results: Patients were divided into two groups based on whether they were treated before or after intraarterial chemotherapy (IAC) was introduced in our center in 2010. Before 2010, primary treatment pattern was enucleation, which was performed in 57.6% of cases, whereas primary treatment pattern after 2010 was IAC combined with intravenous chemotherapy (IVC), which was performed in 78.1%. Intravitreal chemotherapy (IVitC) has been performed to treat vitreous and subretinal seeding since 2015. The 5-year globe salvage rate of IVC alone was 24.0% for Group D and 0% for Group E, whereas that of IVC–IAC was 50.4% for Group D and 49.7% for Group E. Whether IVitC was performed or not did not significantly contribute to globe salvage rate. There was one metastatic death in the IVC alone group., (4) Conclusions: Primary treatment pattern changed from enucleation to IAC-based treatment, which can now save nearly half of eyes with advanced retinoblastoma with excellent safety profile and survival rate.

Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by hepatic accumulation of excess lipids. T cells are commonly classified into various subsets based on their surface markers including T cell receptors, type of antigen presentation and pathophysiological functions. Several studies have implicated various T cell subsets and natural killer (NK) cells in the progression of NAFLD. While NK cells are mainly components of the innate hepatic immune system, the majority of T cell subsets can be part of both the adaptive and innate systems. Several studies have reported that various stages of NAFLD are accompanied by the accumulation of distinct T cell subsets and NK cells with different functions and phenotypes observed usually resulting in proinflammatory effects. More importantly, the overall stimulation of the intrahepatic T cell subsets is directly influenced by the homeostasis of the gut microbiota. Similarly, NK cells have been found to accumulate in the liver in response to pathogens and tumors. In this review, we discussed the nature and pathophysiological roles of T cell subsets including γδ T cells, NKT cells, Mucosal-associated invariant T (MAIT) cells as well as NK cells in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common and increasing liver diseases worldwide. NAFLD is a term that involves a variety of conditions such as fatty liver, steatohepatitis, or fibrosis. Gut microbiota and its products have been extensively studied because of a close relation between NAFLD and microbiota in pathogenesis. In the progression of NAFLD, various microbiota-related molecular and cellular mechanisms, including dysbiosis, leaky bowel, endotoxin, bile acids enterohepatic circulation, metabolites, or alcohol-producing microbiota, are involved. Currently, diagnosis and treatment techniques using these mechanisms are being developed. In this review, we will introduce the microbiota-related mechanisms in the progression of NAFLD and future directions will be discussed.

Acute-on-chronic liver failure (ACLF) is an important syndrome of liver failure that has a high risk of short-term mortality in patients with chronic liver disease. The development of ACLF is associated with proinflammatory precipitating events, such as infection, alcoholic hepatitis, and intense systemic inflammation. Recently, the role of the gut microbiome has increasingly emerged in human health and disease. Additionally, the gut microbiome might have a major role in the development of liver disease. In this review, we examine evidence to support the role of gut dysbiosis in cirrhosis and ACLF. Additionally, we explore the mechanism by which the gut microbiome contributes to the development of ACLF, with a focus on alcohol-induced liver disease.

Background and aims Acute-on-chronic liver failure (ACLF) is considered a main prognostic event in patients with chronic liver disease (CLD). We analyzed the 28-day and 90-day mortality in ACLF patients with or without underlying cirrhosis enrolled in the ACLF Research Consortium (AARC) database. Methods A total of 1,621 patients were prospectively enrolled and 637 (39.3%) of these patients had cirrhosis. Baseline characteristics, complications and mortality were compared between patients with and without cirrhosis. Results Alcohol consumption was more common in cirrhosis than non-cirrhosis (66.4% vs. 44.2%, p p p p p p p Conclusions The 28-day and 90-day mortality rates of ACLF patients without cirrhosis were significantly higher than those with cirrhosis in alcoholic CLD. The presence of cirrhosis and its stage should be evaluated at baseline to guide for management. Thai Clinical Trials Registry, TCTR20191226002.

In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut–liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions.

