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Summary: Vesatolimod is an oral agonist of toll‐like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double‐blind, randomized, placebo‐controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1‐, 2‐ or 4‐mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300‐mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole‐blood interferon‐stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg‐negative (60.9%) at baseline. Among vesatolimod‐treated patients, most (60.4%‐69.1%) experienced ≥1 treatment‐emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e‐antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose‐dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose‐dependent interferon‐α induction that correlated with grade of influenza‐like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose‐dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline. [ABSTRACT FROM AUTHOR]

Summary: Daclatasvir plus asunaprevir (DCV+ASV) treatment is an all‐oral direct‐acting antiviral (DAA) therapy for the genotype 1b HCV‐infected patients. In this study, we investigated how resistance‐associated substitutions (RASs) evolved after treatment failures and assessed the effect of those substitutions on viral fitness. Sequencing of NS5A and NS3 revealed typical RASs after treatment failures. Interestingly, the RASs of NS3 reverted to the wild‐type amino acid within 1 year after treatment failures. However, the RASs of NS5A were stable and did not change. The effect of NS5A and NS3 RASs on viral RNA replication was assessed after mutagenic substitution in the genotype 1b HCV RNA. Among single substitutions, the effect of D168V was more substantial than the others and the effect of the triple mutant combination (D168V+L31V+Y93H) was the most severe. The RAS at NS5A Y93 affected both viral RNA replication and virus production. Finally, the effect of trans‐complementation of NS5A was demonstrated in our co‐transfection experiments and these results suggest that such a trans‐complementation effect of NS5A may help maintain the NS5A RASs for a long time even after cessation of the DAA treatment. In conclusion, the results from this investigation would help understand the emergence and persistence of RASs. [ABSTRACT FROM AUTHOR]

Summary: Background: Sarcopenia is significantly associated with the degree of liver fibrosis. This study investigated the influence of sarcopenia on liver fibrosis in individuals with chronic hepatitis B. Methods: Data from the Korean National Health and Nutrition Examination Surveys 2008‐2011 were analysed. The sarcopenia index (total appendicular skeletal muscle mass [kg]/body mass index [kg/m2]) was calculated using dual‐energy X‐ray absorptiometry. Sarcopenia was defined as the lowest quintile sarcopenia index value (cut‐offs: 0.89 for men and 0.58 for women). The fibrotic burden was assessed using the nonalcoholic fatty liver disease fibrosis score and fibrosis‐4 index. Significant fibrosis was defined as the highest nonalcoholic fatty liver disease fibrosis score quartile and a fibrosis‐4 index ≥2.67. Results: Among the 506 respondents with chronic hepatitis B (258 men and 248 women), the nonalcoholic fatty liver disease fibrosis score and fibrosis‐4 index identified sarcopenia and significant fibrosis in 126 (24.9%) and 217 (42.9%), respectively. Sarcopenia was significantly associated with significant fibrosis, regardless of the fibrosis prediction model used (all P < 0.05). When the study population was stratified according to metabolic factors, sarcopenia was specifically associated with an increased risk of significant fibrosis among subgroups with obesity, insulin resistance, metabolic syndrome and liver steatosis (odds ratio 2.37‐3.57; all P < 0.05). An independent association between sarcopenia and significant fibrosis was identified after adjusting for other confounders (odds ratio 2.67‐3.62 by the nonalcoholic fatty liver disease fibrosis score and 2.04‐2.62 by the fibrosis‐4 index; all P < 0.05). Conclusions: Sarcopenia is associated with significant fibrosis in subjects with chronic hepatitis B, specifically those with obesity, insulin resistance, metabolic syndrome and liver steatosis. [ABSTRACT FROM AUTHOR]

