Yoshio Tokumoto

Background and Aims: Although the widespread use of direct‐acting antivirals (DAAs) has reduced the proportion of hepatitis C virus (HCV) antibody‐positive patients eligible for antiviral treatment, the current proportion requiring referral for DAA therapy in ophthalmology departments, which have both high testing volumes and high HCV antibody‐positive rates, remains unclear. Methods: This nationwide multicenter retrospective cohort study included HCV antibody‐positive patients identified through testing in ophthalmology departments at 20 institutions in Japan between 2019 and 2023. The proportions of patients requiring referral for DAA therapy were assessed by electronic medical record (EMR) review across all 20 institutions and by a combination of EMR review and HCV antibody titer determination across nine institutions where antibody titers could be measured. Results: A total of 2792 HCV antibody‐positive patients were identified across 20 institutions. Based on EMR review, the proportions requiring referral for DAA therapy were 44.4%, 38.7%, 34.2%, 38.9%, and 42.5% in 2019, 2020, 2021, 2022, and 2023, respectively. Among 1255 HCV antibody‐positive patients from 9 institutions where HCV antibody titers could be determined, the corresponding proportions assessed by combined EMR review and antibody titer determination were 28.4%, 23.7%, 20.8%, 22.4%, and 25.9%, respectively. Despite a decline in HCV antibody‐positive rates over time, the proportion requiring referral remained high. Conclusions: Although the number of HCV antibody‐positive patients in ophthalmology departments has decreased, a considerable proportion could still be considered for DAA therapy. Combining HCV antibody titer determination with EMR review improves the efficiency of identifying patients requiring referral.

The long-term changes in liver function and outcomes in patients with cirrhosis after achieving a sustained virological response (SVR) with direct-acting antiviral (DAA) treatment remain unclear. Between 2014 and 2020, we screened 2,030 patients with chronic hepatitis C virus (HCV) infection who achieved an SVR with DAA treatment at participating institutions. Among them, 820 patients had cirrhosis. The median follow-up period was 70 (range, 14–89) months. After excluding patients without hepatocellular carcinoma (HCC) and those who were followed up for less than 1 year after the end of treatment (EOT), 542 patients were included in this retrospective multicenter study. Higher modified albumin-bilirubin (mALBI) grade at SVR at 12 weeks after treatment completion (SVR12) was significantly associated with increased hepatocellular carcinoma incidence and total mortality. Of 157 patients with baseline mALBI grade 2b/3, 83 improved to grade 1/2a by SVR12. Patients were subsequently divided into four patient groups: A (early improvement, n = 73), B (re-exacerbation, n = 10), C (late improvement, n = 19), and D (no improvement, n = 55) based on mALBI changes over 3 years. Predictors for group D were albumin level at SVR12 ( p = 0.004) and prothrombin time at SVR12 ( p = 0.010), with cut-off values on receiver-operating characteristic curve analyses of 3.3 g/dL and 63%, respectively. Improvement in mALBI grade after SVR decreases the risk of HCC and improves outcomes. For patients with persistently impaired albumin and prothrombin time at SVR12, further recovery in liver function is unlikely. These findings highlight the importance of mALBI-based surveillance strategies for cirrhotic patients following SVR.

A high body mass index (BMI) is associated with the onset of diabetes mellitus (DM). However, evidence regarding the association between changes in BMI and DM onset is limited, and the effect of annual BMI (kg/m2/year) change on DM onset is unknown. Therefore, we assessed the effects of changes in BMI and annual BMI on DM onset. We enrolled 13,949 participants aged 21–81 years who underwent an annual health checkup at least twice between April 2003 and March 2021 and examined the effect of BMI change and annual BMI change on DM onset. In total, 462 individuals newly developed DM. Compared with a BMI change of –0.25–<0.25, univariate and multivariate analyses—adjusted for age, sex, BMI, systolic blood pressure, creatinine, total cholesterol, triglycerides, alanine aminotransferase, hemoglobin A1c, and family history of DM—showed that a BMI change <–2 was associated with a lower risk, while 2 ≤ BMI change < 4 and 4 ≤ BMI change were associated with a higher risk of DM onset. In contrast, compared with –0.05 ≤ BMI change per year < 0.05, univariate and multivariate analyses showed a significant association between DM onset and 0.3 ≤ BMI change per year. In the age-stratified analysis, these associations were significant among younger and middle-aged participants but not in older adults. In conclusion, changes in BMI affect DM onset. Therefore, clinicians can prevent DM onset by providing guidance based on BMI and focusing on a ≥2 increase in BMI and a ≥0.3 increase per year of BMI in young and middle-aged individuals.

