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Abstract Background and Aim Magnetic resonance elastography (MRE) is used for the evaluation of liver fibrosis; however, it remains unclear whether MRE‐based liver stiffness is associated with hepatocellular carcinoma (HCC) development, particularly in patients with chronic hepatitis B. Methods A total of 504 patients with chronic hepatitis B receiving MRE were enrolled. The primary endpoint was the association between MRE‐based liver stiffness and HCC. Results In a cross‐sectional analysis at the time of MRE measurement, the median (interquartile range) liver stiffness values in patients with presence or history of HCC and those without HCC were 3.68 (2.89–4.96) and 2.60 (2.22–3.45) kPa, respectively, and liver stiffness was significantly higher in patients with presence or history of HCC than in those without HCC (P

Background and aims: The enhanced liver fibrosis (ELF) score is a blood test that combines three markers linked to liver fibrosis. The utility of the ELF score has been demonstrated primarily in Western countries, but whether it is useful in areas with a high number of elderly people suffering from chronic liver disease has yet to be determined. Methods: This is a prospective study that included 373 consecutive patients who underwent a liver biopsy and had their ELF score measured on the same day. The diagnostic accuracy of the ELF score for liver fibrosis and the effect of age on the ELF score were investigated. Results: The median (interquartile) ELF scores in F0, F1, F2, F3, and F4 are 8.7 (8.2–9.2), 9.3 (8.8–10.0), 10.1 (9.4–10.7), 10.7 (9.9–11.2), and 12.0 (11.2–12.7), respectively. ELF scores increased with increasing liver fibrosis stage (p < 0.001). The diagnostic accuracy of the ELF score and FIB-4 for significant fibrosis (F2–4) and advanced fibrosis (F3–4) was comparable, but the ELF score had a higher diagnostic accuracy for cirrhosis (F4) than FIB-4. When patients were stratified by age of 60 years, the median ELF score did not differ by age in F2, F3, and F4. However, the median FIB-4 increased in patients with ≥60 years compared to those with Conclusions: ELF score has high diagnostic accuracy for liver fibrosis, regardless of age, and it could be used as a primary screening method.

Abstract Background and Aim Hepatocellular carcinoma development can be decreased by achieving and maintaining complete virological response (CVR) in chronic hepatitis B. However, it is unclear whether switching from entecavir (ETV) to tenofovir alafenamide (TAF) could achieve and maintain CVR in patients with low‐level viremia (LLV; HBV DNA ≤ 3.3 log IU/mL) or occasional detectable HBV DNA during ETV treatment. Therefore, we aimed to examine whether the switching from ETV to TAF is effective in achieving CVR in patients with LLV or occasional detectable HBV DNA. Methods This study comprised 45 patients who switched from ETV to TAF. All patients received ETV and TAF for >2 years, and the HBV DNA levels were measured every 3 months. Maintaining undetectable HBV DNA during 2‐year period is defined as CVR. The primary endpoint is the CVR rate during ETV and TAF treatment. Results The CVR rate for each of the 2 years of ETV and TAF therapy was 33.3% (15/45) and 68.9% (31/45, P

Abstract Background Patients with nonalcoholic fatty liver disease (NAFLD) are highly at risk for cardiovascular disease (CVD). However, the risk of developing CVD in patients with lean NAFLD is not yet fully understood. Therefore, this study aimed to compare the CVD incidence in Japanese patients with lean NAFLD and those with non-lean NAFLD. Methods A total of 581 patients with NAFLD (219 with lean and 362 with non-lean NAFLD) were recruited. All patients underwent annual health checkups for at least 3 years, and CVD incidence was investigated during follow-up. The primary end-point was CVD incidence at 3 years. Results The 3-year new CVD incidence rates in patients with lean and non-lean NAFLD were 2.3% and 3.9%, respectively, and there was no significant difference between two groups (p = 0.3). Multivariable analysis adjusted for age, sex, hypertension, diabetes, and lean NAFLD/non-lean NAFLD revealed that age (every 10 years) as an independent factor associated with CVD incidence with an odds ratio (OR) of 2.0 (95% confidence interval [CI]: 1.3–3.4), whereas lean NAFLD was not associated with CVD incidence (OR: 0.6; 95% CI: 0.2–1.9). Conclusions CVD incidence was comparable between patients with lean NAFLD and those with non-lean NAFLD. Therefore, CVD prevention is needed even in patients with lean NAFLD.

Abstract Aims Portopulmonary hypertension (PoPH) is a subtype of pulmonary arterial hypertension related to portal hypertension. The definitive diagnosis of PoPH is made by invasive right heart catheterization. Alternatively, pulmonary arterial hypertension may be recognized noninvasively from the tricuspid regurgitant pressure gradient (TRPG), measured by echocardiography. In this study, we aimed to establish a simple algorithm to identify chronic liver disease patients with a high TRPG value in order to narrow down the candidates to receive echocardiography. Methods and Results TRPG was measured by echocardiography in 152 patients with chronic liver disease. Factors predictive of TRPG >30 mmHg were investigated. There were 28 (18%) cases with TRPG >30 mmHg. Independent factors associated with a high TRPG were the presence of shortness of breath, high serum brain natriuretic peptide (BNP), and low serum albumin. Child–Pugh class or the presence of ascites, varices, or encephalopathy was not associated with TRPG. There was a correlation between the serum BNP and TRPG, and the optimal cutoff value of BNP by the Youden index was 122 pg/mL, and by 100% sensitivity was 50 pg/mL. A combination of these factors identified patients with a high probability of TRPG >30 mmHg (n = 12, positive predictive value [PPV] of 83%), no probability (n = 80, PPV 0%), and intermediate probability (n = 60, PPV 25–34%). This algorithm has reduced the number of patients needing echocardiography by 53%. Conclusions A simple algorithm using the presence of shortness of breath, serum BNP, and albumin levels can narrow down the candidates to receive echocardiography.

Key Clinical Message The liquid CGP was useful for detecting FGFR2 fusion and the patient experienced typical side effects (nail disorders, hyperphosphatemia, and taste disorders) of pemigatinib that required treatment.

