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Background: Delayed anterior cruciate ligament (ACL) reconstruction often causes residual anterolateral rotatory instability (ALRI) and consequent knee osteoarthritis, warranting the recommendation of early ACL reconstruction within 6 months after injury. Nonetheless, some cases show notable instability, even shortly after injury. The purpose of this study was to identify risk factors for an increase in quantitatively measured pivot shift in patients with ACL-deficient knees within 6 months after injury., Methods: Patients with primary ACL reconstruction within 6 months after injury and quantitative triaxial accelerometer measurements of preoperative pivot shift were included. Descriptive statistics were calculated for 11 independent variables (age, gender, time from injury to surgery, KT-1000, knee extension angle, lateral and medial posterior tibial slope angle, medial and lateral meniscus tears, ramp lesion and Tegner active scale). A single regression analysis was performed on the 11 items and acceleration during the pivot shift, and a multiple regression analysis was performed for items with p value less than 0.1., Results: Overall, 111 patients met the inclusion criteria. Single regression analysis showed that medial posterior tibial slope angle, medial meniscus tear and ramp lesion were significantly correlated with acceleration during the pivot shift ( p  < 0.001, p  = 0.04 and p  = 0.001). Multiple regression analysis identified medial posterior tibial slope angles and ramp lesions as independent factors for increased preoperative pivot shift ( p  = 0.005 and 0.01)., Conclusion: A steep medial posterior tibial slope angle and ramp lesion were independent risk factors for increased quantitatively measured pivot shift in patients with ACL-deficient knees., Level of Evidence: Level IV, case series study., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Context: Estimated remnant cholesterol (Rem-C) level, a risk factor for cardiovascular disease (CVD), is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosed via ultrasonography. However, the relationship between accurate serum Rem-C level measurements and histological findings of MASLD remains unclear., Objective: We aimed to elucidate the relationship between accurately measured serum Rem-C levels and histological findings of MASLD., Design: Cross-sectional single-center observational study., Methods: We assessed 222 patients (94 men and 128 women; age 20-80) who were diagnosed with MASLD via liver biopsy with available medical history, physical examination, and biochemical measurement data. Serum ester-type cholesterol and free cholesterol contents in the remnant lipoproteins were measured using an enzymatic method., Results: Serum Rem-C levels were significantly higher in patients with NAFLD activity score (NAS) 5-8, ＞66% steatosis grade, lobular inflammation with ≥5 foci, and many cells/prominent ballooning cells (a contiguous patch of hepatocytes showing prominent ballooning injury) than in patients with NAS 1-4, <33% steatosis grade, lobular inflammation with <2 foci, and few ballooning cells (several scattered balloon cells), respectively. While univariate analysis revealed no significant association between Rem-C levels and advanced fibrosis, a significant association between Rem-C levels and NAS was evident. This relationship remained significant in multivariate analysis adjusted for confounders. Furthermore, in the analysis by sex, these relationships were significant for men but not for women., Conclusion: High serum Rem-C levels were associated with high NAS, but not with fibrosis stage, particularly in men. Controlling serum Rem-C level may improve MASLD activity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Purpose: This retrospective study was conducted to investigate the diagnostic accuracy of ultrasound-derived fat fraction (UDFF) for grading hepatic steatosis using liver histology as the reference standard., Methods: Seventy-three patients with liver disease were assessed using UDFF and liver biopsy. Pearson's test and the Bland-Altman plot were used to assess the correlation between UDFF and histological fat content in liver sections. The UDFF cutoff values for histologically proven steatosis grades were determined using the area under the receiver operating characteristic curve (AUROC)., Results: The median age of the patients was 66 (interquartile range 54-74) years, and 33 (45%) were females. The UDFF values showed a stepwise increase with increasing steatosis grade (p < .001) and were strongly correlated with the histological fat content (r = .7736, p < .001). The Bland-Altman plot revealed a mean bias of 2.384% (95% limit of agreement, - 6.582 to 11.351%) between them. Univariate regression analysis revealed no significant predictors of divergence. The AUROCs for distinguishing steatosis grades of ≥ 1, ≥2, and 3 were 0.956 (95% confidence interval [CI], 0.910-1.00), 0.926 (95% CI, 0.860-0.993), and 0.971 (95% CI, 0.929-1.000), respectively. The UDFF cutoff value of > 6% had a sensitivity and specificity of 94.8% and 82.3%, respectively, for diagnosing steatosis grade ≥ 1. There was no association between UDFF and the fibrosis stage., Conclusion: UDFF shows strong agreement with the histological fat content and excellent diagnostic accuracy for grading steatosis. UDFF is a promising tool for detecting and quantifying hepatic steatosis in clinical practice., (© 2024. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Backgruound: Poor lifestyle habits may worsen nonalcoholic fatty liver disease (NAFLD), with progression to nonalcoholic steatohepatitis (NASH) and cirrhosis. This study investigated the association between glycemic control status and hepatic histological findings to elucidate the effect of glycemic control on NAFLD., Methods: This observational study included 331 patients diagnosed with NAFLD by liver biopsy. Effects of the glycemic control status on histological findings of NAFLD were evaluated by comparing the following four glycemic status groups defined by the glycosylated hemoglobin (HbA1c) level at the time of NAFLD diagnosis: ≤5.4%, 5.5%-6.4%, 6.5%-7.4%, and ≥7.5%., Results: Compared with the lowest HbA1c group (≤5.4%), the higher HbA1c groups (5.5%-6.4%, 6.5%-7.4%, and ≥7.5%) were associated with advanced liver fibrosis and high NAFLD activity score (NAS). On multivariate analysis, an HbA1c level of 6.5%- 7.4% group was significantly associated with advanced fibrosis compared with the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index and uric acid, total cholesterol, and triglyceride levels, the higher HbA1c groups were significantly associated with advanced fibrosis compared with the lowest HbA1c group. On the other hand, compared with the lowest HbA1c group, the higher HbA1c groups were also associated with a high NAS in both multivariate analyses., Conclusion: Glycemic control is associated with NAFLD exacerbation, with even a mild deterioration in glycemic control, especially a HbA1c level of 6.5%-7.4%, contributing to NAFLD progression.