Aim: Patients with chronic liver disease often experience significant physical, psychological, and financial burdens. These burdens result from repeated long‐term hospital visits or admissions caused by progression to decompensated cirrhosis or hepatocellular carcinoma. Patients with viral liver disease may fear discrimination or social prejudice. This study aimed to clarify the employment status of patients with liver disease in Japan and provide basic data to promote support for balancing treatment and work responsibilities. Methods: A cross‐sectional questionnaire survey on employment was conducted among patients attending 22 hospitals across Japan. Results: Of the 4022 respondents, 2183 were analyzed, including 1694 (77.6%) participants with liver disease. Patients with liver disease were predominantly male and in their 60 s. Disclosure of health information to the workplace was significantly lower among patients with viral liver disease (80.8%) than among those without liver disease or with nonviral liver disease. The intention to continue working after diagnosis was significantly higher among patients with malignancies than among those without. However, this intention did not significantly differ between liver disease and non‐liver disease groups. The awareness rate of the support system for balancing treatment and work program was 27.1%, with no significant difference observed between the liver disease and malignancy groups. Awareness was significantly higher in large workplaces, where full‐time occupational health physicians are mandated. Conclusion: Workers with viral liver disease may hesitate to disclose their condition owing to fear of discrimination or prejudice. Therefore, raising awareness of support systems that protect all workers with illnesses, while considering stigma and discrimination, is essential.

Palmitic acid (PA) absorption from the intestine is increased in metabolic dysfunction-associated steatohepatitis (MASH). It induces endoplasmic reticulum (ER) stress and interleukin-1 beta (IL-1β) production in hepatic stellate cells (HSCs). Protein kinase R-like endoplasmic reticulum kinase (PERK) is an ER stress sensor protein involved in HSC activation and liver fibrosis. However, its role in HSCs during hepatocellular carcinoma (HCC) progression remains unclear. This study clarified the process of IL-1β production via PERK in HSCs and explored the mechanism underlying MASH-related HCC progression. HSCs were treated with PA or transfected with PERK small-interfering RNA (siRNA) or PERK plasmid. Proliferation, scratch, and Transwell assays were performed on HCC cells cultured in the conditioned medium (CM) from HSCs. PA treatment increased PERK and IL-1β expression in HSCs. PERK knockdown decreased IL-1β expression, while its overexpression increased it in HSCs. The CM from PA-treated HSCs showed elevated IL-1β levels and enhanced HCC cells’ proliferation, migration, and invasion; however, these effects were suppressed by PERK knockdown in HSCs. RNA-sequencing analysis revealed that p38δ mitogen-activated protein kinase (MAPK) is the intermediate molecule between PERK and IL-1β in HSCs. In the tumor microenvironment of MASH-related HCC, PERK in HSCs promotes HCC progression via the p38δ MAPK/IL-1β axis.

Aspiring to become a physician is a natural expectation for applicants to medical school. However, choosing a career in medicine is a critical decision, especially in countries where high school students can apply to medical school without an undergraduate degree. Students may select a medical career for various reasons, including parental pressure and academic performance. The question of whether there are students who enroll in medical school without clear intentions of becoming doctors has not been extensively investigated in the literature. We conducted a retrospective study at a national university in Japan. Given the scarcity of research examining medical students who did not have a clear intention to become doctors at the time of admission, we created a survey. The questionnaire asked students whether they had clear intentions to become doctors upon enrollment, and those who responded affirmatively were defined as students with clear intentions to become doctors at admission and assigned to the first group. The second group was composed of students who entered medical school without clear intentions to become doctors. We then compared the differences in sociodemographic characteristics and career determinants between these groups using statistical methods, including Chi-square tests and logistic regression. The collection rate of the questionnaire was 76.2%. We found that 28.8% of students at a national medical school in Japan entered medical school without clear intentions of becoming doctors. For these students, ‘parental expectations’ and ‘peer influence’ were identified as significant career determinants. No sociodemographic characteristics showed significant associations with the ambiguity of students’ intentions to pursue a medical career at admission. This study confirmed that some students enroll in medical school without clear intentions of becoming doctors. The background factors related to this type of student were parental expectations and the influence of peers on career choice.

