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Owing to the exceptional porous properties of metal-organic frameworks (MOFs), there has recently been a surge of interest, evidenced by a plethora of research into their design, synthesis, properties, and applications. This expanding research landscape has driven significant advancements in the precise regulation of MOF design and synthesis. Initially dominated by large-scale synthesis approaches, this field has evolved towards more targeted functional modifications. Recently, the integration of computational science, particularly through artificial intelligence predictions, has ushered in a new era of innovation, enabling more precise and efficient MOF design and synthesis methodologies. The objective of this review is to provide readers with an extensive overview of the development process of MOF design and synthesis, and to present visions for future developments.

Zwitterionic materials, known for their high hydrophilicity, are widely used to minimize the nonspecific adsorption of biomolecules in complex biological solutions. However, these materials can also reduce the capture efficiency between targets and peptide probes. To demonstrate how antifouling surfaces affect capture efficiency, we utilize a poly(3,4-ethylenedioxythiophene) (PEDOT)-based surface incorporating varying ratios of phosphorylcholine (PEDOT-PC) and maleimide functional groups to achieve both antifouling properties and peptide-protein binding. As a model system, the peptide YWDKIKDFIGGSSSSC, attached via maleimide groups, is used to capture the target protein, calmodulin (CaM). By systematically monitoring protein binding on both antifouling and peptide-immobilized PEDOT surfaces using a quartz crystal microbalance with dissipation, the results reveal that PEDOT-PC reduces both the specific binding between peptides and target proteins as well as the rate of protein fouling on the electrode surface. From these findings, we propose an equation for quantitative analysis. Furthermore, electrochemical impedance spectroscopy and differential pulse voltammetry are performed to measure the changes in the impedance in CaM solutions. The data indicate that impedance increases with protein adsorption, confirming the practical utility of the designed electrode surface.

Counselling sessions have multiple stages, each with its themes and objectives. This study aimed to apply Hidden Markov Models (HMMs) to analyse counselling sessions from Open Up, an online text-based counselling platform in Hong Kong. The focus was on inferring latent stages over word distributions and identifying distinctive patterns of progression in more versus less satisfying sessions. Transcripts from 2589 sessions were categorized into more satisfying sessions ( n = 1993 ) and less satisfying sessions ( n = 596 ) based on post-session surveys. A message-level HMM identified five distinct stages: Rapport-building, Problem-identification, Problem-exploration, Problem-solving, and Wrap-up. Compared with less satisfying sessions, more satisfying sessions saw significantly more efficient initial rapport building (7.5% of session duration), problem introduction (20.2%), problem exploration (28.5%), elaborated solution development (46.6%), and concise conclusion (8.2%). This study offers insights for improving the efficiency and satisfaction of text-based counselling services through efficient initial engagement, thorough issue exploration, and focused problem-solving., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

This study aimed to assess the characteristics of particulate matter (PM) and polycyclic aromatic hydrocarbons (PAHs) from various stationary and mobile emission sources in Taiwan, with a focus on source apportionment and associated health risks. The northern power plant, equipped with bag filters operating at 150 °C, had significantly lower FPM and CPM levels (0.44 and 0.13 mg/m 3 , respectively) compared to the central and southern power plants, which used electrostatic precipitators operating at 250 °C (FPM, 1.45-8.35 mg/m 3 ; CPM, 2.37-3.73 mg/m 3 ). Additionally, emissions from diesel vehicles under both idle and high-speed conditions exhibited higher FPM levels (3.46-4.67 mg/m 3 ) than gasoline vehicles (0.19-0.40 mg/m 3 ). In terms of PAH toxicity, diesel vehicle emissions had significantly higher BaP-TEQ (87.3 ng/m 3 ) and BaP-MEQ (25.9 ng/m 3 ) levels compared to power plants (BaP-TEQ, 5.49 ng/m 3 ; BaP-MEQ, 2.65 ng/m 3 ). The highest ambient concentrations of PM2.5, BaP-TEQ, and BaP-MEQ were recorded at traffic sites, with values of 48 ± 36 µg/m 3 , 0.29 ng/m 3 , and 0.11 ng/m 3 , respectively. Differences in PAH distributions between stationary and mobile sources were influenced by factors such as pollution control technologies, combustion temperatures, and fuel types. Diesel vehicle emissions were dominated by benzo[g,h,i]perylene (BghiP), indeno[1,2,3-cd]pyrene (IND), benzo[a]pyrene (BaP), and benzo[b]fluoranthene (BbF) under idle conditions, while phenanthrene (PA), pyrene (Pyr), and BghiP were prevalent under high-speed conditions. Source apportionment conducted using principal component analysis (PCA) and positive matrix factorization (PMF) identified diesel and gasoline vehicles as the dominant contributors to atmospheric PAHs in Taiwan, accounting for 38% of the total, followed by coal-fired power plants at 35%. The highest lifetime excess cancer risk (ECR) of 2.5 × 10⁻ 5 was observed in traffic-dense areas, emphasizing the public health implications of vehicle emissions. The study adds credibility to the source apportionment findings, and the health risk analysis highlights variations across different regions, including traffic, urban, rural, and background zones., Competing Interests: Declarations Ethical approval Not applicable. Consent to participate All authors contributed to this work. Consent for publication All authors have approved authorship, read, and consented to publication. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background and Aim: Computed tomography of the abdomen exhibits subtle and complex features of liver lesions, subjectively interpreted by physicians. We developed a deep learning-based localization and classification (DLLC) system for focal liver lesions (FLLs) in computed tomography imaging that could assist physicians in more robust clinical decision-making., Methods: We conducted a retrospective study (approval no. EMRP-109-058) on 1589 patients with 17 335 slices with 3195 FLLs using data from January 2004 to December 2020. The training set included 1272 patients (male: 776, mean age 62 ± 10.9), and the test set included 317 patients (male: 228, mean age 57 ± 11.8). The slices were annotated by annotators with different experience levels, and the DLLC system was developed using generative adversarial networks for data augmentation. A comparative analysis was performed for the DLLC system versus physicians using external data., Results: Our DLLC system demonstrated mean average precision at 0.81 for localization. The system's overall accuracy for multiclass classifications was 0.97 (95% confidence interval [CI]: 0.95-0.99). Considering FLLs ≤ 3 cm, the system achieved an accuracy of 0.83 (95% CI: 0.68-0.98), and for size > 3 cm, the accuracy was 0.87 (95% CI: 0.77-0.97) for localization. Furthermore, during classification, the accuracy was 0.95 (95% CI: 0.92-0.98) for FLLs ≤ 3 cm and 0.97 (95% CI: 0.94-1.00) for FLLs > 3 cm., Conclusion: This system can provide an accurate and non-invasive method for diagnosing liver conditions, making it a valuable tool for hepatologists and radiologists., (© 2024 The Author(s). Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: Achieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical models and clinical trials for chronic hepatitis B (CHB). However, little is known regarding its action on immune effectors within the liver. Our aim was to characterise the transcriptomic changes and intercellular communication events induced by SLGN in the hepatic microenvironment., Design: We identified TLR8 -expressing cell types in the human liver using publicly available single-cell RNA-seq data and established a method to isolate Kupffer cells (KCs). We characterised transcriptomic and cytokine KC profiles in response to SLGN. SLGN's indirect effect was evaluated by RNA-seq in hepatocytes treated with SLGN-conditioned media (CM) and quantification of HBV parameters following infection. Pathways mediating SLGN's effect were validated using transcriptomic data from HBV-infected patients., Results: Hepatic TLR8 expression takes place in the myeloid compartment. SLGN treatment of KCs upregulated monocyte markers (eg, S100A12 ) and downregulated genes associated with the KC identity (eg, SPIC ). Treatment of hepatocytes with SLGN-CM downregulated NTCP and impaired HBV entry. Cotreatment with an interleukin 6-neutralising antibody reverted the HBV entry inhibition., Conclusion: Our transcriptomic characterisation of SLGN sheds light into the programmes regulating KC activation. Furthermore, in addition to its previously described effect on established HBV infection and adaptive immunity, we show that SLGN impairs HBV entry. Altogether, SLGN may contribute through KCs to remodelling the intrahepatic immune microenvironment and may thus represent an important component of future combinations to cure HBV infection., Competing Interests: Competing interests: FZ and BT received grants from Assembly, Beam Therapeutics, Blue Jay and JnJ; FZ had consulting activities with Assembly, Blue Jay and GSK. YCH receives grants from Gilead Sciences and Sysmex. FZ is an associate editor of the journal. SD, LL, NK, JJW, AHL, and SPF are or were employees of Gilead Sc., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Empathy is an important factor in the doctor-patient relationship, but mental illness is more difficult to understand than other diseases. Besides