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., (© 2024 Japan Society of Hepatology.)

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., (© 2024. The Author(s).)

A 79-year-old man received treatment for multiple intrahepatic hepatocellular carcinoma with atezolizumab + bevacizumab. However, he developed lower back pain attributed to spinal metastases upon tumor enlargement; thus, he was admitted to our hospital for a change from atezolizumab + bevacizumab to lenvatinib and radiation therapy for the spinal metastases. On the 11th day after starting lenvatinib treatment, a pulsatile aneurysm appeared in the tumor, detected using abdominal ultrasonography Micro B-flow imaging, which visualized blood flow at a high frame rate; this was diagnosed as a pseudoaneurysm. The patient refused treatment for the pseudoaneurysm; therefore, he was carefully followed up. Fortunately, the pseudoaneurysm disappeared on the 17th day. One month later, the tumor had become completely necrotic. Lenvatinib demonstrated effectiveness in inhibiting angiogenesis in the tumor, as evidenced by a decrease in tumor blood flow. This case report suggests that pseudoaneurysm formation within the tumor occurs early after the administration of lenvatinib; thus, clinicians must be aware of the potential risk of pseudoaneurysm rupture., (© 2024. Japanese Society of Gastroenterology.)

Background and objective Examining the factors influencing the career aspirations of medical students is imperative for understanding their orientation toward rural medicine. Such an investigation can serve as a basis for shaping medical education curricula dedicated to nurturing rural focus. Although previous studies have categorized students based on the presence or absence of orientation toward rural medicine and explored their sociodemographic characteristics, these students may not constitute a homogeneous group; their interests can range from aspiring to establish residence and professional practice in a specific region to being merely willing to endure brief regional placements. There is a scarcity of comprehensive examination of the extent and potential variations of rural orientation in the literature. Our survey addresses this gap by exploring the variations in rural orientation among medical students and the differences in their sociodemographic characteristics and preferred specialties based on their degree of rural orientation. Methods We classified medical students into four groups according to their levels of rural orientation: demonstrating proactive engagement towards it, considering it for a defined duration, indicating a preference for avoiding it, and considering it unfeasible. The distribution within each group was investigated. A subsequent analysis of rural orientation and its associated sociodemographic characteristics was performed: a conventional dichotomous study was conducted based on the presence or absence of rural orientation, and a focused study compared students actively interested in rural healthcare with other students. This approach enabled us to explore differences in the degree of rural orientation and associated factors. Results The study included 531 students, with 89 participants demonstrating proactive engagement towards rural medicine, 283 considering it for a defined period, 95 indicating an inclination to avoid it, and 63 students stating that it is unfeasible for them. Associated sociodemographic characteristics were explored based on the presence or absence of rural orientation and included recommendations for admission by a designated high school, the presence of a physician role model, and aspirations for obstetrics and gynecology departments. Conversely, when exclusively focusing on students with a desire for proactive engagement in rural medicine, positive correlations were observed with characteristics such as being from the same non-urban prefecture as that of the university where the study was conducted, having a history of residing in a rural area, having a physician role model, and expressing aspirations for general practice or family medicine. Aspiring to be an organ-specific specialist showed a negative correlation with high levels of rural orientation. Conclusions Based on our findings, rural orientation is not uniform among medical students; distinct levels of this aspect were observed, each associated with different sociodemographic factors., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Kikuchi et al.)

Van der Waals layered transition-metal chalcogenides are drawing significant attention owing to their intriguing physical properties. This group of materials consists of abundant members with various elements, having a variety of different structures. However, they are all crystalline materials, and the physical properties of van der Waals layered quasicrystals have never been studied to date. Here, we report on the discovery of superconductivity in a van der Waals layered quasicrystal of Ta 1.6 Te. The electrical resistivity, magnetic susceptibility, and specific heat of the quasicrystal unambiguously validate the occurrence of bulk superconductivity at a transition temperature of ~1 K. This discovery can promote new research on assessing the physical properties of novel van der Waals layered quasicrystals as well as two-dimensional quasicrystals; moreover, it paves the way toward new frontiers of superconductivity in thermodynamically stable quasicrystals., (© 2024. The Author(s).)

