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Background: Venous thromboembolic events have been reported in persons with hemophilia A who received emicizumab and activated prothrombin complex concentrate (APCC) concomitantly, but the relevant mechanism(s) remains unclear. We speculated that activated protein C (APC) and antithrombin (AT) resistance might be associated with these adverse events. Objectives: To investigate APC and AT resistance in factor (F)VIII–deficient (FVIIIdef) plasma in the presence of emicizumab and APCC. Methods: In pooled normal plasma or FVIIIdef plasma samples mixed with emicizumab (50 μg/mL) and FVIII-bypassing agents, including recombinant FVIIa (2.2 μg/mL), APCC (1.3 IU/mL), or plasma-derived FVIIa/FX (1.5 μg/mL), the suppression effect of AT (0-2.4 μM) and APC (0-16 nM) was assessed by tissue factor–triggered thrombin generation assay. The APC effects in FVIIIdef plasma with the copresence of emicizumab, FII (1.3 μM), and/or FIXa (280 pM) were also examined. Results: The AT resistance in emicizumab and each bypassing agent was not observed. Moreover, APC dose-dependent suppression effect was observed in pooled normal plasma or FVIIIdef plasma mixed with emicizumab and recombinant FVIIa or plasma-derived FVIIa/FX. However, APC-catalyzed inactivation had little effect on thrombin generation assay potential in FVIIIdef plasma spiked with emicizumab and APCC. The addition of FIXa to emicizumab in FVIIIdef plasma could lead to partial APC resistance. Furthermore, FVIIIdef plasma spiked with emicizumab, FIXa, and FII was markedly resistant to APC-mediated inactivation. Conclusion: FII and FIXa in APCCs were key clotting factors for APC resistance in FVIIIdef plasma supplemented with emicizumab and APCCs. The APC resistance in persons with hemophilia A receiving emicizumab and APCC may contribute to venous thromboembolic events.

Selenoneine is an organic selenium compound contained in blood and dark muscle of fish. It has a strong antioxidative capacity and is considered useful as a new functional food material. However, the distribution and effects of selenoneine in the mammalian body have not been thoroughly examined. In this study, a selenoneine-rich mackerel extract was developed and fed to mice at 0.07% in standard rodent chow (ME diet) for 32 days to examine its distribution in the body. Selenoneine was distributed in the liver, kidney, and spleen in mice fed with mackerel extract, but it was not distributed in the plasma or erythrocytes. Moreover, concentrations of the major selenium-containing protein were not affected by the mackerel extract. The results of this study suggest that selenoneine is absorbed in the body following ingestion of low doses in crude material and preferentially accumulates in organs and later distributes in erythrocytes. Biochemical analyses of plasma in male mice showed that the glucose level was significantly increased and LDL-cholesterol level was significantly decreased by ME diet feeding. The results indicate that male mice are sensitive to ME diet., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To evaluate the efficacy of atezolizumab plus bevacizumab treatment in patients with hepatocellular carcinoma (HCC) previously treated with molecular targeted agents (MTAs). Thirty-one patients treated with atezolizumab plus bevacizumab for unresectable HCC and previously treated with MTAs were enrolled in this study. The treatment lines ranged from second to sixth lines. The treatment effect on HCC differed from that during first-line treatment. The treatment effect was determined using the Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST. The treatment response was different for each MTA immediately prior to atezolizumab + bevacizumab treatment. Tumors treated with lenvatinib followed by atezolizumab + bevacizumab showed rapid growth for a short period of time followed by shrinkage. However, patients who received ramucirumab, sorafenib, and regorafenib did not show such changes. This was likely because of differences in the mechanism of action of the MTA administered immediately beforehand. The side-effect profile differed from that observed in the IMbrave150 phase 3 study of atezolizumab plus bevacizumab, which showed more adverse events related to hepatic reserve. Patients treated with the combination of atezolizumab and bevacizumab after lenvatinib therapy may experience rapid tumor growth and subsequent shrinkage., Competing Interests: RS and KM declare that they have competing interests. The other authors have no conflicts of interest to declare., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Direct-acting antiviral (DAA) treatment has revolutionized hepatitis C virus (HCV) care. We