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Up to half of hepatocellular carcinoma (HCC) cases are diagnosed at an advanced stage, for which effective treatment options are lacking, resulting in a poor prognosis. Over the past few years, the combination of immune checkpoint inhibitors and anti-angiogenic targeted therapy has proven highly efficacious in treating advanced HCC, significantly extending patients' survival and providing a potential for sequential curative surgery. After sequential curative hepatectomy or liver transplantation following conversion therapy, patients can receive long-term survival benefits. In order to improve the long-term survival rate of the overall population with liver cancer and achieve the goal of a 15% increase in the overall 5-year survival rate outlined in the Healthy China 2030 blueprint, the Professional Committee for Prevention and Control of Hepatobiliary and Pancreatic Diseases of Chinese Preventive Medicine Association, Chinese Society of Liver Cancer, and the Liver Study Group of Surgery Committee of Beijing Medical Association organized in-depth discussions among relevant domestic experts in the field. These discussions focused on the latest progress since the release of the Chinese expert consensus on conversion therapy of immune checkpoint inhibitors combined antiangiogenic targeted drugs for advanced hepatocellular carcinoma (2021 Edition) and resulted in a new consensus on the modifications and supplements to related key points. This consensus aims to further guide clinical practice, standardize medical care, and promote the development of the discipline.

Background: Targeted therapy for intrahepatic cholangiocarcinoma (ICC) shows superior survival outcomes but patients with certain targetable alterations are no more than 20%. Genetic alteration screening for all ICC patients is of high cost and not routinely performed. This study intends to develop a histopathology-based artificial intelligence (AI)-assisted system for predicting genetic alteration of ICC., Methods: We constructed a Genetic Alteration Prediction (GAP) system based on multi-instance learning and self-supervised learning to predict genetic alterations using whole-slide images (WSIs) of H&E-stained slides. A total of 2069 WSIs from 232 ICC patients underwent surgery of the FAH-SYSU dataset were used for model construction and adjustment by five-fold cross-validation. Another 150 patients from three medical centres were used as independent external validations. We also compared the cost-effectiveness of GAP-assisted precise treatment and all-sequencing strategy to non-sequencing strategy., Results: The GAP was able to predict actionable genetic alterations of ICC, including FGFR2 and IDH. The area under the receiver operating characteristic curves (AUC) for FGFR2 and IDH were 0.754 and 0.713 in the internal dataset, and 0.724 and 0.656 in the external dataset, respectively. Furthermore, compared to giving chemotherapy without sequencing for every patient, GAP-assisted precise treatment could increase 1 progression-free quality-adjusted life month with a cost of $13871.72, the co-responding figure for all-sequencing strategy is $44538.93. Decision curve analysis showed that AI-assisted strategy provides better clinical benefits., Conclusions: We constructed an AI-assisted genetic alteration screening system which is predictable to ICC actionable targets and has potential to assist precise targeted treatment of advanced ICC., Competing Interests: Competing interests: The authors declare no conflict of interest. Ethical approval: This study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The protocol was reviewed and approved by Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University, approval number No. [2023]107. Informed consent: Informed consent was waived since it’s a retrospective study., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In Asia-Pacific region, hepatocellular carcinoma is a serious health threat attributing to over 600,000 deaths each year and account for over 70% of global cases. Clinically, the major unmet needs are recurrence after curative-intent surgery, liver transplantation or local ablation and disease progression in those with hepatocellular carcinoma not eligible for resection or failed locoregional therapy. In the recent few years, new targeted therapy and immune-checkpoint inhibitors have been registered as systemic therapy to address these issues. Notably, new forms of systemic therapy, either as first-line or second-line therapy for unresectable hepatocellular or those not eligible for locoregional therapy, are now available. New data is also emerging with the use of systemic therapy to prevent hepatocellular carcinoma recurrence after curative-intent resection or local ablation therapy and to retard disease progression after locoregional therapy. In the future, further implementation of immune-checkpoint inhibitors and other forms of immunotherapy are expected to bring a new paradigm to the management of hepatocellular carcinoma. New insight related to immune-related adverse events with the use of immunotherapy has allso enabled optimization of the therapeutic approach to patients with hepatocellular carcinoma. The purpose of this clinical practice guideline is to provide an up-to-date recommendation based on clinical evidence and experience from expert Asia-Pacific key opinion leaders in the field of hepatocellular carcinoma. Three key questions will be addressed, namely: (1) Which patients with hepatocellular carcinoma should be considered for systemic therapy? (2) Which systemic therapy should be used? (3) How should a patient planned for immune checkpoint-based systemic therapy be managed and monitored?, Competing Interests: Declarations. Conflict of interest: George LAU reported lecture fees from AstraZeneca. Shuntaro OBI reported research grants from Eisai, Otsuka pharmaceutical, and Mochida pharmaceutical. Ryosuke TATEISHI reported lecture fees from Abbvie, AstraZeneca, Chugai, Eisai, Gilead Sciences, MSD and Takeda. Sadahisa OGASAWARA reported honoraria from Bayer, Eisai, Eli Lilly, consulting or advisory fees from Bayer, Eisai, Merck & Co. Inc., Chugai Pharma, Eli Lilly, and research grants from Bayer and Eisai. Naoya KATO reported honoraria payment from Bayer and Chugai; research funding from Bayer, Chugai, and Roche. Stephen L CHAN reported consulting or advisory board fees from AstraZeneca, Eisai, and MSD; reports being an invited speaker for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, IPSEN, MSD, and Roche; and research funding from Bayer, Eisai, IPSEN, MSD, and Sirtex Medical. Yoshiyuki UENO reported honoraria payment from Chugai and Eisai. Ann-Lii CHENG reported consulting or advisory board fees from AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Eisai, Genentech/Roche, Ipsen, IQVIA, MSD, Ono Pharmaceutical, and Roche; and honoraria from AstraZeneca, Bayer, Eisai, and Genentech/Roche. Yock Young DAN reported consulting or advisory board fees from Boehringer Ingelheim, MSD, Norvo Nordisk, Roche, and research grants from MSD, Norvo Nordisk, Perspectum, Siemens. Jeong Min LEE reported lecture fees from Samsung Medison, GE Healthcare, Philips Healthcare, Starmed, and research grants from Samsung Medison, Siemens Healthineers, Philips Healthcare, GE Healthcare, Bayer, Guerbet, CMS, Canon Healthcare, Dongkuk Pharma. Diana A. Payawal reported lecture, consulting or advisory board fees from Gilead Sciences, Mylan Pharmaceuticals, Echosense, Getz and Abbott. Ekaphop SIRACHAINAN reported honoraria payment from MSD, Sanofi/Aventis, Merck, Amgen, Roche, Mundipharma, AstraZeneca, LF Asia, Diethelm Keller Group, Bristol Myers Squibb, Boehringer Ingelheim, Taiho Pharmaceutical, Dr Reddy's Laboratories, Zuellig Pharma, Meda Pharmaceuticals, Pfizer, Novo Nordisk, Novartis. Tawesak Tanwandee reported research grants from Bristol Myers Squibb and Merck. Masao Omata reported lecture, consulting or advisory board fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Otsuka, Astellas, Gilead Sciences, Chugai, Mitsubishi Tanabe, Kyorin, Merck Sharp and Dohme, Dainippon Sumitomo, Vertex Pharmaceuticals, Takeda, Merck Serono, and Zeria. Jian ZHOU, Shukui QIN, Haitao ZHAO, Motoyuki OTSUKA, Jacob GEORGE, Pierce KH CHOW, Jianqiang CAI, Shuichiro SHIINA, Osamu YOKOSUKA, Kyoko OURA, Thomas YAU, Ming KUANG, Minshan CHEN, Gregory CHENG, Wan-Long CHUANG, Oidov BAATARKHUU, Feng BI, Rino A GANI, Atsushi TANAKA, Wasim JAFRI, Ji-Dong JIA, Jia-Horng KAO, Kiyoshi HASEGAWA, Patrick LAU, Jun LIANG, Zhenwen LIU, Yinying LU, Hongming PAN, Salimur RAHMAN, Jinsil SEONG, Feng SHEN, Gamal SHIHA, Tianqiang SONG, Hui-Chuan SUN, Tsutomu MASAKI, Lai WEI, Jin Mo YANG, Jose D SALLANO, Yanqiao ZHANG,, A Kadir DOKMECI, Shu-sen ZHENG, Jia FAN, Sheung-Tat FAN and Shiv Kumar Sarin reported that they have no conflict of interest. Ethical approval: Not applicable. Informed consent: Not applicable., (© 2024. Asian Pacific Association for the Study of the Liver.)

