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Linear gravity anomalies (LGAs) on the Moon have been interpreted as ancient magmatic intrusions formed during the lunar expansion. The composition of such ancient subsurface intrusions may offer hints for the lunar thermodynamic state in the initial stage of lunar history. To pose a first compositional constraint on magmatism related to lunar expansion, this study analyzed the spectrum and gravity around craters on LGAs, such as Rowland, Roche, and Edison craters. Using reflectance spectra around the craters, we first surveyed non‐mare basaltic exposures. To test the LGA excavation scenario as a possible origin of the discovered exposures, we then compared the Gravity Recovery and Interior Laboratory data and post‐cratering gravity simulation with the iSALE shock physics code. Our spectral analysis reveals no basaltic exposure around the Rowland crater. Further, the observed termination of LGA at the crater rim contradicts the gravity simulation, which assumes that LGA predates the Rowland crater. These results suggest that LGA formation might postdate the Rowland formation and that lunar expansion lasted even after the Nectarian age. On the other hand, we found that both Roche and Edison craters possess basaltic exposures in their peripheries. Because the gravity reduction inside Roche crater can be reproduced in our simulation, the discovered basaltic exposures are possibly LGA materials ejected from these craters. The composition of those exposures shows that the LGA intrusions at the two locations are composed of low‐titanium magma, indicating that ancient magma during the expansion did not contain ilmenite‐rich melt, perhaps resulting from the low‐ilmenite content of the ancient upper mantle. Plain Language Summary: The Moon has positive, narrow, and long gravity anomalies, so‐called linear gravity anomalies (LGAs), which are thought to be magmatic intrusions formed during the ancient lunar expansion. The composition of these intrusions may provide insights into the early lunar thermal state. This study analyzed the reflectance spectra and gravity data around craters located on LGAs, specifically Rowland, Roche, and Edison craters, which are postulated to have ejected the LGA material. By analyzing the reflectance spectra, we first identified non‐mare basaltic exposures that likely originated from these subsurface formations. We next examine if these exposures are composed of the LGA materials by comparing the observed gravity with cratering simulation results. We found no basaltic exposures around Rowland and that gravity inside Rowland is not consistent with the excavation hypothesis, perhaps suggesting that LGA formation and lunar expansion occurred after the Rowland formation. On the other hand, we discovered basaltic exposures around both Roche and Edison craters, which can be interpreted as ejecta from the LGAs consistent with the gravity inside Roche crater. The composition of these exposures indicates that LGAs are composed of low‐titanium magma, which provides a new constraint on the ancient thermal state of the Moon. Key Points: High‐calcium pyroxene exposures and gravity reduction around Roche crater imply an excavation of lunar linear gravity anomaly materialsLunar subsurface dikes formed during the ancient expansion stage are estimated to be composed of low‐titanium magmaA linear gravity anomaly possibly postdates the Rowland crater, suggesting a potential prolongation of lunar expansion beyond the Nectarian age [ABSTRACT FROM AUTHOR]

Background and Aims: The impact of hepatitis C virus (HCV) eradication via direct-acting antiviral (DAA) therapy on overall mortality, particularly non-liver-related mortality, is understudied., Methods: We recruited 4180 patients with chronic HCV infection who achieved sustained virological response (SVR) (HCV eradication) through DAA therapy (n = 2501, SVR group) or who did not receive antiviral therapy (n = 1679, non-SVR group); 1236 from each group were chosen using propensity score matching. Causes of death and all-cause mortality, including non-liver-related diseases, were investigated., Results: Of the 4180 patients, 592 died during the follow-up period. In the SVR group, the mortality rates from liver-related and non-liver-related diseases were 16.5% and 83.5%, respectively. Compared to the non-SVR group, mortality rates from liver-related and non-liver-related diseases were 50.1% and 49.9%, respectively (p < .001). In non-cirrhotic patients, multivariable analysis revealed that SVR was an independent factor associated with both liver-related (hazard ratio [HR], .251; 95% confidence interval [CI], .092-.686) and non-liver-related (HR, .641; 95% CI, .415-.990) mortalities. In cirrhotic patients, multivariable analysis revealed that SVR remained an independent factor significantly associated with liver-related mortality (HR, .151; 95% CI, .081-.279). In propensity score-matched patients, the eradication of HCV (SVR group) decreased both liver-related (p < .001) and non-liver-related mortality (p = .008) rates compared to persistent HCV infection (non-SVR group)., Conclusions: The elimination of HCV via DAA therapy reduced not only liver-related mortality but also non-liver-related mortality in patients with chronic HCV., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) requires at least one of five cardiometabolic criteria. It is unclear whether these criteria can be used as predictors and treatment targets for complications including liver-related events and major adverse cardiovascular events (MACE)., Aims: To investigate the relationship between cardiometabolic criteria and complications., Methods: We conducted a nationwide, population-based study of 979,352 patients with MASLD. We investigated relationships between a number of criteria at baseline and liver-related events or MACE risks. In a separate longitudinal analysis, we included patients with five criteria at baseline and investigated the relationship between improving the criteria and the incidence of complications after 1 year., Results: The cumulative incidence of MACE, but not liver-related events, increased with increasing baseline cardiometabolic criteria. In the longitudinal study, multivariable analysis using patients with five criteria (no improvement) as the reference, adjusted hazard ratios (95% confidence interval) of MACE in patients with 4, 3, 2, and 0-1 criteria (1 to 4-5 criteria improvement) were 0.55 (0.52-0.58, p < 0.001), 0.20 (0.17-0.22, p < 0.001), 0.13 (0.11-0.16, p < 0.001), and 0.06 (0.02-0.3, p < 0.001), respectively. The risk of MACE decreased as the cardiometabolic criteria improved. There was no significant association between improvement of the criteria and liver-related events., Conclusions: Cardiometabolic criteria can be used as predictors and treatment targets for cardiovascular event risk in MASLD. Developing predictors and therapeutic targets for liver-related events is a future challenge., (© 2024 John Wiley & Sons Ltd.)

