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The trigeminal ganglion (TG) comprises primary sensory neurons responsible for orofacial sensations, subsequently projecting to the trigeminal nuclei in the brainstem. However, the circuit basis of nasal mechanosensation is not well characterized. Here we elucidate the anatomical organization of both peripheral and central projections of the TG. We found that the non-peptidergic nociceptor, MAS-related G protein-coupled receptor member D positive (MrgprD + ) neurons in the TG densely innervate the nasal mucosa, whereas the low-threshold mechanoreceptors subtypes rarely innervate the nasal mucosa. We also identified the central projection pattern of the mechanosensory neurons in TG. The tyrosine kinase receptor C positive (TrkC + ) neurons, tyrosine kinase receptor B positive (TrkB + ) and tyrosine hydroxylase positive (TH + ) neurons project to multiple subregions of brainstem trigeminal complex and solitary nucleus. In contrast, the MrgprD + neurons only densely project to outer edge of Sp5C. In addition, we further determined the ascending pathway of the TG neurons. Taken together, our study demonstrates the peripheral and central projection pattern of mechanosensory neurons in the TG, which provides a basis for the future functional studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Background/aims: The incidence of steatotic liver disease (SLD) is increasing across all age groups as the incidence of obesity increases worldwide. The existing noninvasive prediction models for SLD require laboratory tests or imaging and perform poorly in the early diagnosis of infrequently screened populations such as young adults and individuals with healthcare disparities. We developed a machine learning-based point-of-care prediction model for SLD that is readily available to the broader population with the aim of facilitating early detection and timely intervention and ultimately reducing the burden of SLD., Methods: We retrospectively analyzed the clinical data of 28,506 adults who had routine health check-ups in South Korea from January to December 2022. A total of 229,162 individuals were included in the external validation study. Data were analyzed and predictions were made using a logistic regression model with machine learning algorithms., Results: A total of 20,094 individuals were categorized into SLD and non-SLD groups on the basis of the presence of fatty liver disease. We developed three prediction models: SLD model 1, which included age and body mass index (BMI); SLD model 2, which included BMI and body fat per muscle mass; and SLD model 3, which included BMI and visceral fat per muscle mass. In the derivation cohort, the area under the receiver operating characteristic curve (AUROC) was 0.817 for model 1, 0.821 for model 2, and 0.820 for model 3. In the internal validation cohort, 86.9% of individuals were correctly classified by the SLD models. The external validation study revealed an AUROC above 0.84 for all the models., Conclusions: As our three novel SLD prediction models are cost-effective, noninvasive, and accessible, they could serve as validated clinical tools for mass screening of SLD.

Background/aims: Fibronectin (FN) has recently been identified as being overexpressed in patients with hepatocellular carcinoma (HCC) and deemed a promising biomarker of vascular invasion. The aim of this study was to examine the patterns of FN expression in HCC cells and their clinicopathological significance, such as their association with vascular invasion and angiogenesis patterns., Methods: Immunohistochemical analysis of FN was conducted using tissue microarrays from 258 surgically resected HCCs and matched nontumorous liver tissues. Three distinct FN expression patterns were observed: cytoplasmic, membranous, and sinusoidal. Moderate or strong expression was considered FN-positive., Results: Cytoplasmic or sinusoidal FN expression was significantly more common in HCC cells than in the adjacent liver tissue (p<0.001). FN expression was detected in the membranes of HCC cells and absent in nonneoplastic hepatocytes (p<0.001). Overall survival and disease-free survival in patients with HCC cells with membranous FN expression were significantly shorter than those in patients without membranous FN expression. Membranous FN expression in HCC was significantly associated with high serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (PIVKA-II) levels, infiltrative gross type, poor Edmondson-Steiner grade, major vessel invasion, microvascular invasion, macrotrabecular massive subtype, advanced T stage, and vessel-encapsulating tumor cluster pattern. Sinusoidal pattern of FN expression in HCC was significantly associated with high serum AFP and PIVKA-II levels, infiltrative gross type, large tumor size, microvascular invasion, macrotrabecular massive subtype, and vessel-encapsulating tumor cluster patterns., Conclusions: Evaluating FN expression in HCC cells may be useful for identifying aggressive cases of HCC with vascular invasion via biopsy.

Background: Previous studies have explored the differences in gut microbiota (GM) between individuals with autism spectrum disorder (ASD) and neurotypical controls. However, factors such as diet, lifestyle, and environmental exposure influence GM, leading to significant variability, even among neurotypical individuals. Comparing the GM of ASD individuals with neurotypical siblings, who share similar genes and living conditions, may offer better insights into the GM mechanisms associated with ASD. Therefore, this study aims to analyze the GM composition in ASD by comparing it to that of neurotypical siblings, potentially identifying microbiota that influence ASD., Methods: We explored electronic databases up to July 2024, including EBSCOhost, PubMed, ScienceDirect, Web of Science, and Scopus. Meta-analysis using RevMan 5.4 assessed the relative abundance (RA) of gut bacteria from 8 phyla and 4 genera in ASD individuals and neurotypical siblings., Results: Eight studies were included, involving 248 people with ASD and 197 neurotypical siblings. Significant but unstable differences were observed in the RA of Bacteroidetes, Firmicutes, and Fusobacteria. No significant differences were found in the RA of Proteobacteria, Cyanobacteria, Actinobacteria, Verrucomicrobia, Tenericutes, or Bacteroides, Roseburia, Sutterella, Bifidobacterium., Conclusions: GM composition in ASD individuals closely resembles that of neurotypical siblings, with only a few unstable differences. This suggests that other crucial bacteria or certain interacting environmental factors play a role. Further studies are needed to gather stronger evidence to uncover the differences in GM and their mechanisms in ASD people., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

The objective of this review is to evaluate the contributions of Artificial Intelligence (AI) to Assisted Reproductive Technologies (ART), focusing on its role in enhancing the processes and outcomes of fertility treatments. This study analyzed 48 relevant articles to assess the impact of AI on various aspects of ART, including treatment efficacy, process optimization, and outcome prediction. The effectiveness of different machine learning paradigms-supervised, unsupervised, and reinforcement learning-in improving ART-related procedures was particularly examined. The findings indicate that AI technologies significantly enhance ART processes by refining tasks such as embryo and sperm analysis and facilitating personalized treatment plans based on predictive modeling. Notable improvements were observed in the accuracy of diagnosing and predicting successful outcomes in fertility treatments. AI-driven models provided more precise forecasts of the optimal timing for clinical interventions such as egg retrieval and embryo transfer, which are critical to the success of ART cycles. The integration of AI into ART represents a transformative advancement, substantially improving the precision and efficiency of fertility treatments. The continuous evolution of AI methodologies is likely to further revolutionize this field, enabling more tailored and successful treatment approaches. AI is becoming an indispensable tool in reproductive medicine, enhancing both the effectiveness of treatments and the clinical decision-making process. This review underscores the potential of AI to act as a catalyst for innovative solutions in the optimization of ART., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

There is an increasing demand to boost photosynthesis in rice to increase yield potential. Chloroplasts are the site of photosynthesis, and increasing their number and size is a potential route to elevate photosynthetic activity. Notably, bundle sheath cells do not make a significant contribution to overall carbon fixation in rice, and thus, various attempts are being made to increase chloroplast content specifically in this cell type. In this study, we developed and applied a deep learning tool, Chloro-Count, and used it to quantify chloroplast dimensions in bundle sheath cells of OsHAP3H gain- and loss-of-function mutants in rice. Loss of OsHAP3H increased chloroplast occupancy in bundle sheath cells by 50%. When grown in the field, mutants exhibited increased numbers of tillers and panicles. The implementation of Chloro-Count enabled precise quantification of chloroplasts in loss- and gain-of-function OsHAP3H mutants and facilitated a comparison between 2D and 3D quantification methods. Collectively, our observations revealed that a mechanism operates in bundle sheath cells to restrict chloroplast occupancy as cell dimensions increase. That mechanism is unperturbed in Oshap3H mutants but loss of OsHAP3H function leads to an increase in chloroplast numbers. The use of Chloro-Count also revealed that 2D quantification is compromised by the positioning of chloroplasts within the cell., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Ginsenosides, active compounds derived from Panax ginseng, exhibit promising potential in enhancing physical performance. This study investigates the impact of UG0712 (UG), a novel ginsenoside compound, on endurance capacity, body weight, organ weights, blood parameters, and specific transcriptomic changes in liver and muscle tissues using a C57BL/6N mouse model. The mice received UGs orally at three doses: UG50 (50 mg/kg), UG100 (100 mg/kg), and UG200 (200 mg/kg) for a specified duration. Endurance capacity, physiological parameters, and transcriptome signatures in liver and muscle tissues were assessed. UG administration significantly improved time to exhaustion, with UG50 and UG200 showing substantial enhancements. Body and organ weights exhibited no notable differences, suggesting a lack of adverse effects. Biochemical markers, except for decreased creatine kinase levels in the UG100 group, showed no significant variations. Transcriptome analysis revealed limited group separation and dose-dependent patterns. The UG100 group displayed significant enrichment in lipid metabolism and muscle-related terms. Identified dose-dependent improvements in endurance capacity highlight UGs' potential as supplements. The absence of adverse effects on body and organ weights, along with positive effects on biochemical markers, supports their safety. Despite limited dose-dependent patterns in transcriptomic analyses, the UG100 group showcased significant enrichment in pathways related to muscle and lipid metabolism. These findings offer valuable insights for athletes and aging individuals seeking to enhance physical performance, warranting further exploration into UG effects' on molecular mechanisms.