traditional skills, virtual reality (VR) has been identified as a promising tool in empathy education. This study aimed to investigate the ability of empathy enhancement, the feasibility of depression education, and the changes in thoughts and attitudes in medical students through a single VR experience., Methods: We recruited medical students and randomly assigned them to two groups based on their completed Interpersonal Response Index scores. Two sets of VR systems were provided; the intervention group experienced the daily life of the depressed medical student, while the control group experienced the general medical student scenario. The improvement of empathy was assessed using the Jefferson Scale of Empathy-Health Professional Students (JSE-HPS), and the change of attitude was assessed through the Implicit Association Test. In addition, other questionnaires were used to evaluate the user experience of this VR system, and correlation analysis was conducted to examine the association between the use of VR and changes in the JSE and IAT scores., Results: A total of 59 medical students were enrolled in this study. The intervention group showed a significant increase in the perspective-taking (pre: mean 5.817, SD 0.536; post: mean 5.947, SD 0.620; P = .03) and compassionate care (pre: mean 5.546, SD 0.581; post: mean 5.721, SD 0.629; P = .01) domains of the JSE score and a significant decrease in the standing in the patient's shoes (SP) domain (pre: mean 3.583, SD 1.253; post: mean 2.967, SD 1.252; P = .002). The Pearson correlation analysis found a significant positive correlation between the JSE score with immersion aspect (r = .308, P = .049) and presence aspect (r = .415, P = .01), and we also found a significant negative correlation between the IAT score and presence aspect (r=-.333, P = .04)., Conclusions: This study is the first randomized case-control study to investigate the effect of two different versions of VR on empathy development toward depression for medical students. Although the single VR experience was unable to induce a great improvement in empathy or attitude, the VR system could help medical students enhance their understanding of depressive disorders., Trial Registration: This trial was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) (21/03/2024, ACTRN12624000297527). https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386683&isReview=true ., (© 2024. The Author(s).)

Pain is a sensation that signals the presence of inflammation or injury. In this issue of Developmental Cell, Ben-Shaanan et al. 1 show that beyond its sensory function, pain can activate hair follicle stem cells (HFSCs) by controlling their niche., Competing Interests: Declaration of interests Y.-C.H. is an inventor on a patent filed by the President and Fellows of Harvard College for methods and compositions related to hair growth control., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/aim: Beta2-glycoprotein I (β2-GPI) is a plasma glycoprotein with multiple physiological functions, but its relationship with hepatocellular carcinoma (HCC) is still poorly understood. HCC is one of the most common forms of liver cancer and is a leading cause of cancer-related death worldwide. This study aimed to investigate the association between β2-GPI and liver cancer and further validate its potential as a biomarker for HCC., Patients and Methods: Thirty-six patients diagnosed with HCC at the Division of Gastroenterology and Hepatology, E-Da Hospital, Taiwan, were included in the study. The expression levels of β2-GPI in plasma specimens from patients with HCC were determined by enzyme immunoassay and analyzed in relation to clinicopathological variables using the Chi-square test or Fisher's exact test. The predictive significance of β2-GPI for both overall survival (OS) and disease-free survival (DFS) was assessed using Kaplan-Meier estimates, and the statistical significance of differences was evaluated through the log-rank test. Cox proportional hazards regression models were used to evaluate the association between OS/DFS time and clinicopathological characteristics., Results: Results: Plasma β2-GPI levels were significantly lower in patients with HCC compared to non-cancer controls and significantly correlated with aspartate aminotransferase (AST) levels of HCC. High plasma β2-GPI levels were significantly associated with better OS and DFS in HCC patients. Furthermore, in multiple variates analyses, OS was found to be significantly better in HCC patients with higher plasma β2-GPI expression., Conclusion: Elevated levels of β2-GPI protein in the plasma of HCC patients were identified as an independent factor predictive of improved OS and DFS. Activating β2-GPI in individuals at high risk could serve as a promising way for mitigating the progression of HCC., Competing Interests: The Authors declare that they have no conflicting interests., (©2024 The Author(s). Published by the International Institute of Anticancer Research.)

