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ABSTRACT This paper reports on a microdevice for compartmentalizing the solution microenvironment that can fractionate the space surrounding spheroids during the culture and differentiation processes, with the aim of verifying the effects of cell–cell interactions in the solution microenvironment on iPS cell differentiation. In this paper, we demonstrated that spheroids of iPS cells were successfully formed on the device and fractionated their microenvironment by a detachable compartmentalization frame (DCF) formed by 3D printing technology. [ABSTRACT FROM AUTHOR]

Aim: Patients with chronic hepatitis B (CHB) remain at risk for hepatocellular carcinoma (HCC) even with nucleos(t)ide analog therapy. We evaluated risk factors for HCC development, including serum hepatitis B virus (HBV) RNA, hepatitis B core‐related antigen level, and growth differentiation factor 15 (GDF15) level, a predictor of HCC development in patients with chronic hepatitis C. Methods: We collected clinical data and stored serum from CHB patients without a history of HCC who were receiving nucleos(t)ide analog treatment for more than 1 year and whose HBV DNA level was less than 3.0 log IU/mL. We measured the serum levels of HBV RNA and GDF15. Results: Among 242 CHB patients, 57 had detectable HBV RNA, and GDF15 was quantified in all patients. The median GDF15 level was 0.86 ng/mL. Cox proportional hazards analysis revealed that male sex and higher GDF15, FIB‐4 index, alpha‐fetoprotein and gamma‐glutamyl transpeptidase were independent risk factors for HCC. The presence of HBV RNA above the lower limit of quantification was not a risk factor. When we set cutoff values based on the Youden index, the cumulative incidence of HCC was significantly higher in the male, AFP ≥3.0 ng/mL, gamma‐glutamyl transpeptidase ≥22 U/L, FIB‐4 index ≥1.93, and GDF‐15 ≥1.17 ng/mL groups. In patients with no or more than three of these five risk factors, the 10‐year HCC cumulative incidence rates were 0% and 41.0%, respectively. Conclusions: High serum GDF15 is an independent risk factor for the occurrence of HCC in CHB patients treated with nucleos(t)ide analogs. [ABSTRACT FROM AUTHOR]

Males and females share most of the genome, but many animals show different phenotypes between the sexes, known as sexual dimorphism. Many insect species show extreme sexual dimorphism, including beetles with "weapon traits" represented by extremely developed horns and mandibles. Existing studies of sex‐specific development of beetle weapon traits suggest that sex‐specific gene expression plays an important role. On the other hand, contributions of the Y‐chromosome, which may potentially carry genes necessary for male development, to weapon trait expression have not been examined. In holometabolous insects, including beetles, the feminizing gene transformer (tra) is roughly conserved in its feminizing function. Only females express a functional isoform of Tra, which causes female differentiation. Knocking down tra in females leads to male tissue differentiation, enabling us to analyze male phenotypes in individuals lacking a Y‐chromosome (XX‐males). In this study, we investigate whether the Y‐chromosome is necessary for stag beetles to express male‐specific weapon traits by comparing tra‐knockdown‐induced XX‐males with natural XY males. We show that XX‐males could express weapons (enlarged mandibles) as in XY‐males. These results suggest that the Y‐chromosome does not have a major role in weapon trait expression in this species. Research Highlights: Developmental roles of Y‐chromosome on male‐specific mandible growth in stag beetles were analyzed. "XX‐male" was induced from females by suppressing feminizer gene. These XX‐males had developed mandibles, indicating the Y‐chromosome's limited role. [ABSTRACT FROM AUTHOR]

Background and Aims: This study prospectively compared the diagnostic accuracies of the improved Attenuation Measurement (iATT) algorithm and the Controlled Attenuation Parameter (CAP) and assessed the interchangeability of iATT with magnetic resonance imaging‐derived proton density fat fraction (MRI‐derived PDFF). Methods: Patients with chronic liver disease were prospectively enrolled and underwent iATT, CAP and MRI‐derived PDFF measurements for hepatic steatosis evaluation. According to MRI‐derived PDFF values, steatosis grades were categorised as steatosis (S)0 (< 5.2%), S1 (≥ 5.2%, < 11.3%), S2 (≥ 11.3%, < 17.1%) and S3 (≥ 17.1%). Correlation coefficients (CCs) were determined, diagnostic performances were compared by the area under the receiver operating characteristic curve (AUROC) and agreement was evaluated using the calculated percentage error (PE) and expected limit of agreement (LOA). Results: A total of 414 patients (median age 64 years, 203 females) were evaluated. The CC between iATT and MRI‐derived PDFF was 0.727 (95% confidence interval [CI] 0.678–0.770), which was higher than that between CAP and MRI‐derived PDFF at 0.615 (95% CI 0.551–0.672) (p < 0.001). The AUROCs of iATT for ≥ S1, ≥ S2 and ≥ S3 were 0.901 (95% CI 0.870–0.931), 0.878 (95% CI 0.846–0.910) and 0.839 (95% CI 0.794–0.883), respectively. The diagnostic performances of iATT for ≥ S1 and ≥ S2 showed significantly higher AUROCs than those of CAP (p < 0.001, p = 0.036, respectively). The calculated PE and the expected LOA for CAP and iATT were 38.94% and 22.66% and 32.94% and 30.03%, respectively. Conclusions: iATT was superior to CAP and comparable to MRI‐derived PDFF in assessing hepatic steatosis. Trial Registration: This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000047411) [ABSTRACT FROM AUTHOR]

The karyotype, which is the number and shape of chromosomes, is a fundamental characteristic of all eukaryotes. Karyotypic changes play an important role in many aspects of evolutionary processes, including speciation. In organisms with monocentric chromosomes, it was previously thought that chromosome number changes were mainly caused by centric fusions and fissions, whereas chromosome shape changes, that is, changes in arm numbers, were mainly due to pericentric inversions. However, recent genomic and cytogenetic studies have revealed examples of alternative cases, such as tandem fusions and centromere repositioning, found in the karyotypic changes within and between species. Here, we employed comparative genomic approaches to investigate whether centromere repositioning occurred during karyotype evolution in medaka fishes. In the medaka family (Adrianichthyidae), the three phylogenetic groups differed substantially in their karyotypes. The Oryzias latipes species group has larger numbers of chromosome arms than the other groups, with most chromosomes being metacentric. The O. javanicus species group has similar numbers of chromosomes to the O. latipes species group, but smaller arm numbers, with most chromosomes being acrocentric. The O. celebensis species group has fewer chromosomes than the other two groups and several large metacentric chromosomes that were likely formed by chromosomal fusions. By comparing the genome assemblies of O. latipes, O. javanicus, and O. celebensis, we found that repositioning of centromere‐associated repeats might be more common than simple pericentric inversion. Our results demonstrated that centromere repositioning may play a more important role in karyotype evolution than previously appreciated. [ABSTRACT FROM AUTHOR]

Aim: Recent genome‐wide association studies of European populations have identified rs16906115, a single‐nucleotide polymorphism in the interleukin‐7 gene, as a predictor of immune‐related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single‐nucleotide polymorphism in a Japanese population. Methods: From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow‐up ≥12 weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non‐responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non‐responders. Results: In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non‐responders (p = 0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p = 0.015) in the univariate analysis and 0.315 (p = 0.023) in the multivariate analysis. Conclusions: In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome. Clinical trial registration: UMIN Clinical Trials Registry with the number UMIN000043798. [ABSTRACT FROM AUTHOR]