Objectives: To explore the knowledge, attitudes, behaviors, and self-efficacy of geriatric nurses regarding Advance Care Planning (ACP) for older adults., Methods: Cross-sectional study of 281 geriatric nurses in a Northern Taiwan teaching hospital using ACP knowledge, attitudes, actions, and self-efficacy scales., Results: Nurses showed slightly insufficient ACP knowledge and self-efficacy, positive attitudes, and neutral behaviors. ACP attitudes (β = 0.11, p = 0.02) and self-efficacy (β = -0.37, p < 0.001) significantly correlated with behaviors. The nurses of the medical ward demonstrated more positive ACP behaviors than surgical ward nurses (β = 0.12, p = 0.02). The model explained 48.6 % of variance in ACP behaviors., Conclusions: Enhance nurses' ACP self-efficacy through professional training and experiential learning programs, particularly for surgical ward nurses and those without hospice care consent experience. This can improve nurses' confidence in discussing care plans with patients and families, ensuring better end-of-life care quality., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Flooding is a widespread natural disaster that causes tremendous yield losses of global food production. Rice is the only cereal capable of growing in aquatic environments. Direct seeding by which seedlings grow underwater is an important cultivation method for reducing rice production cost. Hypoxic germination tolerance and root growth in waterlogged soil are key traits for rice adaptability to flooded environments. Alternative oxidase (AOX) is a non-ATP-producing terminal oxidase in the plant mitochondrial electron transport chain, but its role in hypoxia tolerance had been unclear. We have discovered that AOX1a is necessary and sufficient to promote germination/coleoptile elongation and root development in rice under flooding/hypoxia. Hypoxia enhances endogenous H 2 O 2 accumulation, and H 2 O 2 in turn activates an ensemble of regulatory genes including AOX1a to facilitate the conversion of deleterious reactive oxygen species to H 2 O 2 in rice under hypoxia. We show that AOX1a and H 2 O 2 act interdependently to coordinate three key downstream events, that is, glycolysis/fermentation for minimal ATP production, root aerenchyma development and lateral root emergence under hypoxia. Moreover, we reveal that ectopic AOX1a expression promotes vigorous root and plant growth, and increases grain yield under regular irrigation conditions. Our discoveries provide new insights into a unique sensor-second messenger pair in which AOX1a acts as the sensor perceiving low oxygen tension, while H 2 O 2 accumulation serves as the second messenger triggering downstream root development in rice against hypoxia stress. This work also reveals AOX1a genetic manipulation and H 2 O 2 pretreatment as potential targets for improving flooding tolerance in rice and other crops., (© 2024 The Author(s). Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Aims: The frequency of CTNNB1 mutation, one of the most frequent genetic events in hepatocellular carcinoma (HCC), is lower in Asian countries and in hepatitis B virus (HBV)-related HCCs. In this study, we evaluated the prevalence and types of CTNNB1-mutation in HBV-related HCC and correlated the molecular status with the histomorphological and immunohistochemical features., Methods and Results: A total of 108 consecutive cases of treatment-naïve, surgically resected HBV-related HCCs were selected. Targeted sequencing for CTNNB1 exons 3, 7 and 8 was performed, and the results were correlated with the expression pattern of glutamine synthetase (GS), nuclear β-catenin expression status and the histomorphological characteristics of the tumour. CTNNB1 mutations were identified in 13% of HBV-related HCCs; of these cases, mutations were found in D32-S37 (7%), T41 (4%) and S45 (2%) of exon 3. None of the HCCs demonstrated alterations in exons 7 and 8. CTNNB1 mutation was strongly associated with diffuse strong GS expression (P < 0.001), nuclear β-catenin expression (P < 0.001) and the classic CTNNB1 morphology (P = 0.038). Diffuse strong GS expression was observed in 78.6% of the CTNNB1-mutated HCCs, and nuclear β-catenin expression was identified in 64.3% of these cases. The classic CTNNB1 morphology was observed in 57% of all CTNNB1-mutated HCCs. Furthermore, programmed death-ligand 1 (PD-L1) was less frequently expressed in HCCs with classic CTNNB1 morphology., Conclusions: CTNNB1 mutation was observed in 13% of HBV-related HCCs in this Korean cohort, and was associated with diffuse strong GS expression, nuclear β-catenin expression and classic CTNNB1 morphology., (© 2024 John Wiley & Sons Ltd.)

Metabolic dysfunction-associated steatohepatitis (MASH) is a form of chronic liver inflammation associated with metabolic syndrome, such as obesity and a major cause of hepatocellular carcinoma (HCC). Multi-biotics, a soymilk fermented with lactic acid bacteria, are known to alleviate obesity by lowering lipid profile. This study aimed to establish and characterize mouse organoids derived from MASH-related HCC models to evaluate drug responses, particularly focusing on Lenvatinib resistance. Organoids were developed using mouse liver tissues subjected to a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) to mimic MASH-related HCC. The study evaluated the effect of multi-biotics, a fermented product, on tumor regression and drug sensitivity. While multi-biotics did not reduce tumor burden, they enhanced the response to Lenvatinib. Additionally, repeated treatment with Lenvatinib led to the development of drug-resistant organoids. Transcriptomic analysis of these resistant organoids identified key pathways related to KRAS signaling, inflammation, and epithelial-mesenchymal transition (EMT), revealing potential targets for overcoming Lenvatinib resistance. This study provides valuable insights into MASH-related HCC progression and drug resistance, offering a model for further therapeutic research., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Despite numerous efforts to develop FGFR inhibitors for cancer treatment, the widespread clinical application of currently available FGFR inhibitors has been significantly limited due to the serious side effects caused by poor selectivity and resistance. PROTAC technology, a method for protein degradation, has shown notable advantages over conventional inhibitors. In our study, we coupled Erdafitinib, a pan-FGFR inhibitor, with a CRBN binder to synthesize and identify an effective FGFR2 degrader, N5. Our findings demonstrated that N5 displayed notable specificity for FGFR2 and outstanding enzyme inhibitory capabilities, achieving an IC 50 value of 0.08 nM against FGFR2, and strong antiproliferative activity, maintaining an inhibitory rate above 50% on gastric cancer cells at a concentration of 0.17 nM. Mechanistically, N5 induced gastric cancer cell cycle arrest at the G0/G1 phase and apoptosis by decreasing the levels of FGFR downstream proteins. Moreover, N5 demonstrated favorable pharmacokinetic characteristics with a bioavailability of 74.8% when administered intraperitoneally and effectively suppressed the growth of SNU16 xenograft tumors, exhibiting greater potency compared to the parental inhibitor Erdafitinib. This study lays the groundwork for developing and potentially applying therapeutic agents targeting FGFR2 degradation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Cadmium (Cd) is a detrimental heavy metal propagated from soil to the food chain via plants, posing a great risk to human health upon consumption. Despite the understanding of Cd tolerance mechanisms in plants, whether and how plants actively respond to Cd and in turn restrict its uptake and accumulation remain elusive. Here, we identify a cell wall-associated receptor-like kinase 4 (WAKL4) involved in specific tolerance to Cd stress. We show that Cd rapidly and exclusively induces WAKL4 accumulation by promoting WAKL4 transcription and blocking its vacuole-dependent proteolysis in roots. The accumulated WAKL4 next interacts with and phosphorylates the Cd transporter NRAMP1 at Tyr488, leading to the enhanced ubiquitination and vacuole-dependent degradation of NRAMP1, and consequently reducing Cd uptake. Our findings therefore uncover a mechanism conferred by the WAKL4-NRAMP1 module that enables plants to actively respond to Cd and limit its uptake, informing the future molecular breeding of low Cd accumulated crops or vegetables., (© 2024. The Author(s).)