Mutations in various type II transmembrane serine protease (TMPRSS) family members are associated with non-syndromic hearing loss, with some mechanisms still unclear. For instance, the mechanism underlying profound hearing loss and tectorial membrane (TM) malformations in hepsin/TMPRSS1 knockout (KO) mice remains elusive. In this study, we confirmed significantly elevated hearing thresholds and abnormal TM morphology in hepsin KO mice, characterized by enlarged TM with gaps and detachment from the spiral limbus. Transgenic mouse lines were created to express either wild-type or a serine protease-dead mutant of human hepsin in the KO background. The Tg68;KO line, expressing moderate levels of wild-type human hepsin in the cochlea, showed partial restoration of hearing function. Conversely, the Tg5;KO or TgRS;KO lines, with undetectable hepsin or protease-dead hepsin, did not show such improvement. Histological analyses revealed that Tg68;KO mice, but not Tg5;KO or TgRS;KO mice, had a more compact TM structure, partially attached to the spiral limbus. These results indicate that hepsin expression levels correlate with improvements in hearing and TM morphology, and its protease activity is critical for these effects. Hepsin's role was further examined by studying its relationship with α-tectorin (TECTA) and β-tectorin (TECTB), non-collagenous proteins crucial for TM formation. Hepsin was co-expressed with TECTA and TECTB in the developing cochlear epithelium. Immunostaining showed decreased levels of TECTA and TECTB in hepsin KO TM, partially restored in Tg68;KO mice. These findings suggest that hepsin is essential for proper TM morphogenesis and auditory function, potentially by proteolytic processing/maturation of TECTA and TECTB and their incorporation into the TM., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dysregulated protein homeostasis, characterized by abnormal protein accumulation and aggregation, is a key contributor to the progression of neurodegenerative disorders such as Huntington's disease and spinocerebellar ataxia type 3 (SCA3). Previous studies have identified PIAS1 gene variants in patients with late-onset SCA3 and Huntington's disease. This study aims to elucidate the role of PIAS1 and its S510G variant in modulating the pathogenic mechanisms of SCA3. Through in vitro biochemical analyses and in vivo assays, we demonstrate that PIAS1 stabilizes both wild-type and mutant ataxin-3 (ATXN3). The PIAS1 S510G variant, however, selectively reduces the stability and SUMOylation of mutant ATXN3, thereby decreasing its aggregation and toxicity while maintaining the stability of wild-type ATXN3. This effect is mediated by a weakened interaction with the SUMO-conjugating enzyme UBC9 in the presence of mutant ATXN3. In Drosophila models, downregulation of dPIAS1 resulted in reduced levels of mutant ATXN3 and alleviated associated phenotypes, including retinal degeneration and motor dysfunction. Our findings suggest that the PIAS1 S510G variant acts as a genetic modifier of SCA3, highlighting the potential of targeting SUMOylation as a therapeutic strategy for this disease., 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A rapid, sensitive and specific test for blood is reported based on a novel application of recombinase polymerase amplification integrated with CRISPR-Cas and lateral flow assay (LFA). The blood specific marker ALAS2 was used as the target to record the presence of blood. The assay used either RNA extracted from a body fluid as a template, or omitting this extraction step and using a direct approach where the questioned body fluid was added directly to the assay. The assay only detected blood (all peripheral blood and some menstrual blood samples) and no other body fluid (semen, saliva, or vaginal fluid). The limit of detection varied from an initial template of 0.195 ng extracted RNA (2 7 dilution) or 0.0218 μL (2 6 dilution) liquid peripheral blood. The assay gave the expected result when peripheral blood was mixed with saliva: ratios of peripheral blood/saliva at 19:1, 3:1, 1:1, 1:3 and 1:19 all gave a positive result using extracted RNA. By contrast, only three ratios of peripheral blood and saliva gave a positive result for blood (19:1, 3:1 and 1:1) when adding these two body fluids directly. When peripheral blood was mixed with semen there was a strong inhibition of the assay and ALAS2 could only be detected at ratio of 19:1 using RNA. Using reconstituted peripheral bloodstains gave comparable results to liquid peripheral blood. This is the first application of RT-RPA integrated CRISPR and combined with a LFA assay to detect body fluid-specific RNA. The proposed method opens up the potential to perform this method remote from laboratories such as at crime scenes., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Perfusion imaging is useful to assess tissue recovery in patients with acute ischemic stroke (AIS); however, it cannot reflect tissue metabolism. We postulated that amide proton transfer (APT) imaging can characterize the tissue status after reperfusion therapy, thus providing prognostic value for 90-day functional outcomes. We included 63 patients with AIS and large-vessel occlusion (LVO). The APT signals, including APT # and NOE # (nuclear Overhauser enhancement) were quantified. Ischemic lesions observed on APT # and diffusion-weighted imaging (DWI) were classified according to their mismatch patterns (APT #  < DWI; APT # ≥ DWI). Predictors of 90-day good outcomes (modified Rankin scale score 0-2) were evaluated. Patients with successful reperfusion exhibited higher APT # , smaller percentage change of APT # , and a greater likelihood of presenting APT #  < DWI compared to those with poor reperfusion (all P  < 0.05). The APT # (odds ratio [OR] = 11.48, P  = 0.046) and a mismatch pattern of APT #  < DWI (OR = 7.41, P  = 0.020) independently predicted good outcomes besides the clinical parameters. A mismatch pattern of APT # ≥ DWI was a significant marker of poor outcomes despite successful reperfusion ( P  = 0.002). Our study provides preliminary evidence that APT may reveal tissue recovery after reperfusion and predict good outcomes at 90 days in patients with AIS and LVO., 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.