Summary: Background: A proportion of chronic hepatitis B (CHB) patients are diagnosed with advanced hepatocellular carcinoma (HCC) despite regular surveillance. Aims: To determine predictors for HCC detection failure in CHB patients who underwent regular surveillance. Methods: CHB patients with well‐preserved liver function, who underwent ultrasonography and alpha‐foetoprotein (AFP) analysis every 6 months, were enrolled. Cox regression analysis was used to identify predictors for detection failure, defined as HCC initially diagnosed at Barcelona Clinic Liver Cancer (BCLC) stage B or C. Results: Of the 4590 CHB patients (mean age, 52.1 years; men, 61.6%), 169 patients were diagnosed with HCC (3.68%) and 35 (20.7%) HCC patients were initially diagnosed with HCC BCLC stage B or C. The cumulative incidence of HCC detection failure was 0.2% at year 1 and 1.3% at year 5. Multivariate analyses indicated that cirrhosis (hazard ratio [HR], 3.078; 95% CI, 1.389‐6.821; P = 0.006), AFP levels ≥9 ng/mL (HR, 5.235; 95% CI, 2.307‐11.957; P = 0.010), and diabetes mellitus (HR, 3.336; 95% CI, 1.341‐8.296; P = 0.010) were independent predictors of HCC detection failure. Another model that incorporated liver stiffness (LS) values identified LS values ≥11.7 kPa (HR, 11.045; 95% CI, 2.066‐59.037; P = 0.005) and AFP levels ≥9 ng/mL (HR, 4.802; 95% CI, 1.613‐14.297; P = 0.005) as predictors of detection failure. Conclusions: In CHB patients undergoing regular surveillance with ultrasonography and alpha‐foetoprotein (AFP) analysis every 6 months, the HCC detection failure rate was not high (0.8% per person; 0.1% per test). However, careful attention should be paid in patients with advanced liver fibrosis (clinical cirrhosis or LS value >11.7 kPa), high AFP levels, or diabetes mellitus, who are prone to surveillance failure. [ABSTRACT FROM AUTHOR]

Some short procedures require deep neuromuscular blockade, which needs to be reversed at the end of the procedure. Forty-four patients undergoing elective laryngeal micro-surgery were randomly allocated into two groups: rocuronium 0.45 mg.kg-1 with neostigmine (50 μg.kg-1 with glycopyrrolate 10 μg.kg-1 ) reversal (moderate block group) vs. rocuronium 0.90 mg.kg-1 with sugammadex (4 mg.kg-1 ) reversal (deep block group). The primary outcome was the intubating conditions during laryngoscopy secondary outcomes included recovery of neuromuscular block; conditions for tracheal intubation; satisfaction score as determined by the surgeon; onset of neuromuscular block; and postoperative sore throat. The onset of neuromuscular block was more rapid, and intubation conditions and ease of intra-operative laryngoscopy were more favourable, and the satisfaction score was lower in the moderate block group compared with the deep block group. No difference was found in the incidence of postoperative sore throat. In laryngeal micro-surgery, the use of rocuronium 0.9 mg.kg-1 with sugammadex for reversal was associated with better surgical conditions and a shorter recovery time than rocuronium 0.45 mg.kg-1 with neostigmine. [ABSTRACT FROM AUTHOR]

We compared the viral suppressive efficacy of tenofovir disoproxil fumarate ( TDF) mono-rescue therapy ( TDF group) and TDF plus entecavir ( ETV) combination-rescue therapy ( TDF + ETV group) in chronic hepatitis B ( CHB) patients with lamivudine resistance and entecavir resistance. One hundred and thirty-three CHB patients with lamivudine and entecavir resistance were investigated. Ninety-six patients were treated with TDF and 37 with TDF + ETV for at least 6 months. We compared the virologic response rate ( HBV DNA level <20 IU/mL) between the two groups and identified the predictive factors of treatment outcome. There were no significant differences between the two groups in demographic characteristics. Up to 24 months [median: 18 (range 6-24) months], 85.4% and 89.2% of the TDF group and TDF + ETV group, respectively, achieved a virologic response ( P=.068). Only the HBV DNA level at baseline was significantly associated with a virologic response in the multivariate analysis. In a subanalysis of patients with HBV DNA levels ≥4 log ( IU/mL) at baseline, a higher proportion of patients in the TDF + ETV group than the TDF group achieved a virologic response (92.9% vs 68.3%; P<.001), while 90% of patients with HBV DNA ( IU/mL) levels <4 log in all both TDF and TDF + ETV groups achieved a virologic response. TDF mono-rescue therapy is a reasonable option in patients with lamivudine resistance and entecavir resistance. However, the combination strategy should be considered in patients with high baseline HBV DNA levels. [ABSTRACT FROM AUTHOR]

The article discusses a study which proposes a microwave heating system that consists multiple microwave cavity and uses a power-controlled phase-shifting mode for heating uniformity. The improved heating uniformity that can be achieved by the proposed mode is demonstrated, highlighting the reduction of the hot and cold spots in the microwave cavity. The proposed system configuration is outlined.