While mindfulness has demonstrated extensive benefits across diverse populations, research on its integration as a formal course and its effects on subjective well-being (SWB), particularly among Taiwanese university students, remains limited. This pilot study examined changes in SWB among 85 Taiwanese university students (61 males, 24 females) following an 8-week Mindfulness-Based Cognitive Therapy for Life (MBCT-L) course. Participants included 38 lower-grade (pre-internship) and 47 senior (post-internship) students. SWB was measured using the 29-item Oxford Happiness Questionnaire (OHQ), rated on a 6-point Likert scale, and administered before and after the intervention. Results revealed a significant increase in students' overall SWB scores from 3.69 to 3.92 post-intervention. Although females initially exhibited higher baseline SWB compared to males, no significant sex differences were observed after the course. Score discrepancies between pre- and post-test stages varied across sex and internship status, indicating differential impacts of the MBCT-L course on distinct demographic groups. Additionally, this study validated the reliability of the short version of the OHQ (8 items) for use in similar research contexts. By conducting a formal MBCT-L course for Taiwanese university students, this study provides valuable empirical evidence, contributing to the cross-cultural understanding of mindfulness-based interventions and their effects on SWB.

Background/objectives: There is growing interest in herbal medicines for managing age-related diseases, such as Alzheimer's and Parkinson's. Safflower seeds ( Carthamus tinctorius L. seeds, CTS) and dandelions ( Taraxacum coreanum , TC) are widely used to treat bone- or inflammation-related diseases in Oriental countries. This study investigated the protective effect of the CTS-TC combination on scopolamine (Sco)-induced memory deficits through inflammatory response and cholinergic function. Moreover, marker components such as serotonin, N -( p -coumaroyl) serotonin, N -feruloylserotonin, chlorogenic acid, and chicoric acid in the CTS-TC combination were analyzed for their potential benefits on memory function., Materials/methods: Water extracts of CTS, TC, and the CTS-TC combination at various ratios (4:1, 1:1, and 1:4) (100 mg/kg) were orally administered to mice for 14 days. Sco (1 mg/kg) was intraperitoneally injected into the mice before each behavioral test. T-maze and novel object recognition tests were conducted to monitor behavioral changes after the treatment. Western blotting was performed to detect protein expression. In addition, the presence of 5 biomarkers, serotonin, N -( p -coumaroyl) serotonin, N -feruloylserotonin, chlorogenic acid, and chicoric acid, was analyzed using high-performance liquid chromatography (HPLC)., Results: Behavioral tests showed that the CTS-TC combination enhanced memory function in Sco-injected mice. Inflammation-related proteins (inducible nitric oxide synthase, cyclooxygenase-2, and glial fibrillary acidic protein) were downregulated after treatment with the CTS-TC combination. The acetylcholinesterase protein expression was also downregulated. HPLC analysis revealed that N -feruloylserotonin and chicoric acid were the predominant components, followed by N -( p -coumaroyl) serotonin, chlorogenic acid, and serotonin., Conclusion: These findings suggest that the CTS-TC combination protects against Sco-induced memory deficits by inhibiting inflammatory responses and cholinergic dysfunction. N -feruloylserotonin and chicoric acid, along with N -( p -coumaroyl) serotonin, chlorogenic acid, and serotonin, might be biomarkers for the CTS-TC combination, and their effects on memory protection warrant further study., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2024 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: This study aimed to examine whether repeated measurements on noninvasive fibrosis scores during follow-up improve long-term nonalcoholic fatty liver disease (NAFLD) outcome prediction., Methods: A cohort study of 2,280 NAFLD patients diagnosed at the Seoul National University Hospital from 2001 to 2015 was conducted. Multivariable Cox regression models with baseline and designated time-point measurements of the fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) were used to assess the association between these scores and overall mortality, liver-related outcomes, and cardiovascular events., Results: Higher baseline NFS (high versus low probability for advanced fibrosis groups) was associated with higher risk of mortality (adjusted hazard ratio (aHR), (95% confidence interval (CI)), 2.80, [1.39-5.63]) and liver-related outcomes (3.70, [1.27-10.78]). Similar findings were observed for the association of baseline FIB-4 with mortality (2.49, [1.46-4.24]) and liver-related outcomes (11.50, [6.17-21.44]). In models considering designated time-point measurements of the scores, stronger associations were noted. For NFS, a higher time-point measurement was associated with a significantly higher risk of mortality (3.01, [1.65-5.49]) and liver-related outcomes (6.69, [2.62-17.06]). For FIB-4, higher time-point measurements were associated with significantly higher mortality (3.01, [1.88-4.82]) and liver-related outcomes (13.26, [6.89-25.53]). An annual increase in FIB-4 (2.70, [1.79-4.05]) or NFS (4.68, [1.52-14.44]) was associated with an increased risk of liver-related outcomes. No association between NFS/FIB-4 and risk of cardiovascular events was observed in both models., Conclusions: Higher aHRs describing the associations of FIB-4/NFS with overall mortality and liver-related outcomes were observed in the models that included designated time-point measurements of the scores. In addition to the baseline measurement, a routine monitoring on these scores may be important in predicting prognosis of NAFLD patients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Sung Won Chung et al.)

Background: The association between nonalcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) has been inconsistent, and the impact of hepatic fibrosis on this relationship remains uncertain. We investigated the association between NAFLD and the risk of new-onset AF across different age groups., Methods: A total of 3,179,582 participants from the 2009 Korean National Health Screening Program were divided into five groups based on NAFLD status: no NAFLD (fatty liver index [FLI] < 30); grade 1 NAFLD without advanced fibrosis (FLI 30-59 & BARD < 2); grade 1 NAFLD with advanced fibrosis (FLI 30-59 & BARD ≥ 2); grade 2 NAFLD without advanced fibrosis (FLI ≥ 60 & BARD < 2); and grade 2 NAFLD with advanced fibrosis (FLI ≥ 60 & BARD ≥ 2). The primary outcome was incident AF., Results: During the median follow-up of 9.3 years, 62,542 patients were diagnosed with new-onset AF. In the age- and sex-adjusted model, the risk of new-onset AF increased across NAFLD grades and fibrosis categories: grade 1 NAFLD without advanced fibrosis (hazard ratio [HR] 1.120, 95% confidence interval [CI]: 1.081-1.161); grade 1 NAFLD with advanced fibrosis (HR 1.275, 95% CI 1.251-1.300); grade 2 NAFLD without advanced fibrosis (HR 1.305, 95% CI: 1.252-1.360); and grade 2 NAFLD with advanced fibrosis (HR 1.627, 95% CI: 1.586-1.670). In the multivariate model, the excess risk of AF in patients with NAFLD and advanced fibrosis remained significant, even in participants aged 20-39 years., Conclusion: Patients with NAFLD had a higher risk of new-onset AF, which increased progressively with NAFLD severity, particularly in those aged 20-29 years., (© 2024. The Author(s).)