The bioactive compounds in burdock ( Arctium lappa L.) roots, including chlorogenic acid (CGA) and cynarin, are valuable for use in nutraceutical foods. The ultrasound-assisted extraction of bioactive substances from dried burdock root powder (DBR) was investigated with 95% ethanol to reduce the impact of polysaccharide inulin on the extraction of free CGA and cynarin. The ethanolic extraction of CGA and cynarin was evaluated under ultrasound (300 W) at 40 kHz (U40) and 120 kHz (U120) with shaking at 120 rpm (S120) for comparison. Using a 1/30 (g/mL-solvent) solid-to-liquid ratio at 30 °C in 120 min, amounts of CGA and cynarin with U40 were as high as 818.74 μg/g-DBR and 173.68 μg/g-DBR, respectively, being much higher than those with U120 and S120. Total phenolic content, total flavonoid content, and antioxidant activity of the extract using U40 were significantly better than using U120 and S120. For U40 and U120, CGA increased with a decreasing solid-to-liquid ratio, while cynarin showed a decrease with a decreasing solid-to-liquid ratio using U120. Moreover, no observable degradations of free CGA and cynarin in ethanol were detected. By combining ultrasound and ethanol, the extracts with high-content CGA and cynarin from burdock roots were effectively achieved for use in health foods.

Background & Aims: The epidemiology of adult primary liver cancer continues to evolve, related to the increasing prevalence of metabolic disease, rising alcohol consumption, advancements in vaccination for hepatitis B (HBV), and antiviral therapy for hepatitis C (HCV). Disparities in care and the burden of liver cancer between populations persist. We assess trends in the burden of liver cancer and contributions by various etiologies across 204 countries and territories from 2010 to 2021., Methods: Utilizing the methodological framework of the Global Burden of Disease Study 2021, we analyzed global and regional temporal trends in incidence and mortality, and the contributions of various etiologies of liver disease., Results: In 2021, there were an estimated 529202 incident cases and 483875 deaths related to liver cancer. From 2010 to 2021, global liver cancer incident cases and deaths increased by 26% and 25%, respectively. Global age-standardized incidence rates (ASIRs) and death rates (ASDRs) for liver cancer declined but rose in the Americas and Southeast Asia. HBV remained the dominant cause of global incident liver cancer cases and deaths. Metabolic dysfunction-associated steatotic liver disease (MASLD) was the only etiology of liver cancer with rising ASIRs and ASDRs. By contrast, ASIRs and ASDRs remained stable for alcohol-related liver cancer, and declined for HBV- and HCV-related liver cancer., Conclusions: While age-adjusted incidence and deaths from liver cancer have started to decline, the absolute number of incident cases and deaths continues to increase. Population growth and aging contribute to the observed disconnect in the temporal trends of absolute cases and rates. Disparities remain, and MASLD-related liver cancer continues to surge., (Copyright © 2024. Published by Elsevier B.V.)