We present the results of the single-dish observations using the Korean VLBI Network to search for anomalous microwave emission (AME) in nearby galaxies. The targets were selected from ‘Mapping the dense molecular gas in the strongest star-forming galaxies' (MALATANG), a legacy survey project of the James Clerk Maxwell Telescope. The MALATANG galaxies are good representatives of local galaxies with enhanced nuclear activity associated with star formation and/or active galactic nuclei (AGNs), providing IR-bright galaxy samples; thus, they are good candidates for AME hosts. Combining with ancillary data, we investigated the radio–IR spectral energy distribution (SED), while searching for AME signals in five galaxies. The AME in NGC 2903 was well detected at a significant confidence level, whereas that in NGC 2146 and M82 was marginal. NGC 1068 and Arp 299 indicated no significant hints, and we provide upper limits for the AME. The best-fit SED exhibited local peaks of the AME components at higher frequencies and with stronger peak fluxes than those in previous studies. This suggested that AME originates from denser environments such as molecular clouds or photodissociation regions rather than warm neutral/ionized medium as commonly suggested by previous studies. Further, our AME-detected targets were observed to exhibit higher specific star formation rates than the other extragalactic AME hosts. Furthermore, AME favored starburst galaxies among our sample rather than AGN hosts. Consequently, this might imply that AGNs are excessively harsh environments for tiny dust to survive.

We report 850 μ m continuum polarization observations toward the filamentary high-mass star-forming region NGC 2264, taken as part of the B -fields In STar forming Regions Observations large program on the James Clerk Maxwell Telescope. These data reveal a well-structured nonuniform magnetic field in the NGC 2264C and 2264D regions with a prevailing orientation around 30° from north to east. Field strength estimates and a virial analysis of the major clumps indicate that NGC 2264C is globally dominated by gravity, while in 2264D, magnetic, gravitational, and kinetic energies are roughly balanced. We present an analysis scheme that utilizes the locally resolved magnetic field structures, together with the locally measured gravitational vector field and the extracted filamentary network. From this, we infer statistical trends showing that this network consists of two main groups of filaments oriented approximately perpendicular to one another. Additionally, gravity shows one dominating converging direction that is roughly perpendicular to one of the filament orientations, which is suggestive of mass accretion along this direction. Beyond these statistical trends, we identify two types of filaments. The type I filament is perpendicular to the magnetic field with local gravity transitioning from parallel to perpendicular to the magnetic field from the outside to the filament ridge. The type II filament is parallel to the magnetic field and local gravity. We interpret these two types of filaments as originating from the competition between radial collapsing, driven by filament self-gravity, and longitudinal collapsing, driven by the region's global gravity.

Abstract Background and Aim Conversion surgery (CS), which aims to cure after systematic therapy, is only scarcely reported in the field of hepatocellular carcinoma (HCC). However, advancements in systemic therapy for HCC are expected to increase the candidates eligible for CS because of the higher response rate. The aim of this study was to clarify the characteristics of patients who underwent CS after tyrosine kinase inhibitor (TKI) therapy. Methods In all, 364 patients who were treated with first‐line sorafenib (SOR; n = 292) and lenvatinib (LEN; n = 72) from July 2009 to October 2020 were retrospectively enrolled. The endpoint of this analysis was overall survival (OS), and factors associated with CS are revealed. Results Six patients underwent CS after TKI therapy, and of these four (1.4%) and two (2.7%) patients received SOR and LEN, respectively. At baseline, patients who underwent CS were significantly younger (median 52 [range, 46–83] years of age, P = 0.019), and their etiology included viral hepatitis, especially hepatitis B virus (HBV) (P = 0.049). Improvements or maintenance of preoperative modified albumin–bilirubin grade from baseline were observed in five (83.3%) patients, and partial radiologic response was observed in four (66.7%) patients. The median OS and 3‐year survival rate of patients treated with CS were “not reached” and 80.0%, respectively. Conclusion The patients who underwent CS after TKI therapy for HCC experienced long survival, were relatively young, and exhibited radiologic response to TKIs, and their liver function was either maintained or improved. Therefore, CS may lead to a better prognosis in patients with advanced HCC.

Abstract Background and Aim Administration of tenofovir alafenamide (TAF) as prevention or treatment of hepatitis B virus (HBV) reactivation is not well known. The aim of this study is to reveal the efficacy and safety of TAF against HBV reactivation. Methods Entecavir (ETV) and TAF were given to 66 and 11 patients, respectively, as prophylaxis against or treatment of HBV reactivation during chemotherapy or immune suppression therapy from January 2010 to June 2020. The antiviral effects and safety were assessed. Results At week 24, the antiviral effects on patients receiving ETV and TAF were similar in terms of reduction of HBV DNA (−2.83 ± 1.45log IU/mL vs −3.05 ± 2.47log IU/mL; P = 0.857) and achieving undetectable levels of HBV DNA (78.8 vs 90.9%; P = 0.681). There was no significant difference in the decrease in the estimated glomerular filtration rate (eGFR) between the two groups (−0.62 ± 11.2 mL/min/1.73 m2 vs −3.67 ± 13.2 mL/min/1.73 m2; P = 0.291). Conclusion TAF is safe and effective against HBV reactivation.

Abstract Background Therapeutic strategies for unresectable hepatocellular carcinoma (u‐HCC) in geriatric patients are important for real‐world practice. However, there remain no established biomarkers or therapeutic strategies regarding the best second‐line agent after atezolizumab plus bevacizumab therapy. Aim In this study, we investigated the usefulness of modified Geriatric 8 (mG8) score in examining elderly patients (≥75 years old) with unresectable hepatocellular carcinoma (u‐HCC) using sorafenib or lenvatinib as first‐line therapy. Methods and results This study assessed 101 elderly patients with u‐HCC for their mG8 score (excluding elements of age from 8 items) and classified them into 2 groups according to their mG8 score: ≥11 as the high‐score group and ≤ 10 as the low‐score group. Among those taking sorafenib, no significant differences were noted in overall survival (OS) and progression free survival (PFS) between low and high mG8 score groups. Only modified albumin–bilirubin (ALBI) grade (2b/3 vs. 1/2a: HR 0.34; 95% CI, 0.17–0.69; p = .0029) was significantly associated with OS. Among those taking lenvatinib, patients with a high mG8 score (n = 26) had longer survival than those with a low mG8 score (n = 10) (20.0 months vs. 7.7 months: HR 0.31, 95% CI 0.11–0.89; p = .029). Intrahepatic tumor volume (