Background: The efficacy and necessity of prophylactic antibiotics in clean and clean-contaminated surgery remains controversial., Methods: The studies were screened and extracted using databases including PubMed, Embase, Cochrane Library, Web of Science, and Clinical Trials.gov according to predefined eligibility criteria. Randomized controlled trials (RCTs) comparing the effect of preoperative and postoperative prophylactic antibiotic use on the incidence of surgical site infections (SSIs) in patients undergoing any clean or clean-contaminated surgery., Results: A total of 16 189 participants in 48 RCTs were included in the primary meta-analysis following the eligibility criteria. The pooled odds ratio (OR) for SSI with antibiotic prophylaxis versus placebo was 0.60 (95% CI: 0.53-0.68). The pooled OR among gastrointestinal, oncology, orthopedics, neurosurgery, oral, and urology surgery was 3.06 (95% CI: 1.05-8.91), 1.16 (95% CI: 0.89-1.50), 2.04 (95% CI: 1.09-3.81), 3.05 (95% CI: 1.25-7.47), 3.55 (95% CI: 1.78-7.06), and 2.26 (95% CI: 1.12-4.55), respectively. Furthermore, the summary mean difference (MD) for patients' length of hospitalization was -0.91 (95% CI: -1.61, -0.16). The results of sensitivity analyses for all combined effect sizes showed good stability., Conclusion: Antibiotics are both effective, safe, and necessary in preventing surgical wound infections in clean and clean-contaminated procedures, attributed to their reduction in the incidence of surgical site infections as well as the length of patient hospitalization., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Aims: No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes., Approach and Results: Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses., Conclusions: Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background & Aims: The risk of hepatocellular carcinoma (HCC) and hepatic decompensation persists after hepatitis B surface antigen (HBsAg) seroclearance. This study aimed to develop and validate a machine learning model to predict the risk of liver-related outcomes (LROs) following HBsAg seroclearance., Methods: A total of 4,787 consecutive patients who achieved HBsAg seroclearance between 2000 and 2022 were enrolled from six centers in South Korea and a territory-wide database in Hong Kong, comprising the training (n = 944), internal validation (n = 1,102), and external validation (n = 2,741) cohorts. Three machine learning-based models were developed and compared in each cohort. The primary outcome was the development of any LRO, including HCC, decompensation, and liver-related death., Results: During a median follow-up of 55.2 (IQR 30.1-92.3) months, 123 LROs were confirmed (1.1%/person-year) in the Korean cohort. The model with the best predictive performance in the training cohort was selected as the final model (designated as PLAN-B-CURE), which was constructed using a gradient boosting algorithm and seven variables (age, sex, diabetes, alcohol consumption, cirrhosis, albumin, and platelet count). Compared to previous HCC prediction models, PLAN-B-CURE showed significantly superior accuracy in the training cohort (c-index: 0.82 vs. 0.63-0.70, all p <0.001; area under the receiver-operating characteristic curve: 0.86 vs. 0.62-0.72, all p <0.01; area under the precision-recall curve: 0.53 vs. 0.13-0.29, all p <0.01). PLAN-B-CURE showed a reliable calibration function (Hosmer-Lemeshow test p >0.05) and these results were reproduced in the internal and external validation cohorts., Conclusion: This novel machine learning model consisting of seven variables provides reliable risk prediction of LROs after HBsAg seroclearance that can be used for personalized surveillance., Impact and Implications: Using large-scale multinational data, we developed a machine learning model to predict the risk of liver-related outcomes (i.e., hepatocellular carcinoma, decompensation, and liver-related death) after the functional cure of chronic hepatitis B (CHB). The new model named PLAN-B-CURE was constructed using seven variables (age, sex, alcohol consumption, diabetes, cirrhosis, serum albumin, and platelet count) and a gradient boosting machine algorithm, and it demonstrated significantly better predictive accuracy than previous models in both the training and validation cohorts. The inclusion of diabetes and significant alcohol intake as model inputs suggests the importance of metabolic risk factor management after the functional cure of CHB. Using seven readily available clinical factors, PLAN-B-CURE, the first machine learning-based model for risk prediction after the functional cure of CHB, may serve as a basis for individualized risk stratification., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Antiviral therapy (AVT) is required in patients with newly diagnosed hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), if HBV DNA is detectable. We compared the risk of recurrence according to HBV replication activity at the curative treatment of HBV-related HCC., Methods: Patients with HBV-related HCC who underwent surgical resection or radiofrequency ablation between 2013 and 2018 were enrolled in this retrospective cohort study. Patients were categorized into two groups according to HBV replication activity at the curative treatment of HBV-related HCC (group 1: patients who met the AVT indication for HBV-related HCC due to detectable HBV DNA but did not meet the AVT indication if without HCC; group 2: patients who met the AVT indication, regardless of HCC)., Results: In the entire cohort (n = 911), HCC recurred in 303 (33.3%) patients during a median follow-up of 4.7 years. After multivariate adjustment, group 2 showed a statistically similar risk of HCC recurrence (adjusted hazard ratio [aHR] = 1.18, P = 0.332) compared to that of group 1. In addition, group 2 showed statistically similar risks of early (< 2 years; aHR = 1.31) and late (≥ 2 years; aHR = 0.83) recurrence than that of group 1 (all P>0.05). Propensity score matching and inverse probability of treatment weighting analysis also yielded similar risks of HCC recurrence between the two groups (all P>0.05, log-rank tests)., Conclusions: The risk of HCC recurrence in patients who received curative treatment for newly diagnosed HBV-related HCC was similar regardless of HBV replication activity, if AVT was properly initiated., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Radiofrequency ablation (RFA) offers a minimally invasive treatment for small hepatocellular carcinoma (HCC), but it faces challenges such as high local recurrence rates. This prospective study, conducted from January 2020 to July 2022, evaluated a novel approach using a three-channel, dual radiofrequency (RF) generator with separable clustered electrodes to improve RFA's efficacy and safety. The study employed a high-power, gradual, stepwise RFA method on HCCs (≤ 4 cm), utilizing real-time ultrasound-computed tomography (CT)/magnetic resonance imaging (MRI) fusion imaging. Involving 110 participants with 116 HCCs, the study reported no major complications. Local tumor progression (LTP) and intrahepatic remote recurrence (IRR) rates were low, with promising cumulative incidences at 1, 2, and 3 years for LTP (0.9%, 3.6%, 7.0%) and IRR (13.9%, 20.5%, 31.4%). Recurrence-free survival (RFS) rates were similarly encouraging: LTP (99.1%, 96.4%, 93.0%) and IRR (86.1%, 79.5%, 68.6%). This innovative gradual, incremental high-power RFA technique, featuring a dual switching monopolar mode and three electrodes, represents an effective and safer management option for small HCCs. TRIAL REGISTRATION: clinicaltrial.gov identifier: NCT05397860, first registered on 26/05/2022., (© 2024. The Author(s).)

This study presents a framework for determining the prioritization of vaccine introduction in the National Immunization Program (NIP) of the Republic of Korea, with a focus on case examples assessed in 2021 and 2023. We describe the predefined criteria for evaluating the prioritization of vaccines in the NIP and the established process in the Republic of Korea. These criteria included disease characteristics, vaccine characteristics, rationality and efficiency of resource allocation, and the acceptance of immunization. The process of prioritizing NIP introduction involved several sequential steps: a demand survey, evidence collection, preliminary evaluation, priority evaluation, and decision making. In 2021 and 2023, 14 and 25 committee members participated in evaluating the prioritization of vaccines in the NIP, respectively. Overall, 13 and 19 NIP vaccine candidates were included in the 2021 and 2023 evaluations, respectively. Through the Delphi survey and consensus processes, the priority order was determined: vaccination against Rotavirus infection was the top priority in 2021, while Influenza 4v (for chronic disease patients) took precedence in 2023. This study demonstrates an evidence-based decision-making process within the healthcare field. The outlined approach may provide valuable guidance for policymakers in other countries seeking to prioritize the inclusion of new vaccines in their NIP.

Amylosucrase (ASase) efficiently biosynthesizes α-glucoside using flavonoids as acceptor molecules and sucrose as a donor molecule. Here, ASase from Deinococcus wulumuqiensis (DwAS) biosynthesized more naringenin α-glucoside (NαG) with sucrose and naringenin as donor and acceptor molecules, respectively, than other ASases from Deinococcus sp. The biotransformation rate of DwAS to NαG was 21.3% compared to 7.1-16.2% for other ASases. Docking simulations showed that the active site of DwAS was more accessible to naringenin than those of others. The 217th valine in DwAS corresponded to the 221 st isoleucine in Deinococcus geothermalis AS (DgAS), and the isoleucine possibly prevented naringenin from accessing the active site. The DwAS-V217I mutant had a significantly lower biosynthetic rate of NαG than DwAS. The k cat /K m value of DwAS with naringenin as the donor was significantly higher than that of DgAS and DwAS-V217I. In addition, NαG inhibited human intestinal α-glucosidase more efficiently than naringenin., Competing Interests: Declaration of competing interest All of the authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The immune checkpoint blockade represents a pivotal strategy for tumor immunotherapy. At present, various programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies have been successfully applied to tumor treatment. Additionally, numerous small molecule inhibitors of the PD-1/PD-L1 interaction have also been developed, with some advancing into clinical trials. Here, a novel PD-L1 proteolysis-targeting chimera (PROTAC) library was designed and synthesized utilizing the PD-L1 inhibitor BMS202 and the E3 ligand PG as foundational components. Among these, we identified a highly potent molecule PA8 for PD-L1 degradation in 4T1 cells (DC 50 = 0.609 μM). Significantly, compound PA8 potentially inhibits 4T1 cell growth both in vitro and in vivo . Further mechanistic studies revealed that PA8 effectively promoted the immune activation of model mice. Thus, these results suggest that PA8 could be a novel strategy for cancer immunotherapy in the 4T1 tumor model. Although PA8 exhibits weaker degradation activity in some human cancer cells, it still provides a certain basis for further research on PD-L1 PROTAC.