Background and Purpose: Intracranial atherosclerosis-related large-vessel occlusion caused by in situ thrombo-occlusion (ICAS-LVO) has been regarded an important reason for refractoriness to mechanical thrombectomy (MT). To achieve better outcomes for ICAS-LVO, different endovascular strategies should be explored. We aimed to investigate an optimal endovascular strategy for ICAS-LVO.Methods: We retrospectively reviewed three prospective registries of acute stroke underwent endovascular treatment. Among them, patients with ICAS-LVO were assigned to four groups based on their endovascular strategy: (1) MT alone, (2) rescue intracranial stenting after MT failure (MT-RS), (3) glycoprotein IIb/IIIa inhibitor infusion after MT failure (MT-GPI), and (4) a combination of MT-RS and MT-GPI (MT-RS+GPI). Baseline characteristics and outcomes were compared among the groups. To evaluate whether the endovascular strategy resulted in favorable outcome, multivariable analysis was also performed.Results: A total of 184 patients with ICAS-LVO were included. Twenty-four patients (13.0%) were treated with MT alone, 25 (13.6%) with MT-RS, 84 (45.7%) with MT-GPI, and 51 (27.7%) with MT-RS+GPI. The MT-RS+GPI group showed the highest recanalization efficiency (98.0%). Frequency of patent arteries on follow-up (98.0%, p < 0.001) and favorable outcome (84.3%, p < 0.001) were higher in the MT-RS+GPI group than other groups. The MT-RS+GPI strategy remained an independent factor for favorable outcome (odds ratio, 20.4; 95% confidence interval, 1.97–211.4; p = 0.012).Conclusion: Endovascular strategy was significantly associated with procedural and clinical outcomes in acute stroke by ICAS-LVO. A combination of RS and GPI infusion might be an optimal rescue modality when frontline MT fails.

OBJECTIVEThe role of the balloon guide catheter (BGC) has not been evaluated in contact aspiration thrombectomy (CAT) for acute stroke. Here, the authors aimed to test whether the BGC was associated with recanalization success and good functional outcome in CAT.METHODSAll patients who had undergone CAT as the first-line treatment for anterior circulation intracranial large vessel occlusion were retrospectively identified from prospectively maintained registries for six stroke centers. The patients were dichotomized into BGC utilization and nonutilization groups. Clinical findings, procedural details, and recanalization success rates were compared between the two groups. Whether the BGC was associated with recanalization success and functional outcome was assessed.RESULTSA total of 429 patients (mean age 68.4 ± 11.4 years; M/F ratio 215:214) fulfilled the inclusion criteria. A BGC was used in 45.2% of patients. The overall recanalization and good outcome rates were 80.2% and 52.0%, respectively. Compared to the non-BGC group, the BGC group had a significantly reduced number of CAT passes (2.6 ± 1.6 vs 3.4 ± 1.5), shorter puncture-to-recanalization time (56 ± 27 vs 64 ± 35 minutes), lower need for the additional use of thrombolytics (1.0% vs 8.1%), and less embolization to a distal or different site (0.5% vs 3.4%). The BGC group showed significantly higher final (89.2% vs 72.8%) and first-pass (24.2% vs 8.1%) recanalization success rates. After adjustment for potentially associated factors, BGC utilization remained independently associated with recanalization (OR 4.171, 95% CI 1.523–11.420) and good functional outcome (OR 2.103, 95% CI 1.225–3.612).CONCLUSIONSBGC utilization significantly increased the final and first-pass recanalization rates and remained independently associated with recanalization success and good functional outcome.

Although alcohol intake is known to be associated with the development of colorectal cancer, the effect of alcohol consumption on the development of colorectal neoplasm (CRN) is unclear. We performed a retrospective cohort analysis with 1 to 1 propensity score matching in a single center of Korea. Among 1,448 patients who underwent index and surveillance colonoscopy, 210 matched pairs were analyzed. The 5-year cumulative occurrence of overall CRN after index colonoscopy was higher in the significant alcohol consumption group (defined as alcohol consumption more than 30 g/day in men and 20 g/day in women) (vs. without significant alcohol consumption group) (40% vs. 27.6%, p = 0.004). Significant alcohol consumption increased the development of overall CRN (adjusted hazard ratio [aHR]: 1.86, 95% confidence interval [CI]: 1.28–2.70, p = 0.001) at surveillance colonoscopy. However, this effect was not valid on the development of advanced CRN. In subgroup analysis considering the risk classification of index colonoscopy, significant alcohol consumption increased the overall CRN development at surveillance colonoscopy in the normal group (patients with no detected adenoma in the index colonoscopy) (aHR: 1.90, 95% CI: 1.16–3.13, p = 0.01). Alcohol consumption habits should be considered in optimizing time intervals of surveillance colonoscopy.