Background: In two phase 3 studies, tenofovir alafenamide (TAF) showed non-inferior efficacy versus tenofovir disoproxil fumarate (TDF), with more favourable renal and bone safety in patients with chronic hepatitis B (CHB)., Aims: Here, we report the studies' final 8-year results., Methods: CHB patients (hepatitis B e antigen [HBeAg]-negative and HBeAg-positive) were randomised (2:1) to double-blind TAF 25 mg/day or TDF 300 mg/day for up to 3 years, followed by open-label (OL) TAF through year 8. Virological, biochemical, serological and fibrosis responses, and safety, including bone and renal parameters, were evaluated. Resistance to TAF was assessed annually by deep sequencing of polymerase/reverse transcriptase and by phenotyping., Results: Among 1298 patients randomised to double-blind TAF (n = 866) or double-blind TDF (n = 432), 775 in the TAF group and 382 in the TDF group received OL TAF, including 180 and 202 who switched from TDF to TAF at year 2 (TDF2y → TAF6y) or year 3 (TDF3y → TAF5y), respectively. At year 8, among patients in the TAF8y, TDF2y → TAF6y and TDF3y → TAF5y groups, 69%, 66% and 73% (missing-equals-failure analysis) and 95%, 94% and 97% (missing-equals-excluded) of patients, respectively, achieved HBV DNA <29 IU/mL. Estimated glomerular filtration rate (Cockcroft-Gault method; eGFR CG ) and hip/spine bone mineral density (BMD) remained stable in patients receiving double-blind/OL TAF, with only small declines at year 8. Decreases in eGFR CG and hip/spine BMD observed during double-blind TDF improved after switching to OL TAF. No patients developed resistance to TAF., Conclusion: Long-term TAF treatment exhibited favourable safety and tolerability with high rates of viral suppression and no development of resistance., Clinicaltrials: gov numbers NCT01940341 and NCT01940471., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background/aim: Maintaining liver function throughout the treatment of hepatocellular carcinoma (HCC) is crucial, yet the impact of durvalumab plus tremelimumab (DT) treatment on liver function is not well understood. This multicenter study aimed to examine the changes in liver function during DT treatment., Patients and Methods: This nationwide multicenter study included 80 patients who received DT treatment for unresectable HCC. The primary outcome was changes in albumin-bilirubin (ALBI) scores at baseline, week 8, week 12, and at the time of progressive disease (PD)., Results: The median (interquartile range) ALBI scores at baseline, week 8, week 12, and the time of PD were -2.24 (-2.49 to -1.94), -2.13 (-2.51 to -1.86), -2.23 (-2.51 to - 1.77), and -2.06 (-2.53 to -1.72), respectively. No significant differences were observed at 8 weeks (p=0.06), at 12 weeks (p=0.4), and at PD (p=0.8) compared to baseline. Subgroup analyses were conducted for patients with an ALBI grade of 2 at baseline and for those who received DT treatment as a second-line or later treatment. No deterioration in liver function was observed at any time point in both analyses., Conclusion: DT treatment can maintain liver function throughout the treatment period. Maintaining liver function is crucial in managing HCC, and this is an advantage of using DT treatment as a first-line treatment for unresectable HCC., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Although immune checkpoint inhibitors (ICI) are used for unresectable hepatocellular carcinoma (HCC), it is unclear whether sequential ICI treatment-durvalumab plus tremelimumab (DT) after progression on atezolizumab plus bevacizumab (AB)-is effective for HCC. In this nationwide multicenter study, we aimed to investigate the effect of DT treatment based on the timing of treatment. A total of 85 patients receiving DT treatment were enrolled. The primary endpoint is treatment response at week 8 among patients receiving first-line DT treatment, those receiving second-line or later treatment without prior AB therapy, and those receiving second-line or later treatment with prior AB therapy. Objective response rates (ORRs) in patients with first-line treatment, second-line treatment without AB, and second-line treatment with prior AB were 44%, 54%, and 5%, respectively (p < 0.001). Similarly, disease control rates (DCRs) were 69%, 91%, and 26%, respectively (p < 0.001). ORR and DCR were significantly lower in patients with prior AB treatment. Progression free survival (PFS) was significantly shortened in patients receiving second-line therapy following prior AB treatment and an adjusted hazard ratio (95% confidence interval) in those patients for PFS, using first-line therapy as a reference, was 2.35 (1.1-5.1, p = 0.03). In conclusion, the impact of DT sequencing following AB treatment was limited. However, even after second-line treatment, the treatment effect can be equivalent to that of first-line treatment in cases with no history of AB treatment. Thus, prior treatment history should be taken into account when initiating DT treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We investigated supported-MoO 3 materials effective for the chemical looping dry reforming of methane (CL-DRM) to decrease the reaction temperature. Ni-modified molybdenum zirconia (Ni/MoO 3 /ZrO 2 ) showed CL-DRM activity under isothermal reaction conditions of 650 °C, which was 100-200 °C lower than the previously reported oxide-based materials. Ni/MoO 3 /ZrO 2 activity strongly depends on the MoO 3 loading amount. The optimal loading amount was 9.0 wt.% (Ni/MoO 3 (9.0)/ZrO 2 ), wherein two-dimensional polymolybdate species were dominantly formed. Increasing the loading amount to more than 12.0 wt.% resulted in a loss of activity owing to the formation of bulk Zr(MoO 4 ) 2 and/or MoO 3 . In situ Mo K-edge XANES studies revealed that the surface polymolybdate species serve as oxygen storage sites. The Mo 6+ species were reduced to Mo 4+ species by CH 4 to produce CO and H 2 . The reduced Mo species reoxidized by CO 2 with the concomitant formation of CO. The developed Ni/MoO 3 (9.0)/ZrO 2 was applied to the long-term CL-DRM under high concentration conditions (20 % CH 4 and 20 % CO 2 ) at 650 °C, with two pathways possible for converting CH 4 and CO 2 to CO and H 2 via the redox reaction of the Mo species and coke formation., (© 2024 Wiley-VCH GmbH.)