Different antiviral treatments for chronic hepatitis B (CHB) have been known to have different metabolic effects. This study aimed to reveal whether tenofovir alafenamide (TAF)-induced dyslipidemia and its associated outcomes are significant. This study utilized 15-year historical cohort including patients with CHB in Korea and consisted of two parts: the single-antiviral and switch-antiviral cohorts. In the single-antiviral cohort, patients were divided into four groups (entecavir [ETV]-only, tenofovir disoproxil fumarate [TDF]-only, TAF-only, and non-antiviral). Propensity score matching (PSM) and linear regression model were sequentially applied to compare metabolic profiles and estimated atherosclerotic cardiovascular disease (ASCVD) risks longitudinally. In the switch-antiviral cohort, pairwise analyses were conducted in patients who switched NAs to TAF or from TAF. In the single-antiviral cohort, body weight and statin use showed significant differences between groups before PSM, but well-balanced after PSM. Changes in total cholesterol were significantly different between groups (-2.57 mg/dL/year in the TDF-only group and +2.88 mg/dL/year in the TAF-only group; p = 0.002 and p = 0.02, respectively). In the TDF-only group, HDL cholesterol decreased as well (-0.55 mg/dL/year; p < 0.001). The TAF-only group had the greatest increase in ASCVD risk, followed by the TDF-only group and the non-antiviral group. In the switch-antiviral cohort, patients who switched from TDF to TAF had a higher total cholesterol after switching (+9.4 mg/dL/year) than before switching (-1.0 mg/dL/year; p = 0.047). Sensitivity analysis on data with an observation period set to a maximum of 3 years for NA treatment showed consistent results on total cholesterol (-2.96 mg/dL/year in the TDF-only group and +3.09 mg/dL/year in the TAF-only group; p = 0.001 and p = 0.005, respectively). Another sensitivity analysis conducted on statin-treated patients revealed no significant change in cholesterol and ASCVD risk. TAF was associated with increased total cholesterol, whereas TDF was associated with decreased total and HDL cholesterol. Both TAF and TDF were associated with increased ASCVD risks, and statin use might mitigate these risks., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Background/aims: Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment., Methods: Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders., Results: The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.01, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88-1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60-0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81-0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62-0.75, P<0.01; E-value for SHR=2.30)., Conclusion: TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.

Bone age assessment (BAA) is crucial in various fields, including legal proceedings, athletic competitions, and clinical medicine. However, the use of X-ray methods for age estimation without medical indication is subject to ethical debate, especially in forensic and athletic fields. The application of magnetic resonance imaging (MRI) with non-ionizing radiation can overcome this limitation in BAA. This study aimed to compare the application value of several MRI modalities of proximal humeral in BAA. A total of 468 patients with shoulder MRIs were retrospectively collected from a Chinese Han population aged 12-30 years (259 males and 209 females) for training and testing, including T 1 weighted MRI (T 1 WI), T 2 weighted MRI (T 2 WI), and Proton density weighted MRI (PDWI). Optimal regression models were established for age estimation, yielding mean absolute error (MAE) values below 2.0 years. The MAE values of T 1 WI were the lowest, with 1.700 years in males and 1.798 years in females. The area under the curve (AUC) and accuracy values of different MRI modalities of 16-year and 18-year thresholds were all around 0.9. For the 18-year threshold, T 1 WI outperformed T 2 WI and PDWI. In conclusion, the three MRI modalities of the proximal humerus can serve as reliable indicators for age assessment, while the T 1 WI performed better in age assessment and classification., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aim: Antiviral treatment reduces the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. However, there is a lack of high-quality evidence regarding the preventive effects of tenofovir alafenamide (TAF) on HCC. We evaluated the impact of TAF use after curative treatment on HCC recurrence., Methods: Patients who underwent surgery or radiofrequency ablation as a curative treatment for HCC were selected. Those patients who continued antiviral treatment with nucleos(t)ide analogs (NAs; entecavir [ETV] or tenofovir disoproxil fumarate [TDF]) or switched to TAF were included. The primary outcome was HCC recurrence, and the time-varying effect of NA use on HCC recurrence was analyzed using various statistical methods., Results: Among 2794 consecutive patients with chronic hepatitis B who received curative treatment for HCC, 199 subsequently switched from ETV or TDF to TAF. After a median of 3.0 years, 1303 patients (46.6%) experienced HCC recurrence. After propensity score matching (ratio 1:10), switching to TAF was not associated with an increased HCC recurrence (HR 1.00, 95% CI 0.68-1.47; p = 1.00) by time-varying Cox analysis. Switching to TAF was not associated with HCC recurrence in subgroups of NA (HR 1.06, 95% CI 0.67-1.67; p = 0.81 for TDF, and HR 1.09, 95% CI 0.51-2.33; p = 0.82 for ETV). Kaplan-Meier analysis showed comparable HCC recurrence-free survival between patients who switched to TAF and those who continued with their NA (p = 0.08). Time-varying Cox analyses in various subgroups confirmed the primary findings., Conclusions: TAF is as effective as TDF and ETV in preventing HCC recurrence after curative treatment., (© 2024 Japan Society of Hepatology.)

Advancements in anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, B1-PEG , synthesized through PEGylation of an optimized PROTAC molecule, B1 , to enhance its properties. B1-PEG is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed B1-PEG 's superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule B1 . When tested in a H3122 xenograft mouse model, B1-PEG significantly regressed tumors, underscoring its potential as a formidable candidate in targeted cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.

Background: It is unclear whether direct-acting antivirals (DAAs) treatment improves the disease burden in hepatitis C virus (HCV) infection. This study aimed to investigate the effect of DAA treatment on the reduction of disease burden in patients with HCV infection using individual participant data., Methods: This nationwide multicentre retrospective cohort study recruited patients with HCV infection from 29 tertiary institutions in South Korea. The data collection was done from medical records in each institution. The study included the untreated patients and the DAAs-treated patients and excluded those with a history of interferon-based treatments. Disease burden was the primary outcome, as represented by disability-adjusted life years (DALYs). Improvement in fibrosis after DAA treatment was assessed using APRI, FIB-4 index, and liver stiffness (LS) as assessed by transient elastography. Clinical outcomes were hepatocellular carcinoma (HCC), decompensation, and mortality., Findings: Between January 1, 2007, and February 17, 2022, data from 11,725 patients with HCV infection, 8464 (72%) of whom were treated with DAAs, were analysed. DAA treatment significantly improved APRI- (median 0.64 [interquartile range (IQR), 0.35-1.31]-0.33 [0.23-0.52], p < 0.0001), FIB-4- (median 2.42 [IQR, 1.48-4.40]-1.93 [1.31-2.97], p < 0.0001), and liver LS-based fibrosis (median 7.4 [IQR, 5.3-12.3]-6.2 [4.6-10.2] kPa, p < 0.0001). During the median follow-up period of 27.5 months (IQR, 10.6-52.4), 469 patients died (4.0%), 586 (5.0%) developed HCC, and 580 (4.9%) developed decompensation. The APRI-based DALY estimate was significantly lower in the DAA group than in the untreated group (median 4.55 vs. 5.14 years, p < 0.0001), as was the FIB-4-based DALY estimate (median 5.43 [IQR, 3.00-6.44] vs. 5.79 [3.85-8.07] years, p < 0.0001). The differences between the untreated and DAA groups were greatest in patients aged 40-60 years. In multivariable analyses, the DAA group had a significantly reduced risk of HCC, decompensation, and mortality compared with the untreated group (hazard ratios: 0.41 [95% confidence interval (CI), 0.34-0.48], 0.31 [95% CI, 0.30-0.38], and 0.22 [95% CI, 0.17-0.27], respectively; p < 0.0001)., Interpretation: Our findings suggest that DAA treatment is associated with the improvement of liver-related outcomes and a reduction of liver fibrosis-based disease burden in patients with HCV infection. However, further studies using liver biopsy are needed to clarify the effect of DAA treatment on the reduction in the exact fibrosis-based disease burden beyond noninvasive tests., Funding: The Korea Disease Control and Prevention Agency., Competing Interests: All authors declare no financial or non-financial competing interests., (© 2024 The Authors. Published by Elsevier Ltd.)