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for 30% of non‐Hodgkin lymphomas. Although comprehensive analysis of genetic abnormalities has led to the classification of lymphomas, the exact mechanism of lymphomagenesis remains elusive. The Ets family transcription factor, PU.1, encoded by Spi1, is essential for the development of myeloid and lymphoid cells. Our previous research illustrated the tumor suppressor function of PU.1 in classical Hodgkin lymphoma and myeloma cells. In the current study, we found that patients with DLBCL exhibited notably reduced PU.1 expression in their lymphoma cells, particularly in the non‐germinal center B‐cell‐like (GCB) subtype. This observation suggests that downregulation of PU.1 may be implicated in DLBCL tumor growth. To further assess PU.1's role in mature B cells in vivo, we generated conditional Spi1 knockout mice using Cγ1‐Cre mice. Remarkably, 13 of the 23 knockout mice (56%) showed splenomegaly, lymphadenopathy, or masses, with some having histologically confirmed B‐cell lymphomas. In contrast, no wild‐type mice developed B‐cell lymphoma. In addition, RNA‐seq analysis of lymphoma cells from Cγ1‐Cre Spi1F/F mice showed high frequency of each monoclonal CDR3 sequence, indicating that these lymphoma cells were monoclonal tumor cells. When these B lymphoma cells were transplanted into immunodeficient recipient mice, all mice died within 3 weeks. Lentiviral‐transduced Spi1 rescued 60% of the recipient mice, suggesting that PU.1 has a tumor suppressor function in vivo. Collectively, PU.1 is a tumor suppressor in mature B cells, and decreased PU.1 results in mature B‐cell lymphoma development. [ABSTRACT FROM AUTHOR]

Background: Right heart remodeling is noted in patients with severe COVID‐19‐associated acute respiratory distress syndrome (ARDS). There is limited information regarding right heart recovery following lung transplantation in this cohort. Methods: Retrospective review of institutional transplant database from June 2020 to June 2022 was performed at Northwestern University in Chicago, Illinois. Demographic, laboratory, histopathologic, lung transplant outcomes, and pre‐ and postoperative echocardiographic data were recorded and analyzed. Results: Of the 42 patients who underwent lung transplantation for COVID‐19‐related ARDS, 6 patients were excluded due to having either a single‐lung transplant (n = 2), lobar transplant (n = 1), or dual‐organ transplant (n = 1) or for missing postoperative TTE data (n = 2) and 36 were included in the study; there were no 90‐day deaths, and the 1‐year survival rate was 88.8%. Intraoperative hemodynamics data showed a mean pulmonary artery pressure of 49 ± 23 mm Hg. Preoperative echocardiography was evaluated at a median of 15.5 (10–34.3) (IQR) days preoperatively and 140 (108–201) days (IQR) postoperatively. RV size grade improved from an average of 1.7 ± 0.85 to 1.3 ± 0.6 (p < 0.05), while RV function improved from an average of 2.2 ± 1.2 to 1 ± 1 (p < 0.05). There was a reduction in RVSP from 46.5 ± 18 mmHg to 30.1 ± 7.8 mmHg (p < 0.05) and RV free wall strain showed improvement from −13.9 ± 6.1% to −18.5 ± 5.4% (p < 0.05). Conclusions: The results showed that the RV size and systolic function demonstrate improvement with normalization in a relatively short period following lung transplantation for patients with COVID‐19‐associated ARDS. [ABSTRACT FROM AUTHOR]

There are only a few studies on the function of neuronal axon guidance molecules during low brain pH conditions. We previously reported that roundabout (ROBO) 2, a receptor for the axon guidance molecule SLIT, can bind to the neural epidermal growth factor‐like‐like (NELL) ligands in acidic conditions by conformational change of its ectodomain. Here, we show that the ROBO3 receptor also exhibits a pH‐dependent increase in binding to the NELL2 ligand. We found that the Glu592 residue of ROBO3 at the binding interface between NELL2 and ROBO3 is a pH sensor and that the formation of a new hydrogen bonding network, due to protonation of the Glu592, leads to increased binding in acidic conditions. These results suggest that NELL2–ROBO3 signaling could be regulated by extracellular pH. [ABSTRACT FROM AUTHOR]

Summary: Aim: This study aims to investigate the predictive factors for conversion therapy in patients with unresectable hepatocellular carcinoma (uHCC) and to evaluate the prognosis of conversion cases by comparing them with partial response (PR) and complete response (CR) cases. Methods: In this retrospective multicentre study, we included a total of 946 uHCC patients treated with atezolizumab and bevacizumab (Atez/Bev) from September 2020 to September 2023. Results: Out of the patients, 43 (4.5%) received conversion therapy following Atez/Bev treatment. The overall response rate was 65.1% and 23.7% in the conversion and non‐conversion group, respectively, with a statistical significance (p < 0.001). Multivariate analyses identified that BCLC stage B or an earlier stage (p = 0.045), absence of macrovascular invasion and extrahepatic spread (p = 0.045), and a low value of neutrophil to lymphocyte ratio (p = 0.04) were significantly favourable predictive factors associated with conversion therapy. The conversion group showed significantly better survival compared to the non‐conversion group (p < 0.001). In the landmark analysis at 6, 12 and 18 months, the conversion group exhibited better survival compared to PR patients in the non‐conversion group (p = 0.04, 0.01 and 0.03, respectively) and there were no significant differences in the overall survival (OS) between the conversion group and patients who achieved a CR (p = 0.7, 1.0 and 0.3, respectively). Conclusions: Patients with low tumour burden and low value of NLR were more likely to undergo conversion therapy. The OS of patients undergoing conversion therapy showed better survival compared to those achieving PR and was comparable to those with CR patients. Conversion therapy could be considered if feasible. [ABSTRACT FROM AUTHOR]

Multi‐lineage differentiating stress‐enduring (Muse) cells, identified as pluripotent surface marker SSEA‐3(+) cells, are stress tolerant endogenous pluripotent‐like stem cells, and are involved in tissue repair. However, the significance of Muse cells in acute myocarditis has not been evaluated. In the present study, we counted Muse cells/area in biopsied myocardial tissue samples from 17 patients with fulminant myocarditis, and 6 with non‐inflammatory myocardial disease as controls. Compared with controls, patients with fulminant myocarditis had significantly more Muse cells (p = 0.00042). Patients with mechanical circulatory support (p = 0.006) and myocardial degeneration (p = 0.023) had significantly more Muse cells than those without them. The Muse cell number was correlated with acute phase CK‐MB level (ρ = 0.547, p = 0.029), indicating the severity of myocardial injury, and was also correlated with acute/recovery phase ratio of CK‐MB (ρ = 0.585, p = 0.023) and cardiac troponin I (ρ = 0.498, p = 0.047) levels, indicating resilience of myocardial injury. In fulminant myocarditis, the Muse cell number was associated with the severity of clinical features in the acute phase, and also with the recovery from myocardial damage in the chronic phase. Endogenous Muse cells might be mobilized and accumulate to the myocardial tissues in fulminant myocarditis, and might participate in the repair of injured myocardium. [ABSTRACT FROM AUTHOR]

Aim: An association between hepatitis B core‐related antigen (HBcrAg) kinetics and hepatocarcinogenesis during nucleoside (t)id analog (NA) treatment has recently been reported. HBcrAg kinetics and factors associated with HBcrAg response during tenofovir alafenamide (TAF) administration remain unclear. In this multicenter retrospective study, we aimed to clarify the efficacy and safety of TAF in treatment‐naïve patients with chronic hepatitis B, focusing on the reduction in HBcrAg levels. Methods: Patients were treated with TAF monotherapy for 96 weeks, and the kinetics of HBcrAg during treatment and the factors associated with HBcrAg response (defined as a change in HBcrAg of −1 log IU/mL from baseline) were evaluated. Results: The study population comprised 241 patients, 36.9% of whom were HBeAg‐positive. The median baseline HBcrAg level was 4.7 log IU/mL. The median change in HBcrAg from baseline was −1.1 log IU/mL at 96 weeks after treatment. The HBcrAg response rate at 96 weeks was 56.6% (43/76). Multivariate analysis revealed high alanine transaminase level as an independent baseline factor associated with HBcrAg response at 96 weeks of treatment (p = 4.53 × 10−6). No correlation was found between the HBcrAg and hepatitis B surface antigen kinetics in patients treated with TAF monotherapy. Conclusions: In TAF monotherapy for patients with chronic hepatitis B, HBcrAg levels were significantly decreased and baseline alanine transaminase level is an important factor associated with HBcrAg reduction. As no correlation was found between HBcrAg and reduced hepatitis B surface antigen levels in this study, HBcrAg kinetics in addition to hepatitis B surface antigen may need to be monitored during TAF treatment. [ABSTRACT FROM AUTHOR]