We herein report a 63-year-old man who presented with left lower jaw pain and was diagnosed with hepatocellular carcinoma with bone metastases post-examination. All tumors grew after immunotherapy with atezolizumab and bevacizumab, and his jaw pain worsened. After palliative radiation therapy, however, the tumors shrank markedly, with no recurrence seen after stopping immunotherapy. To our knowledge, this is the first case in which a radiotherapy- and immunotherapy-mediated abscopal effect facilitated tumor shrinkage and immunotherapy discontinuation.

The number of plants unpalatable to deer increases with increasing deer numbers. In the Kyushu Mountain area of Southern Japan, Pieris japonica (Ericaceae), an unpalatable shrub, has become the monodominant vegetation under evergreen conifer and deciduous broad-leaved tree stands. The monodominance of unpalatable plants in the understory has potential advantages and drawbacks; however, the effects of Pieris dominance are not well understood. To assess the effects of P. japonica dominances on forest environments and ecosystems, we investigated understory environments and soil microbiomes in Pieris-dominant sites. Under the deciduous broad-leaved trees, Pieris dominance leads to considerable Pieris leaf litter and humus weights and low soil bulk density and canopy openness. In the soil fungal community and fungal functional groups, the relative abundance of symbiotrophic fungi, particularly ectomycorrhizal fungi in Pieris-dominant sites were lower than in other-vegetation understory sites and saprotrophic fungi vice versa. Because few seedlings and saplings were found under Pieris shrubs, Pieris dominance in the understory might exclude other plant species. The results of this study will contribute to the Pieris population and forest management following deer overgrazing., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tokumoto, Katayama. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Aims: Immune checkpoint inhibitors may cause various types of organ damage as immune-related adverse events, of which, liver damage is the most common. Herein, we evaluated the clinicopathological features of immune checkpoint inhibitor-related liver injury and investigated the differences between immune checkpoint inhibitor-related liver injury and drug-induced liver injury or autoimmune hepatitis., Methods: We selected patients with ≥ grade 3 liver injury who were diagnosed with immune checkpoint inhibitor-related liver injury (n=15). Liver biopsies were performed in 10 of the 15 cases. We also selected cases in which a liver biopsy was performed and drug-induced liver injury (n=7) or autoimmune hepatitis [n=21: acute exacerbation (n=13) was diagnosed and cases of acute onset (n=8), in which liver function test results corresponded to ≥ grade 3]., Results: Portal fibrosis and periportal activity scores were significantly higher in the acute exacerbation autoimmune hepatitis group than in the other groups. Portal and lobular activity were not different between the groups. Plasma cell infiltration showed a higher trend in the autoimmune hepatitis group than in the other groups. Granuloma formations were seen in 90% of immune checkpoint inhibitor-related liver injury cases. The CD4/8 ratio was significantly lower in the immune checkpoint inhibitor-related liver injury group than in the other groups. Patients with bile duct injury had poorer response to corticosteroid therapy than those without., Conclusions: There are some obvious differences among immune checkpoint inhibitor-related liver injury, drug-induced liver injury, and autoimmune hepatitis in liver histology. Liver biopsy is helpful for the diagnosis and severity evaluation of liver injury.

Background: The chronological pattern of extrahepatic lymphatic vessel progression in the course of chronic liver disease has not been clarified. This study aimed to clarify the chronological changes in lymphatic vessels with liver disease progression., Methods: This was a prospective cross-sectional study that enrolled a total of 199 patients. The maximum diameter of the cisterna chyli (CC) or terminal thoracic duct (tTD) was measured using computed tomography or ultrasonography, respectively. Changes in the maximum diameters of the CC and tTD were evaluated with patients with chronic liver disease as the pilot set (n = 138). Subsequently, we examined whether CC/tTD could be used to re-allocate unclassified patients by the Baveno-VII criteria to appropriately diagnose clinically significant portal hypertension (CSPH) in the pilot and validation sets., Results: In the pilot set, a scatter-plot showed that both CC and tTD were narrowed as terminal features in chronic liver disease after dilation. Because there was a significant correlation between the CC diameter and hepatic venous pressure gradient (r = 0.724) in unclassified patients, the diagnostic value of CC and tTD for CSPH was good (AUC: 0.961 and 0.913, respectively). After re-allocation, 68 and 27 unclassified patients were reduced to 4 and 5 in the pilot and validation sets, respectively., Conclusion: Both the CC and tTD narrow in the course of liver disease after dilation. Moreover, the maximum diameter of the CC and tTD can be used to re-allocate patients who are unclassified according to the Baveno-VII criteria., Clinical Trial Number: UMIN trial no. 000044857., (© 2023. Asian Pacific Association for the Study of the Liver.)