Competing Interests: Disclosure: The authors declare that they have nothing to disclose.

Introduction: The rising demand for knowledge updates and technological innovations in China has made clinical placement teaching challenging. Reforms for innovative teaching models through pilot classes have shown to improve students' academic performance. This novel integration led to the announcement of healthcare collaboration in the Guangdong-Hong-Kong-Macao Greater Bay Area for projects within China's "Global-Innovation-Hub" zones. First Affiliated Hospital (FAH) of Sun Yat-sen University (SYSU) in Guangzhou and the Faculty of Medicine (FMD) of Macau University of Science & Technology (MUST) in Macau have developed an inaugural project for FMD/MUST medical students to perform pre-internships at FAH-SYSU. This study aimed to reflect on students' experiences with collaborative teaching and learning through medical curricular integration in the "Global-Innovation-Hub" zones designed by both institutions for developing integrated curriculum., Methods: FMD/MUST students attended medical clerkships at FAH-SYSU using a system-integrated curriculum in China's "Global-Innovation-Hub" zones, allowing different education systems at different locations. Post-clerkship surveys ranked teaching models in conjunction with written reflections in response to post-clerkship questionnaires for all participating students. The teaching models were defined by the way supervisors' interaction with students, and written reflections in response to the post-clerkship questionnaire were descriptively and semantically analysed., Results: The top-ranked teaching models include first "Student-led consultation under supervision in observers' chair with discussion", second "Observe consultation and discuss with the teacher in-between patients in observers' chair" and third "Student-led consultation under supervision in consultants' chair with discussion". The post-clerkship questionnaires showed positive outcomes., Conclusion: This study demonstrates the successful delivery of collaborative teaching and learning through medical curricular integration in China's "Global-Innovation-Hub" zones. This integration enables the development of a consistent and student-preferred teaching model being introduced into clinical placement curriculum. The unique location of China's "Global-Innovation-Hub" zones in the Guangdong-Hong-Kong-Macao Greater Bay Area allows this integration to significantly improve students' clinical reasoning learning., Competing Interests: Jianrong Zhang, Shaoting Feng, Io Nam Wong and Dan Xu are equal first authors. The authors report no conflicts of interest in this work., (© 2024 Zhang et al.)

Background: To develop a laparoscopic training course that combines a smartphone application (APP) and virtual reality (VR), and initially evaluate the feasibility and effectiveness of its implementation., Methods: The Exploring Laparoscopy (Ex-Lap) app was developed to meet training demands. The course was designed by integrating the app with a VR simulator (LapSim ® ) and animal organ perfusion simulators. From January 2021 to December 2023, 91 participants were enrolled in the study and then divided into 5 separate batches to undergo the first stage of the course. The performance of the participants was evaluated by rating scale, the overall Training and Assessment of Basic Laparoscopic Techniques (TABLT) scores, and pass rates. Statistical analyses were conducted using SPSS 26.0, employing Kruskal-Wallis tests, Chi-squared analysis, and Fisher's exact test, depending on the data type., Results: The Staged Training and Assessment of Laparoscopic Skills (STALS) course was developed, consisting of three stages. The overall pass rates for the first stage across the five batches ranged from 85 to 100%, with no significant difference (P = 0.387). No significant differences were found in the scale scores or TABLT scores for the training tasks among students from different batches (all P > 0.05)., Conclusions: The STALS course is applicable in residency training, demonstrating satisfactory teaching effectiveness and replicability., (© 2024. The Author(s).)

Background: The first-line treatment for polycystic ovary syndrome (PCOS) is lifestyle modification. However, it is currently unknown whether digital medicine can assist patients with PCOS in maintaining a healthy lifestyle while alleviating PCOS symptoms., Objective: This study aims to evaluate the efficacy of WeChat-based digital intervention versus metformin treatment in women with PCOS and insulin resistance., Methods: A total of 80 women with PCOS and insulin resistance were recruited from an endocrinology clinic and randomly assigned to receive either a WeChat-based digital intervention (n=40, 50%) or metformin (n=40, 50%) for 12 weeks. The WeChat-based digital intervention consisted of 3 modules; a coach assisted the patients in using the intervention. The primary outcome was the change in a homeostatic model assessment for insulin resistance. At baseline and after the 12-week intervention, anthropometric parameters, menstruation frequency, sex hormone levels, metabolic factors, and body fat distribution were measured in the clinic. Furthermore, self-assessed web-based questionnaires on diet, exercise, sleep, anxiety, and depression were obtained., Results: A total of 72 participants completed the follow-up (for a 90% follow-up rate), including 35 of 40 (88%) participants from the digital intervention group and 37 of 40 (93%) participants from the metformin group. The homeostatic model assessment for insulin resistance in the digital intervention group was significantly improved after 12 weeks of treatment with a mean change of -0.93 (95% CI -1.64 to -0.23), but no statistical difference was observed between the groups (least squares mean difference -0.20; 95% CI -0.98 to 0.58; P=.62). Both digital intervention and metformin treatment significantly improved menstruation frequency (digital intervention: P<.001; metformin: P<.001) and reduced body weight (digital intervention: P<.001; metformin: P<.001) and total fat mass (digital intervention: P<.001; metformin: P<.001). Furthermore, the digital intervention had a significant advantage over metformin in improving waist circumference (least squares mean difference -1.84; 95% CI -3.44 to -0.24; P=.03), waist-to-hip ratio (least squares mean difference -0.02; 95% CI -0.03 to 0.00; P=.03), total fat mass (least squares mean difference -1.59; 95% CI -2.88 to -0.30; P=.02), and dehydroepiandrosterone sulfate (least squares mean difference -69.73; 95% CI -129.70 to -9.75; P=.02). In terms of safety, the main adverse events were sensations of hunger in the digital intervention group (2/40, 5%) and gastrointestinal adverse events in the metformin group (12/40, 30%)., Conclusions: Our data suggest that digital intervention is an effective treatment option for patients with PCOS, with an efficacy comparable to that of metformin, and that it can also alleviate the negative effects of medications and make it easier and more efficient to adhere to lifestyle treatments. WeChat-based digital interventions have the potential to provide a new path for the improvement and health of women with PCOS in China., Trial Registration: ClinicalTrials.gov NCT05386706; https://clinicaltrials.gov/study/NCT05386706., (©Diliqingna Dilimulati, Xiaowen Shao, Lihua Wang, Meili Cai, Yuqin Zhang, Jiayi Lu, Yao Wang, Hongying Liu, Ming Kuang, Haibing Chen, Manna Zhang, Shen Qu. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 02.10.2024.)

Background: Eating while watching TV was found associated with unhealthy food preferences and obesity in adolescents in foreign studies, which is not clear in China. The study aims to explore the influence of eating while watching TV on food preferences and overweight/obesity in Chinese adolescents., Methods: Data from 1768 adolescents (aged 12-17 years) in the 2006, 2009, 2011, and 2015 China Health and Nutrition Survey (CHNS) was analyzed. The height and weight were measured. Mixed effect models were used to identify the associations between eating while watching TV and adolescents' food preferences and overweight/obesity., Results: Adolescents eating while watching TV ≥1 time/week were more likely to prefer fast food, salty snacks and soft drinks than those eating while watching TV <1 time/week. Adolescents eating meals while watching TV ≥1 time/week were less likely to prefer vegetables than those eating meals while watching TV <1 time/week. In addition, adolescents eating snacks while watching TV ≥1 time/week were more likely to be overweight/obesity than those eating meals while watching TV <1 time/week (odds ratio [OR] = 7.16; 95% confidence interval [CI] 1.39-36.93)., Conclusion: Eating snacks while watching TV was positively associated with adolescents' unhealthy food preferences and overweight/obesity. Eating meals while watching TV was associated with adolescents' unhealthy food preferences. Implementing web-based Community-based participatory research (CBPR) about reducing eating while watching TV may be a practical strategy to develop healthy food preferences and prevent overweight/obesity in Chinese adolescents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xian, Ren and Kuang.)

Objectives: To establish a nomogram for differentiating malignant and benign focal liver lesions (FLLs) using ultrasomics features derived from contrast-enhanced ultrasound (CEUS)., Methods: 527 patients were retrospectively enrolled. On the training cohort, ultrasomics features were extracted from CEUS and b-mode ultrasound (BUS). Automatic feature selection and model development were performed using the Ultrasomics-Platform software, outputting the corresponding ultrasomics scores. A nomogram based on the ultrasomics scores from artery phase (AP), portal venous phase (PVP) and delayed phase (DP) of CEUS, and clinical factors were established. On the validation cohort, the diagnostic performance of the nomogram was assessed and compared with seniorexpert and resident radiologists., Results: In the training cohort, the AP, PVP and DP scores exhibited better differential performance than BUS score, with area under the curve (AUC) of 84.1-85.1% compared with the BUS (74.6%, P < 0.05). In the validation cohort, the AUC of combined nomogram and expert was significantly higher than that of the resident (91.4% vs. 89.5% vs. 79.3%, P < 0.05). The combined nomogram had a comparable sensitivity with the expert and resident (95.2% vs. 98.4% vs. 97.6%), while the expert had a higher specificity than the nomogram and the resident (80.6% vs. 72.2% vs. 61.1%, P = 0.205)., Conclusions: A CEUS ultrasomics based nomogram had an expert level performance in FLL characterization., (© 2024. The Author(s).)