Introduction Secondary bladder, colon, and rectal cancers are relatively common after prostate radiotherapy. However, secondary squamous cell carcinoma of the prostate is rare. Case presentation An 85‐year‐old man presented with dysuria and low‐serum prostate‐specific antigen levels. His medical history included localized prostate adenocarcinoma (Gleason score of 4 + 5) treated with combined three‐dimensional conformal radiotherapy and androgen deprivation therapy, 11 years ago. Urethroscopy and magnetic resonance imaging showed a bulging mass around the prostatic urethra. Transurethral resection of the prostate performed for histopathological diagnosis revealed squamous cell carcinoma. Conclusion Hereby, a rare case of secondary squamous cell carcinoma of the prostate after radiotherapy for adenocarcinoma was reported, which was found after 11 years of radiotherapy with symptom of dysuria including urinary hesitancy, difficulty, pain during urination, and low‐serum prostate‐specific antigen levels.

Background and Aim Loss of hepatitis B surface antigen (HBsAg) is an important goal in the treatment of chronic hepatitis B. We investigated whether switching from long‐term entecavir (ETV) administration to tenofovir (TFV) (tenofovir alafenamide [TAF] or tenofovir disoproxil fumarate [TDF]) could contribute to the reduction of HBsAg levels. Methods The degree of HBsAg reduction by 48 weeks in 30 patients following switching from ETV to TFV was compared with results from 147 patients who continued ETV as a control. Results TFV group switched to TFV after mean 6.79 years of ETV administration. HBV‐DNA levels remained below 1.0 log IU/mL in all cases in both groups during 48 weeks. Median HBsAg reduction at 48 weeks was 0.075 (−0.05 to 0.38) log/IU/mL in the TFV switch group, and 0.070 (−0.28 to 0.50) in the ETV continuation group, which was not statistically significant (p = 0.5). In a subgroup of hepatitis B e antigen negative patients whose HBsAg had not been reduced (HBsAg reduction ≤0 log IU/mL) in the 48 weeks prior to entry into the study, HBsAg reduction was significantly higher in the TFV switch group than in the ETV continuation group (0.15 [0.07–0.135] in TFV, 0.09 [−0.14 to 0.25] log IU/mL in ETV, p = 0.04). Conclusion Although HBsAg reduction is equivalent with ETV continuation and switching to TFV in all patients at 48 weeks, switching from ETV to TFV could provide an alternative therapeutic strategy toward HBsAg elimination in a specific subpopulation of patients.

Background and aim The long-term prognosis of hepatocellular carcinoma (HCC) treated at a very-early-stage (the Barcelona Clinical Liver Cancer (BCLC) classification stage 0) was unclear, especially in terms of background liver disease. Methods This single-center, retrospective study included 302 patients with BCLC stage 0 HCC treated with radiofrequency ablation (RFA) and followed for at least six months. We examined the impact of background liver disease on overall survival and recurrence. Results The median age was 72 (range; 36–91) years; the median tumor diameter was 15 (range; 8–20) mm. The etiologies of background liver disease were hepatitis B virus infection (HBV) in 24 cases, hepatitis C virus infection (HCV) in 195 cases, and non-viral (NBNC) in 83 cases. Among the patients with HCV, 63 had achieved sustained virological response (SVR) by antiviral therapy (HCV SVR) before developing HCC (n = 37) or after HCC treatment (n = 26), and 132 had active HCV infection (HCV non-SVR). The median overall survival was 85 (95% CI; 72–98) months, and the median recurrence-free survival was 26 (95% CI; 20–30) months. Active infection with hepatitis C virus negatively contributed to overall survival (HR 2.91, 95% CI 1.31–3.60, p = 0.003) and recurrence-free survival (HR 1.47, 95% CI 1.06–2.05, p = 0.011). Conclusions The prognosis of RFA treatment for very early-stage HCC was favorable. Achieving SVR in hepatitis C was important for further prognosis improvement.

Background Prothrombin induced by vitamin K absence-II (PIVKA-II) was reported as a diagnosis and prognosis marker for hepatocellular carcinoma (HCC). Although the development of systemic therapies for advanced HCC has been remarkable, the role of PIVKA-II is unclear. This prospective study aimed to verify Elecsys PIVKA-II compared with Lumipulse PIVKA-II in a cohort with advanced HCC undergoing systemic therapy. Methods A total of 62 HCC patients who were treated with atezolizumab and bevacizumab (ATZ+BEV) and molecular targeted agents (MTAs) were prospectively enrolled at Musashino Red Cross Hospital from January 2020 to December 2020. A total of 208 serum samples from 52 patients were tested using Elecsys PIVKA-II and Lumipulse PIVKA-II assays. Furthermore, the relationship of Elecsys PIVKA-II and progression-free survival (PFS) was investigated with 48 patients (24 ATZ+BEV and 24 MTAs) whose Lumipulse PIVKA-II levels were >40 mAU/mL. Results In the test accuracy analysis, the Elecsys assay has a correlation coefficient (R) of 0.92 compared with that of the Lumipulse assay (ATZ+BEV, 0.95; MTAs, 0.91). In the PFS analysis, the number of patients who received ATZ+BEV and MTAs as first- and late-line therapy were 9 and 13, and 15 and 11, respectively. The PIVKA-II response was defined for patients who had a reduction in the Elecsys PIVKA-II level on the first month of treatment evaluation. The PFS of patients with Elecsys PIVKA-II response was significantly longer than that of nonresponse patients (5.8 months vs 3.8 months, p = 0.0205). Conclusion The Elecsys PIVKA-II was not only as useful as the Lumipulse PIVKA-II but also for stratifying the PFS of patients with advanced HCC.

We present observations of polarized dust emission at 850 μ m from the L43 molecular cloud, which sits in the Ophiuchus cloud complex. The data were taken using SCUBA-2/POL-2 on the James Clerk Maxwell Telescope as a part of the BISTRO large program. L43 is a dense ( ${N}_{{{\rm{H}}}_{2}}\sim {10}^{22}$ –10 ^23 cm ^−2 ) complex molecular cloud with a submillimeter-bright starless core and two protostellar sources. There appears to be an evolutionary gradient along the isolated filament that L43 is embedded within, with the most evolved source closest to the Sco OB2 association. One of the protostars drives a CO outflow that has created a cavity to the southeast. We see a magnetic field that appears to be aligned with the cavity walls of the outflow, suggesting interaction with the outflow. We also find a magnetic field strength of up to ∼160 ± 30 μ G in the main starless core and up to ∼90 ± 40 μ G in the more diffuse, extended region. These field strengths give magnetically super- and subcritical values, respectively, and both are found to be roughly trans-Alfvénic. We also present a new method of data reduction for these denser but fainter objects like starless cores.