Treatment modalities for advanced hepatocellular carcinoma (HCC) have changed dramatically, with systemic therapy as the primary option. However, the effect of sequential treatment on prognosis remains unclear. This retrospective study included patients who began systemic therapy between 2009 and 2022. The patients were separated into three groups according to systemic therapy commencement. The number of therapy lines, treatment efficacy, and overall survival (OS) were compared. Multivariate analyses of the prognostic factors were analyzed using the Cox proportional hazards model. Overall, 336 patients were included (period 1: 2009-2013, n = 86; period 2: 2014-2018, n = 132; period 3: 2019-2022, n = 118). A significant etiological trend was observed with decreasing viral hepatitis-related HCC and increasing non-viral hepatitis-related HCC. Across periods 1-3, the proportion of patients who were administered >2 lines progressively increased (1.2%, 12.9%, and 17.0%, respectively; p < 0.001) and the median OS was significantly prolonged (14.3, 16.8, and 31.0 months; p < 0.001). The use of <3 lines, the non-complete and partial response of the first line, modified albumin-bilirubin at grade 2b or 3, an intrahepatic tumor number ≥ 5, extrahepatic metastasis, and alpha-fetoprotein at ≥400 ng/mL were the strongest factors associated with shorter OS. Sequential therapies have contributed to significant improvements in HCC prognosis, suggesting that sequential treatment post-progression is worthwhile for better survival.

Purpose: We aimed to compare vibration-controlled transient elastography (VCTE) with shear wave elastography (SWE) without previous analysis and generate regression equations between VCTE and new point SWE using combination-elastography., Methods: Overall, 829 patients with chronic liver disease were enrolled in this study. Patients with a skin-liver capsule distance > 25 mm were excluded. The reproducibility of VCTE and SWE was confirmed in a phantom study and a clinical study. Considering that combination-elastography allows measurement based on strain elastography, a similar analysis was performed for the liver fibrosis index (LFI), which is a quantitative value for evaluation of liver fibrosis calculated using strain elastography image features. Regression equations between the VCTE and SWE values were obtained based on linear regression analysis., Results: In the phantom study and clinical study, there was a strong correlation between VCTE and SWE [r = 0.995 (p < 0.001) and r = 0.747 (p < 0.001), respectively). The regression equation between VCTE and SWE was VCTE (kPa) = 1.09 × point SWE (kPa) - 0.17. The Bland-Altman plots revealed no statistically significant bias. Meanwhile, there was no correlation between VCTE and LFI (r = 0.279). There was a statistically significant bias between VCTE and LFI in the Bland-Altman plots. The inter-operator reliability showed a good intraclass correlation coefficient of 0.760 (95% confidence interval: 0.720-0.779)., Conclusion: Liver stiffness measured using point SWE was comparable to that measured using VCTE., (© 2023. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Rural career preference is known to be affected by rural self-efficacy. This study aims to explore whether the presence of a physician role model and having a medical department of interest influence rural self-efficacy among medical students. The study sample comprised 813 students (464 male and 349 female). We assessed rural self-efficacy using a validated scale that comprised 15 questions. The effect of the presence of a physician role model and the choice of medical department on rural self-efficacy score was examined. Multivariable-adjusted regression analysis showed that the presence of a physician role model was significantly associated with the rural self-efficacy score (β = 0.236, p < 0.001), as were gender (β = -0.096, p = 0.004), admission while living in hometown (β = 0.077, p = 0.041), receiving a scholarship for regional duty (β = 0.079, p = 0.025), admission based on school recommendation (β = 0.077, p = 0.031), and subjective difficulty with living in a rural area (β = -0.201, p < 0.001). Moreover, a higher rural self-efficacy score was significantly associated with students who listed general medicine/family medicine (β = 0.204, p < 0.001), pediatrics (β = 0.098, p = 0.004), or obstetrics and gynecology (β = 0.108, p = 0.002) as their department of choice, while anesthesiology (β = -0.075, p = 0.023) was significantly associated with a lower rural self-efficacy score. These relationships were consistent for both males and females. The presence of a physician role model and the choice of medical department are important factors for higher rural self-efficacy scores., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Kawamoto et al.)

Hepatitis B vaccine induces the production of antibodies against hepatitis B surface antigen (anti-HBs) and prevents hepatitis B virus (HBV) infection. However, 5-10% of individuals cannot develop anti-HBs even after multiple vaccinations (HB vaccine non-responders). We developed an intranasal vaccine containing both HBs antigen (HBsAg) and HB core antigen (HBcAg) and mixed it with a viscosity enhancer, carboxyl vinyl polymer (CVP-NASVAC). Here, we investigated the prophylactic capacity of CVP-NASVAC in HB vaccine non-responders. Thirty-four HB vaccine non-responders were administered three doses of intranasal CVP-NASVAC. The prophylactic capacity of CVP-NASVAC was assessed by evaluating the induction of anti-HBs and anti-HBc (IgA and IgG) production, HBV-neutralization activity of sera, and induction of HBs- and HBc-specific cytotoxic T lymphocytes (CTLs). After CVP-NASVAC administration, anti-HBs and anti-HBc production were induced in 31/34 and 27/34 patients, respectively. IgA anti-HBs and anti-HBc titers significantly increased after CVP-NASVAC vaccination. HBV-neutralizing activity in vitro was confirmed in the sera of 26/29 CVP-NASVAC-administered participants. HBs- and HBc-specific CTL counts substantially increased after the CVP-NASVAC administration. Mild adverse events were observed in 9/34 participants; no serious adverse events were reported. Thus, CVP-NASVAC could be a beneficial vaccine for HB vaccine non-responders.