Volatile organic compounds (VOCs) are representative indoor air pollutants that negatively affect the human body owing to their toxicity. One of the most promising methods for VOC removal is photocatalytic degradation using TiO 2 . In this study, the addition of carbon black (CB) and heavy metal nanoparticles (NPs) was investigated to improve the efficiency of a TiO 2 -based photocatalytic VOC decomposition system combined with ultrasonic atomization and ultraviolet irradiation, as described previously. The addition of CB and Ag NPs significantly improved the degradation efficiency. A comparison with other heavy metal nanoparticles and their respective roles are discussed.

Aims: Optimizing glycemic control may prevent liver-related events and major adverse cardiovascular events (MACE) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, the optimal hemoglobin A1c (HbA1c) threshold associated with a lower risk of complications, particularly liver-related events as well as MACE is unknown., Methods: We investigated a nationwide population-based cohort and identified 633 279 patients with MASLD, with a mean follow-up of 4.2 years. Hemoglobin A1c levels were measured annually. The primary endpoint was the risk of liver-related events and MACE and to determine the optimal HbA1c level associated with the risk of complications., Results: Mean HbA1c (per 1%) was associated with liver-related events (subdistribution hazard ratio [sHR] 1.26; 95% confidence interval [CI], 1.12-1.42) as well as MACE (sHR 1.36; 95% CI, 1.32-1.41) after adjustment for confounders. Multivariable sHR (95% CI) for HbA1c of <5.0%, 6.0%-6.9%, 7.0%-7.9%, 8.0%-8.9%, and ≥9.0% (reference, 5.0%-5.9%) were 14 (9.1-22), 1.70 (1.2-2.3), 3.32 (2.3-4.8), 3.81 (2.1-6.8), and 4.83 (2.4-9.6) for liver-related events, and 1.24 (0.8-1.8), 1.27 (1.2-1.4), 1.70 (1.5-2.0), 2.36 (1.9-2.9), and 4.17 (3.5-5.0) for MACE. An HbA1c level of 7% was selected as the optimal threshold for predicting complications (sHR 2.40 [1.8-3.2] for liver-related events and 1.98 [1.8-2.2] for MACE)., Conclusion: The risk of liver-related events as well as MACE increased in a dose-dependent fashion with an increase in HbA1c levels, except for patients with HbA1c <5.0% for liver-related events. An HbA1c level of 7% was the optimal threshold associated with a lower risk of complications and may be utilized as a target for glycemic control in patients with MASLD., (© 2024 Japan Society of Hepatology.)

Objective: Visual analog scale (VAS) can be used to evaluate multiple parameters. There have been no reports on the verification of order effects or reproducibility of the VAS method for overall palatability of oral dosage forms. The purpose of this study was to assess the validity of a method for evaluating the palatability of orally disintegrating tablets (ODTs) using a 100-mm VAS., Materials and Methods: We conducted clinical trials to evaluate the overall palatability, taste, and scent of 3 ODTs (F1, F2, F3) that contained famotidine (20, 10, and 5 mg, respectively). The study protocol was approved by the Research Ethics Committee of the University of Shizuoka, Japan (No. 21 - 36). To investigate the intergroup reproducibility of the VAS evaluation, 40 participants were divided into three groups, and each group underwent human gustatory sensation test of F1, F2, and F3, performed using a crossover design with 6 different tasting sequences. To evaluate intragroup reproducibility of the VAS evaluation, the participants assessed the same ODTs twice., Results: The VAS scores for overall palatability followed the same order (F3>F2>F1) in all groups. The VAS scores for the overall palatability of F1, F2, and F3 did not significantly differ between the first and second evaluations. The Kruskal-Wallis test indicated a minimal impact of the assessment order on ODT evaluations. We confirm the reliability and reproducibility of the VAS method for evaluating ODT palatability., Conclusion: The VAS method for assessing ODT palatability provides accurate information and can contribute to the design and manufacture of patient-friendly pharmaceutical products.