Recently, lifestyle medicine (LSM) application has shown feasibility for musculoskeletal pain patients with co-existing lifestyle-related chronic diseases. This study describes early results of a LSM program for musculoskeletal patients with goals to optimize health prior to orthopedic surgery. Fifty-four patients (age: 61 ± 11 years; 39 [72%] females) completed the program from 3/8/22-12/1/23. Data included patient goals, utilization, goal attainment, and patient outcomes. Most patients (41/54 [76%]) enrolled with established surgical dates. Mean BMI was 43.2 ± 5.3 kg/m 2 , and 89% had ≥2 lifestyle-related chronic diseases. The majority reported impaired sleep (79%) and zero cumulative minutes of physical activity/week (57%). Mean program duration was 13 ± 8 weeks involving 5 ± 4 visits with members of the interprofessional team. Fifty-two (96%) patients successfully attained pre-program goals, and 49/54 (91%) met their surgical goal. Of the patients enrolled without surgical dates, 11/13 (85%) optimized their health and proceeded to surgery. Forty-two (78%) patients reported decreases in weight and BMI, averaging 11 ± 7 lbs and 1.8 ± 1.3 kg/m 2 , respectively. Rates of improvement in pain, PROMIS-10 physical and mental health, and PHQ-4 were 52%, 37%, 45%, and 47%, respectively. These data demonstrate the feasibility and effectiveness of a LSM program to address whole-person health optimization and enable orthopedic patients to improve lifestyle behaviors and proceed to orthopedic surgery., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 The Author(s).)

Background: Itch is the most common symptom of atopic dermatitis (AD) and significantly decreases the quality of life. Skin microbiome is involved in AD pathogenesis, whereas its role in the regulation of itch remains elusive. In this study, we aimed to investigate the effects of skin microbial metabolite propionate on acute and chronic pruritus and to explore the mechanism., Methods: Using various mouse models of itch, the roles of propionate were explored by behavioral tests and histopathology/immunofluorescent analysis. Primary-cultured dorsal root ganglion neurons and HEK293 cells expressing recombinant human TRP channels were utilized for in vitro calcium imaging/in vivo miniature two-photon imaging in combination with electrophysiology and molecular docking approaches for investigation of the mechanism., Results: Propionate significantly alleviated itch and alloknesis in various mouse models of pruritus and AD and decreased the density of intraepidermal nerve fibers. Propionate reduced the responsiveness of dorsal root ganglion neurons to pruritogens in vitro, attenuated the hyper-excitability in sensory neurons in MC903-induced AD model, and inhibited capsaicin-evoked hTRPV1 currents (IC 50  = 20.08 ± 1.11 μM) via interacting with the vanilloid binding site. Propionate also decreased the secretion of calcitonin gene-related peptide by nerves in MC903-induced AD mouse model, which further attenuated itch and skin inflammation., Conclusion: Our study revealed a protective effect of propionate against persistent itch through direct modulation of sensory TRP channels and neuropeptide production in neurons. Regulation of itch via the skin microbiome might be a novel strategy for the treatment of AD., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Transforaminal epidural steroid injection (TFESI) is commonly used for radicular pain, but can lead to an unintentional injection into the retrodural Space of Okada (RSO), an extradural space located dorsal to the ligamentum flavum, instead of the epidural space., Objectives: To determine the prevalence and describe the fluoroscopic imaging features of an unintentional injection into the RSO during a TFESI and to review the history of injections into the RSO., Study Design: Observational study and original research., Setting: This work was conducted at Jeju National University School of Medicine, Jeju, Republic of Korea., Methods: A total of 5,429 lumbar TFESIs performed from the September 1, 2018 through October 31, 2021 were analyzed for unintentional RSO injections using fluoroscopic-guided contrast medium patterns., Results: The rate of unintentional injection into the RSO was 0.20% (11 incidents). Contrast medium patterns in the RSO had a sigmoid or ovoid shape confined to the affected facet joint, or a butterfly-shaped pattern extending into the contralateral facet joint, but rarely extending beyond the upper or lower level., Limitation: The rarity of unintentional injection into the RSO prevented a randomized controlled study design., Conclusions: Careful fluoroscopic examination of contrast medium patterns during lumbar TFESI is crucial to identify needle placement in the RSO. If detected, the procedure can be corrected by slightly advancing the needle into the foramen.

Objective: To evaluate the therapeutic outcomes of no-touch radiofrequency ablation (NT-RFA) using twin cooled wet (TCW) electrodes in patients experiencing recurrent hepatocellular carcinoma (HCC) after undergoing locoregional treatments., Materials and Methods: We conducted a prospective, single-arm study of NT-RFA involving 102 patients, with a total of 112 recurrent HCCs (each ≤ 3 cm). NT-RFA with TCW electrodes was implemented under the guidance of ultrasonography (US)-MR/CT fusion imaging. If NT-RFA application proved technically challenging, conversion to conventional tumor puncture RFA was permitted. The primary metric for evaluation was the mid-term cumulative incidence of local tumor progression (LTP) observed post-RFA. Cumulative LTP rates were estimated using the Kaplan-Meier method. Multivariable Cox proportional hazard regression was used to explore factors associated with LTP. Considering conversion cases from NT-RFA to conventional RFA, intention-to-treat (ITT; including all patients) and per-protocol (PP; including patients not requiring conversion to conventional RFA alone) analyses were performed., Results: Conversion from NT-RFA to conventional RFA was necessary for 24 (21.4%) out of 112 tumors. Successful treatment was noted in 111 (99.1%) out of them. No major complications were reported among the patients. According to ITT analysis, the estimated cumulative incidences of LTP were 1.9%, 6.0%, and 6.0% at 1, 2, and 3 years post-RFA, respectively. In PP analysis, the cumulative incidence of LTP was 0.0%, 1.3%, and 1.3% at 1, 2, and 3 years, respectively. The number of previous locoregional HCC treatments (adjusted hazard ratio [aHR], 1.265 per 1 treatment increase; P = 0.004), total bilirubin (aHR, 7.477 per 1 mg/dL increase; P = 0.012), and safety margin ≤ 5 mm (aHR, 9.029; P = 0.016) were independently associated with LTP in ITT analysis., Conclusion: NT-RFA using TCW electrodes is a safe and effective treatment for recurrent HCC, with 6.0% (ITT analysis) and 1.3% (PP analysis) cumulative incidence of LTP at 2 and 3-year follow-ups., Competing Interests: Jeong Min Lee, who hold respective positions on the Editorial Board Member of the Korean Journal of Radiology, were not involved in the editorial evaluation or decision to publish this article and reports grants from Philips Healthcare, grants from GE Healthcare, grants from CMS, grants from Guerbet, grants from Samsung Medison, grants from Bracco, personal fees from Bayer Healthcare, personal fees from Siemens Healthineer, personal fees from Samsung Medison, personal fees from Guerbet, outside the submitted work. The remaining author has declared no conflicts of interest., (Copyright © 2024 The Korean Society of Radiology.)