Insulin resistance (IR) is the major mechanism in the pathogenesis of type 2 diabetes mellitus (T2DM). Early identification of IR is of great significance for preventing the onset of T2DM and delaying the progression of the disease. Previous studies have shown that triglyceride-glucose (TyG) index can be used as an effective surrogate marker for IR. There is a significant correlation between TyG index and T2DM and its common complications. In addition, the predictive efficacy of TyG index is better than that of other IR surrogate indicators. TyG index may not only become an important marker to identify people at high risk of T2DM and its complications, but is also expected to become a strong predictor of the prognosis of these diseases. However, there are still some challenges in the widespread application of TyG index in clinical practice. In the future, more high-quality studies are needed to clarify the assessment methods of TyG index for the prognosis of T2DM and its complications. Further investigations of the relationship between TyG index and T2DM and its complications will be expected to provide new ideas and methods for the prevention and treatment of T2DM and its complications., Competing Interests: The authors declare no conflicts of interest related to this review article., (© 2024 Pan et al.)

Background: This study examines incidence, mortality, medical expenditure and prescription patterns for asthma on a national scale, particularly in Asian countries for asthma is limited. Our aim is to investigate incidence, mortality, prescription patterns and provide a comprehensive overview of healthcare utilization trends for asthma from 2009 to 2018., Methods: We included patients diagnosed with asthma between 2009 and 2018. We excluded patients with missing demographic data. Our analysis covered comorbidities, including diabetes mellitus, hypertension, allergic rhinitis, eczema, atopic dermatitis, coronary artery disease, congestive heart failure, chronic kidney disease, chronic hepatitis, stroke, and cancer. Investigated medications comprised oral and intravenous steroids, short-acting beta-agonists, inhaled corticosteroids (ICS), combinations of ICS and long-acting beta-agonists, long-acting muscarinic antagonists, and leukotriene receptor antagonists montelukast. We also assessed the number of outpatient visits, emergency visits, and hospitalizations per year, as well as the average length of hospitalization and average medical costs., Results: The study included a final count of 88,244 subjects from 1,998,311 randomly selected samples between 2000 and 2019. Over the past decade, there was a gradual decline in newly diagnosed asthma patients per year, from 10,140 to 6,487. The mean age annually increased from 47.59 in 2009 to 53.41 in 2018. Over 55% of the patients were female. Eczema was diagnosed in over 55% of the patients. Around 90% of the patients used oral steroids, with a peak of 97.29% in 2018, while the usage of ICS varied between 86.20% and 91.75%. Intravenous steroids use rose from 40.94% in 2009 to 54.14% in 2018. The average annual hospital stay ranged from 9 to 12 days, with a maximum of 12.26 days in 2013. Lastly, the average medical expenses per year ranged from New Taiwan dollars 5558 to 7921., Conclusions: In summary, both asthma incidence and all-cause mortality rates decreased in Taiwan from 2009 to 2018. Further analysis of medical expenses in patients with asthma who required multiple hospitalizations annually revealed an increase in outpatient and emergency visits and hospitalizations, along with longer hospital stays and higher medical costs., (© 2024. The Author(s).)

Competing Interests: The authors report no conflicts of interest in this communication.

Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS- tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG + plasma cells (PCs), while TLS- tumors are characterized with IgA + PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19 + fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM., Competing Interests: Declaration of interests M.K., C.Y., and Z.C. have been named inventors on a pending patent application related to the use of CRLM-targeting antibodies identified in this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: Apoptosis Signal-regulating Kinase 1 (ASK1) is activated by various pathological stimuli and induces cell apoptosis through downstream p38 activation. We studied the effect of pharmacological ASK1 inhibition on cirrhosis and its sequelae using comprehensive preclinical in vivo and in vitro systems., Approach and Results: Short-term (4-6 wk) and long-term (24-44 wk) ASK1 inhibition using small molecule GS-444217 was tested in thioacetamide-induced and BALB/c. Mdr2-/- murine models of cirrhosis and HCC, and in vitro using primary hepatocyte cell death assays. Short-term GS-444217 therapy in both models strongly reduced phosphorylated p38, hepatocyte death, and fibrosis by up to 50%. Profibrogenic release of mitochondrial DAMP mitochondrial deoxyribonucleic acid from dying hepatocytes was blocked by ASK1 or p38 inhibition. Long-term (24 wk) therapy in BALBc.Mdr2 - / - model resulted in a moderate 25% reduction in bridging fibrosis, but not in net collagen deposition. Despite this, the development of cirrhosis was effectively prevented, with strongly reduced p21 + hepatocyte staining (by 72%), serum ammonia levels (by 46%), and portal pressure (average 6.07 vs. 8.53 mm Hg in controls). Extended ASK1 inhibition for 44 wk in aged BALB/c. Mdr2-/- mice resulted in markedly reduced tumor number and size by ~50% compared to the control group., Conclusions: ASK1 inhibition suppresses the profibrogenic release of mitochondrial deoxyribonucleic acid from dying hepatocytes in a p38-dependent manner and protects from liver fibrosis. Long-term ASK1 targeting resulted in diminished net antifibrotic effect, but the progression to liver cirrhosis and cancer in BALBc/ Mdr2- / - mice was effectively inhibited. These data support the clinical evaluation of ASK1 inhibitors in fibrotic liver diseases., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Importance: Transarterial chemoembolization (TACE) is commonly used to treat patients with recurrent intermediate-stage hepatocellular carcinoma (HCC) and positive microvascular invasion (MVI); however, TACE alone has demonstrated unsatisfactory survival benefits. A previous retrospective study suggested that TACE plus sorafenib (SOR-TACE) may be a better therapeutic option compared with TACE alone., Objective: To investigate the clinical outcomes of SOR-TACE vs TACE alone for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive MVI., Design, Setting, and Participants: In this phase 3, open-label, multicenter randomized clinical trial, patients with recurrent intermediate-stage HCC and positive MVI were randomly assigned in a 1:1 ratio via a computerized minimization technique to either SOR-TACE treatment or TACE alone. This trial was conducted at 5 hospitals in China, and enrolled patients from October 2019 to December 2021, with a follow-up period of 24 months. Data were analyzed from June 2023 to September 2023., Interventions: Randomization to on-demand TACE (conventional TACE: doxorubicin, 50 mg, mixed with lipiodol and gelatin sponge particles [diameter: 150-350 μm]; drug-eluting bead TACE: doxorubicin, 75 mg, mixed with drug-eluting particles [diameter: 100-300 μm or 300-500 μm]) (TACE group) or sorafenib, 400 mg, twice daily plus on-demand TACE (SOR-TACE group) (conventional TACE: doxorubicin, 50 mg, mixed with lipiodol and gelatin sponge particles [diameter, 150-350 μm]; drug-eluting bead TACE: doxorubicin, 75 mg, mixed with drug-eluting particles [diameter: 100-300 μm or 300-500 μm])., Main Outcomes and Measures: The primary end point was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment., Results: A total of 162 patients (median [range] age, 55 [28-75] years; 151 males [93.2%]), were randomly assigned to be treated with either SOR-TACE (n = 81) or TACE alone (n = 81). The median overall survival was significantly longer in the SOR-TACE group than in the TACE group (22.2 months vs 15.1 months; hazard ratio [HR], 0.55; P < .001). SOR-TACE also prolonged progression-free survival (16.2 months vs 11.8 months; HR, 0.54; P < .001), and improved the objective response rate when compared with TACE alone based on the modified Response Evaluation Criteria in Solid Tumors criteria (80.2% vs 58.0%; P = .002). Any grade adverse events were more common in the SOR-TACE group, but all adverse events responded well to treatment. No unexpected adverse events or treatment-related deaths occurred in this study., Conclusions and Relevance: The results of this randomized clinical trial demonstrated that SOR-TACE achieved better clinical outcomes than TACE alone. These findings suggest that combined treatment should be used for patients with recurrent intermediate-stage HCC after R0 hepatectomy with positive MVI., Trial Registration: ClinicalTrials.gov Identifier: NCT04103398.