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study., (© 2024. The Author(s).)

Catalytic propane dehydrogenation (PDH) has mainly been studied using metal- and metal oxide-based catalysts. Studies on dehydrogenation catalysis by metal hydrides, however, have rarely been reported. In this study, PDH reactions using group IIIB and IVB metal hydride catalysts were investigated under relatively low-temperature conditions of 450 °C. Lanthanum hydride exhibited the lowest activation energy for dehydrogenation and the highest propylene yield. Based on kinetics studies, a comparison between the reported calculation results and isotope experiments, the hydrogen vacancies of metal hydrides were involved in low-temperature PDH reactions., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Background: A multi-society consensus group proposed a new nomenclature for steatotic liver disease (SLD) including metabolic-dysfunction associated steatotic liver disease (MASLD), MASLD and increased alcohol intake (MetALD) and alcohol-associated liver disease (ALD). However, the risk of liver-related events, major adverse cardiovascular events (MACE) and all-cause mortality among various sub-groups is unknown., Aims: To evaluate the risk of liver-related events, MACE and death among patients with SLD., Methods: We conducted a nationwide, population-based study and enrolled 761,400 patients diagnosed with MASLD, MetALD or ALD. The primary endpoint was the occurrence of liver-related events, MACE and death in patients with MASLD, MetALD and ALD., Results: The cumulative incidence of liver-related events and death were highest in ALD, followed by MetALD and MASLD (p < 0.001 for both liver-related events and death), while the incidence of MACE was highest in MASLD, followed by MetALD and ALD (p < 0.001). Using MASLD as the reference and adjusting for age, sex, smoking, diabetes mellitus, dyslipidaemia and hypertension, the adjusted hazard ratios (95% confidence intervals) for liver-related events, MACE and death in MetALD were 1.42 (1.1-1.8), 0.68 (0.63-0.73) and 1.13 (0.98-1.3), respectively. In ALD, they were 3.42 (2.6-4.6), 0.58 (0.49-0.67) and 1.60 (1.3-2.0), respectively, for liver-related events, MACE and death., Conclusions: The new consensus nomenclature can be used to stratify the risk of complications and prognosis. The nomenclature is beneficial for risk stratification and identifying new mechanisms for disease-specific therapeutic implications., (© 2024 John Wiley & Sons Ltd.)

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

Background: Conflicting evidence regarding the prognosis of lean metabolic dysfunction-associated steatotic liver disease (MASLD) has raised substantial questions., Aim: This study aimed to elucidate the prognosis of lean MASLD by conducting a comprehensive analysis of a vast Asian cohort., Methods: This study used a nationwide, population-based database and analyzed 2.9 million patients. The primary endpoints were liver-related events (LREs) and cardiovascular events (CVEs) in patients with lean MASLD, non-lean MASLD, and normal liver control groups., Results: The median observation period was 4.2 years. The 5-year incidence values of LREs in the lean MASLD, non-lean MASLD, and normal liver control groups were 0.065%, 0.039%, and 0.006%, respectively. The LRE risk of lean MASLD was significantly higher than that of normal liver control (adjusted hazard ratio [aHR]: 5.94, 95% confidence interval [CI]: 3.95-8.92) but comparable to that of non-lean MASLD (aHR: 1.35, 95% CI: 0.87-2.08). By contrast, for CVEs, the non-lean MASLD group exhibited a higher 5-year cumulative incidence rate (0.779%) than the lean MASLD (0.600%) and normal liver control (0.254%) groups. The lean MASLD group had a reduced risk of CVEs compared with the non-lean MASLD group (aHR, 0.73; 95% CI: 0.64-0.84), and comparable risk of CVEs to the normal liver control group (aHR, 0.99; 95% CI: 0.88-1.12)., Conclusion: Lean MASLD exhibits a similar LRE risk and a lower CVE risk to non-lean MASLD. Therefore, follow-up and treatment strategies should be tailored to the specific MASLD condition., (© 2024. Japanese Society of Gastroenterology.)