Background: There exists a paucity of data regarding whether gamma-glutamyl transferase is associated with disease-specific mortality in patients with type 2 diabetes mellitus. This study aimed to investigate the association of serum gamma-glutamyl transferase levels with all-cause and disease-specific mortality in patients with diabetes mellitus using a Korean nationwide health-screening database., Methods: A total of 9 687 066 patients without viral hepatitis or liver cirrhosis who underwent health examination in 2009 were included. These patients were divided into four groups according to sex-specific quartiles of serum gamma-glutamyl transferase levels., Results: During a median follow-up period of 8.1 years, 222 242 deaths were identified. The all-cause mortality rate increased as the serum gamma-glutamyl transferase levels became higher (highest quartile vs lowest quartile: hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.55-1.59; p for trend <.001). Similar trends were observed for cardiovascular disease (HR, 1.57; 95% CI, 1.53-1.62), ischemic heart disease (HR, 1.40; 95% CI, 1.33-1.48), and stroke (HR, 1.72; 95% CI, 1.60-1.85) in the highest quartile, as compared with the lowest quartile (p for trend <.001). As the gamma-glutamyl transferase quartiles became higher, mortality rates related to cancer (HR, 1.56; 95% CI, 1.52-1.60), liver disease (HR, 9.42; 95% CI, 8.81-10.07), respiratory disease (HR, 1.55; 95% CI, 1.49-1.62), and infectious disease (HR, 1.73; 95% CI, 1.59-1.87) also increased in the highest quartile, compared with the lowest quartile (p for trend <.001)., Conclusions: Serum gamma-glutamyl transferase levels may be useful for the risk assessment of all-cause and disease-specific mortality among patients with type 2 diabetes mellitus., (© 2024 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Root architecture and function are critical for plants to secure water and nutrient supply from the soil, but environmental stresses alter root development. The phytohormone jasmonic acid (JA) regulates plant growth and responses to wounding and other stresses, but its role in root development for adaptation to environmental challenges had not been well investigated. We discovered a novel JA Upregulated Protein 1 gene (JAUP1) that has recently evolved in rice and is specific to modern rice accessions. JAUP1 regulates a self-perpetuating feed-forward loop to activate the expression of genes involved in JA biosynthesis and signalling that confers tolerance to abiotic stresses and regulates auxin-dependent root development. Ectopic expression of JAUP1 alleviates abscisic acid- and salt-mediated suppression of lateral root (LR) growth. JAUP1 is primarily expressed in the root cap and epidermal cells (EPCs) that protect the meristematic stem cells and emerging LRs. Wound-activated JA/JAUP1 signalling promotes crosstalk between the root cap of LR and parental root EPCs, as well as induces cell wall remodelling in EPCs overlaying the emerging LR, thereby facilitating LR emergence even under ABA-suppressive conditions. Elevated expression of JAUP1 in transgenic rice or natural rice accessions enhances abiotic stress tolerance and reduces grain yield loss under a limited water supply. We reveal a hitherto unappreciated role for wound-induced JA in LR development under abiotic stress and suggest that JAUP1 can be used in biotechnology and as a molecular marker for breeding rice adapted to extreme environmental challenges and for the conservation of water resources., (© 2024 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Background: Gut microbial dysbiosis is implicated in chronic liver disease and hepatocellular carcinoma (HCC), but the role of microbiomes from various body sites remains unexplored. We assessed disease-specific alterations in the urinary microbiome in HCC patients, investigating their potential as diagnostic biomarkers., Methods: We performed cross-sectional analyses of urine samples from 471 HCC patients and 397 healthy controls and validated the results in an independent cohort of 164 HCC patients and 164 healthy controls. Urinary microbiomes were analyzed by 16S rRNA gene sequencing. A microbial marker-based model distinguishing HCC from controls was built based on logistic regression, and its performance was tested., Results: Microbial diversity was significantly reduced in the HCC patients compared with the controls. There were significant differences in the abundances of various bacteria correlated with HCC, thus defining a urinary microbiome-derived signature of HCC. We developed nine HCC-associated genera-based models with robust diagnostic accuracy (area under the curve [AUC], 0.89; balanced accuracy, 81.2%). In the validation, this model detected HCC with an AUC of 0.94 and an accuracy of 88.4%., Conclusions: The urinary microbiome might be a potential biomarker for the detection of HCC. Further clinical testing and validation of these results are needed in prospective studies., (© 2024. The Author(s).)

Background/aim: Atezolizumab plus bevacizumab and lenvatinib are currently available as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). However, comparative efficacy studies are still limited. This study aimed to investigate the effectiveness of these treatments in HCC patients with portal vein tumor thrombosis (PVTT)., Methods: We retrospectively included patients who received either atezolizumab plus bevacizumab or lenvatinib as first-line systemic therapy for HCC with PVTT. Primary endpoint was overall survival (OS), and secondary endpoints included progressionfree survival (PFS) and disease control rate (DCR) determined by response evaluation criteria in solid tumors, version 1.1., Results: A total of 52 patients were included: 30 received atezolizumab plus bevacizumab and 22 received lenvatinib. The median follow-up duration was 6.4 months (interquartile range, 3.9-9.8). The median OS was 10.8 months (95% confidence interval [CI], 5.7 to not estimated) with atezolizumab plus bevacizumab and 5.8 months (95% CI, 4.8 to not estimated) with lenvatinib (P=0.26 by log-rank test). There was no statistically significant difference in OS (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.34-1.49; P=0.37). The median PFS was similar (P=0.63 by log-rank test), with 4.1 months (95% CI, 3.3-7.7) for atezolizumab plus bevacizumab and 4.3 months (95% CI, 2.6-5.8) for lenvatinib (aHR, 0.93; 95% CI, 0.51-1.69; P=0.80). HRs were similar after inverse probability treatment weighting. The DCRs were 23.3% and 18.2% in patients receiving atezolizumab plus bevacizumab and lenvatinib, respectively (P=0.74)., Conclusion: The effectiveness of atezolizumab plus bevacizumab and lenvatinib was comparable for the treatment of HCC with PVTT.

Background and Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses heterogeneous fatty liver diseases associated with metabolic disorders. We aimed to evaluate the association between MAFLD and extrahepatic malignancies based on MAFLD subtypes., Methods: This nationwide cohort study included 9 298 497 patients who participated in a health-screening programme of the National Health Insurance Service of Korea in 2009. Patients were further classified into four subgroups: non-MAFLD, diabetes mellitus (DM)-MAFLD, overweight/obese-MAFLD and lean-MAFLD. The primary outcome was the development of any primary extrahepatic malignancy, while death, decompensated liver cirrhosis and liver transplantation were considered competing events. The secondary outcomes included all-cause and extrahepatic malignancy-related mortality., Results: In total, 2 500 080 patients were diagnosed with MAFLD. During a median follow-up of 10.3 years, 447 880 patients (6.0%) with extrahepatic malignancies were identified. The DM-MAFLD (adjusted subdistribution hazard ratio [aSHR] = 1.13; 95% confidence interval [CI] = 1.11-1.14; p < .001) and the lean-MAFLD (aSHR = 1.12; 95% CI = 1.10-1.14; p < .001) groups were associated with higher risks of extrahepatic malignancy than the non-MAFLD group. However, the overweight/obese-MAFLD group exhibited a similar risk of extrahepatic malignancy compared to the non-MAFLD group (aSHR = 1.00; 95% CI = .99-1.00; p = .42). These findings were reproduced in several sensitivity analyses. The DM-MAFLD was an independent risk factor for all-cause mortality (adjusted hazard ratio [aHR] = 1.41; 95% CI = 1.40-1.43; p < .001) and extrahepatic malignancy-related mortality (aHR = 1.20; 95% CI = 1.17-1.23; p < .001)., Conclusion: The diabetic or lean subtype of MAFLD was associated with a higher risk of extrahepatic malignancy than non-MAFLD. As MAFLD comprises a heterogeneous population, appropriate risk stratification and management based on the MAFLD subtypes are required., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Human papillomavirus (HPV) infection is a major global disease burden and the main cause of cervical cancer. Certain HPV genotypes, with are the most common etiologic pathogens and cause a significant disease burden, are being targeted for vaccine development. However, few studies have focused on the comparative effectiveness of the bivalent HPV (2v-HPV), quadrivalent HPV (4v-HPV), and nonavalent HPV (9v-HPV) vaccines against HPV strain-specific infection. This study investigated the comparative effects of these vaccines against genotype-specific infection., Materials and Methods: We conducted a pairwise and network meta-analysis of published randomized clinical trials of HPV vaccines according to sex and HPV infection status for nine HPV genotypes (HPV 6/11/16/18/31/33/45/52/58)., Results: Overall, 10 randomized controlled trials (12 articles) were included in this study. In the network meta-analysis, no statistically significant differences were observed in the prevention of carcinogenic HPV strains (16/18/31/33/45/52/58) between the 2v-HPV and 4v-HPV vaccines in female HPV infection-naïve populations. However, the 9v-HPV vaccine showed a significantly superior effect compared with 2v-HPV and 4v-HPV vaccines in preventing HPV 31/33/45/52/58 infections. Although 2v-HPV and 4v-HPV vaccines provided some cross-protection against HPV 31/33/45/52/58 infections, the effect was significant only on HPV 31 infection. For HPV 16 and 18, neither statistically significant nor small differences were found in the prevention of HPV infection among the 2v-HPV, 4v-HPV, and 9v-HPV vaccines., Conclusion: Our study complements previous understanding of how the effect of HPV vaccines differs according to the HPV genotype. This is important because HPV genotype prevalence varies among countries. We advocate for continued efforts in vaccinating against HPV, while public health agencies should consider the difference in the vaccine effect and HPV genotype prevalence when implementing HPV vaccination in public vaccination programs., Competing Interests: No conflict of interest., (Copyright © 2024 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.)