Background & Aims: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer and is highly lethal. Clonorchis sinensis (C. sinensis) infection is an important risk factor for iCCA. Here we investigated the clinical impact and underlying molecular characteristics of C. sinensis infection-related iCCA., Methods: We performed single-cell RNA sequencing, whole-exome sequencing, RNA sequencing, metabolomics and spatial transcriptomics in 251 patients with iCCA from three medical centers. Alterations in metabolism and the immune microenvironment of C. sinensis-related iCCAs were validated through an in vitro co-culture system and in a mouse model of iCCA., Results: We revealed that C. sinensis infection was significantly associated with iCCA patients' overall survival and response to immunotherapy. Fatty acid biosynthesis and the expression of fatty acid synthase (FASN), a key enzyme catalyzing long-chain fatty acid synthesis, were significantly enriched in C. sinensis-related iCCAs. iCCA cell lines treated with excretory/secretory products of C. sinensis displayed elevated FASN and free fatty acids. The metabolic alteration of tumor cells was closely correlated with the enrichment of tumor-associated macrophage (TAM)-like macrophages and the impaired function of T cells, which led to formation of an immunosuppressive microenvironment and tumor progression. Spatial transcriptomics analysis revealed that malignant cells were in closer juxtaposition with TAM-like macrophages in C. sinensis-related iCCAs than non-C. sinensis-related iCCAs. Importantly, treatment with a FASN inhibitor significantly reversed the immunosuppressive microenvironment and enhanced anti-PD-1 efficacy in iCCA mouse models treated with excretory/secretory products from C. sinensis., Conclusions: We provide novel insights into metabolic alterations and the immune microenvironment in C. sinensis infection-related iCCAs. We also demonstrate that the combination of a FASN inhibitor with immunotherapy could be a promising strategy for the treatment of C. sinensis-related iCCAs., Impact and Implications: Clonorchis sinensis (C. sinensis)-infected patients with intrahepatic cholangiocarcinoma (iCCA) have a worse prognosis and response to immunotherapy than non-C. sinensis-infected patients with iCCA. The underlying molecular characteristics of C. sinensis infection-related iCCAs remain unclear. Herein, we demonstrate that upregulation of FASN (fatty acid synthase) and free fatty acids in C. sinensis-related iCCAs leads to formation of an immunosuppressive microenvironment and tumor progression. Thus, administration of FASN inhibitors could significantly reverse the immunosuppressive microenvironment and further enhance the efficacy of anti-PD-1 against C. sinensis-related iCCAs., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objectives: Long-acting bronchodilators are important treatments for chronic obstructive pulmonary disease (COPD) and adequate medication adherence decreases COPD exacerbations, especially in reducing the hazard of influenza infection. Therefore, the study aim was to evaluate adherence of long-acting bronchodilator treatment and the risk of influenza in patients with COPD., Methods: This retrospective nested case-control study included patients with newly diagnosed COPD from 2012 to 2018. Cases with influenza infection were defined and matched to 2 randomly selected controls. The influenza infection date was the index date. Conditional logistic regressions were used to estimate odds ratios of influenza from proportion of days covered (PDC) of long-acting bronchodilators measured in one year before the index date. Adherence was divided into high adherence (PDC ≥80 %) and low adherence (PDC <80 %)., Results: This population-based study included 6,073 patients in the case group and 12,146 in the control group. High PDC of long-acting bronchodilators in COPD was associated with a 0.811-fold (95 % confidence interval: 0.754-0.883, P < 0.001) decreased influenza risk, where 906 (14.92 %) high PDC in case and 2,130 (17.54 %) in control. Low PDC without influenza vaccination in COPD patients is associated with increased influenza risk, regardless of exposure period., Conclusion: In Taiwan, COPD patients with high PDC were associate with lower COPD exacerbation. Different long-acting bronchodilator exposure or dose need to be further investigated in COPD patients., Competing Interests: 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., (© 2024 The Authors.)

Purpose: Liver resection and ablation remain the most common therapeutic options for Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC), but there is a lack of evidence to show which is the most suitable therapy. This study aimed to make concurrent multi-arm comparisons of the short-term and long-term outcomes of percutaneous ablation (PA), open (OLR) or laparoscopic liver resection (LLR) for these patients., Patients and Methods: This was a retrospective observational cohort study. A series of generalized propensity score methods for multiple treatment groups were performed to concurrently compare the clinical outcomes of these three treatment options to balance potential confounders. Regression standardization was used to account for hazard of all-cause mortality and recurrence of intergroup differences., Results: Of the 1778 patients included, 1237, 307 and 234 underwent OLR, LLR and PA, respectively. After overlap weighting, which was the optimal adjustment strategy, patients in the minimally invasive group (LLR and PA groups) had few postoperative complications and short postoperative hospital stays (both P < 0.001). The 5-year recurrence-free survival (RFS) rate and 5-year overall survival (OS) rate were significantly higher in the LLR group when compared with the OLR and PA groups (RFS: 55.6% vs 48.0% vs 30.2%, P < 0.001; OS: 89.1% vs 79.7% vs 84.0%, P = 0.020). Multivariable Cox analysis and regression standardization showed that LLR was an independent factor for better RFS when compared with OLR and PA. In subgroup analysis, the long-term outcomes of patients with BCLC stage A HCC were consistent with the whole population., Conclusion: In the observational study using various covariate adjustment analysis with excellent balance, LLR is not only minimally invasive, but also provides better RFS and equivalent OS for patients with BCLC stage 0-A HCC when compared with OLR and PA., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Chen et al.)

Introduction: Secondary spontaneous pneumothorax (SSP) is often linked to chronic obstructive pulmonary disease (COPD). The frequency of SSP occurrence in COPD patients varies among different research findings. SSPs are more commonly found in the elderly population diagnosed with COPD. Previous studies have reported a pneumothorax rate of 26 per 100,000 COPD patients. There is, however, a notable lack of detailed epidemiological information regarding SSP in Asia. Our study focused on determining the occurrence rate of SSP among COPD patients in Taiwan using an extensive national database. Additionally, this study aimed to identify comorbidities associated with SSP in this patient group., Methods: In this study, we used the Longitudinal Health Insurance Database, which contains records of 2 million people who were randomly chosen from among the beneficiaries of the Taiwan National Health Insurance program. The dataset includes information from 2005 to the end of 2017. Our focus was on individuals diagnosed with COPD, identified through ICD-9-CM codes in at least one hospital admission or two outpatient services, with the COPD diagnosis date as the index date. The exclusion criteria included individuals younger than 40 years, those with incomplete records, or those with a previous diagnosis of pneumothorax before the index date. We conducted a matched comparison by pairing COPD patients with control subjects of similar age, sex, and comorbidities using propensity score matching. The follow-up for all participants started from their index date and continued until they developed pneumothorax, reached the study's end, withdrew from the insurance program, or passed away. The primary objective was to evaluate and compare the incidence of pneumothorax between COPD patients and matched controls., Results: We enrolled 65,063 patients who were diagnosed with COPD. Their mean age (±SD) was 66.28 (±12.99) years, and approximately 60 % were male. During the follow-up period, pneumothorax occurred in 607 patients, equivalent to 9.3 % of the cohort. The incidence rate of SSP in COPD patients was 12.10 per 10,000 person-years, whereas it was 6.68 per 10,000 person-years in those without COPD. Furthermore, COPD patients with comorbidities such as atrial fibrillation, congestive heart failure, coronary artery disease, diabetes mellitus, hypertension, and cancer exhibited an increased incidence of SSP compared to COPD patients without such comorbidities. This was observed after conducting a multivariable Cox regression analysis adjusted for age, sex, and other comorbidities., Conclusion: Our study revealed an elevated risk of SSP in patients with COPD. It has also been suggested that COPD patients with comorbidities, such as atrial fibrillation, congestive heart failure, coronary artery disease, diabetes mellitus, hypertension, and cancer, have an increased risk of developing SSP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Kuang-Ming Liao reports article publishing charges was provided by Chi Mei Medical Center, Chiali. Kuang-Ming Liao reports a relationship with Chi Mei Medical Center, Chiali that includes: employment. If there are other authors, they 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.)