Aim: A multisociety consensus group proposed a new nomenclature for metabolic dysfunction-associated steatotic liver disease (MASLD). Although patients with nonalcoholic fatty liver disease (NAFLD) are expected to be reclassified as patients with MASLD under the new nomenclature, the concordance between MASLD and NAFLD remains unclear. Moreover, waist circumference could be adjusted by ethnicity for diagnosing MASLD; however, there are limited data on the optimal waist circumference in the Japanese population., Methods: This cross-sectional study was conducted on 3709 Japanese patients with NAFLD. The primary endpoint was the prevalence of MASLD in patients with NAFLD. The difference between the original waist circumference criteria (>94 cm for men and >80 cm for women) and the Japanese metabolic syndrome criteria (≥85 cm for men and ≥90 cm for women) for concordance between NAFLD and MASLD was also investigated., Results: According to the original criteria, the prevalence of MASLD in patients with NAFLD was 96.7%. Similarly, according to the Japanese waist circumference criteria, 96.2% of patients with NAFLD could be reclassified as those with MASLD. The concordance rate was significantly higher in the original criteria than in the Japanese criteria (p = 0.02)., Conclusions: NAFLD could be considered MASLD using the original MASLD criteria in the Japanese population, and insights from NAFLD research could be applied to MASLD., (© 2024 Japan Society of Hepatology.)

Background and Aim: Immune checkpoint inhibitors pose the risk of immune-related adverse events (irAEs). Recent data suggest that irAEs may be associated with a favorable prognosis. This study aimed to investigate and analyze the association between these adverse events and the clinical benefits in patients with unresectable hepatocellular carcinoma., Methods: The study enrolled 130 patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab between November 2020 and January 2023 at a single center. The relationship between irAEs and both response rate and post-treatment outcomes was investigated., Results: Out of the 130 patients, irAEs developed in 36 (27.7%) patients. The irAE group exhibited a significantly longer progression-free survival (PFS) than the non-irAE group, with a median PFS of 8.9 compared with 4.6 months (P < 0.01). No difference was found in the overall survival between the irAE and non-irAE groups. The irAE group demonstrated significantly higher disease control rate (DCR) than the non-irAE group (97.0% vs 65.5%, P < 0.01). The analysis by irAE severity revealed that the grade 1/2 group exhibited significantly longer PFS (7.9 vs 4.6 months, P = 0.007) and higher DCR (100% vs 65.5%, P < 0.01) than the non-irAE group. Furthermore, hypothyroidism correlated with a favorable PFS (8.9 vs 5.4 months, P = 0.02), DCR (100% vs 71.3%, P = 0.03), and overall response rate (58.3% vs 18.5%, P = 0.005)., Conclusion: The presence of irAEs is associated with prolonged PFS and higher DCR. Specifically, mild irAEs (grade 1/2) and hypothyroidism displayed prolonged PFS and higher DCR., (© 2024 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background & Aims: The natural progression of hepatic decompensation in metabolic dysfunction-associated steatotic liver disease (MASLD) is not well-characterised. We aimed to describe it by conducting a retrospective analysis., Methods: This longitudinal, retrospective analysis of well-characterised MASLD cohorts followed for hepatic decompensation and death. The sequence of liver-related events was evaluated, and the median time between hepatic decompensation episodes and death versus. transplantation was measured., Results: Of the 2016 patients identified, 220 (11%) developed at least one episode of hepatic decompensation during a median follow-up of 3.2 years. Ascites was the most common first liver-related event [153 (69.5%)], followed by hepatic encephalopathy (HE) [55 (25%)] and variceal haemorrhage (VH) [30 (13.6%)]. Eighteen out of the 220 (8.1%) patients had more than one liver-related event as their first hepatic decompensation. Among the patients who had the first episode, 87 (39.5%) had a second episode [44 (50.5%) HE, 31 (35.6%) ascites, and 12 (13.7%) VH]. Eighteen out of 220 (8.1%) had a third episode [10 (55.5%) HE, 6 (33.3%) VH, and 2 (11.1%) ascites]. Seventy-three out of 220 (33.1%) died, and 31 (14%) received liver transplantation. The median time from the first episode to the second was 0.7 years and 1.3 years from the second episode to the third. The median survival time from the first episode to death or transplantation was 2.0 years., Conclusion: The most common first liver-related event in MASLD patients is ascites. The median survival from the first hepatic decompensation to either death or transplantation is 2 years., (© 2024 John Wiley & Sons Ltd.)

Silicon (Si) uptake is generally beneficial for plants that need protection from insect herbivores. In pursue of mechanisms involved in Si-mediated defense, we comprehensively explored the impact of Si on several defensive and metabolic traits in rice exposed to simulated and real herbivory of Mythimna loreyi Duponchel larvae. Hydroponic experiments showed that Si-deprived rice supplemented with Si 72 h prior to insect infestation were similarly resistant to larvae as plants continuously grown in Si-containing media. Both Si and herbivory altered primary metabolism in rice, including the levels of several sugars, amino acids, and organic acids. While the accumulation of sugars was generally positively correlated with Si presence, multiple amino acids showed a negative correlation trend with Si supplementation. The levels of secondary metabolites, including isopentylamine, p -coumaroylputrescine and feruloylputrescine, were typically higher in the leaves of Si-supplemented plants exposed to herbivory stress compared to Si-deprived plants. In addition, simulated herbivory treatment in Si-supplemented plants induced more volatile emissions relative to Si-deprived plants, which was consistent with the increased transcripts of key genes involved in volatile biosynthesis. In ecological interactions, Si alone did not affect the oviposition choice of M. loreyi but gravid females showed a significant preference for simulated herbivory-treated/Si-deprived compared to Si-supplemented plants. Our data suggest that apart from mechanical defense, Si may affect rice metabolism in multiple ways that might enhance/modulate defense responses of rice under herbivory stress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Osibe, Hojo, Shinya, Mitani-Ueno and Galis.)