Background: Cartilage defects are some of the most common causes of arthritis. Cartilage lesions caused by inflammation, trauma or degenerative disease normally result in osteochondral defects. Previous studies have shown that decellularized extracellular matrix (ECM) derived from autologous, allogenic, or xenogeneic mesenchymal stromal cells (MSCs) can effectively restore osteochondral integrity., Aim: To determine whether the decellularized ECM of antler reserve mesenchymal cells (RMCs), a xenogeneic material from antler stem cells, is superior to the currently available treatments for osteochondral defects., Methods: We isolated the RMCs from a 60-d-old sika deer antler and cultured them in vitro to 70% confluence; 50 mg/mL L-ascorbic acid was then added to the medium to stimulate ECM deposition. Decellularized sheets of adipocyte-derived MSCs (aMSCs) and antlerogenic periosteal cells (another type of antler stem cells) were used as the controls. Three weeks after ascorbic acid stimulation, the ECM sheets were harvested and applied to the osteochondral defects in rat knee joints., Results: The defects were successfully repaired by applying the ECM-sheets. The highest quality of repair was achieved in the RMC-ECM group both in vitro (including cell attachment and proliferation), and in vivo (including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular hyaline cartilage integrated with surrounding native tissues). Notably, the antler-stem-cell-derived ECM (xenogeneic) performed better than the aMSC-ECM (allogenic), while the ECM of the active antler stem cells was superior to that of the quiescent antler stem cells., Conclusion: Decellularized xenogeneic ECM derived from the antler stem cell, particularly the active form (RMC-ECM), can achieve high quality repair/reconstruction of osteochondral defects, suggesting that selection of decellularized ECM for such repair should be focused more on bioactivity rather than kinship., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Meju is a traditional Korean soybean brick characterized by diverse microbial communities. The microbial communities in Meju were identified at the phylum and genus levels using high-throughput sequencing. During Meju fermentation, diverse factors such as total bacterial cell numbers, moisture content, salinity, pH, enzyme activities, and free amino acids were monitored. After 30 days of fermentation, microbial adaptation and increased protease activity resulted in significant changes, including an increase in pH and alterations in free amino acid content by day 70. Bacterial community analysis revealed significant changes in Bacillus , Lactococcus , and Enterococcus levels as fermentation progressed. The decrease in pH during fermentation was influenced by lactic acid bacteria, which affected bacterial dynamics. At the end of fermentation, the fungal community was dominated by Monascus , Aspergillus , and Scopulariopsis , which affected the free amino acid levels. These results indicate that pH and moisture content may be significant factors in determining microbial communities., Competing Interests: Conflict of interestThe authors declared that they have no conflicts of interest., (© The Korean Society of Food Science and Technology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Studies have substantiated the anti-inflammatory and anti-thrombotic effects of (C. pinnatifida); however, research on its antibacterial activity using organic solvent remains limited. Therefore, in this study, we aimed to validate the antibacterial activity of C. pinnatifida as a natural extract against Enterococcus faecalis (E. faecalis), a multidrug-resistant bacterium. E. faecalis was treated with different concentrations of C. pinnatifida to determine the optimal concentration for the most effective antibacterial effect. Fifteen different concentrations were applied for 6 and 24 h. The experimental method centered on confirming antibacterial activity using colony-forming units. The experimental results demonstrated a proportional increase in antibacterial activity with elevated C. pinnatifida concentration. Notably, 99.99% and 100% antibacterial activity were observed at 10 mg/mL and 40 mg/mL concentrations, respectively. Our results suggest that C. pinnatifida holds potential as an antibacterial agent against the multidrug-resistant E. faecalis.

Purpose: This study aimed to explore the nutritional status and examine the demographic, clinical, nutritional, and psychosocial characteristics associated with malnutrition among people with liver cancer., Methods: A descriptive cross-sectional design was used. Data were collected from a convenience sample of 162 liver cancer outpatients at a tertiary university hospital. Nutritional status was evaluated using the Patient-Generated Subjective Global Assessment (PG-SGA). Self-administered structured questionnaires were administered, and medical records were reviewed for demographic, clinical, nutritional, and psychosocial characteristics., Results: Based on PG-SGA scores, 27 patients (16.7%) were classified into the malnutrition group. The stages of liver cancer, chemotherapy, physical and psychological symptom distress, global distress index, levels of alpha-fetoprotein and protein induced by vitamin K absence or antagonists, body mass index, appetite, hemoglobin and albumin levels, and depression were statistically significantly associated with malnutrition. Logistic regression model revealed that physical symptom distress, liver cancer stage, depression, and body mass index influenced statistically significantly malnutrition., Conclusions: In this study, clinical, nutritional, and psychosocial characteristics predicted malnutrition among people with liver cancer. Nurses should consider these characteristics when evaluating the nutritional status of people with liver cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Photothermal therapy is an anti-cancer strategy that induce cell death by converting light energy into heat energy. During photothermal therapy, cancer cells were treated with photothermal agents, such as indocyanine green, and irradiated with a laser. Heat stress in cancer cells results in cellular death and inflammatory responses. In the present study, we demonstrated how ex vivo photothermal (PT)-treated cells underwent immunogenic cell death. PT treatment caused significant expression of heat shock protein (HSP) 27, HSP70, and HSP90 in murine tumor cells. To evaluate the immunogenicity of heat-stressed cells, lysate from PT-treated tumor cells or water-based heated cells was pulsed to syngeneic bone-marrow-derived dendritic cells (DCs) to generate a DC-based vaccine. Administration with PT-treated tumor lysates-pulsed DC vaccine resulted in significant inhibition of tumor growth in BALB/c and C57BL/6 syngeneic tumor-bearing mice. The immunogenicity of PT-treated cancer cells was reduced in the presence of HSP inhibitors, J2, VER-155008 or 17-AAG. Our study elucidates how PT techniques have distinct mechanisms from water-based heating and might be a potentially robust and efficient solution to developing an anti-cancer vaccine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background/aims: : This study aimed to assess whether hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) could have favorable prognoses with proper treatment under selective conditions., Methods: : This retrospective, single-center study involved 1,168 patients diagnosed with HCC between January 2005 and December 2006, before the introduction of sorafenib. Overall survival (OS) was estimated using the Kaplan-Meier method, and the Cox proportional hazards model was used to identify and adjust the variables associated with OS., Results: : In nodular-type HCC, the OS differed significantly according to the presence of PVTT (log-rank p<0.001), and the level of PVTT, not only its presence, was a major independent factor affecting OS. PVTT at the Vp1-3 branch was associated with significantly longer OS than was PVTT at the Vp4 level (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.04 to 3.21). In multivariate analysis, the OS was further stratified according to the PVTT level and tumor type, representing that nodular HCC without PVTT exhibited the best OS, whereas nodular HCC with Vp4 PVTT (adjusted HR, 2.59; 95% CI, 1.57 to 4.28) showed a poor prognosis similar to that of infiltrative HCC. The PVTT level was consistently correlated with OS in patients treated with transarterial chemoembolization. Nodular HCC without PVTT showed the best prognosis, while nodular HCC with Vp1-3 PVTT also exhibited a favorable OS, although inferior to that without PVTT (adjusted HR, 1.47, 95% CI, 0.92 to 2.36)., Conclusions: : Active treatment such as transarterial chemoembolization can be considered for selected PVTT cases. The level of PVTT and type of HCC were independent prognostic factors.