aimed to evaluate the risk for the development of hepatocellular carcinoma (HCC) in patients aged 75-84 years with chronic hepatitis C after HCV elimination., Methods: This multicenter cohort study included 2405 consecutive patients with chronic hepatitis C without a history of HCC who achieved HCV elimination by DAAs. Patients in whom HCC developed within 1 year of DAA initiation were excluded. Propensity score matching analysis was used to evaluate differences in HCC risk between patients aged 75-84 versus 60-74 years., Results: The median observational period was 3.5 years. Among patients aged 75-84 years with a high Fibrosis-4 (FIB-4) index (≥3.25 at baseline), there was no significant difference in the annual incidence of HCCs between groups with an FIB-4 index ≥3.25 (2.75 per 100 person-years [PY]) versus <3.25 (2.16 per 100 PY) at 12 weeks after the end of treatment, unlike the results in those aged 60-74 years (3.61 and 1.51 per 100 PY, respectively) (adjusted hazard ratio, 2.20; P = .04). In 495 pairs matched by propensity score matching, in patients without cirrhosis, the cumulative HCC incidence was significantly higher in the 75-84-year than in the 60-74-year age group (P = .04)., Conclusions: Older patients aged 75-84 years remained at high risk for the development of HCC, even after HCV elimination and the improvement of the FIB-4 index to <3.25., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Tenofovir alafenamide (TAF) may be preferable to other nucleos(t)ide analogues (NA) regarding outcomes against chronic hepatitis B virus (HBV) infection., Aims: To evaluate the longer term virological/biochemical effectiveness of TAF and the renal safety of sequential therapy to TAF in real-world settings METHODS: This multi-centre, retrospective cohort study included consecutive adult patients who were switched from other NAs to TAF. We assessed the virological and biochemical responses up to 144 weeks. We performed sensitivity analyses for a subgroup with chronic kidney disease (CKD) at baseline., Results: We analysed the data of 391 patients with chronic hepatitis B previously treated with entecavir (ETV) (n = 174), tenofovir disoproxil fumarate (TDF) (n = 116) or an NA combination (n = 101) for ≥ 24 months. HBV DNA <10 IU/ml at week 144 was found for 99% of patients, regardless of prior NA regimen or HBV DNA level at baseline. For patients who switched from TDF to TAF, total, low-density lipoprotein, high-density lipoprotein cholesterol and triglycerides were significantly increased after the switch. Patients who switched from a nucleotide analogue to TAF had an improved estimated glomerular filtration rate, although the rate of hypophosphataemia (<2.5 mg/dl) remained 9.7% at week 144. The virological and biochemical responses of patients with CKD were similar to the overall results., Conclusions: Switching to TAF remained effective and safe for up to 3 years. Given the increasing comorbidities related to ageing, it will be important to carefully follow the change in the lipid levels of patients with a prior TDF-based regimen., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims: Outcome data of sequential hepatitis B virus treatment with tenofovir alafenamide (TAF) are limited. We aimed to assess the effectiveness and renal safety of TAF in chronic hepatitis B (CHB) patients who were previously treated with entecavir (ETV), tenofovir disoproxil fumarate (TDF), or a nucleos(t)ide analogue (NA) combination., Methods: This multicenter, retrospective, cohort study included 458 consecutive CHB patients who switched to TAF monotherapy after at least 2 years of treatment with another NA. The longitudinal virological/laboratory responses were evaluated up to 96 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 ., Results: The proportions of complete viral suppression (CVS) (HBV DNA < 20 IU/mL) at week 96 were 99.0%, 98.5%, and 98.4% in the prior ETV (n = 198), TDF (n = 137), and NA combination (n = 123) groups, respectively. Almost all patients with HBV DNA of 20-2000 IU/mL at baseline achieved CVS at week 96. On multivariable generalized estimated equation analysis, a low quantitative hepatitis surface antigen (qHBsAg) level at baseline was associated with a lower follow-up qHBsAg level (coefficient 0.81, p < 0.001). The eGFR showed greater improvement in patients with CKD compared to those without (coefficient 21.7, p < 0.001). However, the increase of eGFR reached a peak between weeks 24 and 48., Conclusions: Based on this longitudinal data analysis up to 96 weeks, sequential NA therapy with a switch to TAF is a good option to achieve high viral suppression and renal safety., (© 2022. Asian Pacific Association for the Study of the Liver.)