Background The clinical course of esophagogastric varices (EGV) after sustained virological response (SVR) with direct-acting antiviral (DAA) therapy has not been clearly elucidated. The predictors for the worsening/improvement of EGV after SVR with DAA therapy were investigated. Methods Of the cirrhosis patients who achieved SVR with DAA therapy, 328 patients who underwent endoscopic examinations both before and after DAA therapy were enrolled. The predictors of EGV worsening or improvement were investigated. Results Multivariate analysis identified a history of ascites retention, albumin at baseline, and MELD score at baseline as independent factors that contributed to EGV exacerbation. On multivariate analysis, two factors, BMI and platelet count, were related to EGV improvement. An integrated scoring system was created using these risk factors with or without weighting according to each hazard ratio, and the patients were divided into three groups. A scoring system with weighting of each factor appeared to be more useful, with fewer intermediate patients and more cases classified into the low-risk and high-risk groups. Conclusion Esophagogastric varices after SVR have a varied clinical course. Using this scoring system that can accurately predict EGV outcomes in clinical settings, it may be feasible to establish a risk-based EGV surveillance plan following SVR.

Aim: Advanced fibrosis has a strong influence on the occurrence of liver‐related events in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD), while diabetes mellitus (DM), which is often complicated by MASLD, is associated with the progression of MASLD. We stratified patients with MASLD according to the severity of liver pathological findings and the presence of DM, aiming to examine whether these indices could be used to accurately assess the risk of developing liver‐related events.Methods: A total of 282 patients with liver biopsy‐proven MASLD were included. Liver‐related events were defined as the occurrence of hepatocellular carcinoma (HCC) and complications of liver cirrhosis, such as ascites, hepatic encephalopathy, Child–Pugh class B and C, as well as treatment‐eligible esophageal and gastric varices.Results: Multivariate analysis adjusted for age, sex, body mass index, alanine aminotransferase, creatinine, hemoglobin A1c, smoking habits, dyslipidemia, hypertension, nonalcoholic fatty liver disease activity score (NAS), or fibrosis stage showed that advanced fibrosis with or without DM was a risk factor for liver‐related events. The combined effect of DM and advanced fibrosis increased the risk of HCC onset. However, DM alone or in combination with NAS did not affect the development of liver‐related events, including the occurrence of HCC and complications of liver cirrhosis.Conclusions: While the assessment of fibrosis in patients with MASLD is important for evaluating the risk of developing liver‐related events, combining the assessment of DM may be possible to stratify groups at higher risk of developing HCC.

Double-stranded RNA-activated protein kinase R (PKR) is highly expressed in colorectal cancer (CRC). However, the role of PKR in CRC remains unclear. The aim of this study was to clarify whether C16 (a PKR inhibitor) exhibits antitumor effects and to identify its target pathway in CRC. We evaluated the effects of C16 on CRC cell lines using the MTS assay. Enrichment analysis was performed to identify the target pathway of C16. The cell cycle was analyzed using flow cytometry. Finally, we used immunohistochemistry to examine human CRC specimens. C16 suppressed the proliferation of CRC cells. Gene Ontology (GO) analysis revealed that the cell cycle-related GO category was substantially enriched in CRC cells treated with C16. C16 treatment resulted in G1 arrest and increased p21 protein and mRNA expression. Moreover, p21 expression was associated with CRC development as observed using immunohistochemical analysis of human CRC tissues. C16 upregulates p21 expression in CRC cells to regulate cell cycle and suppress tumor growth. Thus, PKR inhibitors may serve as a new treatment option for patients with CRC.