Background In patients with chronic hepatitis B, tenofovir disoproxil fumarate ( TDF) plus pegylated interferon ( PEG- IFN) for 48-weeks results in higher rates of hepatitis B surface antigen ( HBsAg) loss than either monotherapy. Aim To identify baseline and on-treatment factors associated with HBsAg loss at Week 72 and provide a model for predicting HBsAg loss in patients receiving combination therapy for 48 weeks. Methods A secondary analysis of data from an open-label study where patients were randomised to TDF (300 mg/day, oral) plus PEG- IFN (PI, 180 μg/week, subcutaneous) for 48 weeks ( TDF/ PI-48w); TDF plus PEG- IFN for 16 weeks, TDF for 32 weeks ( TDF/ PI-16w+ TDF-32w); TDF for 120 weeks ( TDF-120w) or PEG- IFN for 48 weeks ( PI-48w). Logistic regression methods were used to identify models that best predicted HBsAg loss at Week 72. Results Rates of HBsAg loss at Week 72 were significantly higher in the TDF/ PI-48w group (6.5%) than in the TDF/PI-16w+TDF-32w (0.5%), TDF-120w (0%) and PI-48w (2.2%) groups ( P = 0.09). The only baseline factor associated with response was genotype A. HBsAg decline at Week 12 or 24 of treatment was associated with HBsAg loss at Week 72 ( P < 0.001). HBsAg decline >3.5 log10 IU/mL at Week 24 in the TDF/ PI-48w group resulted in a positive predictive value of 85% and a negative predictive value of 99% for HBsAg loss at Week 72. Conclusions HBsAg decline at Week 24 of TDF plus PEG- IFN combination therapy may identify patients who, after completing 48 weeks of treatment, have a better chance of achieving HBsAg loss at Week 72. [ABSTRACT FROM AUTHOR]

In Korea, patients with chronic hepatitis C virus ( HCV) infection are typically treated with pegylated interferon-alpha plus ribavirin, but interferons are contraindicated in many patients and are often poorly tolerated, particularly by the elderly and those with advanced liver disease. No interferon-free treatment regimens are approved in Korea. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV nonstructural 5B RNA polymerase. It is approved in the USA, European Union and Japan for treating a number of HCV genotypes, including genotype 2. Genotype 2 has a seroprevalence of 38-46% in Korea. This single-arm, phase 3b study ( NCT02021643) examined the efficacy and safety of sofosbuvir plus ribavirin (12-week duration) in chronic genotype 2 HCV-infected treatment-naive and treatment-experienced Korean patients with and without cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation ( SVR12) was 97% (125/129), with 96% (101/105) of treatment-naive and 100% (24/24) of treatment-experienced patients achieving SVR12. Two patients experienced virologic failure ( n = 1, on-treatment failure; n = 1, relapse). No patient discontinued study treatment due to an adverse event ( AE). The most common treatment-emergent AEs were headache (18%, 23/129) and pruritus (15%, 19/129). Few patients had grade 3 AEs (5%, 6/129) or grade 3 laboratory abnormalities (12%, 15/129). No grade 4 AE was reported. These data suggest that 12 weeks of treatment with the all-oral, interferon-free regimen of sofosbuvir plus ribavirin is effective and well tolerated in Korean patients with chronic genotype 2 HCV infection. [ABSTRACT FROM AUTHOR]

Patients with hepatitis B e antigen ( HBe Ag)-positive chronic hepatitis B ( CHB) have suppressed TLR2 expression, function and cytokine production. The aim of this study was to explore the importance of hepatitis B virus ( HBV) genotype in innate immune responses and investigate whether Toll-like receptor ( TLR) expression/function has potential roles as predictive biomarkers of successful therapy with pegylated interferon ( Peg- IFN) therapy of HBe Ag seroconversion in HBe Ag-positive patients. We showed that as early as 4 weeks after initiation of Peg- IFN, future HBe Ag seroconverters had significantly elevated levels of TLR2 expression on monocytes. TLR2-associated IL-6 production at baseline and week 4 of therapy and TLR4 IL-6 production at week 4 were also markedly elevated in HBe Ag seroconverters. HBV genotype also influenced treatment response, with genotypes A and B more likely to seroconvert than D. We were able to demonstrate that these differences were due in part to the interaction of the specific HBe Ag proteins with TLR pathway adaptor molecules, and these interactions were genotype dependent. HBe Ag-mediated modulation of TLR signalling was also observed in Huh7 cells, following stimulation with Pam3 Cys. Importantly, the addition of IFN-α to TLR2-stimulated cells cotransfected with an HBe Ag expression plasmid reversed HBe Ag-mediated suppression of hepatocytes. These findings demonstrate that patients with an activated inflammatory response are much more likely to respond to IFN therapy, with TLR responses showing promise as potential biomarkers of HBe Ag seroconversion in this setting. Furthermore, our findings suggest there is differential genotype-specific HBe Ag suppression of innate signalling pathways which may account for some of the clinical differences observed across the CHB spectrum. [ABSTRACT FROM AUTHOR]