Aim: Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver-related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance., Methods: This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti-hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75-g oral glucose tolerance test results., Results: Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver-related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome., Conclusions: Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver-related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow-up is required for patients with hepatitis C based on their glucose tolerance status., (© 2023 Japan Society of Hepatology.)

The time point of the most precise predictor of hepatocellular carcinoma (HCC) development after viral eradication with direct-acting antiviral (DAA) therapy is unclear. In this study we developed a scoring system that can accurately predict the occurrence of HCC using data from the optimal time point. A total of 1683 chronic hepatitis C patients without HCC who achieved sustained virological response (SVR) with DAA therapy were split into a training set (999 patients) and a validation set (684 patients). The most accurate predictive scoring system to estimate HCC incidence was developed using each of the factors at baseline, end of treatment, and SVR at 12 weeks (SVR12). Multivariate analysis identified diabetes, the fibrosis-4 (FIB-4) index, and the α-fetoprotein level as independent factors at SVR12 that contributed to HCC development. A prediction model was constructed with these factors that ranged from 0 to 6 points. No HCC was observed in the low-risk group. Five-year cumulative incidence rates of HCC were 1.9% in the intermediate-risk group and 15.3% in the high-risk group. The prediction model at SVR12 most accurately predicted HCC development compared with other time points. This simple scoring system combining factors at SVR12 can accurately evaluate HCC risk after DAA treatment., (© 2023. The Author(s).)

Background: Many of the existing research studies have shown that serum uric acid (SUA) is a predictor of renal disease progression. More recently, studies have suggested an association between renal function-normalized SUA and all-cause mortality in adults. This study aims to examine the association between the ratio of SUA to creatinine (SUA/Cr) and all-cause mortality with a focus on hypertensive patients., Methods: This study is based on 2,017 participants, of whom 916 were male (mean age, 67 ± 11 years) and 1,101 were female (mean age, 69 ± 9 years). All participants were part of the Nomura Cohort Study in 2002 (cohort 1) and 2014 (cohort 2), as well as the follow-up period (2002 follow-up rate, 94.8%; 2014 follow-up rate, 98.0%). We obtained adjusted relative risk estimates for all-cause mortality from a basic resident register. In addition, we employed a Cox proportional hazards model and adjusted it for possible confounders to determine the hazard ratio (HR) and 95% confidence interval (CI)., Results: Of the total participants, 639 (31.7%) were deceased; of these, 327 (35.7%) were male and 312 (28.3%) were female. We found an independent association between a higher ratio of SUA/Cr and a higher risk of all-cause mortality in female participants only (HR, 1.10; 95% CI, 1.02-1.18). The multivariable-adjusted HRs (95% CI) for all-cause mortality across quintiles of baseline SUA/Cr were 1.28 (0.91-1.80), 1.00, 1.38 (0.95-1.98), 1.37 (0.94-2.00), and 1.57 (1.03-2.40) for male participants, and 0.92 (0.64-1.33), 1.00, 1.04 (0.72-1.50), 1.56 (1.06-2.30), and 1.59 (1.06-2.38) for female participants. When the data were further stratified on the basis of age (< 65 or ≥ 65 years), body mass index (< 22.0 or ≥ 22.0 kg/m 2 ), estimated glomerular filtration rate (< 60 or ≥ 60 mL/min/1.73 m 2 ), and presence of SUA-lowering medication, trends similar to those of the full population were found in all groups., Conclusion: Baseline SUA/Cr is independently and significantly associated with future all-cause mortality among hypertensive patients., (© 2023. The Author(s).)