OBJECTIVES Acute insults from viruses, infections, or alcohol are established causes of decompensation leading to acute-on-chronic liver failure (ACLF). Information regarding drugs as triggers of ACLF is lacking. We examined data regarding drugs producing ACLF and analyzed clinical features, laboratory characteristics, outcome, and predictors of mortality in patients with drug-induced ACLF. METHODS We identified drugs as precipitants of ACLF among prospective cohort of patients with ACLF from the Asian Pacific Association of Study of Liver (APASL) ACLF Research Consortium (AARC) database. Drugs were considered precipitants after exclusion of known causes together with a temporal association between exposure and decompensation. Outcome was defined as death from decompensation. RESULTS Of the 3,132 patients with ACLF, drugs were implicated as a cause in 329 (10.5%, mean age 47 years, 65% men) and other nondrug causes in 2,803 (89.5%) (group B). Complementary and alternative medications (71.7%) were the commonest insult, followed by combination antituberculosis therapy drugs (27.3%). Alcoholic liver disease (28.6%), cryptogenic liver disease (25.5%), and non-alcoholic steatohepatitis (NASH) (16.7%) were common causes of underlying liver diseases. Patients with drug-induced ACLF had jaundice (100%), ascites (88%), encephalopathy (46.5%), high Model for End-Stage Liver Disease (MELD) (30.2), and Child-Turcotte-Pugh score (12.1). The overall 90-day mortality was higher in drug-induced (46.5%) than in non-drug-induced ACLF (38.8%) (P = 0.007). The Cox regression model identified arterial lactate (P < 0.001) and total bilirubin (P = 0.008) as predictors of mortality. DISCUSSION Drugs are important identifiable causes of ACLF in Asia-Pacific countries, predominantly from complementary and alternative medications, followed by antituberculosis drugs. Encephalopathy, bilirubin, blood urea, lactate, and international normalized ratio (INR) predict mortality in drug-induced ACLF.

BACKGROUND AND PURPOSE: Mechanical thrombectomy with proximal flow control and forced aspiration may improve the outcome of endovascular revascularization therapy for patients with acute stroke. The purpose of this study was to compare the impact of balloon-guiding catheter locations in patients treated for anterior circulation acute ischemic stroke using mechanical thrombectomy. MATERIALS AND METHODS: The influence of the balloon-guiding catheter location (proximal, balloon-guiding catheter tip proximal to C1 vertebral body; distal, between the skull base and the C1 vertebral body) was analyzed in patients with acute anterior circulation stroke treated with stent-retriever thrombectomy. The baseline angiographic/clinical characteristics, time intervals, recanalization rates, and clinical outcomes were compared. RESULTS: The clinical analysis included 102 patients (mean age, 69.5 ± 12.8 years; male/female ratio = 52:50). The balloon-guiding catheter was located distally in 49 patients and proximally in 53 patients for flow control and forced aspiration during stent retrieval. The puncture-to-recanalization time was shorter in the distal group than in the proximal group (40 versus 56 minutes, P = .02). Successful and complete recanalizations were more frequently achieved in the distal group compared with the proximal group (98.0% versus 75.5%. P = .003; 67.3% versus 45.3%, P = .04, respectively). Multivariate analysis showed that the distal catheterization location was independently associated with successful recanalization (adjusted OR, 13.4; 95% CI, 2.4–254.8; P = .02). CONCLUSIONS: Location of the balloon-guiding catheter has a significant impact on recanalization in patients with acute stroke. The balloon-guiding catheter should be positioned as distally as safely possible in the cervical ICA for maximally effective thrombectomy.