Objective: This study aimed to evaluate the current situation of Chinese mobile apps for hypertension management and explore patients' real requirements for app use, providing a theoretical basis for the future improvement of hypertension apps., Methods: We reviewed hypertension management apps from mobile app platforms, and summarized their functional characteristics. In addition, we conducted an online survey among 1000 hypertensive patients, collected valid responses, and analyzed the feedback data., Results: Forty hypertension management apps were analyzed, with 72.5% offering no more than six functions, indicating limited coverage of advanced and comprehensive functionalities. Among the 934 valid survey responses, patients emphasized four main functions in apps for hypertension management: long-term dynamic blood pressure monitoring, scientific lifestyle management, strict medication management and systematic health knowledge delivering., Conclusion: The existing hypertension management apps mainly serve as "Digital Health" tools with unclear clinical efficacy. The future development of these apps lies in how they transition to "Digital Therapeutics" solutions to better meet patients' needs and provide clear clinical advantages., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims of this assessment were to describe requirements for physicians to engage in CME/CPD; explore perceptions of In-Country SMEs of their CME/CPD systems; describe perceptions of In-Country physicians about interprofessional continuing education (IPCE) and independent CME/CPD; and provide recommendations that may be adopted to improve quality and effectiveness. This assessment used a mixed-methods approach that included 1:1 interviews with in-country subject matter experts and an electronic survey capturing qualitative and quantitative data from practicing in-country physicians. This assessment reflects a country invested in the education of its physician workforce. CME/CPD systems have embedded governance structures, organizations authorized to provide education, and a recognized credit system. Governing bodies have implemented regulations to limit influence from commercial interest organizations on CME/CPD, and there is opportunity to expand delivery systems to reach physicians across diverse geographic regions, better align content to individual physicians' gaps and learning needs, and reduce cost. There is opportunity to invest in IPCE within a country with a strong professional hierarchy system. This assessment reflects CME/CPD systems that are relatively mature and identifies several opportunities to expand and enhance systems to better meet educational needs of physicians and to positively impact practice and patient outcomes., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objective: Whether and how the PI3K-AKT pathway, a central node of metabolic homeostasis, is responsible for high-fat-induced non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain a mystery. Characterisation of AKT regulation in this setting will provide new strategies to combat HCC., Design: Metabolite library screening disclosed that palmitic acid (PA) could activate AKT. In vivo and in vitro palmitoylation assay were employed to detect AKT palmitoylation. Diverse cell and mouse models, including generation of AKT1 C77S and AKT1 C224S knock-in cells, Zdhhc17 and Zdhhc24 knockout mice and Akt1 C224S knock-in mice were employed. Human liver tissues from patients with NASH and HCC, hydrodynamic transfection mouse model, high-fat/high-cholesterol diet (HFHCD)-induced NASH/HCC mouse model and high-fat and methionine/choline-deficient diet (HFMCD)-induced NASH mouse model were also further explored for our mechanism studies., Results: By screening a metabolite library, PA has been defined to activate AKT by promoting its palmitoyl modification, an essential step for growth factor-induced AKT activation. Biologically, a high-fat diet could promote AKT kinase activity, thereby promoting NASH and liver cancer. Mechanistically, palmitoyl binding anchors AKT to the cell membrane in a PIP3-independent manner, in part by preventing AKT from assembling into an inactive polymer. The palmitoyltransferases ZDHHC17/24 were characterised to palmitoylate AKT to exert oncogenic effects. Interestingly, the anti-obesity drug orlistat or specific penetrating peptides can effectively attenuate AKT palmitoylation and activation by restricting PA synthesis or repressing AKT modification, respectively, thereby antagonising liver tumorigenesis., Conclusions: Our findings elucidate a novel fine-tuned regulation of AKT by PA-ZDHHC17/24-mediated palmitoylation, and highlight tumour therapeutic strategies by taking PA-restricted diets, limiting PA synthesis, or directly targeting AKT palmitoylation., Competing Interests: Competing interests: WW is a co-founder and consultant for the ReKindle Therapeutics., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Certain patients with hepatocellular carcinoma with portal vein tumor thrombus could benefit from surgical resection, and postoperative adjuvant therapy may lower the incidence of tumor recurrence., Objective: To compare the efficacy and safety of sorafenib plus transarterial chemoembolization vs sorafenib alone as postoperative adjuvant therapy for patients with hepatocellular carcinoma with portal vein tumor thrombus., Design, Setting, and Participants: This was a phase 3, multicenter, randomized clinical trial conducted in 5 hospitals in China. A total of 158 patients were enrolled and randomized from October 2019 to March 2022, with a median follow-up of 28.4 months. Portal vein tumor thrombus was graded by the Cheng classification. Eligible patients with hepatocellular carcinoma with Cheng grade I to III portal vein tumor thrombus (ie, involving segmental or sectoral branches, right- or left-side branch, or main trunk of portal vein) were included., Interventions: Patients were randomly assigned 1:1 to receive transarterial chemoembolization with sorafenib or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400 mg orally twice a day. In the transarterial chemoembolization with sorafenib group, transarterial chemoembolization was performed 1 day after the first administration of sorafenib., Main Outcomes and Measures: The primary end point was recurrence-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in patients who received at least 1 dose of study treatment., Results: Of 158 patients included, the median (IQR) age was 54 (43-61) years, and 140 (88.6%) patients were male. The median (IQR) recurrence-free survival was significantly longer in the transarterial chemoembolization with sorafenib group (16.8 [12.0-NA] vs 12.6 [7.8-18.1] months; hazard ratio [HR], 0.57; 95% CI, 0.39-0.83; P = .002). The median (IQR) overall survival was also significantly longer with transarterial chemoembolization with sorafenib than with sorafenib alone (30.4 [20.6-NA] vs 22.5 [15.4-NA] months; HR, 0.57; 95% CI, 0.36-0.91; P = .02). The most common grade 3/4 adverse event was hand-foot syndrome (23 of 79 patients in the transarterial chemoembolization with sorafenib group [29.1%] vs 24 of 79 patients in the sorafenib alone group [30.4%]). There were no treatment-related deaths in either group. The transarterial chemoembolization with sorafenib group did not show additional toxicity compared with the sorafenib monotherapy group., Conclusion and Relevance: In this study, the combination of sorafenib and transarterial chemoembolization as postoperative adjuvant therapy in patients with hepatocellular carcinoma with portal vein tumor thrombus resulted in longer recurrence-free survival and overall survival than sorafenib alone and was well tolerated., Trial Registration: ClinicalTrials.gov Identifier: NCT04143191.

Competing Interests: The authors declare no conflicts of interest for this article.

Cerebral infarction (CI) is a common cerebrovascular disease worldwide, and the burden caused by the sequelae of CI has increased significantly. However, current treatment guidelines lack standardized recommendations for pharmacotherapy of sequelae of CI. This retrospective study collected and analyzed 1.98 million prescriptions concerning sequelae of CI from patients admitted to Zhiyun Health Internet Hospital in 2022. The mean age of patients was 66.2 ± 11.4 years, and 52.40% were male. 79.73% had one or more comorbidities. For treatment, the prescriptions of 1-, 2- and ≥ 3-drug accounted for 64.55%, 23.77% and 11.68% respectively. Chinese patent medicine (CPM) prescriptions, western medicine (WM) prescriptions, and CPM and WM combined (CPM + WM) prescriptions accounted for 53.81%, 27.33%, and 18.86% respectively. In CPM prescriptions, the most frequently prescribed medications were Salvia miltiorrhiza (34.81%), Ginkgo biloba (24.96%), Panax notoginseng (20.67%), Gastrodia (7.15%) and Ligusticum Wallichii (4.90%). For WM prescriptions, the most commonly prescribed agents were anti-hypertensive (32.82%), anti-thrombotic (16.06%), vasodilator (15.70%), anti-dementia (10.88%), and lipid-lowering (9.58%) drugs. Among CPM + WM prescriptions, 72.61% had CPM/WM = 1, 21.20% had CPM/WM < 1, and 6.19% had CPM/WM > 1. This research utilized real-world data extracted from internet hospitals in China to present valuable evidence of online prescription patterns among patients experiencing sequelae of CI., (© 2024. The Author(s).)

Background: In patients with chronic obstructive pulmonary disease (COPD) and acute respiratory failure, approximately 10% of them are considered to be at high risk for prolonged mechanical ventilation (PMV, > 21 days). PMV have been identified as independent predictors of unfavorable outcomes. Our previous study revealed that patients aged 70 years older and COPD severity were at a significantly higher risk for PMV. We aimed to analyze the impact of comorbidities and their associated risks in patients with COPD who require PMV., Methods: The data used in this study was collected from Kaohsiung Medical University Hospital Research Database. The COPD subjects were the patients first diagnosed COPD (index date) between January 1, 2012 and December 31, 2020. The exclusion criteria were the patients with age less than 40 years, PMV before the index date or incomplete records. COPD and non-COPD patients, matched controls were used by applying the propensity score matching method., Results: There are 3,744 eligible patients with COPD in the study group. The study group had a rate of 1.6% (60 cases) patients with PMV. The adjusted HR of PMV was 2.21 (95% CI 1.44-3.40; P < 0.001) in the COPD patients than in non-COPD patients. Increased risks of PMV were found significantly for patients with diabetes mellitus (aHR 4.66; P < 0.001), hypertension (aHR 3.20; P = 0.004), dyslipidemia (aHR 3.02; P = 0.015), congestive heart failure (aHR 6.44; P < 0.001), coronary artery disease (aHR 3.11; P = 0.014), stroke (aHR 6.37; P < 0.001), chronic kidney disease (aHR 5.81 P < 0.001) and Dementia (aHR 5.78; P < 0.001)., Conclusions: Age, gender, and comorbidities were identified as significantly higher risk factors for PMV occurrence in the COPD patients compared to the non-COPD patients. Beyond age, comorbidities also play a crucial role in PMV in COPD., (© 2024. The Author(s).)