Aims: HBsAg loss with anti-HBs acquisition is considered a functional cure and ideal treatment goal for patients with CHB. Our group have reported the efficacy of therapeutic vaccine with HBsAg and HBcAg (NASVAC) by intranasal and subcutaneous injection. In this study, we investigated the safety and efficacy of newly developed CVP-NASVAC, which contained NASVAC with mucoadhesive carboxyl vinyl polymer (CVP) in the dedicated device., Methods: A single dose, open-label, phase IIa clinical trial of CVP-NASVAC was conducted. Patients with CHB treated with nucleoside/nucleotide analogs (NAs) and HBV carriers not undergoing anti-HBV treatment were enrolled. CVP-NASVAC was injected through the nose for, in total, 10 times. Participants were followed-up for 18 months, and their HBsAg reduction and anti-HBs induction assessed as endpoints., Results: Among the patients with CHB treated with NAs (n = 27) and HBV carriers without NAs (n = 36), 74.1% and 75.0% exhibited reductions in their baseline HBsAg, and the mean reductions were -0.1454 log 10  IU/ml (p < 0.05) and -0.2677 log 10  IU/ml (p < 0.05), respectively. Anti-HBs antibody was detected in 40.7% and 58.3% of patients treated with and without NAs, respectively. Six of 71 (9.5%) patients were functionally cured after the CVP-NASVAC treatment., Conclusions: Anti-HBs induction and HBsAg reduction was observed after CVP-NASVAC treatment in some patients with CHB. The CVP-NASVAC is a safe treatment, which might expect to achieve functional cure for patients with CHB., (© 2022 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Background: The novel 2-D shear wave elastography (2D-SWE) can measure two ultrasound parameters: shear wave dispersion (SWD) and shear wave speed (SWS). We investigated the ability of 2D-SWE in measuring spleen stiffness using ultrasound multiparametric imaging., Methods: This cross-sectional study included patients with chronic liver disease who underwent esophagogastroduodenoscopy and ultrasonographic examinations of the spleen between September 2018 and December 2021. In total, 157 patients were enrolled in this study: 81 and 67 patients were included in the pilot set for hepatic venous pressure gradient (HVPG) measurements and validation cohort without HVPG measurements, respectively. To confirm reproducibility between the two examiners, an additional 30 patients were enrolled., Results: The Bland-Altman plots revealed no significant bias in the SWD as measured by two examiners. The splenic SWS (r = 0.752) and SWD (r = 0.444) were correlated with the HVPG. Regarding high-risk varices, as per the Youden index, the cut-off value for splenic SWS was 3.30 m/s, with a sensitivity of 85.7%, specificity of 92.5%, positive predictive value of 85.7%, and negative predictive value of 92.4% in the pilot set. In the validation set, good diagnostic performance by the splenic SWS was observed. However, SWD did not perform as well as SWS., Conclusions: The splenic SWS, measured using ultrasound multiparametric imaging, was closely correlated with the HVPG. Thus, SWS is a useful predictive marker for high-risk varices., (© 2022 Japan Society of Hepatology.)

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease all over the world. Therapeutic strategies targeting its multidirectional pathways are required. Particularly, fibrosis is closely associated with its prognosis. We previously found that B cell-activating factor (BAFF) is associated with severity of NAFLD. Here, we determined the direct in vivo role of BAFF in the development of liver fibrosis. Histological and biochemical analyses were performed using wild-type and BAFF-deficient mice. We established a murine model of non-alcoholic steatohepatitis (NASH) using carbon tetrachloride injection accompanied by high-fat/high-cholesterol diet feeding. Additionally, in vitro analysis using mouse macrophage-like cell line RAW264.7 and primary hepatic stellate cells was performed. Hepatic steatosis and inflammation, and most importantly, the progression of liver fibrosis, were ameliorated in BAFF-deficient mice compared to those wild-type mice in our model. Additionally, BAFF deficiency reduced the number of CD11c + M1-type macrophages in the liver. Moreover, BAFF stimulated RAW264.7 cells to secrete nitric oxide and tumor necrosis factor α, which drove the activation of hepatic stellate cells. This indicates that BAFF plays a crucial role in NASH development and may be a promising therapeutic target for NASH.

Wood biomass conversion for fossil resource replacement could result in the sustainable production of chemicals, although lignin represents an obstacle to efficient polysaccharide use. White-rot fungus Phlebia sp. MG-60 reportedly selectively and aerobically degrades lignin in hardwood, then it begins cellulose saccharification from the delignified wood to produce ethanol. Environmental conditions might change white-rot fungi-driven biomass conversion. However, how the environmental response sensor affects ethanol fermentation in white-rot fungi remains elusive. In this study, we focused on MGHOG1, the yeast Hog1 homolog in Phlebia sp. MG-60, a presumably important player in osmoresponse. We generated MGHOG1 overexpressing (OE) transformants in Phlebia sp. MG-60, exhibiting slower mycelial growth compared with the wild-type under salinity stress. MGHOG1 overexpressing liquid cultures displayed suppressed mycelial growth and ethanol fermentation. Therefore, MGHOG1 potentially influences ethanol fermentation and mycelial growth in Phlebia sp. MG-60. This study provides novel insights into the regulation of white-rot fungi-mediated biomass conversion., (© Crown copyright 2023.)