We study the H ii regions associated with the NGC 6334 molecular cloud observed in the submillimeter and taken as part of the B -fields In STar-forming Region Observations Survey. In particular, we investigate the polarization patterns and magnetic field morphologies associated with these H ii regions. Through polarization pattern and pressure calculation analyses, several of these bubbles indicate that the gas and magnetic field lines have been pushed away from the bubble, toward an almost tangential (to the bubble) magnetic field morphology. In the densest part of NGC 6334, where the magnetic field morphology is similar to an hourglass, the polarization observations do not exhibit observable impact from H ii regions. We detect two nested radial polarization patterns in a bubble to the south of NGC 6334 that correspond to the previously observed bipolar structure in this bubble. Finally, using the results of this study, we present steps (incorporating computer vision; circular Hough transform) that can be used in future studies to identify bubbles that have physically impacted magnetic field lines.

We present BISTRO Survey 850 μ m dust emission polarization observations of the L1495A-B10 region of the Taurus molecular cloud, taken at the James Clerk Maxwell Telescope (JCMT). We observe a roughly triangular network of dense filaments. We detect nine of the dense starless cores embedded within these filaments in polarization, finding that the plane-of-sky orientation of the core-scale magnetic field lies roughly perpendicular to the filaments in almost all cases. We also find that the large-scale magnetic field orientation measured by Planck is not correlated with any of the core or filament structures, except in the case of the lowest-density core. We propose a scenario for early prestellar evolution that is both an extension to, and consistent with, previous models, introducing an additional evolutionary transitional stage between field-dominated and matter-dominated evolution, observed here for the first time. In this scenario, the cloud collapses first to a sheet-like structure. Uniquely, we appear to be seeing this sheet almost face on. The sheet fragments into filaments, which in turn form cores. However, the material must reach a certain critical density before the evolution changes from being field dominated to being matter dominated. We measure the sheet surface density and the magnetic field strength at that transition for the first time and show consistency with an analytical prediction that had previously gone untested for over 50 yr.

Human induced pluripotent stem (hiPS) cells have been used as a cell source for regenerative therapy and disease modeling. The purity of hiPS-cardiomyocytes (hiPS-CMs) has markedly improved with advancements in cell culture and differentiation protocols. However, the morphological features and molecular properties of the relatively immature cells are still unclear, which has hampered their clinical application. The aim of the present study was to investigate the extent to which topographic substrates actively influence hiPS-CMs. hiPS-CMs were seeded on randomized oriented fiber substrate (random), anisotropic aligned fiber substrate (align), and flat non-scaffold substrate (flat). After culturing for one week, the hiPS-CMs on the aligned patterns showed more mature-like properties, including elongated rod shape, shorter duration of action potential, accelerated conduction velocity, and elevated cardiac gene expression. Subsequently, to determine whether this development was irreversible or was altered after withdrawal of the structural support, the hiPS-CMs were harvested from the three different patterns and reseeded on the non-scaffold (flat) pattern. After culturing for one more week, the improvements in morphological and functional properties diminished, although hiPS-CMs pre-cultured on the aligned pattern retained the molecular features of development, which were even more significant as compared to that observed during the pre-culture stage. Our results suggested that the anisotropic fiber substrate can induce the formation of geometrical mimic-oriented heart tissue in a short time. Although the morphological and electrophysiological properties of hiPS-CMs obtained via facilitated maturation somehow rely on the existence of an exterior scaffold, the molecular developmental features were preserved even in the absence of the external support, which might persist throughout hiPS-CM development.

Lenvatinib is an approved first-line therapy for unresectable hepatocellular carcinoma (HCC), but the effect of dose modification on its efficacy is unclear. We analyzed the relationship between the relative dose intensity during the initial 4 weeks of therapy [4W-relative dose intensity (RDI)] and the efficacy of lenvatinib therapy in the real-world setting. A total of 48 consecutive patients with unresectable HCC who received lenvatinib therapy for more than 4 weeks were included. The 4W-RDI was calculated as the cumulative dose in the initial 4 weeks divided by the weight-based standard dose, and we evaluated its association with overall survival (OS) and best response by modified Response Evaluation Criteria in Solid Tumor (mRECIST). The baseline factors predicting high 4W-RDI were analyzed further. The median durations of follow-up and of therapy among the 48 participants were 7.6 and 6.6 months, respectively. The median OS was not reached. Drug interruption and/or dose reduction were necessary in 30 patients (62.5%) and the median 4W-RDI was 70% (range 22%-100%). Patients with 4W-RDI ≥70% had longer OS [hazard ratio (HR) 0.28, 95% confidential interval (CI):0.09-0.90, p = 0.03], and longer duration of lenvatinib therapy (HR 0.39, 95%CI:0.16-0.92, p = 0.03). Patients with 4W-RDI ≥70% showed higher disease control rate compared to those with 4W-RDI 3.4g/dL or ALBI score less than -2.171 were significantly associated with achieving 4W-RDI ≥70%. In conclusion, 4W-RDI of lenvatinib therapy is associated with favorable radiological response and longer OS.