Objective: The development of acquired middle ear cholesteatoma is associated with a single nucleotide polymorphism, 538G>A, in the human adenosine triphosphate‐binding cassette transporter C11 (ABCC11) gene, which is a determinant of the earwax morphotype, such as wet‐ and dry‐type earwax; however, the mechanism underlying this association is unclear. We focused on the earwax pH and aimed to elucidate the mechanism between ABCC11 genotypes and acquired middle ear cholesteatoma. Study Design: Prospective observational study. Setting: Single‐center, academic hospital. Methods: We recruited 40 patients with acquired middle ear cholesteatoma who underwent surgery and 115 controls with no history of middle ear cholesteatoma. We assessed the earwax pH and ABCC11 genotypes in all participants. Clinical information was collected from the patients with cholesteatoma. Results: The earwax pH was significantly less acidic in patients with cholesteatoma and those carrying wet earwax genotypes (ABCC11 538G/G or 538G/A) than in the controls and those carrying the dry earwax genotype (ABCC11 538A/A), respectively. Furthermore, earwax pH was significantly positively correlated with high preoperative cholesteatoma stages in the patients with cholesteatoma. Conclusion: Our results show that the less acidic earwax pH was significantly related to the development and progression of acquired middle ear cholesteatoma. The less acidic earwax pH may play an important role in the mechanism underlying the association between acquired middle ear cholesteatoma and the ABCC11 gene at site 538. [ABSTRACT FROM AUTHOR]

Subbandgap optical absorption (SOA) in undoped GaN and 90 nm‐thick Al1−xInxN thin films grown on sapphire substrates is investigated using photothermal deflection spectroscopy (PDS) and photoluminescence (PL). An Al1−xInxN alloy (x = 0.17) is grown on a GaN/sapphire template by metal–organic chemical vapor deposition (MOCVD), and the SOA is observed using PDS. To develop an estimation method for the absorption coefficient (α) of SOA in GaN and Al1−xInxN thin films, the use of a thick GaN substrate is proposed, which is grown by hydride vapor‐phase epitaxy, as a converter of the PDS signal intensity to α, and the accuracies of the estimated α are discussed. Comparing the PDS and PL results, it is revealed that nonradiative recombination centers leading to the reduction of the near‐band‐edge PL intensity are not the dominant sources of SOAs in GaN. Other in‐gap states formed by impurities and/or their complexes with vacancy‐type defects are possible sources of a large SOA in the MOCVD‐grown GaN template. Considering the PDS results and reported peak reflectivity of Al1−xInxN/GaN distributed Bragg reflectors, the α value of sub‐100 nm‐thick Al1−xInxN alloy grown on GaN/sapphire template is expected to be ≈100 cm−1 or less below 3.0 eV. [ABSTRACT FROM AUTHOR]

Mutations of KRAS, CDKN2A, TP53, and SMAD4 are the four major driver genes for pancreatic ductal adenocarcinoma (PDAC), of which mutations of KRAS and TP53 are the most frequently recognized. However, molecular‐targeted therapies for mutations of KRAS and TP53 have not yet been developed. To identify novel molecular targets, we newly established organoids with the Kras mutation (KrasmuOR) and Trp53 loss of function using Cre transduction and CRISPR/Cas9 (Krasmu/p53muOR) from murine epithelia of the pancreatic duct in KrasLSL‐G12D mice, and then analyzed the proteomic and metabolomic profiles in both organoids by mass spectrometry. Hyperfunction of the glycolysis pathway was recognized in Krasmu/p53muOR compared with KrasmuOR. Loss of function of triosephosphate isomerase (TPI1), which is involved in glycolysis, induced a reduction of cell proliferation in human PDAC cell lines with the TP53 mutation, but not in PDAC or in human fibroblasts without TP53 mutation. The TP53 mutation is clinically recognized in 70% of patients with PDAC. In the present study, protein expression of TPI1 and nuclear accumulation of p53 were recognized in the same patients with PDAC. TPI1 is a potential candidate therapeutic target for PDAC with the TP53 mutation. [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. [ABSTRACT FROM AUTHOR]

Background and Aims: Because the accuracy of the Fibrosis‐4 (FIB‐4) index for predicting liver fibrosis changes with age, the need for different cut‐offs in various age groups has frequently been discussed. We developed the age‐independent score, the Fibrosis‐3 (FIB‐3) index, and have shown its usefulness in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB‐3 index to predict fibrosis progression using a large new patient cohort. Methods: The ability of the FIB‐3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB‐4 index using data from 1398 patients with MASLD enrolled in the Asia‐based clinical outcome NAFLD study. Results: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB‐3 and FIB‐4 indices in the entire cohort. Using the single ideal cut‐offs of the indices (3.41 for FIB‐3 index and 2.01 for FIB‐4 index), the predictive accuracy of the FIB‐3 index was not significantly different from that of the FIB‐4 index among patients aged <60 years; however, the accuracy of the FIB‐3 index was significantly higher than that of the FIB‐4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001). Conclusion: The high ability of the FIB‐3 index with a single cut‐off to predict liver fibrosis in patients with MASLD was confirmed. The FIB‐3 index could serve as a useful tool for assessing liver fibrosis regardless of age. [ABSTRACT FROM AUTHOR]

Background: As the incidence of obesity increases worldwide, laparoscopic gastrectomy (LG) in obese patients with gastric cancer is more common. It is unclear how visceral fat obesity (obesity disease [OD]) may influence short‐ and long‐term outcomes after LG. Methods: This study included 170 gastric cancer patients who underwent curative LG at Minoh City Hospital from 2008 to 2020. Patients were classified based on preoperative body mass index (BMI) and visceral fat area (VFA): normal (N; n = 95), visceral fat accumulation alone (VF; n = 35), obesity with visceral fat accumulation (OD; n = 35), and obesity alone (n = 5). Results: Compared with normal VFA, high preoperative VFA (≥100 cm2) was significantly associated with longer operation time, greater blood loss, more frequent postoperative complications, and longer hospital stay. Multivariate analysis revealed the following independent risk factors for postoperative intra‐abdominal infectious complications: Charlson Comorbidity Index ≥4 (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.2–8.5), dissected lymph node area (D2) (OR: 3.0, 95% CI: 1.2–7.1), and preoperative VFA (≥100 cm2) (OR: 3.7, 95% CI: 1.6–8.8). Intraoperative and postoperative courses were comparable between groups VF and OD. The 3‐year overall survival rate was significantly worse in group VF (73.2%) compared with groups OD (96.7%) and N (96.7%) (p <.0001). Recurrence‐free survival and cancer‐specific survival were comparable between groups VF, OD, and N. Conclusion: Visceral fat accumulation strongly predicted postoperative morbidity. Despite increased perioperative risk, OD did not negatively impact successful lymphadenectomy or survival following LG. [ABSTRACT FROM AUTHOR]

Splicing modulation by a small compound offers therapeutic potential for diseases caused by splicing abnormality. However, only a few classes of compounds that can modulate splicing have been identified. We previously identified BAY61‐3606, a multiple kinase inhibitor, as a compound that relaxes the splicing fidelity at the 3′ splice site recognition. We have also reported the synthesis of derivatives of BAY61‐3606. In this study, we tested those compounds for their splicing modulation capabilities and identified two contrasting compounds. These compounds were further investigated for their effects on the whole transcriptome, and analysis of changes in transcription and splicing revealed that the highly active derivative in the splicing reporter assay also showed significantly higher activity in modulating the splicing of endogenously expressed genes. Particularly, cassette exon inclusion was highly upregulated by this compound, and clustering analysis revealed that these effects resembled those in splicing factor 3b subunit 1 (SF3B1) K700E mutant cells but contrasted with those of the splicing inhibitor H3B‐8800. Additionally, a group of serine/arginine‐rich (SR) protein genes was identified as representatively affected, likely via modulation of poison exon inclusion. This finding could guide further analysis of the mode of action of these compounds on splicing, which could be valuable for developing drugs for diseases associated with splicing abnormalities. [ABSTRACT FROM AUTHOR]