Background It remains unclear whether initial compact lipiodol uptake after transarterial chemoembolisation ( TACE) is associated with improved survival in patients with hepatocellular carcinoma ( HCC). Aim To reveal the clinical relevance of compact lipiodolisation after TACE. Methods We studied 490 patients with unresectable HCC who had first been treated with TACE. Compact lipiodolisation was defined as the absence of an arterial enhancing lesion, reflecting complete lipiodol uptake, as assessed by dynamic computed tomography ( CT) 1 month after treatment. The rate of initial compact lipiodolisation was analysed according to multiplicity and size of tumour, and survival of patients who achieved compact lipiodolisation was compared to that of patients who did not. Results Of the 490 patients, 409 (83.5%) were in Child- Pugh class A and 81 (16.5%) in class B. The rate of initial compact lipiodolisation in single HCCs was higher than that in multinodular HCCs (33.7% vs. 14.6%, P < 0.001). Among single HCCs, the rate of compact lipiodolisation in tumours ≤5, 5-10 and >10 cm was 46.6%, 13.6%, and 0% respectively. The 1-, 3- and 5-year survival rates of patients with compact uptake were 92.7%, 70.7% and 52.4% compared to 60.8%, 28.0% and 16.9% in patients with noncompact lipiodolisation. Multivariate analysis revealed that Child-Pugh class, alpha-fetoprotein level, tumour node metastasis stage, portal vein thrombosis and initial compact lipiodolisation were independent predictors of survival. Conclusions Initial compact lipiodol uptake after transarterial chemoembolisation is associated with improved survival in patients with unresectable hepatocellular carcinoma. Accordingly, initial complete lipiodolisation should be considered a relevant therapeutic target. [ABSTRACT FROM AUTHOR]

To cite this article: Kim YH, Yang TY, Park C-S, Ahn S-H, Son BK, Kim JH, Lim DH, Jang TY. Anti-IL-33 antibody has a therapeutic effect in a murine model of allergic rhinitis. Allergy 2012; 67: 183-190. Abstract Background: Interleukin (IL)-33 is involved in the Th2 immune response and could play an essential role in nasal allergy. Therefore, we aimed to investigate the therapeutic potential of anti-IL-33 for allergic rhinitis (AR). Methods: Twenty-four BALB/c mice were used. In group A (control group, n = 6), mice were sensitized and challenged with saline. Group B [ovalbumin (OVA) group, n = 6] mice received intraperitoneal and intranasal OVA challenge. In group C (control IgG group, n = 6), mice were injected intraperitoneally with rabbit control IgG before OVA challenge. In group D (anti-IL-33 group, n = 6), anti-IL-33 was injected before challenge. We evaluated the number of nose-scratching events and external morphology; serum total and OVA-specific IgE; number of eosinophils, neutrophils, and lymphocytes in bronchoalveolar lavage (BAL) fluid; histopathologic examination of nasal cavity; and IL-4, IL-5, and IL-13 in BAL fluid. Results: Anti-IL-33 treatment significantly reduced the nose-scratching events and ameliorated skin denudation. Serum total and OVA-specific IgE was significantly decreased in group D. The number of eosinophils in BAL fluid was also significantly decreased. Eosinophilic infiltration in the nasal cavity was significantly decreased in group D. IL-4, IL-5, and IL-13 in BAL fluid were also significantly decreased after treatment. Conclusions: Anti-IL-33 antibody has a therapeutic potential for experimental AR. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 2010; 32: 498–505 Background Interquartile range/median value (IQR/M) of liver stiffness measurement (LSM) is a factor in chronic hepatitis C (CHC) leading to over estimation of fibrosis by Fibroscan. Aim To investigate factors that affect the accuracy of LSM in chronic hepatitis B (CHB). Methods One hundred and ninety-nine patients were enrolled. Only procedures yielding ≥10 valid measurements were considered reliable. Liver fibrosis was evaluated using the Batts and Ludwig system. Liver biopsy (LB) specimens <15 mm were considered ineligible. Results The mean age (142 men and 57 women) was 40.1 years. A significant discordance (discordance of at least two stages between LB and LSM) was identified in 38 (19.1%) and 47 (23.6%) patients respectively, according to Marcellin et al. and Chan et al.’s cutoff values. In multivariate analyses, BMI and fibrosis stage (F0–2 vs. F3–4) were identified as independent predictors for significant discordance ( P = 0.040; hazard ratio [HR], 1.126; 95% confidence interval [CI], 1.005–1.261 and P = 0.036; HR, 0.450; 95% CI, 0.213–0.949 respectively) with Marcellin et al.’s cutoffs, whereas fibrosis stage was the only independent predictor ( P = 0.004; HR, 0.300; 95% CI, 0.131–0.685) with Chan’s cutoffs . Conclusions Success rate and IQR/M were not predictive factors of the accuracy for diagnosing liver fibrosis by Fibroscan in CHB. Fibrosis stage (F0-2) was the only factor to predict significant discordance between LB and LSM. [ABSTRACT FROM AUTHOR]