Abstract Histological molecular classification of hepatocellular carcinoma (HCC) is clinically important for predicting the prognosis. However, a reliable serum marker has not been established. The aim of this study was to evaluate the diagnostic value of serum Wisteria Floribunda agglutinin-positive sialylated mucin 1 (WFA-sialylated MUC1), which is a novel biliary marker, as a marker of HCC with hepatic progenitor cell (HPC)/biliary features and of prognosis. A total of 144 consecutive patients who underwent complete radiofrequency ablation of primary HCC were enrolled. A serum WFA-sialylated MUC1 level of 900 μL/mL was determined as the optimal cutoff value for prediction of immunohistochemical staining for HPC/biliary features [sialylated MUC1 and cytokeratin 19 (CK19)]. Positive staining rate of sialylated MUC1 and CK19 was significantly higher in patients with WFA-sialylated MUC1 ≥900 than those with WFA-sialylated MUC1

Ectopic foci from pulmonary veins (PVs) comprise the main trigger associated with the initiation of atrial fibrillation (AF). An abrupt anatomical narrow-to-wide transition, modeled as in vitro geometrical patterning with similar configuration in the present study, is located at the junction of PVs and the left atrium (LA). Complex cellular composition, i.e., constituent cell heterogeneity, is also observed in PVs and the PVs-LA junction. High frequency triggers accompanied with anatomical irregularity and constituent cell heterogeneity provoke impaired conduction, a prerequisite for AF genesis. However, few experiments investigating the effects of these factors on electrophysiological properties using human-based cardiomyocytes (CMs) with atrial properties have been reported. The aim of the current study was to estimate whether geometrical patterning and constituent cell heterogeneity under high frequency stimuli undergo conduction disturbance utilizing an in vitro two-dimensional (2D) monolayer preparation consisting of atrial-like CMs derived from human induced pluripotent stem cells (hiPSCs) and atrial fibroblasts (Fbs). We induced hiPSCs into atrial-like CMs using a directed cardiac differentiation protocol with the addition of all-trans retinoic acid (ATRA). The atrial-like hiPSC-derived CMs (hiPSC-CMs) and atrial Fbs were transferred in defined ratios (CMs/Fbs: 100%/0% or 70%/30%) on manually fabricated plates with or without geometrical patterning imitating the PVs-LA junction. High frequency field stimulation emulating repetitive ectopic foci originated in PVs were delivered, and the electrical propagation was assessed by optical mapping. We generated high purity CMs with or without the ATRA application. ATRA-treated hiPSC-CMs exhibited significantly higher atrial-specific properties by immunofluorescence staining, gene expression patterns, and optical action potential parameters than those of ATRA-untreated hiPSC-CMs. Electrical stimuli at a higher frequency preferentially induced impaired electrical conduction on atrial-like hiPSC-CMs monolayer preparations with an abrupt geometrical transition than on those with uniform geometry. Additionally, the application of human atrial Fbs to the geometrically patterned atrial-like hiPSC-CMs tended to further deteriorate the integrity of electrical conduction compared with those using the atrial-like hiPSC-CM alone preparations. Thus, geometrical narrow-to-wide patterning under high frequency stimuli preferentially jeopardized electrical conduction within in vitro atrial-like hiPSC-CM monolayers. Constituent cell heterogeneity represented by atrial Fbs also contributed to the further deterioration of conduction stability.

Background and aimsThe present study aimed to report our real-life experience of the TPO receptor agonist lusutrombopag for cirrhotic patients with low platelet counts.MethodsWe studied platelet counts in 1,760 cirrhotic patients undergoing invasive procedures at our hospital between January 2014 and December 2017. In addition, we studied 25 patients who were administered lusutrombopag before invasive procedures between June 2017 and January 2018. Effectiveness of lusutrombopag to raise platelet counts and to avoid transfusion and treatment-related adverse events were analyzed.ResultsIn 1,760 cirrhotic patients without lusutrombopag prior to invasive procedures, proportion of patients whose platelet counts 30,000/μL (n = 17) (50,000 ± 20,000 vs 86,000 ± 26,000/μL, p = 0.002). Patients with a baseline platelet count ≤30,000/μL with spleen index (calculated by multiplying the transverse diameter by the vertical diameter measured by ultrasonography) ≥40 cm2 (n = 3) had a lower response rate to lusutrombopag compared to those with spleen index ConclusionsLusutrombopag is an effective and safe drug for thrombocytopenia in cirrhotic patients, and can reduce the frequency of platelet transfusions.

Chronic liver disease is generally widespread, and a test for screening fibrotic subjects in a large population is needed. The ability of Wisteria floribunda agglutinin-positive mac-2 binding protein (WFA+-M2BP) to detect significant fibrosis was investigated in health checkup subjects in this research. Of 2021 health checkup subjects enrolled in this prospective cross-sectional study, those with WFA+-M2BP ≥ 1.0 were defined as high risk. Liver fibrosis was evaluated using magnetic resonance elastography (MRE) in subjects with high risk. The primary outcome was the positive predictive value (PPV) of WFA+-M2BP for significant fibrosis (liver stiffness ≥ 2.97 kPa by MRE). This trial was registered with the UMIN clinical trial registry, UMIN000036175. WFA+-M2BP ≥ 1.0 was observed in 5.3% of the 2021 subjects. The PPV for significant fibrosis with the threshold of WFA+-M2BP at ≥1.0, ≥1.1, ≥1.2, ≥1.3, ≥1.4, and ≥1.5 was 29.2%, 36.4%, 43.5%, 42.9%, 62.5%, and 71.4%, respectively. A WFA+-M2BP of 1.2 was selected as the optimal threshold for significant fibrosis among high-risk subjects, and the PPV, negative predictive value, sensitivity, and specificity for significant fibrosis were 43.5%, 84.0%, 71.4%, and 61.8%, respectively. WFA+-M2BP ≥ 1.2 was significantly associated with significant fibrosis, with an odds ratio (OR) of 4.04 (95% confidence interval (CI): 1.1–16, p = 0.04), but not FIB-4 ≥ 2.67 (OR: 2.40, 95%CI: 0.7–8.6, p-value = 0.2). In conclusion, WFA+-M2BP is associated with significant fibrosis and could narrow down potential subjects with liver fibrosis. The strategy of narrowing down fibrosis subjects using WFA+-M2BP may be used to screen for fibrotic subjects in a large population.