Germline loss-of-function mutations in USP9X have been reported to cause a wide spectrum of congenital anomalies. Here, we report a Japanese girl with a novel heterozygous nonsense mutation in USP9X who exhibited intellectual disability with characteristic craniofacial abnormalities, including hypotelorism, brachycephaly, hypodontia, micrognathia, severe dental crowding, and an isolated submucous cleft palate. Our findings provide further evidence that disruptions in USP9X contribute to a broad range of congenital craniofacial abnormalities., (© 2024. The Author(s).)

Objective Pemafibrate is a recently developed selective peroxisome proliferator-activated receptor alpha modulator that can improve alanine aminotransferase (ALT) levels in patients with nonalcoholic fatty liver disease (NAFLD). However, the effectiveness of ALT normalization with pemafibrate and bezafibrate, a traditional fibrate, has not been compared. Methods In this retrospective study, we compared the effects of pemafibrate and bezafibrate on ALT normalization in patients with NAFLD. The primary endpoint was the ALT normalization rate at 12 months after administration. Patients Twenty and 14 patients with NAFLD receiving pemafibrate and bezafibrate, respectively, were included in this retrospective analysis. All patients had elevated ALT levels and dyslipidemia at entry. Results The ALT normalization rates at 3, 6, and 12 months were 40%, 55%, and 60% for pemafibrate and 14.3%, 28.6%, and 14.3% for bezafibrate, respectively. The ALT normalization rate at 12 months was significantly higher in patients treated with pemafibrate than in those treated with bezafibrate (p=0.01). Pemafibrate, when compared with bezafibrate, was shown to be a significant factor for ALT normalization in a multivariable analysis with an adjusted odds ratio (95% confidence interval) of 13.8 (1.6-115, p=0.01). Conclusion Pemafibrate is effective in ALT normalization in patients with NAFLD and may be used as a treatment for NAFLD.

We report on the development of an on-site therapeutic drug monitoring (TDM) method for vancomycin (VCM) utilizing a portable spectrometer and commercially available immunoturbidimetric assay reagents designed for automated clinical chemistry analyzers. The method enables the quantification of VCM in plasma samples within 10 min, with a good correlation between the measured values and the theoretical values (r 2  = 0.995). The intra and inter-day precisions were found to be below 12.5% and 17.7%, respectively. Moreover, we established a correlation between the quantitative values using this method and those measured through HPLC-UV and automated clinical chemistry analyzers, showing good reliability (R 2  = 0.970 and 0.951, respectively). This method allows anyone to rapidly perform TDM at the bedside and is expected to be used to evaluate appropriate drug therapy., (© 2024. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

Background and Aim: Magnetic resonance elastography (MRE) is used for the evaluation of liver fibrosis; however, it remains unclear whether MRE-based liver stiffness is associated with hepatocellular carcinoma (HCC) development, particularly in patients with chronic hepatitis B., Methods: A total of 504 patients with chronic hepatitis B receiving MRE were enrolled. The primary endpoint was the association between MRE-based liver stiffness and HCC., Results: In a cross-sectional analysis at the time of MRE measurement, the median (interquartile range) liver stiffness values in patients with presence or history of HCC and those without HCC were 3.68 (2.89-4.96) and 2.60 (2.22-3.45) kPa, respectively, and liver stiffness was significantly higher in patients with presence or history of HCC than in those without HCC ( P  < 0.001). In a longitudinal analysis of patients without HCC, the 1-, 3-, and 5-year cumulative incidence of HCC in patients with liver stiffness ≥3.6 kPa and those with liver stiffness <3.6 kPa were 3.8%, 7.0%, and 22.9%, and 0%, 0.9%, and 1.5%, respectively ( P  < 0.001). In the multivariable analysis, MRE-based liver stiffness (per 1 kPa) or liver stiffness ≥3.6 kPa was an independent factor for HCC development with an adjusted hazard ratio (aHR) of 1.61 (95% confidence interval [CI], 1.3-2.0) or aHR of 8.22 (95% CI, 2.1-31)., Conclusion: MRE-based liver stiffness is associated with HCC risk in patients with chronic hepatitis B and may be used for the early prediction of HCC development and determination of indications for treatment., (© 2024 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: In patients with chronic hepatitis C, 8 weeks of glecaprevir and pibrentasvir (GLE/PIB) treatment for chronic hepatitis (non-cirrhosis) and 12 weeks for cirrhosis have been approved in Japan. However, whether 8 weeks of treatment for cirrhosis may reduce treatment efficacy has not been adequately investigated., Methods: This prospective, nationwide, multicenter cohort study enrolled 1275 patients with chronic hepatitis C who received GLE/PIB therapy. The effect of liver fibrosis and treatment periods on the efficiency of GLE/PIB therapy was investigated. The primary endpoint was the sustained virological response (SVR) rate in patients with chronic hepatitis (non-cirrhosis) and cirrhosis. The association between treatment periods and liver fibrosis on the SVR after 12 weeks of treatment rate was investigated., Results: The SVR rates in patients with chronic hepatitis with 8 weeks of treatment, chronic hepatitis with 12 weeks of treatment, cirrhosis with 8 weeks of treatment, and cirrhosis with 12 weeks of treatment were 98.9% (800/809), 100% (87/87), 100% (166/166), and 99.1% (211/213), respectively, and were was not different among these groups ( P  = 0.4)., Conclusion: GLE/PIB therapy for chronic hepatitis C had high efficacy regardless of liver fibrosis status and treatment periods. Periods of GLE/PIB therapy could be chosen with available modalities, and high SVR rates could be achieved regardless of the decision., (© 2024 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Azabora[6]helicene as a new heterohelicene analogue was synthesized by a one-pot reaction of commercially available 2,6-diaminopyridine and benzo[ c , d ]indole-2(1 H )-one and subsequent boron coordination. While the single-crystal X-ray diffraction analysis elucidated a helical structure in the solid state, a dynamic helicity inversion was observed in solution.