Purpose: Deep attenuation transducers (DAX) are capable of imaging at diagnostic depths of up to 40 cm. The feasibility of DAX for liver stiffness measurement (LSM) has not been reported clinically. We aimed to assess the feasibility and reliability of DAX for LSM., Methods: Overall, 219 patients with chronic liver disease were enrolled. The success rate (acquired after ≥ 10 valid measurements) and inadequate measurements (interquartile range/median ≥ 0.3) for DAX were compared with those of conventional convex (c-convex) probes and M and XL probes of vibration-controlled transient elastography., Results: LSM was successfully performed for all patients using DAX through all degrees of skin-to-liver capsular distance (SCD). Especially in patients with an SCD ≥ 30 mm, the difference in the rate of acquisition of 10 valid measurements was remarkable: M probe (8/33, 24.2%), XL probe (26/33, 78.8%), c-convex probe (33/43, 76.7%), and DAX (44/44, 100%). In patients with an SCD ≥ 30 mm, the inadequate measurement rate of M probe (1/8, 12.5%), XL probe (8/26, 30.8%), and c-convex probe (6/33, 18.2%) was higher than that of DAX (1/43, 2.3%). The areas under the curve for diagnosis of F4 with shear wave speed by c-convex and DAX were 0.916 and 0.918, respectively. Between DAX and c-convex probes, the intraclass correlation coefficient of 0.937 (95% CI 0.918-0.952) was excellent. Bland-Altman plots revealed that there was no statistically significant bias., Conclusion: Liver stiffness measured by DAX is feasible and reliable for all patient populations, while the XL probe is limited to use in obese patients., (© 2022. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid composition in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) and evaluate the relationship between histological findings and fatty acid composition. Overall, 235 patients (134 women) with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. Multivariate analyses adjusted for age, sex, body mass index, alanine aminotransferase, hemoglobin A1c, creatinine, total cholesterol, triglyceride, and NAFLD Activity Score values showed that lower levels of arachidic, behenic, α-linolenic, eicosatetraenoic, docosapentaenoic, and docosahexaenoic acids and higher levels of mead acid were associated with fibrosis stage 3-4. Furthermore, higher lauric acid, myristic acid, and palmitic acid levels and monounsaturated fatty acids such as palmitoleic acid and oleic acid were significantly associated with high NAS in analyses adjusted for the same factors and fibrosis stage. The plasma fatty acid composition was associated with the histological evidence of NASH. Increased synthesis of fatty acids is associated with NASH; insufficient intake of n-3 essential fatty acids and reduced elongation of fatty acids are associated with fibrosis in NASH. These features may help clinicians to understand and treat advanced NASH cases.

Aims/introduction: To investigate whether the Fibrosis-4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease., Materials and Methods: Based on fatty liver disease and Fibrosis-4 index (cut-off value 1.3), we retrospectively divided 9,449 individuals, who underwent at least two annual health checkups, into four groups stratified by sex: normal; high Fibrosis-4 index without fatty liver disease; low Fibrosis-4 index with fatty liver disease; and high Fibrosis-4 index with fatty liver disease., Results: Onset rates for diabetes mellitus in the normal, high Fibrosis-4 index without fatty liver disease, low Fibrosis-4 index with fatty liver disease and high Fibrosis-4 index with fatty liver disease groups were 1.6%, 4.3%, 6.8% and 10.2%, respectively, in men, and 0.6%, 0.9%, 5.3% and 7.0%, respectively, in women. Compared with the normal group, the high Fibrosis-4 index without fatty liver disease, low Fibrosis-4 index with fatty liver disease and high Fibrosis-4 index with fatty liver disease groups were at a significant risk for diabetes mellitus onset in both male and female participants. Furthermore, in both sexes, high Fibrosis-4 index with fatty liver disease remained a significant risk factor on multivariate analysis (high fibrosis-4 index with fatty liver disease group: adjusted hazard ratio 4.03, 95% confidence interval 2.19-7.42 [men] and adjusted hazard ratio 6.40, 95% confidence interval 1.77-23.14 [women])., Conclusions: Individuals with fatty liver disease and high Fibrosis-4 index had a higher risk of diabetes mellitus onset. Therefore, Fibrosis-4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease and identify patients requiring intervention., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Acetylcholine is a neuromodulator critical for learning and memory. The cholinesterase inhibitor donepezil increases brain acetylcholine levels and improves Alzheimer's disease (AD)-associated learning disabilities. Acetylcholine activates striatal/nucleus accumbens dopamine receptor D2-expressing medium spiny neurons (D2R-MSNs), which regulate aversive learning through muscarinic receptor M1 (M1R). However, how acetylcholine stimulates learning beyond M1Rs remains unresolved. Here, we found that acetylcholine stimulated protein kinase C (PKC) in mouse striatal/nucleus accumbens. Our original kinase-oriented phosphoproteomic analysis revealed 116 PKC substrate candidates, including Rac1 activator β-PIX. Acetylcholine induced β-PIX phosphorylation and activation, thereby stimulating Rac1 effector p21-activated kinase (PAK). Aversive stimulus activated the M1R-PKC-PAK pathway in mouse D2R-MSNs. D2R-MSN-specific expression of PAK mutants by the Cre-Flex system regulated dendritic spine structural plasticity and aversive learning. Donepezil induced PAK activation in both accumbal D2R-MSNs and in the CA1 region of the hippocampus and enhanced D2R-MSN-mediated aversive learning. These findings demonstrate that acetylcholine stimulates M1R-PKC-β-PIX-Rac1-PAK signaling in D2R-MSNs for aversive learning and imply the cascade's therapeutic potential for AD as aversive learning is used to preliminarily screen AD drugs., (© 2022. The Author(s).)