Abstract Radiofrequency ablation (RFA) is considered the most effective treatment for early‐stage hepatocellular carcinoma (HCC) patients unsuitable for resection. However, poor outcome after RFA has occasionally been reported worldwide. To predict such an outcome, we investigated imaging findings using contrast‐enhanced ultrasonography (CEUS) with Sonazoid and serum tumor markers before RFA. This study included 176 early‐stage HCC patients who had initially achieved successful RFA. Patients were examined using CEUS; their levels of alpha‐fetoprotein (AFP), Lens culinaris agglutinin‐reactive fraction of AFP (AFP‐L3), and des‐gamma‐carboxy prothrombin before RFA were measured. Sonazoid provided parenchyma‐specific contrast imaging and facilitated tumor vascular architecture imaging through maximum intensity projection (MIP). Kaplan–Meier analysis examined cumulative rates of local tumor progression, intrasubsegmental recurrence, and survival; factors associated with these were determined with Cox proportional hazards analysis. Local tumor progression (n = 15), intrasubsegmental recurrence (n = 46), and death (n = 18) were observed. Irregular pattern in MIP classification and serum AFP‐L3 level (>10%) before RFA were identified as independent risk factors for local tumor progression and intrasubsegmental recurrence. These two factors were independently associated with poor survival after RFA (irregular pattern in MIP: hazard ratio, (HR) = 8.26; 95% confidence interval, (CI) = 2.24–30.3; P = 0.002 and AFP‐L3 > 10%: HR = 2.94; 95% CI = 1.09–7.94; P = 0.033). Irregular MIP pattern by CEUS and high level of serum AFP‐L3 were independent risk factors for poor outcome after successful RFA. The Patients with these findings should be considered as special high‐risk group in early‐stage HCC.

Identification of high-risk patients for hepatocellular carcinoma (HCC) after sustained virological responses (SVR) is necessary to define candidates for long-term surveillance. In this study, we examined whether serum markers after 1 year of SVR could predict subsequent HCC development. Total 734 chronic hepatitis C patients without a history of HCC who achieved SVR with direct-acting antivirals were included. The regular surveillance for HCC started from 24 weeks after the end of treatment (SVR24). Factors at SVR24 and 1 year after SVR24 were analyzed for predicting HCC development. During the mean observation period of 19.7 ± 10 months, 24 patients developed HCC. At SVR24, Wisteria floribunda agglutinin-positive mac-2 binding protein (WFA±M2BP) ≥ 1.85 and α-fetoprotein (AFP) ≥ 6.0 ng/mL were independent factors of HCC development. However, at 1 year after SVR24, WFA±M2BP ≥ 1.85 was associated with subsequent HCC development (hazard ratio: 23.5, 95% confidence interval: 2.68–205) but not AFP. Among patients with WFA±M2BP ≥ 1.85 at SVR24, 42% had WFA±M2BP < 1.85 at 1 year after SVR24 (WFA±M2BP declined group). Subsequent HCC development was significantly lower in the declined group than in the non-declined group (1 year HCC rate: 0% vs. 9.4%, p = 0.04). In conclusion, WFA±M2BP but not AFP could identify high and no-risk cases of HCC at 1 year after SVR. Therefore, it was useful as a real-time monitoring tool to identify the candidates for continuous surveillance for HCC.

Background: A test to narrow down patients who require esophagogastroduodenoscopy (EGD) with a high probability of having gastroesophageal varices (GEV) and a high-risk of liver-related events is an unmet need. Methods: The measurement of serum fibrosis markers and EGD was performed in 166 consecutive chronic hepatitis C patients. The correlation between the grades of GEV and fibrosis markers and the subsequent occurrence of liver-related and fibrosis markers were examined. Results: Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+−M2BP) levels increased according to the grade of GEV (3.4 (0.2−18.6) for no GEV, 7.9 (1.8−20.0) for small GEV, and 11.4 (4.0−20.0) for large GEV; p < 0.001). The diagnostic accuracy of the WFA+−M2BP was superior compared to other serum fibrosis markers, and WFA+−M2BP was an independent predictor of GEV in the multivariate analysis. Furthermore, the cumulative incidence of liver-related events at one year was 2.3% in patients with WFA+−M2BP levels ≤ 7.0 and 37.5% in patients with WFA+−M2BP levels > 7.0 (p < 0.001). WFA+−M2BP > 7.0 was a significant predictive factor for liver-related events (Hazard ratio 6.7, p = 0.004) independent of Child−Pughclass. Conclusions: WFA+−M2BP could be used to estimate the presence and grade of GEV and is linked to liver-related events in chronic hepatitis C patients.

BACKGROUND:The present study aimed to investigate the impact of pre-sarcopenia on the prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. METHODS:We enrolled 214 patients (71 ± 10 years old; 166 men and 48 women; 90% Child-Pugh grade A and 10% Child-Pugh grade B) treated with sorafenib in our hospital from July 2009 to August 2016. The muscle volume was measured from CT images just before sorafenib administration using software (SliceOmatic). Skeletal muscle mass index was calculated, and the presence of pre-sarcopenia was judged according to the standard (42 cm2/m2 for men and 38 cm2/m2 for women) proposed by the Japan Society of Hepatology. RESULTS:Pre-sarcopenia was found in 123 patients (57%). The overall survival (OS) in patients with pre-sarcopenia tended to be worse than in patients without pre-sarcopenia (median 252 vs. 284 days, respectively; p = 0.16). Multivariate Cox hazard analysis revealed a baseline serum albumin level of ≤3.5 g/dl [hazard ratio (HR) 1.9; p = 0.0006], a baseline alpha-fetoprotein(AFP) level of ≥100 ng/ml (HR 2.1; p = 0.002), presence of lesions in bilateral hepatic lobes (HR 1.7; p = 0.03), and presence of major portal vein invasion (HR 1.8; p = 0.01) to be independent prognostic factors. In the 68 patients who had three or more negative prognostic factors, the presence of pre-sarcopenia did not correlate with prognosis. Of the 146 patients who had two or less prognostic factors, OS was significantly worse in 84 patients (58%) with pre-sarcopenia than in 62 patients without pre-sarcopenia (median 417 vs. 562 days, respectively; p = 0.047), and Cox hazard analysis revealed pre-sarcopenia to be an important prognostic factor (HR 1.6; p = 0.047). CONCLUSION:In sorafenib treatment for advanced HCC, pre-sarcopenia is a significant prognostic factor in patients with two or less negative prognostic factors, and could be the target of intervention to improve prognosis.