Synthetic breakthroughs diversify the molecules and polymers available to chemists. We now report the first successful synthesis of a series of optically-pure 2,2'-tethered binaphthyl-embedded helical ladder polymers based on quantitative and chemoselective ladderization by the modified alkyne benzannulations using the 4-alkoxy-2,6-dimethylphenylethynyl group as the alkyne source, inaccessible by the conventional approach lacking the 2,6-dimethyl substituents. Due to the defect-free helix formation, the circular dichroism signal increased by more than 6 times the previously reported value. The resulting helical secondary structure can be fine-tuned by controlling the binaphthyl dihedral angle in the repeating unit with variations in the 2,2'-alkylenedioxy tethering groups by one carbon atom at a time. The optimization of the helical ladder structures led to a strong circularly polarized luminescence with a high fluorescence quantum yield (28 %) and luminescence dissymmetry factor (2.6×10 -3 )., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Purpose: The effect of hepatic fibrosis stage on quantitative ultrasound based on the attenuation coefficient (AC) for liver lipid quantification is controversial. The objective of this study was to determine how the degree of fibrosis assessed by magnetic resonance (MR) elastography affects AC based on the ultrasound-guided attenuation parameter according to the grade of hepatic steatosis, using magnetic resonance imaging (MRI)-derived proton density fat fraction (MRIderived PDFF) as the reference standard., Methods: Between February 2020 and April 2021, 982 patients with chronic liver disease who underwent AC and MRI-derived PDFF measurement as well as MR elastography were enrolled. Multiple regression was used to investigate whether AC was affected by the degree of liver stiffness., Results: AC increased as liver stiffness progressed in 344 patients without hepatic steatosis (P=0.009). In multivariable analysis, AC was positively correlated with skin-capsule distance (P<0.001), MR elastography value (P=0.037), and MRI-derived PDFF (P<0.001) in patients without hepatic steatosis. In 52 of 982 patients (5%), the correlation between AC and MRIderived PDFF fell outside the 95% confidence interval for the regression line slope. Patients with MRI-derived PDFF lower than their AC (n=36) had higher fibrosis-4 scores, albumin-bilirubin scores, and MR elastography values than patients with MRI-derived PDFF greater than their AC (n=16; P=0.018, P=0.001, and P=0.011, respectively)., Conclusion: AC is affected by liver fibrosis (MR elastography value ≥6.7 kPa) only in patients without hepatic steatosis (MRI-derived PDFF <5.2%). These values should be interpreted with caution in patients with advanced liver fibrosis.

Introduction: The results from 2 phase 3 studies, through 2 years, in chronic hepatitis B infection showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior renal and bone safety. We report updated results through 5 years., Methods: Patients with HBeAg-negative or HBeAg-positive chronic hepatitis B infection with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, and serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses., Results: Of 1,298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDF→TAF3y) or year 3 (n = 202; TDF→TAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA <29 IU/mL (missing = failure) in the TAF, TDF→TAF3y, and TDF→TAF2y groups, respectively; no patient developed TAF or TDF resistance. Median estimated glomerular filtration rate (by using Cockcroft-Gault) declined <2.5 mL/min, and mean declines of <1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDF→TAF groups had improvements in these parameters at year 5 after switching to OL TAF., Discussion: Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

The number of cancer cases diagnosed during the coronavirus disease 2019 (COVID-19) pandemic has decreased. This study investigated the impact of the pandemic on the clinical practice of hepatocellular carcinoma (HCC) using a novel nationwide REgistry for Advanced Liver diseases (REAL) in Japan. We retrieved data of patients initially diagnosed with HCC between January 2018 and December 2021. We adopted tumor size as the primary outcome measure and compared it between the pre-COVID-19 (2018 and 2019) and COVID-19 eras (2020 and 2021). We analyzed 13,777 patients initially diagnosed with HCC (8074 in the pre-COVID-19 era and 5703 in the COVID-19 era). The size of the maximal intrahepatic tumor did not change between the two periods (mean [SD] = 4.3 [3.6] cm and 4.4 [3.6] cm), whereas the proportion of patients with a single tumor increased slightly from 72.0 to 74.3%. HCC was diagnosed at a similar Barcelona Clinic Liver Cancer stage. However, the proportion of patients treated with systemic therapy has increased from 5.4 to 8.9%. The proportion of patients with a non-viral etiology significantly increased from 55.3 to 60.4%. Although the tumor size was significantly different among the etiologies, the subgroup analysis showed that the tumor size did not change after stratification by etiology. In conclusion, the characteristics of initially diagnosed HCC remained unchanged during the COVID-19 pandemic in Japan, regardless of differences in etiology. A robust surveillance system should be established particularly for non-B, non-C etiology to detect HCC in earlier stages., (© 2024. The Author(s).)