Introduction: Nonalcoholic fatty liver disease (NAFLD) is diagnosed after excluding other liver diseases. The pathogenesis of NAFLD when complicated by other liver diseases has not been established completely. Metabolic dysfunction-associated fatty liver disease (MAFLD) involves more metabolic factors than NAFLD, regardless of complications with other diseases. This study aimed to clarify the effects of fatty liver occurring with metabolic disorders, such as MAFLD without diabetes mellitus (DM), on the development of DM., Materials and Methods: We retrospectively assessed 9,459 participants who underwent two or more annual health check-ups. The participants were divided into the MAFLD group (fatty liver disease with overweight/obesity or non-overweight/obesity complicated by metabolic disorders), simple fatty liver group (fatty liver disease other than MAFLD group), metabolic disorder group (metabolic disorder without fatty liver disease), and normal group (all other participants)., Results: The DM onset rates in the normal, simple fatty liver, metabolic disorder, and MAFLD groups were 0.51, 1.85, 2.52, and 7.36%, respectively. In the multivariate analysis, the MAFLD group showed a significantly higher risk of DM onset compared with other three groups (P < 0.01). Additionally, the risk of DM onset was significantly increased in fatty liver disease with overweight/obesity or pre-diabetes (P < 0.01)., Conclusions: Fatty liver with metabolic disorders, such as MAFLD, can be used to identify patients with fatty liver disease who are at high risk of developing DM. Additionally, patients with fatty liver disease complicated with overweight/obesity or prediabetes are at an increased risk of DM onset and should receive more attention., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: In Japan, community medicine clerkships facilitate positive attitudes toward rural medical practice and encourage rural recruitment. Rural self-efficacy has been shown to influence rural career intent following a rural clinical placement. However, the impact of subjective difficulties of living in a rural area on future rural career intent is also important. This study aims to explore whether rural self-efficacy influences the relationship between difficulty with living in a rural area and rural career intent.  METHODS: The subjects included 308 male and 255 female participants aged 20-41 [median (interquartile range): 22 (21-22)] years. Rural self-efficacy was based on a validated scale consisting of 15 questions. Difficulty with living in a rural area was measured asking students. A cohort survey was conducted to evaluate the effect of the rural self-efficacy score on the rural career intent of Japanese medical students after they completed their rural clinical training., Results: The following variables were significantly associated with a higher rural self-efficacy score: female sex (p = 0.003), age < 21 years (p = 0.013), having a doctor as a role model (p < 0.001), gaining admission through a school recommendation (p = 0.016), living in a rural or remote area until the age of 18 years (p = 0.018), and orientation towards general medicine (p < 0.001). In addition, baseline difficulty with living in a rural area was significantly associated with a lower self-efficacy score (p < 0.001). Participants with a stronger intent to practice in a rural area before rural clinical training had higher rural self-efficacy and showed a stronger positive rural career intent after rural clinical training (p < 0.001). A multivariable logistic regression analysis demonstrated that difficulty with living in a rural area [odds ratio (OR): 0.61; 95% confidence interval (CI), 0.39-0.84] was still associated with lower rural career intent after rural clinical training, independent of all confounders such as gender, age, scholarship for regional duty, rural background, and orientation towards general medicine. However, when rural self-efficacy (OR, 1.12; 95% CI, 1.07-1.16) was added as a factor for rural career intent, difficulty with living in a rural area (OR, 0.68; 95% CI, 0.43-1.06) was no longer observed as an associated factor., Conclusion: Subjective difficulty with living in a rural area was shown to reduce future rural career intent, but high rural self-efficacy ameliorated this decline., (© 2022. The Author(s).)

To the best of our knowledge, this is the first report on the rapid one-pot synthesis of a unique core-shell-structured zeolitic imidazolate framework (ZIF) using Co(III) and Zn(II) precursors. The key to obtaining this unique structure is the use of a Co(III) precursor as the starting material. Transmission electron microscopy (TEM) reveals that Co was present within a 30-nm-thick shell layer of the ZIF material. Thermal decomposition of the ZIF material affords core-shell-structured carbon nanoparticles that have Co on the external surface of the carbon grain. We have previously demonstrated that this carbonaceous material obtained by thermal decomposition exhibited high performance as an adsorbent for nitric oxide, even in the presence of excess oxygen and water vapor, and therefore, it was a suitable material for NO x elimination at low temperatures. The growth mechanism of the synthesized ZIF particles and the differences between synthesized ZIF and conventional Co(II)-ZIF-67 are discussed. The reactivity of the Co(III) precursor is much lower than that of the Co(II) species, leading to slower precipitation of Co(III) than that of Zn(II), thus forming the core-shell structure.

For patients with cirrhosis, no definitive predictor of the efficacy and prognosis of tolvaptan treatment exists. We assessed the cisterna chyli's utility as an optimal marker. We retrospectively enrolled 172 patients with cirrhosis. The effect of tolvaptan was evaluated using post-treatment survival time. The overall response to tolvaptan was 52.3%. The median cisterna chyli diameter was 4.1 mm. Of 172 patients, 100 were included in the pilot set and 72 in the validation set. According to the Youden index, the cisterna chyli diameter's cutoff value was 4 mm, with a sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of 92%, 83%, 86%, 91%, 5.43, and 0.09, respectively, in the pilot set. The area under the curve of the cisterna chyli diameter for evaluating tolvaptan's effect was 0.911 and 0.988 in the pilot and validation sets, respectively. During multivariate analysis, cisterna chyli narrowing and furosemide treatment were significant predictive factors for tolvaptan's insufficient effect. Cumulative liver transplantation-free survival rates were significantly higher in patients with cisterna chyli dilatation than in those without (p = 0.028). Our findings suggest a strong association of cisterna chyli with tolvaptan treatment response in patients with cirrhosis and hepatic edema., (© 2022. The Author(s).)