Senescence of nondividing neurons remains an immature concept, with especially the regulatory molecular mechanisms of senescence-like phenotypes and the role of proteins associated with neurodegenerative diseases in triggering neuronal senescence remaining poorly explored. In this study, we reveal that the nucleolar polyglutamine binding protein 3 (PQBP3; also termed NOL7), which has been linked to polyQ neurodegenerative diseases, regulates senescence as a gatekeeper of cytoplasmic DNA leakage. PQBP3 directly binds PSME3 (proteasome activator complex subunit 3), a subunit of the 11S proteasome regulator complex, decreasing PSME3 interaction with Lamin B1 and thereby preventing Lamin B1 degradation and senescence. Depletion of endogenous PQBP3 causes nuclear membrane instability and release of genomic DNA from the nucleus to the cytosol. Among multiple tested polyQ proteins, ataxin-1 (ATXN1) partially sequesters PQBP3 to inclusion bodies, reducing nucleolar PQBP3 levels. Consistently, knock-in mice expressing mutant Atxn1 exhibit decreased nuclear PQBP3 and a senescence phenotype in Purkinje cells of the cerebellum. Collectively, these results suggest homologous roles of the nucleolar protein PQBP3 in cellular senescence and neurodegeneration. Synopsis: Senescence of nondividing cells such as neurons is thought to promote neurodegenerative diseases, however, its molecular control remains unclear. Here, the nucleolar protein PQBP3 (also termed NOL7), associated with polyQ diseases, is shown to prevent cellular senescence by antagonising genomic DNA leakage to the cytosol. PQBP3 is an intrinsically disordered protein localized primarily at the periphery of the nucleolus. PQBP3 depletion increases nuclear membrane instability and cytoplasmic DNA leakage in human cells, inducing senescence. PQBP3 interacts with the proteasome activator subunit PSME3, stabilizing Lamin B1 and the nuclear membrane. Decreased nuclear PQBP3, the polyQ protein ATXN1, and cellular senescence are associated with polyQ disease pathology in cerebellar Purkinje cells in mice. The nucleolar polyQ-binding protein PQBP3/NOL7 protects neurons from cellular senescence by stabilizing the nuclear membrane and preventing genomic DNA leakage. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to establish the shear wave measurement (SWM) cut‐off value for each fibrosis stage using magnetic resonance (MR) elastography values as a reference standard. Methods: We prospectively analyzed 594 patients with chronic liver disease who underwent SWM and MR elastography. Correlation coefficients (were analyzed, and the diagnostic value was evaluated by the area under the receiver operating characteristic curve. Liver stiffness was categorized by MR elastography as F0 (<2.61 kPa), F1 (≥2.61 kPa, <2.97 kPa, any fibrosis), F2 (≥2.97 kPa, <3.62 kPa, significant fibrosis), F3 (≥3.62 kPa, <4.62 kPa, advanced fibrosis), or F4 (≥4.62 kPa, cirrhosis). Results: The median SWM values increased significantly with increasing fibrosis stage (p < 0.001). The correlation coefficient between SWM and MR elastography values was 0.793 (95% confidence interval 0.761–0.821). The correlation coefficients between SWM and MR elastography values significantly decreased with increasing body mass index and skin–capsular distance; skin–capsular distance values were associated with significant differences in sensitivity, specificity, accuracy, or positive predictive value, whereas body mass index values were not. The best cut‐off values for any fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis were 6.18, 7.09, 8.05, and 10.89 kPa, respectively. Conclusions: This multicenter study in a large number of patients established SWM cut‐off values for different degrees of fibrosis in chronic liver diseases using MR elastography as a reference standard. It is expected that these cut‐off values will be applied to liver diseases in the future. [ABSTRACT FROM AUTHOR]

Background: There are diverse indications for heart transplantation (HTx), often categorized into ischemic (ICM) and nonischemic (NICM) cardiomyopathy. Although there is extensive research comparing the outcomes for these disease processes following certain therapeutic interventions, there are limited data on how recipient etiology impacts post‐HTx survival. Our investigation seeks to identify this relationship. Methods: We conducted a retrospective analysis using adult HTx patients from the United Network for Organ Sharing database between 2000 and 2021. Patients with a combined heart–lung transplant or previous HTx were excluded. ICM included coronary artery disease (CAD) and ischemic dilated cardiomyopathy. NICM included nonischemic dilated (NIDCM), hypertrophic (HCM), and restrictive (RCM) cardiomyopathy. Overall survival was analyzed using Kaplan–Meier curves, log‐rank tests, and multivariable Cox regression models. Results: A total of 42 268 patients were included in our study. Recipients with ICM were older and more likely to be males, obese, diabetics, and smokers. We found that patients with ICM had an increased incidence of transplant CAD (OR = 1.23, p < 0.001) and risk of mortality (hazard ratio [HR] = 1.22, p < 0.001) compared to NICM. When NICM was expanded, RCM had a similar hazard risk compared to ICM (HR = 1.03, p = 0.650), whereas both NIDCM (HR = 0.81, p < 0.001) and HCM (HR = 0.70, p < 0.001) had improved survival. Conclusion: Our study provides evidence to suggest that ICM has decreased survival when compared to NICM. When NICM was expanded, RCM was found to have an increased mortality risk similar to ICM, whereas NIDCM and HCM both had superior outcomes. The clinical implication of this investigation will allow clinicians to better understand the prognosis of certain patient groups. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Although metabolic dysfunction‐associated steatotic liver disease (MASLD) patients with a Fib‐4 index >1.3 are recommended for fibrosis evaluation via elastography or biopsy, a more convenient method identifying high‐risk populations requiring follow‐up is needed. We explored the utility of serum levels of growth differentiation factor‐15 (GDF15), a cell stress‐responsive cytokine related to metabolic syndrome, for stratifying the risk of clinical events in MASLD patients. Methods: Serum GDF15 levels were measured in 518 biopsy‐performed MASLD patients, 216 MASLD patients for validation, and 361 health checkup recipients with MASLD. Results: In the biopsy‐MASLD cohort, multivariate analysis indicated that the serum GDF15 level was a risk factor for liver cancer, independent of the fibrosis stage or Fib‐4 index. Using a GDF15 cutoff of 1.75 ng/mL based on the Youden index, high‐GDF15 patients, regardless of fibrosis status, had a higher liver cancer incidence rate. While patients with a Fib‐4 index <1.3 or low‐GDF15 rarely developed liver cancer, high‐GDF15 patients with a Fib‐4 index >1.3 developed liver cancer and decompensated liver events at significantly higher rates and had poorer prognoses. In the validation cohort, high‐GDF15 patients had significantly higher incidences of liver cancer and decompensated liver events and poorer prognoses than low‐GDF15 patients, whether limited to high‐Fib‐4 patients. Among health checkup recipients with MASLD, 23.0% had a Fib‐4 index >1.3, 2.7% had a Fib‐4 index >1.3 and >1.75 ng/mL GDF15. Conclusions: Serum GDF15 is a biomarker for liver cancer with high predictive capability and is useful for identifying MASLD patients requiring regular surveillance. [ABSTRACT FROM AUTHOR]

Aim: To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium‐glucose cotransporter‐2 (SGLT2) inhibitor and glucagon‐like peptide 1 receptor agonist (GLP‐1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP‐1RA first. Methods: We included 438 patients with CKD (GLP‐1RA‐first group, n = 223; SGLT2 inhibitor‐first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)‐matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only. Results: Using the PS‐matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP‐1RA‐first group, 10%; SGLT2 inhibitor‐first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP‐1RA‐first group versus the SGLT2 inhibitor‐first group was 1.83 (95% CI 1.71 to 1.95; p < 0.001). Conclusion: Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP‐1RA‐first group versus the SGLT2 inhibitor‐first group was significant. These results suggest that, in GLP‐1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP‐1RA treatment may lead to more favourable renal outcomes. [ABSTRACT FROM AUTHOR]