3,3'-Diindolymethane (DIM) is a dimeric condensation product of indole-3-carbinol (I3C) that is found in broccoli and cabbage. Although DIM has been reported to exhibit anticancer properties against multiple tumor types, the direct target proteins of DIM have not been fully investigated. In the present study, we report that DIM is a novel COX1/2 and ERK1/2 inhibitor that suppresses growth of colon cancer in vitro and in vivo. To identify possible molecular targets of DIM, 11 potential candidate proteins were validated by an in vitro kinase or enzyme assay. We found that DIM directly inhibits COX1/2 and ERK1/2 protein activities in vitro. Additionally, the PGE2 production (COX-mediated metabolite) and phosphorylated RSK expression (ERK1/2 direct downstream kinase) were strongly suppressed by DIM in colon cancer cells. The inhibition of cell growth by DIM is dependent on the expression of COX1/2 or ERK1/2 proteins. Notably, oral administration of DIM suppressed patient-derived xenograft colon tumor growth in an in vivo mouse model. Overall these results suggest that DIM is a potent and dual COX1/2 and ERK1/2 inhibitor that might be used for chemotherapy against colon cancer.

BACKGROUND It remains controversial whether carotid artery stenting (CAS) is needed in cases of tandem cervical internal carotid artery occlusion (cICAO) and intracranial large vessel occlusion (LVO). OBJECTIVE To investigate the efficacy and safety of CAS in combination with endovascular thrombectomy (CAS-EVT) in cICAO-LVO patients and to compare its outcomes with those of EVT without CAS (EVT-alone). METHODS We identified all patients who underwent EVT for tandem cICAO-LVO from the prospectively maintained registries of 17 stroke centers. Patients were classified into 2 groups: CAS-EVT and EVT-alone. Clinical characteristics and procedural and clinical outcomes were compared between 2 groups. We tested whether CAS-EVT strategy was independently associated with recanalization success. RESULTS Of the 955 patients who underwent EVT, 75 patients (7.9%) had cICAO-LVO. Fifty-six patients underwent CAS-EVT (74.6%), and the remaining 19 patients underwent EVT-alone (25.4%). The recanalization (94.6% vs 63.2%, P = .002) and good outcome rates (64.3% vs 26.3%, P = .007) were significantly higher in the CAS-EVT than in the EVT-alone. Mortality was significantly lower in the CAS-EVT (7.1% vs 21.6%, P = .014). There was no significant difference in the rate of symptomatic intracranial hemorrhage between 2 groups (10.7 vs 15.8%; P = .684) and according to the use of glycoprotein IIb/IIIa inhibitor (10.0% vs 12.3%; P = .999) or antiplatelet medications (10.2% vs 18.8%; P = .392). CAS-EVT strategy remained independently associated with recanalization success (odds ratio: 24.844; 95% confidence interval: 1.445-427.187). CONCLUSION CAS-EVT strategy seemed to be effective and safe in cases of tandem cICAO-LVO. CAS-EVT strategy was associated with recanalization success, resulting in better clinical outcome.

OBJECTIVE We report the results of a pilot clinical study that evaluated the safety and efficacy of a newly-developed, retrievable flow diverter (FloWise; Taewoong Medical) for the treatment of internal carotid artery (ICA) aneurysm. MATERIALS AND METHODS A total of 10 patients were enrolled. Inclusion criteria were 1) unruptured aneurysm with a dome size of ≥ 8 mm and a neck size of ≥ 4 mm at the ICA, or 2) two or more unruptured aneurysms of any size able to be spanned by a single FloWise at the ICA. Co-primary effectiveness end points were technical success of FloWise placement, and a 50% or greater decrease in aneurysm volume at the 6-month follow-up angiogram. The primary safety end point was the new development of neurological deficits persisting for more than 1-month post-treatment. RESULTS Ten patients harboring 14 ICA aneurysms (median diameter, 9.4 mm; range, 2.3-31.0 mm) were enrolled between January 2016 and July 2017. FloWise placement was successful in all patients. There were no newly-developed neurological deficits during the 6-month clinical follow-up period. One patient did not receive follow-up imaging due to pregnancy. Nine patients with 12 aneurysms received a 6-month angiographic follow-up. Ten aneurysms (83.3%) showed decreases in volume greater than 50% (mean volume decrease, 82.8 ± 32.9%), of which 8 (66.7%, 95% confidence interval, 35.4-98.0%) showed complete occlusion. One patient was retreated due to mass symptom aggravation. CONCLUSIONS In this pilot study, FloWise appeared to be safe and effective for ICA aneurysm treatment. A prospective multicenter study to validate the effectiveness and safety of FloWise would be worthwhile.