BACKGROUND:Tolvaptan is vasopressin type 2 receptor antagonist that inhibits water reabsorption. It is used in combination with standard diuretics to treat ascites unresponsive to standard diuretic therapy or hyponatremia because of liver cirrhosis. This study evaluated the effectiveness and safety of tolvaptan in clinical practice and aimed to determine the factors related to its effectiveness. METHODS:Tolvaptan was administered to 88 consecutive cirrhotic patients with ascites unresponsive to standard diuretic therapy. An effective treatment response was a ≥2% reduction in body weight on day 7. The association of patient pretreatment characteristics with therapeutic effects was analyzed. RESULTS:Mean weight reduction on day 7 of tolvaptan therapy was -2.9% ± 3.2%, and treatment was effective in 52% of patients. Multivariate analysis revealed that spot urine Na/K ratio ≥2.5 at baseline was the only factor independently related to therapeutic effect, with an odds ratio of 7.85 (95% confidence interval 2.64-23.40, p = 0.0002). Weight reduction percentage on day 7 was -4.0% ± 2.8% in patients with spot urine Na/K ≥2.5, which was significantly greater than the 0.7% ± 2.7% loss in those with urine Na/K < 2.5 (p < 0.05). A spot urine Na/K ratio ≥2.5 had a sensitivity of 85% and specificity of 60% for predicting effective treatment. No adverse events of treatment led to treatment discontinuation. CONCLUSIONS:Baseline spot urine Na/K was predictive of an effective response to tolvaptan therapy. It is simple to perform and readily available and might serve as an indicator of optimal timing of tolvaptan administration in patients with inadequate response to conventional Na diuretic therapy.

The sympathetic nervous system is critical in maintaining the normal physiological function of the heart. Its dysfunction in pathological states may exacerbate the substrate for arrhythmias. Obviously, knowledge of its three-dimensional (3D) structure is important, however, it has been revealed by conventional methods only to a limited extent. In this study, a new method of tissue clearance in combination with immunostaining unravels the 3D structure of the sympathetic cardiac network as well as its changes after myocardial infarction.Hearts isolated from adult male mice were optically cleared using the CUBIC-perfusion protocol. After making the hearts transparent, sympathetic nerves and coronary vessels were immunofluorescently labeled, and then images were acquired. The spatial distribution of sympathetic nerves was visualized not only along the epicardial surface, but also transmurally. They were distributed over the epicardial surface and penetrated into the myocardium to twist around coronary vessels, but also independent from the coronary vasculature. At 2 weeks after myocardial infarction, we were able to quantify both denervation distal from the site of infarction and nerve sprouting (hyperinnervation) at the ischemic border zone of the hearts in a 3D manner. The nerve density at the ischemic border zone was more than doubled in hearts with myocardial infarction compared to intact mice hearts (3D analyses; n = 5, p

We studied large-scale magnetic field reversals of a galaxy based on a magnetic vector map of NGC6946. The magnetic vector map was constructed based on the polarization maps in the C and X bands after the determination of the geometrical orientation of a disk with the use of an infrared image and the velocity field, according to the trailing spiral arm assumption. We examined the azimuthal variation of the magnetic vector and found that the magnetic pitch angle changes continually as a function of the azimuthal angle in the inter-arm region. However, the direction of the magnetic field had 180 ∘ jumps at the azimuthal angles of 20 ∘ , 110 ∘ , 140 ∘ , 220 ∘ , 280 ∘ , and 330 ∘ . These reversals seem to be related to the spiral arms since the locations of the jumps are coincident with those of the spiral arms. These six reversals of the magnetic field were seen only in the inner region of NGC6946 whereas four reversals can be identified in the outer region.

We present a method for determining the directions of magnetic-field vectors in a spiral galaxy using two synchrotron polarization maps, an optical image, and a velocity field. The orientation of the transverse magnetic field is determined with a synchrotron polarization map of a higher-frequency band, and the 180°-ambiguity is solved by using a sign of Rotation Measure (RM) after determining the geometrical orientation of a disk based on an assumption of trailing spiral arms. The advantage of this method is that the direction of a magnetic vector for each line of sight throughout the galaxy can inexpensively be determined, with easily available data and simple assumptions. We applied this method to three nearby spiral galaxies using archival data obtained with a Very Large Array (VLA) to demonstrate how it works. The three galaxies have both clockwise and counterclockwise magnetic fields, which implies that none of the three galaxies is classified in a simple Axis-Symmetric type, but types of higher modes, and that magnetic reversals commonly exist.

Magnetic fields in the universe play an essential role in observations of the radio synchrotron continuum; however, we do not know enough about them, either observationally or theoretically. We are interested in galactic magnetic fields because they affect the structural formation of galaxies in terms of star-forming regions, spiral arms, and threads at the galactic center. To clarify the importance of magnetic fields, we carried out numerical simulations of the galactic gaseous disk with magnetic fields. We also calculated observables, such as the rotation measure and Stokes parameters, from the results of numerical simulation. FD maps and intensity maps have been reported, and the relation between azimuthal angle and FD has been shown to depend on the inclination of the observer. Furthermore, it has been shown that a polarized intensity below 800 MHz reflects field structure in the halo region, although the intensity is weak. The present paper summarizes the effects of Faraday depolarization and the relation between magnetic-field structure and Stokes parameters.

A jet termination region provides us with useful information about how a jet interacts with the interstellar medium. Identifying the strength and orientation of magnetic fields at the terminal is crucially important to understanding the mechanism of cosmic-ray acceleration. In this article, we report results of our Faraday-tomography analysis of the eastern region of the radio nebula W50, where a jet from the microquasar SS433 seems to terminate. We apply QU-fitting, a method of Faraday-tomography, to data from the Australia Telescope Compact Array (ATCA) at 1.3⁻3.0 GHz. In the analysis, we distinguish multiple polarized sources along the line of sight. We identify Galactic emission candidates at Faraday depths around 0 rad m−2 and 300 rad m−2. The Galactic emission around 0 rad m−2 is possibly located in front of W50. We also find emission from W50 with Faraday depths between φ = −112 to 228 rad m−2.

Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug's toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43% (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77x10(-3), odds ratio (OR) = 1.04, 95%CI = 1.01-1.07) and ABCG2 421C>A (P = 1.87x10(-2), OR = 1.71, 95%CI = 1.09-2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41x10(-3), OR = 1.86, 95% CI = 1.17-2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.