Fem is a W‐linked gene that encodes a piRNA precursor, and its product, Fem piRNA, is a master factor of female determination in Bombyx mori. Fem has low similarity to any known sequences, and the origin of Fem remains unclear. So far, two hypotheses have been proposed for the origin of Fem: The first hypothesis is that Fem is an allele of Masc, which assumes that the W chromosome was originally a homologous chromosome of the Z chromosome. The second hypothesis is that Fem arose by the transposition of Masc to the W chromosome. To explore the origin of Fem, we determined the W chromosome sequences of B. mori and, as a comparison, a closely relative bombycid species of Trilocha varians with a Fem‐independent sex determination system. To our surprise, although the sequences of W and Z chromosomes show no homology to each other, a few pairs of homologues are shared by W and Z chromosomes, indicating the W chromosome of both species originated from Z chromosome. In addition, the W chromosome of T. varians lacks Fem, while the W chromosome of B. mori has over 100 copies of Fem. The high‐quality assembly of the W chromosome of B. mori arose the third hypothesis about the origin of Fem: Fem is a chimeric sequence of multiple transposons. More than half of one transcriptional unit of Fem shows a significant homology to RTE‐BovB. Moreover, the Fem piRNA‐producing region could correspond to the boundary of the two transposons, gypsy and satellite DNA. [ABSTRACT FROM AUTHOR]

Summary: Background: Atezolizumab plus bevacizumab (Atezo/Bev) is frequently selected as the primary systemic therapy for hepatocellular carcinoma (HCC). Aims: To investigate the outcomes of patients with HCC treated with Atezo/Bev in a real‐world setting based on whether they met the inclusion criteria for the phase 3 IMbrave150 trial. Methods: A total of 936 patients were enrolled. There were 404 patients who met the inclusion criteria of the phase 3 IMbrave150 trial (IMbrave150 group) and 532 who did not (non‐IMbrave150 group). Results: Median progression‐free survival (PFS) in the IMbrave150 and non‐IMbrave150 groups was 7.4 months and 5.6 months (p = 0.002). Multivariable analysis revealed that non‐B, non‐C HCC aetiology (hazard ratio [HR], 1.173), α‐fetoprotein ≥100 ng/mL (HR, 1.472), Barcelona Clinic Liver Cancer stage ≥ C (HR, 1.318), and modified albumin–bilirubin (mALBI) grade 2b or 3 (HR, 1.476) are independently associated with PFS. Median overall survival (OS) in the IMbrave150 and non‐Imbrave150 groups was 26.5 and 18.8 months (p < 0.001). Multivariable analysis revealed that Eastern Cooperative Oncology Group performance status ≥2 (HR, 1.986), α‐fetoprotein ≥100 ng/mL (HR, 1.481), and mALBI grade 2b or 3 (HR, 2.037) are independently associated with OS. In subgroup analysis, there were no significant differences in PFS or OS between these groups among patients with mALBI grade 1 or 2a. Conclusions: Patients who are treated with Atezo/Bev and meet the inclusion criteria for the phase 3 IMbrave150 trial, as well as those who do not meet the inclusion criteria but have good liver function, have a good prognosis for survival. [ABSTRACT FROM AUTHOR]

SUMMARY: Green feather algae (Bryopsidales) undergo a unique life cycle in which a single cell repeatedly executes nuclear division without cytokinesis, resulting in the development of a thallus (>100 mm) with characteristic morphology called coenocyte. Bryopsis is a representative coenocytic alga that has exceptionally high regeneration ability: extruded cytoplasm aggregates rapidly in seawater, leading to the formation of protoplasts. However, the genetic basis of the unique cell biology of Bryopsis remains poorly understood. Here, we present a high‐quality assembly and annotation of the nuclear genome of Bryopsis sp. (90.7 Mbp, 27 contigs, N50 = 6.7 Mbp, 14 034 protein‐coding genes). Comparative genomic analyses indicate that the genes encoding BPL‐1/Bryohealin, the aggregation‐promoting lectin, are heavily duplicated in Bryopsis, whereas homologous genes are absent in other ulvophyceans, suggesting the basis of regeneration capability of Bryopsis. Bryopsis sp. possesses >30 kinesins but only a single myosin, which differs from other green algae that have multiple types of myosin genes. Consistent with this biased motor toolkit, we observed that the bidirectional motility of chloroplasts in the cytoplasm was dependent on microtubules but not actin in Bryopsis sp. Most genes required for cytokinesis in plants are present in Bryopsis, including those in the SNARE or kinesin superfamily. Nevertheless, a kinesin crucial for cytokinesis initiation in plants (NACK/Kinesin‐7II) is hardly expressed in the coenocytic part of the thallus, possibly underlying the lack of cytokinesis in this portion. The present genome sequence lays the foundation for experimental biology in coenocytic macroalgae. Significance Statement: The exceptionally coenocytic body and remarkable regeneration ability of Bryopsis have attracted biologists for years. However, molecular biological tools remain underdeveloped, partly due to the lack of genome information. Here, we report high‐quality assembly and annotation of the genome, providing a crucial resource for experimental biology and genomics studies of Bryopsis. Furthermore, comparative genomic analysis reveals a unique gene repertoire that possibly underlies the highly regenerative coenocytic body. [ABSTRACT FROM AUTHOR]

Background & Aims: The predictors of progression from steatosis to more advanced stages of metabolic dysfunction-associated steatotic liver disease (MASLD) remain unclear. We evaluated the association between the quantity of hepatic steatosis and longitudinal changes in liver stiffness measurements (LSMs) using magnetic resonance elastography (MRE) in patients with MASLD. Methods: We retrospectively analysed patients with MASLD who underwent at least two serial MRE and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) examinations at least 1year apart. Fine-Gray competitive proportional hazard regression was used to identify LSM progression and regression factors. Results: A total of 471 patients were enrolled. Factors linked to LSM progression were steatosis grade 3 (MRI-PDFF ≥17.1%, adjusted hazard ratio [aHR] 2.597; 95% confidence interval [CI] 1.483-4.547) and albumin-bilirubin grade 2 or 3 (aHR 2.790; 95% CI 1.284-6.091), while the only factor linked to LSM regression was % decrease rate of MRI-PDFF ≥5% (aHR 2.781; 95% CI 1.584-4.883). Steatosis grade 3 correlated with a higher incidence rate of LSM progression than steatosis grade 1 (MRI-PDFF <11.3%) in patients with LSM stage 0 (<2.5 kilopascal [kPa]), and a % annual decrease rate of MRI-PDFF >5% correlated with a higher incidence rate of LSM regression than that of MRI-PDFF ≥-5% and <5% in patients with LSM stage 1 or 2-4 (≥2.5 kPa). Conclusions: Severe hepatic steatosis was linked to significant LSM progression in patients with MASLD and low LSM (<2.5 kPa). [ABSTRACT FROM AUTHOR]