Rice is a staple food for half of the world's population, but it is a poor dietary source of calcium (Ca) due to the low concentration. It is an important issue to boost Ca concentration in this grain to improve Ca deficiency risk, but the mechanisms underlying Ca accumulation are poorly understood. Here, we obtained a rice (Oryza sativa) mutant with high shoot Ca accumulation. The mutant exhibited 26%-53% higher Ca in shoots than did wild-type rice (WT) at different Ca supplies. Ca concentration in the xylem sap was 36% higher in the mutant than in the WT. There was no difference in agronomic traits between the WT and mutant, but the mutant showed 25% higher Ca in the polished grain compared with the WT. Map-based cloning combined with a complementation test revealed that the mutant phenotype was caused by an 18-bp deletion of a gene, OsK5.2, belonging to the Shaker-like K + channel family. OsK5.2 was highly expressed in the mature region of the roots and its expression in the roots was not affected by Ca levels, but upregulated by low K. Immunostaining showed that OsK5.2 was mainly expressed in the pericycle of the roots. Taken together, our results revealed a novel role for OsK5.2 in Ca translocation in rice, and will be a good target for Ca biofortification in rice., (© 2023 Institute of Botany, Chinese Academy of Sciences.)

Orally disintegrating tablets (ODTs) can be easily swallowed without drinking water and are a convenient dosage form for the elderly and infirmed patients, as well as other patients, such as businesspeople. A major challenge in the development of ODTs is masking the unpleasant taste of the drug, which can make ODTs palatable. Flavors are often used for taste-masking. A few comprehensive studies have been conducted on the selection of suitable flavors for ODTs. This study aimed to evaluate the effects of different flavors on the taste sensation of ODTs using a visual analog scale (VAS). Sixteen flavors were studied for their effects on the taste sensation of pioglitazone ODTs in a randomized single-blind study involving the gustatory sensation testing of ODTs. Healthy volunteers were enrolled and asked to periodically evaluate the bitterness, sweetness, astringency, sourness, and overall palatability of ODTs, both during and after disintegration in the oral cavity, using the VAS. Most flavors improved the sweetness of ODTs without the addition of a sweetener, and some suppressed bitterness, astringency, and sourness. In particular, blueberry, and yoghurt flavors significantly improved sweetness and overall palatability during disintegration of the pioglitazone ODT. The approach of using VAS score analysis was effective in selecting the most suitable flavor for improving the overall palatability of ODT. Furthermore, the addition of a suitable flavor can successfully mask the unpleasant taste of the drug and effectively improve the overall palatability of ODT.

Background: Progression to cirrhosis in non-alcoholic steatohepatitis (NASH) is associated with a decrease in liver fat. However, the prognostic significance of liver fat content in NASH-related significant fibrosis and cirrhosis is unclear., Aim: To investigate the risk of decompensation, hepatocellular carcinoma (HCC) and mortality stratified by liver fat content in NASH-related significant fibrosis and cirrhosis., Methods: In this meta-analysis of individual participant data, 456 patients with both magnetic resonance elastography (MRE) and MRI-derived protein density fat fraction (MRI-PDFF) were enrolled, and 296 patients with longitudinal follow-up were analysed. MRE combined with fibrosis-4 (MEFIB-index), and MRI-PDFF were used to measure liver fibrosis and fat, respectively. MEFIB-negative, MEFIB-positive+ MRI-PDFF ≥5% and MEFIB-positive+ MRI-PDFF <5% were defined as no significant liver fibrosis, NASH with significant fibrosis and higher liver fat content, and NASH with significant fibrosis and low liver fat content groups, respectively. The primary outcome was hepatic decompensation, HCC and death., Results: The rates of decompensation, HCC and mortality were highest in the NASH with significant fibrosis and low liver fat group (33%, 17% and 17%, respectively), followed by the NASH with significant fibrosis and higher liver fat group (18%, 13% and 13% respectively), and lowest in the no significant fibrosis (MEFIB-negative) group (0%, 1% and 2% respectively). In multivariable-adjusted analysis, low liver fat content was strongly associated (HR = 42.2 [95% CI: 7.5-235.5, p < 0.0001]) with HCC, decompensation and death. Sensitivity analyses for patients with cirrhosis (MRE ≥5 kPa) determined consistent findings., Conclusions: Low liver fat content in patients with burnt-out NASH-related significant fibrosis and cirrhosis is associated with an increase in hepatic decompensation, HCC and mortality., (© 2023 John Wiley & Sons Ltd.)