Objective: As patient life expectancy has increased and people are living longer than before, the rate of mechanical ventilation among elderly patients in the intensive care unit has increased. Older patients who receive mechanical ventilation and have multiple comorbidities are more likely to have a do not resuscitate order than are younger patients with fewer comorbidities. The aim of our study was to describe the patient characteristics and predictive factors of do not resuscitate orders during hospitalization among elderly patients who received ventilation in the intensive care unit., Methods: This was a retrospective review of the electronic medical records of patients in the intensive care unit of a teaching hospital in southern Taiwan. We enrolled patients admitted to the general intensive care unit from January 1, 2018, to September 31, 2020, and patients older than 80 years who experienced respiratory failure, were intubated and received mechanical ventilation. We analyzed patient demographics, disease severity during hospitalization and comorbidities. If a patient had multiple admissions to the intensive care unit, only the first admission was recorded., Results: Of the 305 patients over 80 years of age with respiratory failure who were intubated and placed on a ventilator, 66 were excluded because of incomplete data, and 13 were excluded because they had already signed a do not resuscitate order prior to admission to the hospital. Ultimately, 226 patients were included in this study. A higher acute physiology and chronic health evaluation II score (>30) was also associated with an increased likelihood of a do not resuscitate order (odds ratio (OR) = 3.85, 95% CI = 1.09-13.62, p  = 0.0362). Patients who had acute kidney injury or cerebrovascular accident were more likely to have a do not resuscitate order (OR = 2.74, 95% CI = 1.03-7.28, p  = 0.0428 and OR = 7.32, 95% CI = 2.02-26.49, p  = 0.0024, respectively)., Conclusion: Our study showed that older age, greater disease severity, and certain critical interventions were associated with a greater propensity for do not resuscitate orders, which is crucial for understanding patient preferences and guiding end-of-life care discussions. These findings highlight the importance of clinical severity and specific health events in predicting end-of-life care preferences in older patient groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Ho, Lin, Chang and Liao.)

Atrial fibrillation (AF) commonly occurs in approximately 2% of cancer patients, and the incidence of AF among cancer patients is greater than in the general population. This observational study presented the incidence risk of AF among cancer patients, including specific cancer types, using a population database. The Taiwan Cancer Registry was used to identify cancer patients between 2008 and 2017. The diagnosis of AF was based on the International Classification of Diseases codes (ICD-9-CM: 427.31 or ICD-10-CM: I48.0, I48.1, I48.2, and I48.91) in Taiwan national health insurance research datasets. The incidence of developing AF in the cancer population was calculated as the number of new-onset AF cases per person-year of follow-up during the study period. The overall incidence of AF among cancer patients was 50.99 per 100,000 person-years. Patients aged older than 65 years and males had higher AF incidence rates. Lung cancer males and esophageal cancer females showed the highest AF incidence risk (185.02 and 150.30 per 100,000 person-years, respectively). Our findings identified esophageal, lung, and gallbladder cancers as the top three cancers associated with a higher incidence of AF. Careful monitoring and management of patients with these cancers are crucial for early detection and intervention of AF.

Systemic therapy is typically the primary treatment choice for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. Some patients may achieve partial response (PR) or complete response (CR) with systemic treatment, leading to the possibility of their primary tumor becoming resectable. This study aimed to investigate whether these patients could achieve longer survival through surgical resection of their primary tumor. We retrospectively collected data from 150 HCC patients with extrahepatic metastases treated at 15 different centers from January 1st, 2015, to November 30th, 2022. We evaluated their overall survival (OS) and progress-free survival (PFS) and analyzed risk factors impacting both OS and PFS were analyzed. Patients who received surgical treatment had longer OS compared to those who did not (median OS 16.5 months vs. 11.3 months). However, there was no significant difference in progression-free survival between the two groups. Portal vein invasion (P = 0.025) was identified as a risk factor for poor prognosis in patients, while effective first-line treatment (P = 0.039) and surgical treatment (P = 0.005) were protective factors. No factors showed statistical significance in the analysis of PFS. Effective first-line treatment (P = 0.027) and surgical treatment (P = 0.006) were both independent protective factors for prolonging patient prognosis, while portal vein invasion was an independent risk factor (P = 0.044). HCC patients with extrahepatic metastases who achieve PR/CR with conversion therapy may experience longer OS through surgical treatment. This study is the first to analyze the clinical outcomes of patients receiving surgical treatment for HCC with extrahepatic metastases., (© 2024. The Author(s).)

Objective: The healthcare challenge driven by an aging population and rising demand is one of the most pressing issues leading to emergency department (ED) overcrowding. An emerging solution lies in machine learning's potential to predict ED dispositions, thus leading to promising substantial benefits. This study's objective is to create a predictive model for ED patient dispositions by employing ensemble learning. It harnesses diverse data types, including structured and unstructured information gathered during ED visits to address the evolving needs of localized healthcare systems., Methods: In this cross-sectional study, 80,073 ED patient records were amassed from a major southern Taiwan hospital in 2018-2019. An ensemble model incorporated structured (demographics, vital signs) and pre-processed unstructured data (chief complaints, preliminary diagnoses) using bag-of-words (BOW) and term frequency-inverse document frequency (TF-IDF). Two random forest base-learners for structured and unstructured data were employed and then complemented by a multi-layer perceptron meta-learner., Results: The ensemble model demonstrates strong predictive performance for ED dispositions, achieving an area under the receiver operating characteristic curve of 0.94. The models based on unstructured data encoded with BOW and TF-IDF yield similar performance results. Among the structured features, the top five most crucial factors are age, pulse rate, systolic blood pressure, temperature, and acuity level. In contrast, the top five most important unstructured features are pneumonia, fracture, failure, suspect, and sepsis., Conclusions: Findings indicate that utilizing ensemble learning with a blend of structured and unstructured data proves to be a predictive method for determining ED dispositions., (© 2024. The Author(s).)

Liver metastasis is the leading cause of mortality in patients with colorectal cancer. Given the significance of both epithelial-mesenchymal transition (EMT) of tumor cells and the immune microenvironment in colorectal cancer liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multiomics analysis of 130 samples from 18 patients with synchronous CRLM integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of nonmalignant cells between primary tumors from patients with metastatic colorectal cancer (mCRC) and non-metastatic colorectal cancer, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK-Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid nanoparticle-encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared with wild-type mice, while cotransfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in patients with colorectal cancer. In addition, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM., Significance: TWEAK secreted by Th17 cells promotes EMT by binding to Fn14 on colorectal cancer cells, suggesting that blocking the TWEAK-Fn14 interaction may be a promising therapeutic approach to inhibit liver metastasis., (©2024 American Association for Cancer Research.)