Although measurements of blood triiodothyronine (T3), thyroxine (T4), and thyroid‐stimulating hormone (TSH) levels in rodent toxicity studies are useful for detection of antithyroid substances, assays for these measurements are expensive and can show high variability depending on blood sampling conditions. To develop more efficient methods for detecting thyroid disruptors, we compared histopathological and immunohistochemical findings in the thyroid and pituitary glands with blood hormone levels. Six‐week‐old male and female Sprague–Dawley rats (five rats per group) were treated with multiple doses of the thyroid peroxidase inhibitors propylthiouracil (PTU) and methimazole by gavage for 28 days. Significant decreases in serum T3 and T4 and increases in TSH were observed in the ≥1 mg/kg PTU and ≥3 mg/kg methimazole groups. An increase in TSH was also detected in male rats in the 0.3 mg/kg PTU group. Histopathological and immunohistochemical analyses revealed that follicular cell hypertrophy and decreased T4 and T3 expressions in the thyroid gland were induced at doses lower than doses at which significant changes in serum hormone levels were observed, suggesting that these findings may be more sensitive than blood hormone levels. Significant increases in thyroid weights, Ki67‐positive thyroid follicular cell counts, and TSH‐positive areas in the pituitary gland were detected at doses comparable with those at which changes in serum T4 and TSH levels were observed, indicating that these parameters may also be useful for evaluation of antithyroid effects. Combining these parameters may be effective for detecting antithyroid substances without relying on hormone measurements. In rats treated with PTU and MMI for 28 days, histopathological and immunohistochemical findings and serum hormone levels were compared to establish a simplified method for detecting antithyroid chemicals. The results demonstrated that histopathological analysis and T4 immunostaining in the thyroid gland were more sensitive parameters than blood hormone levels and that immunohistochemistry for thyroid Ki67 and pituitary TSH may also be useful for evaluation. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to evaluate the diagnostic performance of attenuation measurement (ATT; dual‐frequency method) and improved algorithm of ATT (iATT; reference method) for the assessment of hepatic steatosis using magnetic resonance imaging (MRI)‐derived proton density fat fraction (PDFF) as the reference standard. Methods: We prospectively analyzed 427 patients with chronic liver disease who underwent ATT, iATT, or MRI‐derived PDFF. Correlation coefficients were analyzed, and diagnostic values were evaluated by area under the receiver operating characteristic curve (AUROC). The steatosis grade was categorized as S0 (<5.2%), S1 (≥5.2%, <11.3%), S2 (≥11.3%, <17.1%), and S3 (≥17.1%) according to MRI‐derived PDFF values. Results: The median ATT and iATT values were 0.61 dB/cm/MHz (interquartile range 0.55–0.67 dB/cm/MHz) and 0.66 dB/cm/MHz (interquartile range 0.57–0.77 dB/cm/MHz). ATT and iATT values increased significantly as the steatosis grade increased in the order S0, S1, S2, and S3 (p < 0.001). The correlation coefficients between ATT or iATT values and MRI‐derived PDFF values were 0.533 (95% confidence interval [CI] 0.477–0.610) and 0.803 (95% CI 0.766–0.834), with a significant difference between them (p < 0.001). For the detection of hepatic steatosis of ≥S1, ≥S2, and ≥S3, iATT yielded AUROCs of 0.926 (95% CI 0.901–0.951), 0.913 (95% CI 0.885–0.941), and 0.902 (95% CI 0.869–0.935), with significantly higher AUROC values than for ATT (p < 0.001, p < 0.001, p = 0.001). Conclusion: iATT showed excellent diagnostic performance for hepatic steatosis, and was strongly correlated with MRI‐derived PDFF, with AUROCs of ≥0.900. [ABSTRACT FROM AUTHOR]

Background and Aim: Direct‐acting antivirals (DAAs) have been accessible in Japan since 2014. The aim of this study is to compare how the prognosis of patients with hepatitis C virus (HCV)‐associated hepatocellular carcinoma (HCV‐HCC) changed before and after DAA development. Methods: A retrospective analysis of 1949 Japanese HCV‐HCC patients from January 2000 to January 2023 categorized them into pre‐DAA (before 2013, n = 1169) and post‐DAA (after 2014, n = 780) groups. Changes in clinical features and prognosis were assessed. Results: Despite no significant differences in BCLC stage between groups, the post‐DAA group exhibited higher rates of sustained virological response (SVR) (45.6% vs. 9.8%), older age (73 vs 69 years), lower levels of AST (40 vs 56 IU/L), ALT (31 vs 46 IU/L), and AFP (11.7 vs 23.6 ng/mL), higher platelet count (13.5 vs 10.8 × 104/μL), better prothrombin time (88.0% vs 81.9%), and better ALBI score (−2.54 vs −2.36) (all P < 0.001). The post‐DAA group also showed higher rates of curative treatments (74.1% vs 65.2%) and significantly improved recurrence‐free survival (median 2.8 vs 2.1 years). Adjusted for inverse probability weighting, overall survival was superior in the post‐DAA group (median 7.4 vs 5.6 years, P < 0.001). Subanalysis within the post‐DAA group revealed significantly shorter overall survival for patients without SVR (median 4.8 years vs NA vs NA) compared to pre‐SVR or post‐SVR patients (both P < 0.001). No significant difference in OS was observed between the pre‐SVR and post‐SVR groups (P = 1.0). Conclusion: The development of DAA therapy has dramatically improved the prognosis of HCV‐HCC patients. [ABSTRACT FROM AUTHOR]

Most cervical cancers are caused by human papillomavirus (HPV) infection. In HeLa cells, the HPV18 viral genome is integrated at chromosome 8q24.21 and activates transcription of the proto‐oncogene c‐Myc. However, the mechanism of how the integrated HPV genome and its transcribed RNAs exhibit transcription activation function has not been fully elucidated. In this study, we found that HPV18 transcripts contain an enhancer RNA‐like function to activate proximal genes including CCAT1‐5L and c‐Myc. We showed that the human genome‐integrated HPV18 genes are activated by transcription coregulators including BRD4 and Mediator. The transcribed HPV18 RNAs form a liquid‐like condensate at chromosome 8q24.21 locus, which in turn accumulates RNA polymerase II. Moreover, we focused on a relatively uncharacterized transcript from the upstream region of CCAT1, named URC. The URC RNA is transcribed as a chimera RNA with HPV18 and is composed of the 3′‐untranslated region of the HPV18 transcript. We experimentally showed that the URC contributes to stabilization of HPV18 RNAs by supplying a polyadenylation site for the HPV18 transcript. Our findings suggest that integrated HPV18 at 8q24.21 locus produces HPV18‐URC chimera RNA and promotes tumorigenesis through RNA‐based condensate formation. [ABSTRACT FROM AUTHOR]

Summary: Aims: A multi‐stakeholder consensus has proposed MASLD (metabolic dysfunction‐associated steatotic liver disease). We aimed to investigate the pathological findings related to the mid‐term mortality of patients with biopsy‐proven MASLD in Japan. Methods: We enrolled 1349 patients with biopsy‐proven MASLD. The observational period was 8010 person years. We evaluated independent factors associated with mortality in patients with MASLD by Cox regression analysis. We also investigated pathological profiles related to mortality in patients with MASLD using data‐mining analysis. Results: The prevalence of MASH and stage 3/4 fibrosis was observed in 65.6% and 17.4%, respectively. Forty‐five patients with MASLD died. Of these, liver‐related events were the most common cause at 40% (n = 18), followed by extrahepatic malignancies at 26.7% (n = 12). Grade 2/3 lobular inflammation and stage 3/4 fibrosis had a 1.9‐fold and 1.8‐fold risk of mortality, respectively. In the decision‐tree analysis, the profiles with the worst prognosis were characterised by Grade 2/3 hepatic inflammation, along with advanced ballooning (grade 1/2) and fibrosis (stage 3/4). This profile showed a mortality at 8.3%. Furthermore, the random forest analysis identified that hepatic fibrosis and inflammation were the first and second responsible factors for the mid‐term prognosis of patients with MASLD. Conclusions: In patients with biopsy‐proven MASLD, the prevalence of MASH and advanced fibrosis was approximately 65% and 20%, respectively. The leading cause of mortality was liver‐related events. Hepatic inflammation and fibrosis were significant factors influencing mid‐term mortality. These findings highlight the importance of targeting inflammation and fibrosis in the management of patients with MASLD. [ABSTRACT FROM AUTHOR]

SUMMARY: Plants have developed the ability to adjust to the day/night cycle through the expression of diel genes, which allow them to effectively respond to environmental changes and optimise their growth and development. Diel oscillations also have substantial implications in many physiological processes, including photosynthesis, floral development, and environmental stress responses. The expression of diel genes is regulated by a combination of the circadian clock and responses to environmental cues, such as light and temperature. A great deal of information is available on the transcriptional regulation of diel gene expression. However, the extent to which translational regulation is involved in controlling diel changes in expression is not yet clear. To investigate the impact of translational regulation on diel expression, we conducted Ribo‐seq and RNA‐seq analyses on a time‐series sample of Arabidopsis shoots cultivated under a 12 h light/dark cycle. Our results showed that translational regulation is involved in about 71% of the genes exhibiting diel changes in mRNA abundance or translational activity, including clock genes, many of which are subject to both translational and transcriptional control. They also revealed that the diel expression of glycosylation and ion‐transporter‐related genes is mainly established through translational regulation. The expression of several diel genes likely subject to translational regulation through upstream open‐reading frames was also determined. Significance Statement: For plants, adaptation to diel oscillations in the environment is important for many biological processes; however, the impact of translational regulation on diel gene expression is not fully understood. In this study, time‐series ribosome profiling (Ribo‐seq) revealed that many diel genes, including clock genes, are translationally regulated; moreover, genes exhibiting diel oscillation solely in terms of translational activity tend to be more highly expressed at night. [ABSTRACT FROM AUTHOR]