The gut microbiota has been known to modulate the immune responses in chronic liver diseases. Recent evidence suggests that effects of dietary foods on health care and human diseases are related to both the immune reaction and the microbiome. The gut-microbiome and intestinal immune system play a central role in the control of bacterial translocation-induced liver disease. Dysbiosis, small intestinal bacterial overgrowth, translocation, endotoxemia, and the direct effects of metabolites are the main events in the gut-liver axis, and immune responses act on every pathways of chronic liver disease. Microbiome-derived metabolites or bacteria themselves regulate immune cell functions such as recognition or activation of receptors, the control of gene expression by epigenetic change, activation of immune cells, and the integration of cellular metabolism. Here, we reviewed recent reports about the immunologic role of gut microbiotas in liver disease, highlighting the role of diet in chronic liver disease.

In ischemic brain tissue, hypoperfusion severity can be assessed using the hypoperfusion intensity ratio (HIR). We evaluated the link between HIR and clinical outcomes after successful recanalization by endovascular treatment. We retrospectively reviewed 162 consecutive patients who underwent endovascular treatment for intracranial large vessel occlusion. The HIR was calculated using an automated software program, with initial computed tomography perfusion images. The HIR was compared between patients with and without favorable outcomes. To observe the modifying effect of the HIR on the well-known major outcome determinants, regression analyses were performed in the low and high HIR groups. The median HIR value was significantly lower in patients with a favorable outcome, with an optimal cut-off point of 0.54. The HIR was an independent factor for a favorable outcome in a specific multivariable model and was significantly correlated with the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). In contrast to the high HIR group, the low HIR group showed that ASPECTS and onset-to-recanalization time were not independently associated with a favorable outcome. Finally, the low HIR group had a more favorable outcome even in cases with an unfavorable ASPECTS and onset-to-recanalization time. The HIR could be useful in predicting outcomes after successful recanalization.

The prevalence of osteoporosis and sarcopenia is significantly higher in patients with liver disease than in those without liver disease and osteoporosis and sarcopenia negatively influence morbidity and mortality in liver disease, yet these musculoskeletal disorders are frequently overlooked in clinical practice for patients with chronic liver disease. The objective of this review is to provide a comprehensive understanding of the molecular mechanisms of musculoskeletal disorders accompanying the pathogenesis of liver disease. The increased bone resorption through the receptor activator of nuclear factor kappa (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system and upregulation of inflammatory cytokines and decreased bone formation through increased bilirubin and sclerostin and lower insulin-like growth factor-1 are important mechanisms for osteoporosis in patients with liver disease. Sarcopenia is associated with insulin resistance and obesity in non-alcoholic fatty liver disease, whereas hyperammonemia, low amount of branched chain amino acids, and hypogonadism contributes to sarcopenia in liver cirrhosis. The bidirectional crosstalk between muscle and bone through myostatin, irisin, β-aminoisobutyric acid (BAIBA), osteocalcin, as well as the activation of the RANK and the Wnt/β-catenin pathways are associated with osteosarcopenia. The increased understandings for these musculoskeletal disorders would be contributes to the development of effective therapies targeting the pathophysiological mechanism involved.

The 69th World Health Assembly endorsed the Global Health Sector Strategy for Viral Hepatitis, embracing a goal to eliminate hepatitis infection as a public health threat by 2030. This was followed by the World Health Organization's (WHO) global targets for the care and management of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These announcements and targets were important in raising awareness and calling for action; however, tracking countries’ progress towards these elimination goals has provided insights to the limitations of these targets. The existing targets compare a country's progress relative to its 2015 values, penalizing countries who started their programmes prior to 2015, countries with a young population, or countries with a low prevalence. We recommend that (1) WHO simplify the hepatitis elimination targets, (2) change to absolute targets and (3) allow countries to achieve these disease targets with their own service coverage initiatives that will have the maximum impact. The recommended targets are as follows: reduce HCV new chronic cases to ≤5 per 100000, reduce HBV prevalence among 1-year-olds to ≤0.1%, reduce HBV and HCV mortality to ≤5 per 100000, and demonstrate HBV and HCV year-to-year decrease in new HCV- and HBV-related HCC cases. The objective of our recommendations is not to lower expectations or diminish the hepatitis elimination standards, but to provide clearer targets that recognize the past and current elimination efforts by countries, help measure progress towards true elimination, and motivate other countries to follow suit.