For patients receiving endoscopic submucosal dissection (ESD), there is urgent need pertaining to the prevention of postoperative bleeding. We conducted a retrospective propensity score-matched study that evaluated whether pre-ESD gastric lavage prevents postoperative bleeding after ESD for gastric neoplasms.From September 2002 to October 2015, the 760 consecutive patients receiving ESD for gastric neoplasm were enrolled and data regarding them were retrospectively analyzed. All patients received conventional preventive treatment against delayed bleeding after ESD, including the administration of proton pump inhibitor and preventive coagulation of visible vessels, at the end of the ESD procedure.Pre-ESD risk factors for postoperative bleeding included tumor size and no gastric lavage. Using multivariate analysis tumor size >2.0 cm (HR 2.90, 95% CI 1.65-5.10, p = 0.0002) and no gastric lavage (HR 3.20, 95% CI 1.13-9.11, p = 0.029) were found to be independent risk factors. Next, we evaluated the effect of gastric lavage on the prevention of post-ESD bleeding using a propensity score-matching method. A total of 284 subjects (142 per group) were selected. Adjusted odds ratio of gastric lavage for post-ESD bleeding was 0.25 (95% CI 0.071-0.886, p = 0.032).Pretreatment gastric lavage reduced postoperative bleeding in patients receiving ESD for gastric neoplasm.

[This corrects the article DOI: 10.1371/journal.pone.0154558.].

The fibrosis stage, which is evaluated by the distribution pattern of collagen fibers, is a major predictor for the development of hepatocellular carcinoma (HCC) for patients with hepatitis C. Meanwhile, the role of elastin fibers has not yet been elucidated. The present study was conducted to determine the significance of quantifying both collagen and elastin fibers.We enrolled 189 consecutive patients with hepatitis C and advanced fibrosis. Using Elastica van Gieson-stained whole-slide images of pretreatment liver biopsies, collagen and elastin fibers were evaluated pixel by pixel (0.46 μm/pixel) using an automated computational method. Consequently, fiber amount and cumulative incidences of HCC within 3 years were analyzed.There was a significant correlation between collagen and elastin fibers, whereas variation in elastin fiber was greater than in collagen fiber. Both collagen fiber (p = 0.008) and elastin fiber (p < 0.001) were significantly correlated with F stage. In total, 30 patients developed HCC during follow-up. Patients who have higher elastin fiber (p = 0.002) in addition to higher collagen fiber (p = 0.05) showed significantly higher incidences of HCC. With regard to elastin fiber, this difference remained significant in F3 patients. Furthermore, for patients with a higher collagen fiber amount, higher elastin was a significant predictor for HCC development (p = 0.02).Computational analysis is a novel technique for quantification of fibers with the added value of conventional staging. Elastin fiber is a predictor for the development of HCC independently of collagen fiber and F stage.

A 78-year-old man was implanted with a cardiac resynchronization therapy defibrillator. One month later, chest X-ray and electrocardiography suggested left ventricular (LV) lead dislodgement. However, the LV lead pacing threshold obtained by a programmer was unchanged because anodal capture had developed, which made it difficult to confirm the LV lead dislodgement. Radiographs obtained in the catheterization laboratory revealed that the tip of the LV lead had dislodged into the right atrium. The LV lead was relocated into another lateral coronary vein. Electrocardiography showed the QRS duration to be shorter than prior to this revision.

RNA interference (RNAi) technology is currently being tested in clinical trials for a limited number of diseases. However, systemic delivery of small interfering RNA (siRNA) to solid tumors has not yet been achieved in clinics. Here, we introduce an in vivo pH-sensitive delivery system for siRNA using super carbonate apatite (sCA) nanoparticles, which is the smallest class of nanocarrier. These carriers consist simply of inorganic ions and accumulate specifically in tumors, yet they cause no serious adverse events in mice and monkeys. Intravenously administered sCA-siRNA abundantly accumulated in the cytoplasm of tumor cells at 4 h, indicating quick achievement of endosomal escape. sCA-survivin-siRNA induced apoptosis in HT29 tumors and significantly inhibited in vivo tumor growth of HCT116, to a greater extent than two other in vivo delivery reagents. With innovative in vivo delivery efficiency, sCA could be a useful nanoparticle for the therapy of solid tumors.

The assessment of individual risk of fibrosis progression in patients with chronic hepatitis C is an unmet clinical need. Recent genome-wide association studies have highlighted several genetic alterations as predictive risk factors of rapid fibrosis progression in chronic hepatitis C. However, most of these results require verification, and whether the combined use of these genetic predictors can assess the risk of fibrosis progression remains unclear. Therefore, genetic risk factors associated with fibrosis progression were analyzed in 176 chronic hepatitis C patients who did not achieve sustained virological response by interferon-based therapy and linked to the fibrosis progression rate (FPR). FPR was determined in all patients by paired liver biopsy performed before and after therapy (mean interval: 6.2 years). Mean FPR in patients with IL28B (rs8099917) TG/GG and PNPLA3 (rs738409) CG/GG were significantly higher than in those with IL28B TT (FPR: 0.144 vs. 0.034, P < 0.001) and PNPLA3 CC (FPR: 0.10 vs. 0.018, P = 0.005), respectively. IL28B TG/GG [hazard ratio (HR): 3.9, P = 0.001] and PNPLA3 CG/GG (HR: 3.1, P = 0.04) remained independent predictors of rapid fibrosis progression upon multivariate analysis together with average alanine aminotransferase after interferon therapy ≥40 IU/l (HR: 4.2, P = 0.002). Based on these data, we developed a new clinical score predicting the risk of fibrosis progression (FPR-score). The FPR-score identified subgroups of patients with a low (FPR: 0.005), intermediate (FPR: 0.103, P < 0.001), and high (FPR: 0.197, P < 0.001) risk of fibrosis progression. In conclusion, IL28B and PNPLA3 genotypes are associated with rapid fibrosis progression, and the FPR-score identifies patients who has a high risk of fibrosis progression and require urgent antiviral treatment.

The presence of resistance-associated variants (RAVs) of hepatitis C virus (HCV) attenuates the efficacy of direct acting antivirals (DAAs). The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy.Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined.By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days) in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%- 97.4%) at baseline which significantly decreased to 29.7% (0.16%- 98.3%) within 7 days of initiation of treatment (p = 0.023). The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4%) and a marked reduction of more than 10% was observed in 14 cases (48.7%). HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day) than the Y93 wild type (-3.35±1.0 logIU/mL/day) (p