Background: Accurate estimation of the long-term risk of recurrence in patients with non-metastatic colorectal cancer (CRC) is crucial for clinical management. Histology-based deep learning is expected to provide more abundant information for risk stratification., Methods: We developed and validated a weakly supervised deep-learning model for predicting 5-year relapse-free survival (RFS) to stratify patients with different risks based on histological images from three hospitals of 614 cases with non-metastatic CRC. A deep prognostic factor (DL-RRS) was established to stratify patients into high and low-risk group. The areas under the curve (AUCs) were calculated to evaluate the performances of models., Results: Our proposed model achieves the AUCs of 0.833 (95% CI: 0.736-0.905) and 0.715 (95% CI: 0.647-0.776) on validation cohort and external test cohort, respectively. The 5-year RFS rate was 45.7% for high DL-RRS patients, and 82.5% for low DL-RRS patients respectively in the external test cohort (HR: 3.89, 95% CI: 2.51-6.03, P < 0.001). Adjuvant chemotherapy was associated with improved RFS in Stage II patients with high DL-RRS (HR: 0.15, 95% CI: 0.06-0.38, P < 0.001)., Conclusions: DL-RRS has a good predictive performance of 5-year recurrence risk in CRC, and will better serve the clinical decision-making., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Defining the oxygen level that induces cell death within 3-D tissues is vital for understanding tissue hypoxia; however, obtaining accurate measurements has been technically challenging. In this study, we introduce a noninvasive, high-throughput methodology to quantify critical survival partial oxygen pressure (pO 2 ) with high spatial resolution within spheroids by using a combination of controlled hypoxic conditions, semiautomated live/dead cell imaging, and computational oxygen modeling. The oxygen-permeable, micropyramid patterned culture plates created a precisely controlled oxygen condition around the individual spheroid. Live/dead cell imaging provided the geometric information of the live/dead boundary within spheroids. Finally, computational oxygen modeling calculated the pO 2  at the live/dead boundary within spheroids. As proof of concept, we determined the critical survival pO 2 in two types of spheroids: isolated primary pancreatic islets and tumor-derived pseudoislets (2.43 ± 0.08 vs. 0.84 ± 0.04 mmHg), indicating higher hypoxia tolerance in pseudoislets due to their tumorigenic origin. We also applied this method for evaluating graft survival in cell transplantations for diabetes therapy, where hypoxia is a critical barrier to successful transplantation outcomes; thus, designing oxygenation strategies is required. Based on the elucidated critical survival pO 2 , 100% viability could be maintained in a typically sized primary islet under the tissue pO 2 above 14.5 mmHg. This work presents a valuable tool that is potentially instrumental for fundamental hypoxia research. It offers insights into physiological responses to hypoxia among different cell types and may refine translational research in cell therapies. NEW & NOTEWORTHY Our study introduces an innovative combinatory approach for noninvasively determining the critical survival oxygen level of cells within small cell spheroids, which replicates a 3-D tissue environment, by seamlessly integrating three pivotal techniques: cell death induction under controlled oxygen conditions, semiautomated imaging that precisely identifies live/dead cells, and computational modeling of oxygen distribution. Notably, our method ensures high-throughput analysis applicable to various cell types, offering a versatile solution for researchers in diverse fields.

Malignant liver cancer is characterized by rapid tumour progression and a high mortality rate, whereas the molecular mechanisms underlying liver cancer initiation and progression are still poorly understood. The dynamic and reversible RNA modifications have crucial functions in gene expression regulation by modulating RNA processing and mRNA translation. Emerging evidence has revealed that alterations in RNA modifications facilitate the selective translation of oncogenic transcripts and promote the diverse tumorigenic processes of liver cancer. In this Review, we first highlight the current progress on the functions and mechanisms underlying RNA modifications in the regulation of mRNA translation and then summarize the exciting discoveries on aberrant RNA modification-mediated mRNA translation in the regulation of tumour initiation, metastasis, metabolism, tumour microenvironment, and drug and radiotherapy resistance in liver cancer. Finally, we discuss the diagnostic and therapeutic potentials of targeting RNA modifications and mRNA translation for the clinical management of liver cancer., (© 2024. Springer Nature Limited.)

Objective: Olfactory disturbance is one of the main symptoms of coronavirus disease-2019 (COVID-19). Various olfactory disorders caused by viral infections are treated with nasal corticosteroids. This study aimed to evaluate the safety and efficacy of nasal corticosteroids in the treatment of olfactory disorders caused by the severe acute respiratory syndrome coronavirus 2., Data Sources: We searched the Web of Science, Embase, PubMed, and Cochrane Library databases for clinical trials of nasal corticosteroids for treating COVID-19 olfactory dysfunction., Review Methods: We assessed the effect of nasal corticosteroids on olfactory function in COVID-19-affected individuals using a Meta-analysis of published studies, considering the number of patients who fully recovered from olfactory dysfunction, olfactory scores following treatment, and olfactory recovery time., Results: Seven studies involving 930 patients were analyzed. The Meta-analysis results revealed that the olfactory score of the experimental group was 1.40 points higher than that of the control group (standardized mean difference [MD]: 1.40, 95% confidence interval [95% CI]: 0.34-2.47, P < .00001). However, the differences in the outcomes of cure rate (risk ratio: 1.18, 95% CI: 0.89-1.69, P = .21) and recovery time (MD: -1.78, 95% CI: -7.36 to 3.81, P = .53) were not statistically significant. Only 1 study reported adverse effects of nasal steroid treatment, namely tension, anger, and stomach irritation., Conclusion: Although nasal steroid therapy does not result in significant adverse effects, it proves ineffective in the treatment of COVID-19 olfactory dysfunction., (© 2023 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Background and Aims: Scirrhous HCC (SHCC) is one of the unique subtypes of HCC, characterized by abundant fibrous stroma in the tumor microenvironment. However, the molecular traits of SHCC remain unclear, which is essential to develop specialized therapeutic approaches for SHCC., Approach and Results: We presented an integrative analysis containing single-cell RNA-sequencing, whole-exome sequencing, and bulk RNA-sequencing in SHCC and usual HCC samples from 134 patients to delineate genomic features, transcriptomic profiles, and stromal immune microenvironment of SHCC. Multiplexed immunofluorescence staining, flow cytometry, and functional experiments were performed for validation. Here, we identified SHCC presented with less genomic heterogeneity while possessing a unique transcriptomic profile different from usual HCC. Insulin-like growth factor 2 was significantly upregulated in SHCC tumor cells compared to usual HCC, and could serve as a potential diagnostic biomarker for SHCC. Significant tumor stromal remodeling and hypoxia were observed in SHCC with enrichment of matrix cancer-associated fibroblasts and upregulation of hypoxic pathways. Insulin-like growth factor 2 was identified as a key mediator in shaping the hypoxic stromal microenvironment of SHCC. Under this microenvironment, SHCC exhibited an immunosuppressive niche correlated to enhanced VEGFA signaling activity, where CD4 + T cells and CD8 + T cells were dysfunctional. Furthermore, we found that another hypoxic-related molecule SPP1 from SHCC tumor cells suppressed the function of dendritic cells via the SPP1-CD44 axis, which also probably hindered the activation of T cells., Conclusion: We uncovered the genomic characteristics of SHCC, and revealed a hypoxia-driven tumor stroma remodeling and immunosuppressive microenvironment in SHCC., (Copyright © 2023 American Association for the Study of Liver Diseases.)

In this research, we aimed to harness machine learning to predict the imminent risk of acute exacerbation in chronic obstructive pulmonary disease (AECOPD) patients. Utilizing retrospective data from electronic medical records of two Taiwanese hospitals, we identified 26 critical features. To predict 3- and 6-month AECOPD occurrences, we deployed five distinct machine learning algorithms alongside ensemble learning. The 3-month risk prediction was best realized by the XGBoost model, achieving an AUC of 0.795, whereas the XGBoost was superior for the 6-month prediction with an AUC of 0.813. We conducted an explainability analysis and found that the episode of AECOPD, mMRC score, CAT score, respiratory rate, and the use of inhaled corticosteroids were the most impactful features. Notably, our approach surpassed predictions that relied solely on CAT or mMRC scores. Accordingly, we designed an interactive prediction system that provides physicians with a practical tool to predict near-term AECOPD risk in outpatients., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s).)

Purpose: Australian general practice training uses external clinical teaching (ECT) visits for formative work-based assessments. ECT visits appoint senior general-practitioners (GPs) observe trainee GPs' consultations, provide feedback, and make performance-enhancing recommendations. As ECT visits are one of the best assessment tools in Australian GP training, there is limited evidence of its use in undergraduate teaching. This study aims to introduce ECT visits and evaluate assessment tools during senior medical students' GP placement., Methods: This study included external and internal GP supervisors and twenty-five Chinese and Australian students during GP placements. The supervisors provided structured in-person feedback, while the ECT assessment tool used a standardised, validated feedback platform to assess every component of a consultation. Students' feedback was recorded and collected by both internal and external supervisors, and then semantically analysed by external supervisors., Results: Twenty-five ECT visit feedbacks were collected and analysed semantically. All participating students rated ECT visits excellently and confirmed the relevance of assessment tools for discussions with supervisors to achieve the designed learning outcomes. Chinese students rated the assessment tools as innovative from a cultural perspective and recommended the ECT visit teaching model and assessment tools to their home university, whereas Australian students suggested more ECT visits during GP placements. Time management was a limitation for both the students and supervisors., Conclusion: ECT visit is an innovative placement teaching model and work-based assessment tool for senior medical students' GP placements, and is rated as the most preferred formative assessment tool. The limitations of this study include small group of students/supervisors and lack of patient feedback; however, all of these limitations can be overcome by involving multiple GP clinics in ongoing large-scale study. ECT visits can be introduced quantitatively into students' GP placement curricula to improve clinical reasoning, learning, and quality assurance with assessments during clinical placements., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Feng et al.)