Over the last decade, increased research into the cognizance of the gut–liver–brain axis in medicine has yielded powerful evidence suggesting a strong association between alcoholic liver diseases (ALD) and the brain, including hepatic encephalopathy or other similar brain disorders. In the gut–brain axis, chronic, alcohol-drinking-induced, low-grade systemic inflammation is suggested to be the main pathophysiology of cognitive dysfunctions in patients with ALD. However, the role of gut microbiota and its metabolites have remained unclear. Eubiosis of the gut microbiome is crucial as dysbiosis between autochthonous bacteria and pathobionts leads to intestinal insult, liver injury, and neuroinflammation. Restoring dysbiosis using modulating factors such as alcohol abstinence, promoting commensal bacterial abundance, maintaining short-chain fatty acids in the gut, or vagus nerve stimulation could be beneficial in alleviating disease progression. In this review, we summarize the pathogenic mechanisms linked with the gut–liver–brain axis in the development and progression of brain disorders associated with ALD in both experimental models and humans. Further, we discuss the therapeutic potential and future research directions as they relate to the gut–liver–brain axis.

Endovascular treatment (EVT) of posterior communicating artery aneurysms (PcomA) is challenging because of posterior communicating artery (Pcom) architecture. Additionally, these aneurysms have a high risk of recanalization compared with those located elsewhere. The radiographic findings of 171 patients treated with EVT at two institutions were retrospectively reviewed. Univariate and multivariate analyses were performed, and subgroup analyses were performed based on Pcom characteristics. Recanalization of PcomAs occurred in 53 patients (30.9%). Seven patients (4.0%) were retreated (six endovascularly and one with microsurgical clipping). The mean follow-up duration was 27.7 months (range: 3.5–78.6). The maximum diameter (odds ratio [OR] 1.23, P = .006, 95% CI 1.07–1.44), a Raymond–Roy classification of grade II or III (OR 2.26, P = .03, 95% CI 1.08–4.82), and the presence of reinforcement (balloon or/and stent, OR 0.44, P = .03, 95% CI 0.20–0.91) were associated with recanalization using multivariate logistic regression. Significant differences were found in maximum aneurysm diameter (P = .03) between normal- and fetal-type Pcoms on analysis of variance. The recanalization rate of PcomAs after EVT was 30.9%; the retreatment rate was 4.0%. Maximum diameter, Raymond–Roy classification, and presence of reinforcement were significantly associated with recanalization but not associated with fetal-type Pcom. Aneurysm size was larger in patients with a fetal-type Pcom than in those with a normal Pcom. Pcom size was not related to recanalization rate.

Malnutrition and cognitive dysfunction are typical features of alcoholic liver disease (ALD) and are correlated with the development of complications. The aim of this study is to explore the effect of nutritional state and diet on cognitive function in ALD. A total of 43 patients with compensated alcoholic cirrhosis were enrolled, and a neuropsychological test was assessed according to body mass index (BMI, &lt, 22 and &ge, 22). In the ALD animal study, mice were divided into five groups (n = 9/group, normal liquid, 5% EtOH + regular liquid, 5% EtOH + high-carbohydrate liquid, 5% EtOH + high-fat liquid, and 5% EtOH + high-protein liquid diet) and fed the same calories for eight weeks. To assess cognitive function, we performed T-maze studies weekly before/after alcohol binging. In cognitive function (BMI &lt, 22/&ge, 22), language score of Korea mini-mental state (7.4 &plusmn, 1.4/7.9 &plusmn, 0.4), Boston naming (11.7 &plusmn, 2.7/13.0 &plusmn, 1.8), forward digit span (6.7 &plusmn, 1.8/7.5 &plusmn, 1.6), Korean color word stroop (24.2 &plusmn, 26.5/43.6 &plusmn, 32.4), and interference score (33.9 &plusmn, 31.9/52.3 &plusmn, 33.9) revealed significant differences. In the T-maze test, alcohol significantly delayed the time to reach food, and binge drinking provided a temporary recovery in cognition. The alcohol-induced delay was significantly reduced in the high-carbohydrate and high-fat diet groups. Synaptic function exhibited no changes in all groups. Cognitive dysfunction is affected by nutritional status and diet in ALD.

Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related deaths. However, there are few effective therapeutic targets for CRC patients. Here, we found that CDK15 was highly expressed in human CRC and negatively correlated with patient prognosis and overall survival in tissue microarray. Knockdown of CDK15 suppressed cell proliferation and anchorage-independent growth of CRC cells and inhibited tumor growth in cell line-derived xenograft (CDX) model. Importantly, knockout of CDK15 in mice retarded AOM/DSS-induced tumorigenesis and CDK15 silencing by lentivirus significantly suppressed tumor progression in patient-derived xenograft (PDX) model. Mechanistically, CDK15 could bind PAK4 and phosphorylate PAK4 at S291 site. Phosphorylation of PAK4 at the S291 residue promoted cell proliferation and anchorage-independent growth through β-catenin/c-Myc, MEK/ERK signaling pathway in CRC. Moreover, inhibition of PAK4 reversed the tumorigenic function of CDK15 in CRC cells and pharmacological targeting PAK4 suppressed tumor growth in PDX models. Thus, our data reveal the pivotal role of CDK15 in CRC progression and demonstrate CDK15 promotes CRC tumorigenesis by phosphorylating PAK4. Hence, the CDK15-PAK4 axis may serve as a novel therapeutic target for CRC.

BackgroundExtranodal natural killer T cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma with invariable infection of lymphoma cells with Epstein-Barr virus (EBV), and the presence of EBV-DNA in the blood is a well-known prognosticator. However, there is no consensus on which blood compartment is more optimal for predicting survival outcomes.MethodsWe analyzed 60 patients who were newly diagnosed with ENKTL from a prospectively collected database. EBV-DNA was measured in the whole-blood (WB) and plasma at the time of diagnosis and after treatment completion.ResultsEBV-DNA was detected in pre-treatment WB and plasma in 37 (61.7%) and 23 (38.3%) patients, respectively. The presence of pre-treatment plasma EBV-DNA was significantly associated with advanced stage while presence of WB EBV-DNA did not. Positivity of pre-treatment plasma-EBV, but not WB EBV-DNA, was independently associated with poor PFS (HR, 4.22;95% CI, 1.79–9.97; P=0.001) and OS (HR, 8.38; 95% CI, 3.03–23.19; PP=0.002) and OS (HR, 32.38; 95% CI, 3.25–322.56; P=0.003), whereas no significant association was observed between WB-EBV status and survival outcomes.ConclusionsOur results suggest that EBV-DNA in the plasma has better prognostic values than WB in patients with ENKTL.

Background and Aim: Previous studies reported that serum myostatin is associated with sarcopenia. We aimed to elucidate the association between serum myostatin levels and hepatocellular carcinoma (HCC) development in patients with alcoholic liver cirrhosis (ALC). Methods: This retrospective, multicenter study assessed 1077 Asian ALC patients enrolled from 2007 to 2017. The primary endpoint was the development of HCC within 5 years. Cox proportional hazards model analyses were used to assess the association of serum myostatin levels and HCC development. The time-dependent areas under the receiver operating characteristic curve (AUROC) of serum myostatin for 5-year HCC development were calculated. Serum myostatin levels were measured using an enzyme-linked immunosorbent assay with samples collected on the index date. Results: During a median follow-up of 2.5 years, 5-year cumulative HCC incidence rates were 6.7% in the total population. The median level of serum myostatin was 3.3 ng/mL (interquartile, 2.1&ndash, 5.2 ng/mL). The AUROC of serum myostatin for 5-year HCC development was 0.78 (95% confidence interval [CI], 0.76&ndash, 0.81). In Cox proportional hazards model analyses, age, gender, platelet counts, and serum myostatin levels were independent risk factors for HCC development (adjusted hazard ratios [HRs] of age, male gender, platelet counts, and serum myostatin: 1.03, 2.79, 0.996, 1.18, respectively, all p &lt, 0.05). Patients with high myostatin levels had a significantly higher risk of 5-year HCC development than those with low myostatin levels (HR 7.53, p &lt, 0.001). Conclusion: Higher serum myostatin levels were significantly associated with a higher risk of developing HCC in ALC patients, which could identify high-risk patients who need stringent surveillance.