Background and Aim: The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)‐related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. Methods: A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all‐cause, liver‐related, and non‐liver‐related mortality between patients receiving ETV and those receiving TDF. Results: The annual incidence of all‐cause mortality in the entire cohort was 1.0/100 person‐years (follow‐up, 15 757.5 person‐years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e‐antigen seropositivity than those who received ETV. The factors associated with all‐cause mortality were fibrosis‐4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15–4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04–1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996–0.999, P = 0.003), and γ‐glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001–1.003, P < 0.001). No significant difference in all‐cause mortality was observed between the ETV and TDF groups (log–rank test, P = 0.69). After propensity score matching, no significant differences in all‐cause, liver‐related, or non‐liver‐related mortality were observed between the two groups. Conclusions: Long‐term outcomes of all‐cause mortality and liver‐related and non‐liver‐related mortality did not differ between patients treated with ETV and those receiving TDF. [ABSTRACT FROM AUTHOR]

Background and Aim: The study aims to develop a novel predictive model including the fibrosis (FIB)‐3 index for hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C virus (HCV) who achieved sustained virological response (SVR) with direct‐acting antiviral (DAA) therapy. Methods: This study included 2529 patients in whom HCV was eradicated with DAA therapy. The after DAA recommendation for surveillance (ADRES) score, which is based on sex, FIB‐4 index, and α‐fetoprotein, was used to predict HCC development. We developed a modified ADRES (mADRES) score, in which the FIB‐4 index was replaced by the FIB‐3 index, and evaluated its usefulness in predicting HCC development compared with the ADRES score. Results: In the training set (n = 1770), multivariate analysis with Cox proportional hazards modeling showed that male sex (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.48–3.01), FIB‐3 index (HR, 1.36; 95% CI, 1.28–1.45), and α‐fetoprotein (HR, 1.05; 95% CI, 1.03–1.07) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES or mADRES score in multiple comparisons. Univariate Cox proportional hazards models showed that compared with the mADRES score 0 group, the HR for HCC development was 2.07 (95% CI, 1.02–4.19) for the mADRES score 1 group, 11.37 (95% CI, 5.80–22.27) for the mADRES score 2 group, and 21.95 (95% CI, 10.17–47.38) for the mADRES score 3 group. Similar results were obtained for mADRES score but not for ADRES score in the validation set (n = 759). Conclusion: The mADRES score is useful for predicting HCC development after SVR. [ABSTRACT FROM AUTHOR]

Objectives: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian‐specific NOTCH3 p.R75P mutation. Methods: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi‐Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations. Results: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45–37.31), multiple CMB (3.00, 1.34–6.71), and absence of temporopolar lesions (4.91, 2.29–10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83–35.89), multiple CMB (1.90, 1.01–3.56), and absence of temporopolar lesions (2.32, 1.08–4.97). Structural analysis revealed solvent‐exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations. Interpretation: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040–1054 [ABSTRACT FROM AUTHOR]

Background and Aim: While several predictive models for the development of hepatocellular carcinoma (HCC) have been proposed, including those for patients with chronic hepatitis C virus (HCV) infection who have achieved sustained virologic response (SVR), the best model may differ between regions. We compared the ability of six reported models to stratify the risk of post‐SVR HCC in Japan, where rigorous surveillance and early detection of HCC is common. Methods: A total of 6048 patients with no history of HCC who achieved SVR by oral direct‐acting antiviral drugs were enrolled in this nationwide study. Patients continued HCC surveillance every 6 months after SVR. The incidence of post‐SVR HCC was compared between risk groups using the aMAP score, FIB‐4 index, Tahata model, GAF4 criteria, GES score, and ADRES score. Results: During the observation period with a median duration of 4.0 years after SVR, post‐SVR HCC developed in 332 patients (5.5%). All six models performed significantly at stratifying the incidence of HCC. However, Harrell's C‐index was below 0.8 for all models (range, 0.660–0.748), indicating insufficient stratification ability. Conclusion: Although all six proposed models demonstrated a good ability to predict the development of post‐SVR HCC, their ability to stratify the risk of post‐SVRHCC was unsatisfactory. Further studies are necessary to identify the best model for assessing the risk of post‐SVR HCC in regions where early detection of HCC is common. [ABSTRACT FROM AUTHOR]

Aim: Elderly patients are believed to have a reduced immune capacity, which may make immunotherapy less effective. The aim of this study was to compare the therapeutic outcome of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) for advanced hepatocellular carcinoma (HCC) in patients aged 80 years and older. Methods: From March 2018 to July 2022, 170 and 92 elderly patients who received LEN and Atez/Bev as first‐line treatment, respectively, were retrospectively analyzed. Results: The median ages of the Atez/Bev and LEN groups were 83.0 (8.01–86.0) and 83.0 (82.0–86.0) years (p = 0.3), respectively. Men accounted for approximately 70% of the patients in both groups. The objective response rate was 35.9% in the LEN group and 33.7% in the Atez/Bev group (p = 0.8), whereas the disease control rates in the LEN and Atez/Bev groups were 62.9% and 63.0%, respectively (p = 1.0). The median progression‐free survival (PFS) in the LEN and Atez/Bev groups was 6.3 and 7.2 months, respectively, which were not significantly different (p = 0.2). The median overall survival (OS) was 17.9 months in the LEN group and 14.0 months in the Atez/Bev group. This difference was not statistically significant (p = 0.7). In multivariate analyses, the choice of treatment (LEN vs. Atez/Bev) showed no association with PFS or OS. The Atez/Bev group had a significantly higher rate of postprogression treatment (59.0% vs. 35.7%, p = 0.01) and a lower rate of discontinuation due to adverse events (69 [40.6%] vs. 19 [20.7%], p < 0.001) compared to the LEN group. Conclusions: Atezolizumab plus bevacizumab showed comparable effectiveness to LEN in HCC patients aged 80 years and older. Given the results of postprogression treatment and discontinuation due to adverse events, Atez/Bev could serve as a first‐line treatment even for elderly HCC patients. [ABSTRACT FROM AUTHOR]