N6-methyladenosine (m6A) RNA modification is the most common and conserved epigenetic modification in mRNA and has been shown to play important roles in cancer biology. As the m6A reader YTHDF1 has been reported to promote progression of hepatocellular carcinoma (HCC), it represents a potential therapeutic target. In this study, we evaluated the clinical significance of YTHDF1 using human HCC samples and found that YTHDF1 was significantly upregulated in HCCs with high stemness scores and was positively associated with recurrence and poor prognosis. Analysis of HCC spheroids revealed that YTHDF1 was highly expressed in liver cancer stem cells (CSC). Stem cell-specific conditional Ythdf1 knockin (CKI) mice treated with diethylnitrosamine showed elevated tumor burden as compared with wild-type mice. YTHDF1 promoted CSCs renewal and resistance to the multiple tyrosine kinase inhibitors lenvatinib and sorafenib in patient-derived organoids and HCC cell lines, which could be abolished by catalytically inactive mutant YTHDF1. Multiomic analysis, including RNA immunoprecipitation sequencing, m6A methylated RNA immunoprecipitation sequencing, ribosome profiling, and RNA sequencing identified NOTCH1 as a direct downstream of YTHDF1. YTHDF1 bound to m6A modified NOTCH1 mRNA to enhance its stability and translation, which led to increased NOTCH1 target genes expression. NOTCH1 overexpression rescued HCC stemness in YTHDF1-deficient cells in vitro and in vivo. Lipid nanoparticles targeting YTHDF1 significantly enhanced the efficacy of lenvatinib and sorafenib in HCC in vivo. Taken together, YTHDF1 drives HCC stemness and drug resistance through an YTHDF1-m6A-NOTCH1 epitranscriptomic axis, and YTHDF1 is a potential therapeutic target for treating HCC., Significance: Inhibition of YTHDF1 expression suppresses stemness of hepatocellular carcinoma cells and enhances sensitivity to targeted therapies, indicating that targeting YTHDF1 may be a promising therapeutic strategy for liver cancer., (©2024 American Association for Cancer Research.)

Background and Aims: Hepatoblastoma (HB) is the most common liver cancer in children, posing a serious threat to children's health. Chemoresistance is the leading cause of mortality in patients with HB. A more explicit definition of the features of chemotherapy resistance in HB represents a fundamental urgent need., Approach and Results: We performed an integrative analysis including single-cell RNA sequencing, whole-exome sequencing, and bulk RNA sequencing in 180 HB samples, to reveal genomic features, transcriptomic profiles, and the immune microenvironment of HB. Multicolor immunohistochemistry staining and in vitro experiments were performed for validation. Here, we reported four HB transcriptional subtypes primarily defined by differential expression of transcription factors. Among them, the S2A subtype, characterized by strong expression of progenitor ( MYCN , MIXL1 ) and mesenchymal transcription factors ( TWIST1 , TBX5 ), was defined as a new chemoresistant subtype. The S2A subtype showed increased TGF-β cancer-associated fibroblast and an immunosuppressive microenvironment induced by the upregulated TGF-β of HB. Interestingly, the S2A subtype enriched SBS24 signature and significantly higher serum aflatoxin B1-albumin (AFB1-ALB) level in comparison with other subtypes. Functional assays indicated that aflatoxin promotes HB to upregulate TGF-β. Furthermore, clinical prognostic analysis showed that serum AFB1-ALB is a potential indicator of HB chemoresistance and prognosis., Conclusions: Our studies offer new insights into the relationship between aflatoxin and HB chemoresistance and provide important implications for its diagnosis and treatment., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Chronic obstructive pulmonary disease (COPD) is a preventable and treatable chronic condition characterized by progressive, partially reversible airflow obstruction. Osteoporosis represents a significant comorbidity in individuals with COPD. However, the incidence and prevalence of osteoporosis among the COPD population remain unclear in Taiwan. Therefore, our objective is to investigate the incidence and prevalence of osteoporosis in patients with COPD., Methods: In this cross-sectional study, we enrolled a COPD population retrieved from the Taiwan National Health Insurance Research Database (NHIRD) spanning the years 2003 to 2016. Osteoporosis patients were identified using diagnosis codes. The study included newly diagnosed COPD patients from 2003 to 2016. The case group comprised patients who developed osteoporosis or osteoporotic fractures after their COPD diagnosis. We calculated the prevalence and incidence of osteoporosis in individuals with COPD and conducted trend tests., Results: A total of 1,297,579 COPD patients were identified during the period from 2003 to 2016, with 275,233 of them in the osteoporosis group. The average prevalence of osteoporosis among individuals with COPD was 21.21% from 2003 to 2016 in Taiwan. The number of osteoporosis cases increased from 6,727 in 2003 to 24,184 in 2016. The prevalence of osteoporosis among COPD patients increased from 3.62% in 2003 to 18.72% in 2016. The number of osteoporosis cases among individuals with COPD continued to rise over the years, reaching its highest point in 2016 with 24,184 new cases. The incidence of osteoporosis fluctuated during the study period but generally remained around 3,000 cases per 100,000 person-years. Notably, there was a significant upward trend in incidence from 2003 to 2006, after which the trend stabilized and remained relatively constant., Conclusions: Our study highlights an increase in both the prevalence and incidence of osteoporosis in individuals with COPD. Given the significant medical, economic, and social implications associated with osteoporosis, a comprehensive and robust assessment of its healthcare burden can offer valuable insights for healthcare system planning and policymaking., (© 2024. The Author(s).)

Background and Aims: NASH-HCC is inherently resistant to immune checkpoint blockade, but its tumor immune microenvironment is largely unknown., Approach and Results: We applied the imaging mass cytometry to construct a spatially resolved single-cell atlas from the formalin-fixed and paraffin-embedded tissue sections from patients with NASH-HCC, virus-HCC (HBV-HCC and HCV-HCC), and healthy donors. Based on 35 biomarkers, over 750,000 individual cells were categorized into 13 distinct cell types, together with the expression of key immune functional markers. Higher infiltration of T cells, myeloid-derived suppressor cell (MDSCs), and tumor-associated macrophages (TAMs) in HCC compared to controls. The distribution of immune cells in NASH-HCC is spatially heterogeneous, enriched at adjacent normal tissues and declined toward tumors. Cell-cell connections analysis revealed the interplay of MDSCs and TAMs with CD8 + T cells in NASH-HCC. In particular, exhausted programmed cell death 1 (PD-1 + )CD8 + T cells connected with programmed cell death-ligand 1 (PD-L1 + )/inducible T cell costimulator (ICOS + ) MDSCs and TAMs in NASH-HCC, but not in viral HCC. In contrast, CD4 + /CD8 + T cells with granzyme B positivity were reduced in NASH-HCC. Tumor cells expressed low PD-L1 and showed few connections with immune cells., Conclusions: Our work provides the first detailed spatial map of single-cell phenotypes and multicellular connections in NASH-HCC. We demonstrate that interactions between MDSCs and TAMs with effector T cells underlie immunosuppression in NASH-HCC and are an actionable target., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Chronic airway diseases have been associated with an increased risk of tuberculosis (TB); however, data in patients with bronchiectasis is limited. Statins have been shown to exhibit anti-inflammatory effects by modulating the inflammatory response. This study investigated whether statin treatment could reduce the risk of TB in patients with bronchiectasis., Methods: We conducted a retrospective cohort study using a nationwide population database of patients with bronchiectasis who did or did not receive statin treatment. The defined daily dose (DDD) of statin, current or past statin user and statin exposure time were measured for the impact of statin use. The primary outcome was the incidence of new-onset TB. Considering of potential immortal time bias due to stain exposure time, Cox regression models with time-dependent covariates were employed to estimate HRs with 95% CIs for TB incidence among patients with bronchiectasis., Results: Patients with bronchiectasis receiving statin treatment had a decreased risk of TB. After adjusting for age, sex, income, comorbidities and Charlson Comorbidity Index, statin users had a 0.59-fold lower risk of TB incidence compared with non-statin users (95% CI 0.40 to 0.88; p=0.0087). Additionally, compared with non-statin users, statin treatment was a protective factor against TB in users with a cumulative DDD greater than 180 per year, with an HR of 0.32 (95% CI 0.12 to 0.87; p=0.0255)., Conclusions: Statin treatment demonstrated a dose-dependent protective effect and was associated with a reduced risk of TB in patients with bronchiectasis. These findings suggest that statins may play a role in lowering TB risk by modulating airway inflammation in this patient population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)