Current treatment guidelines suggest that antiviral therapy be considered for chronic hepatitis B (CHB) patients with high viral load if a biopsy shows significant liver disease despite alanine aminotransferase (ALT) levels two times or less than the upper limit of normal (ULN). We evaluated the histological findings in CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels. Between January 2003 and June 2006, 105 consecutive treatment-naive patients with CHB who underwent ultrasonography-guided percutaneous liver biopsy, had detectable serum HBV DNA (>105 copies/mL) in a direct hybridization assay and normal or slightly elevated serum ALT levels (≤2 × ULN) for at least 12 months were included in a prospective study. Histological assessment was based on the METAVIR scoring system. Significant histology was defined as fibrosis stage ≥F2 or necroinflammation grade ≥A2. Among the 105 CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels for at least 12 months, significant fibrosis (F2–F4 fibrosis) was observed in 63 patients (60.0%) and the actual significant histology was found in 65 patients (61.9%). On multivariate analysis, serum ALT levels and age at which they entered the study were independent factors associated with significant histology. Odds ratios for significant histology increased progressively according to serum ALT levels and age. In conclusion, a large proportion of CHB patients with genotype C, high viral load and ALT ≤2 × ULN had significant liver disease on liver biopsy and should be considered for antiviral therapy. [ABSTRACT FROM AUTHOR]

To measure excessive electrical stimulus time during pulp testing via electromyography (EMG) in the anterior belly of the digastric muscle, voice and finger movement, and to determine whether excessive stimulus time could be attenuated by a specially designed automatic circuit breaker on the basis of the EMG signal. The signals from three human responses (EMG, finger and voice), induced by the DigitestTM (Parkell Inc., Farmingdale, NY, USA) electric pulp tester, were captured using a MP100 (Biopac System Inc., Goleta, CA, USA) and recorded into a personal computer. The excessive stimulus time from activation to the end of electrical stimulation was calculated for each of these three responses. The automatic circuit breaker was designed to disconnect the electrical output of the electric pulp testing (EPT) unit immediately after detecting the preset EMG level (100 mV). Each of the right central incisors and first premolars of 23 healthy individuals (16 males and seven females) was tested to see whether there was a difference in tooth type or gender. This was analysed by Wilcoxon signed rank test (nonparametric paired t-test) and Mann–Whitney test (nonparametric independent t-test), respectively. Amongst three human responses, the electrical onset occurred in the order of EMG, finger and voice. Excessive stimulus time was 347.8 ± 78.3 ms when observed by the EMG, 264.9 ± 63.9 ms when observed by finger span and 229.4 ± 41.8 ms when observed by the voice, which were all found to be significantly different ( P < 0.05). When the automatic circuit breaker was used, the excessive stimulus time was 61.0 ms, which was 286.8 ms shorter than that measured from EMG onset when using the conventional EPT. When the automatic circuit breaker was used, excessive stimulus time on the basis of EMG was attenuated on average by 286.8 ms. [ABSTRACT FROM AUTHOR]

A letter to the editor on the recurrent vertigo from hypoplastic vertebral artery is presented.