Background: The potential of learning analytics dashboards in virtual reality simulation‐based training environments to influence occupational self‐efficacy via self‐reflection phase processes in the Chemical industry is still not fully understood. Learning analytics dashboards provide feedback on learner performance and offer points of comparison (i.e., comparison with one's own past performance or comparison with peer performance) to help learners make sense of their feedback. Objectives: We present a theoretical framework for describing learning analytics reference frames and investigate the impact of feedback delivered through dashboards with different reference frames on occupational self‐efficacy, while controlling for workplace self‐reflection. Methods: This experimental study engaged 42 chemical operator employees, aged between 18 and 55 years, each with at least one year of experience. We utilised a two‐group design to ask two research question each with three competing hypotheses related to changes in occupational self‐efficacy, employing Bayesian informative hypothesis evaluation. Results and Conclusions: Results for the primary research question suggest that dashboards with progress reference frames do not elicit greater change to self‐efficacy than those with social reference frames, however, they may elicit equal change. Furthermore, dashboards with social reference frames may elicit greater change to self‐efficacy than those with progress reference frames. Exploratory results found that dashboards with progress reference frames may elicit greater positive directional change than those with social reference frames and that they may elicit equal directional change. These findings contribute to the understanding of self‐efficacy beliefs within the Chemical industry, with potential impacts on skill development. The research may inform the design of targeted interventions and training programs to influence self‐efficacy. From a practical perspective, this research suggests that careful consideration is needed when choosing reference frames in learning analytics dashboards due to their potential consequences on the formation of learner self‐efficacy. Lay Description: What is already known about this topic?: Learning analytics dashboards often aim to stimulate self‐regulated learning by providing feedback.Feedback plays a crucial role in simulation‐based learning and learning analytics dashboards can be a valuable tool to deliver feedback and facilitate the learning process by providing learners with insights into their performance and progress.Previous research has highlighted the importance of reference frames as critical design features of learning analytics dashboards, as they assist learners in making sense of learning analytics feedback.Self‐efficacy is a powerful determine factor of workplace performance and is influenced by mastery experiences and social modelling information. What the paper adds?: A theoretical framework describes the mediating role self‐reflection phase processes of the self‐regulated learning cycle plays in the formation of occupational self‐efficacy.This paper introduces the concept of three learning analytics reference frame components which include the performance outcome component, point of comparison component and score delta component.The paper indicates that learning analytics dashboards designed with a progress reference frame does not elicit greater change to occupational self‐efficacy than the social reference frame.Exploratory results suggest dashboards with progress reference frames might produce greater positive directional change compared to social reference frames or elicit equal change. Implications for practice?: Learning analytics system designers who use reference frames to help learners make sense of their feedback should carefully consider which reference frames they use as these decisions likely have consequences on the formation of learner self‐efficacy beliefs.For LAD designers and stakeholders, recognising the absolute change and directional shift in self‐efficacy is crucial, as LAD designs significantly influence these dynamics and guide the tailoring of effective tools.In industries like the chemical sector, where overconfidence can result in severe consequences, understanding the nuance of self‐efficacy changes is especially pertinent. [ABSTRACT FROM AUTHOR]

Aims: Atrial fibrillation (AF) and heart failure (HF) often coexist. Older age is strongly associated with stroke, HF, and mortality. The association between coexistence of HF and a risk of clinical outcomes and the effectiveness of anticoagulation therapy including direct oral anticoagulants (DOACs) in elderly patients with AF and HF have not been investigated. We aimed to evaluate 2 years of outcomes and to elucidate the efficacy of DOACs or warfarin in elderly AF patients in the All Nippon AF In the Elderly (ANAFIE) Registry with and without a history of HF. Methods and results: The ANAFIE Registry is a multicentre, prospective observational study following elderly non‐valvular AF patients aged ≥75 years for 2 years. Hazard ratios (HRs) were calculated based on the presence or absence of an HF diagnosis and DOAC or warfarin use at enrolment. Among 32 275 eligible patients, 12 116 (37.5%) had been diagnosed with HF. Patients with HF had significantly higher rates of HF hospitalization or cardiovascular death (HR 1.94, P < 0.001), cardiovascular events (HR 1.59, P < 0.001), cardiovascular death (HR 1.49, P < 0.001), all‐cause death (HR 1.32, P < 0.001), and net clinical outcome including stroke/systemic embolism, major bleeding, and all‐cause death (HR 1.23, P < 0.001), compared with those without HF; however, HRs for stroke/systemic embolism (HR 0.96, P = 0.56) and major bleeding (HR 1.14, P = 0.13) were similar. DOAC use was associated with a low risk of stroke/systemic embolism (HR 0.86, P = 0.19 in HF; HR 0.79, P = 0.016 in non‐HF; P for interaction = 0.56), major bleeding (HR 0.71, P = 0.008 in HF; HR 0.75, P = 0.016 in non‐HF; P for interaction = 0.74), HF hospitalization or cardiovascular death (HR 0.81, P < 0.001 in HF; HR 0.78, P < 0.001 in non‐HF; P for interaction = 0.26), cardiovascular events (HR 0.83, P < 0.001 in HF; HR 0.82, P = 0.001 in non‐HF; P for interaction = 0.65), cardiovascular death (HR 0.84, P = 0.12 in HF; HR 0.75, P = 0.035 in non‐HF; P for interaction = 0.18), all‐cause death (HR 0.89, P = 0.082 in HF; HR 0.80, P = 0.001 in non‐HF; P for interaction = 0.091), and net clinical outcome (HR 0.88, P = 0.019 in HF; HR 0.81, P < 0.001 in non‐HF; P for interaction = 0.21) compared with warfarin, irrespective of the presence or absence of HF. Analysis using the propensity score matching method showed similar associations. Conclusions: Non‐valvular AF patients aged ≥75 years with a history of HF had higher risks of cardiovascular events and mortality. DOACs were favourable to warfarin regardless of the coexistence of HF. These results might encourage the use of DOACs in elderly patients with non‐valvular AF with or without HF. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Glucagon plays an essential role in hepatic glucogenesis by enhancing glycogen breakdown, inducing gluconeogenesis, and suppressing glycogenesis. Moreover, glucagon increases cyclic adenosine monophosphate (cAMP) levels, thereby activating protein kinase A (PKA) and cAMP guanine nucleotide exchange factor (also known as Epac). Although the function of PKA in the liver has been studied extensively, the function of hepatic Epac is poorly understood. The aim of this study was to elucidate the role of Epac in mediating the action of glucagon on the hepatocytes. Materials and Methods: Epac mRNA and protein expression, localization, and activity in the hepatocytes were analyzed by reverse transcription polymerase chain reaction, western blotting, immunofluorescence staining, and Rap1 activity assay, respectively. Additionally, we investigated the effects of an Epac‐specific activator, 8‐CPT, and an Epac‐specific inhibitor, ESI‐05, on glycogen metabolism in isolated rat hepatocytes. Further mechanisms of glycogen metabolism were evaluated by examining glucokinase (GK) translocation and mRNA expression of gluconeogenic enzymes. Results: Epac2, but not Epac1, was predominantly expressed in the liver. Moreover, 8‐CPT inhibited glycogen accumulation and GK translocation and enhanced the mRNA expression of gluconeogenic enzymes. ESI‐05 failed to reverse glucagon‐induced suppression of glycogen storage and partially inhibited glucagon‐induced GK translocation and the mRNA expression of gluconeogenic enzymes. Conclusions: Epac signaling plays a role in mediating the glucogenic action of glucagon in the hepatocytes. [ABSTRACT FROM AUTHOR]

Summary: Background: Racial and ethnic disparities exist for hepatitis C virus (HCV) treatment and hepatocellular carcinoma (HCC) survival. Aim: To evaluate the impact of HCV treatment on such disparities. Methods: In a retrospective cohort study, we analysed 6069 patients with HCV‐related HCC (54.2% Asian, 30.1% White, 8.5% Black, and 7.3% Hispanic) from centres in the United States and Asia. Results: The mean age was 61, 60, 59 and 68, respectively, for White, Black, Hispanic and Asian patients. Black patients were most likely to have Barcelona Clinic Liver Cancer stage D, vascular invasion and distant metastasis (23% vs. 5%–15%, 20% vs. 10%–17% and 10% vs. 5%–7%, respectively; all p < 0.0001). Treatment rate with direct‐acting antiviral agents (DAA) was 35.9% for Asian, 34.9% for White, 30.3% for Hispanic (30.3%), and 18.7% for Black patients (p < 0.0001). Among those untreated or without sustained virologic response (SVR), 10‐year survival rates were 35.4, 27.5, 19.3 and 14.0, respectively, for Asian, Hispanic, White and Black patients (p < 0.0001). There were no statistically significant differences among those with SVR (p = 0.44). On multivariable analysis adjusted for relevant confounders, there was no statistically significant association between survival and being Hispanic (aHR: 0.68, p = 0.26) or Black (aHR: 1.18, p = 0.60) versus White. There was a significant association between being Asian American and survival (aHR: 0.24, p = 0.001; non‐U.S. Asian: aHR: 0.66, p = 0.05), and for SVR (aHR: 0.30, p < 0.0001). Conclusion: DAA treatment rates were suboptimal. Racial and ethnic disparities resolved with HCV cure. Early diagnosis and improved access to HCV treatment is needed for all patients with HCV infection. [ABSTRACT FROM AUTHOR]