Background: Increasingly, more evidence has shown that inflammation stress and the tumor microenvironment pose a negative effect on targeted therapy. The neutrophil-to-lymphocyte ratio is considered to be a surrogate biomarker of inflammation and can predict pazopanib treatment effect in non-adipocytic soft-tissue sarcoma (STS). The role of the pan-immune-inflammation value (PIV) in STS is still yet to be determined., Objectives: We sought whether the pre-treatment PIV could be applied to predict the response of pazopanib in STS., Design: We conducted a retrospective analysis of 75 patients who had been treated with pazopanib for recurrent or metastatic non-adipocytic STS., Methods: Our cohort was stratified into either a pre-treatment high PIV group with PIV ⩾310 ( n  = 45) or a low PIV group with PIV <310 ( n  = 30). We compared their clinical features and outcomes. Cox regression analysis was employed to determine the risk factors of disease progression and mortality. Kaplan-Meier survival curves were utilized to assess both the progression-free survival (PFS) and overall survival (OS)., Results: The results revealed that a pre-treatment high PIV (⩾310) is a risk factor for progression under pazopanib (hazard ratio: 1.91; 95% confidence interval: 1.08-3.36; p  = 0.025). The median PFS and OS of the pre-treatment high PIV group were found to be significantly lower than the low PIV group (0.33 vs 0.75 years; p  = 0.023, 0.46 vs 1.63 years; p  = 0.025)., Conclusion: High pre-treatment PIV in STS patients may indicate an elevated risk of disease progression and mortality. Pre-treatment PIV reflects inflammation stress and acts as a practical biomarker for STS patients treated with pazopanib., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Background: To identify the association between daytime activity with objectively monitor and subjective variables at a different time-zone of day as well as the sex differences., Methods: Participants aged 50 years and older living in the community in Taiwan were recruited. The activity was measured by wearable actigraphy devices, diaries, and self-reported questionnaires. The study used nonparametric analysis to examine the association between mean activity level and demographic and subjective measurement variables., Results: Among the 55 participants enrolled in the study, data of 34 (62 %) participants who meet the criteria that wore a wearable actigraphy device for at least 7 completed days were analyzed. There is no significant relationship between each demographics and subjective measurement variables. However, actigraphy counts are significantly related to female's nutrition (Z = -2.367, p = 0.017*), and male's retirement status (Z = -2.132, p = 0.033*)., Conclusions: The activity in morning is highest of the day with significant correlation to evening activities. Moreover, actigraphy counts that indicating objective measure of physical activity in female is significantly related to physiological variables (nutritional status), while male are predicted by social variables (retired status)., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jia-Chian Hu reports financial support was provided by Ministry of Science and Technology. Jia-Chian Hu reports financial support was provided by National Cheng Kung University College of Medicine. Jia-Chian Hu reports a relationship with Ministry of Science and Technology that includes: funding grants. Jia-Chian Hu reports a relationship with National Cheng Kung University College of Medicine that includes: funding grants. 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Interpreting genetic variants remains a challenge in prostate cancer (PCa). Although many annotation tools are available for prioritizing causal variants, the clinical relevance of these variants is rarely studied., Methods: We collected a cohort study that included 274 PCa patients from June 2017 to December 2020 and sequenced 19 DNA damage repair (DDR) genes in these patients and explored the clinical consequence of these different approaches. We also examined all-cause and PCa-specific survival in DDR gene mutation carriers compared to non-carriers after androgen receptor (AR)-directed therapy., Results: We identified 13 variants from 19 DDR genes in a total of 14 (5.1%) patients who had at least one presumed pathogenic mutation using different annotation methods. Four variants were annotated as pathogenic, 11 variants were predicted as protein-truncating variants (PTVs), four variants received proxy-deleterious (Combined Annotation-Dependent Depletion scores of > 30), and only one variant was identified as a pathogenic variant or as having a functional effect by all three methods. PCa patients with PTVs were significantly associated with early onset, high cancer stage, and a worse response to AR-directed treatment. However, patients carrying a proxy-deleterious variant were only associated with a higher T (tumor) stage and N (node) stage than those without such a variant, but not associated with other clinical characteristics. In patients treated with AR-directed therapy, patients with a PTV showed an increased risk of all-cause death (adjusted hazard ratio (aHR) = 3.51, 95% confidence interval (CI): 1.06 ~ 11.56) and PCa-specific death (aHR = 4.49, 95% CI: 1.87 ~ 10.77) compared to non-PTV carriers after adjustment. We were unable to examine gene-specific risks due to the small number of patients., Conclusions: PTVs may assist in guiding treatment and early screening in PCa, while population-specific data for pathogenic variants are still being amassed., (© 2024. The Author(s).)

Background: The global prevalence of ischemic stroke in young adults is increasing, leading to a significant social impact. Fabry disease is a recognized cause of ischemic stroke in young patients, and although disease-modifying treatments are available, further evidence is needed to confirm their effectiveness in reducing the incidence of ischemic strokes., Aims: This study aimed to identify undiagnosed Fabry disease in young adult patients with ischemic stroke in a Taiwanese cohort., Methods: This multicenter, prospective cohort study enrolled patients aged 20-55 years who had experienced an ischemic stroke or transient ischemic attack (TIA) within 10 days, from 1 January 2016 to 31 December 2020. Screening for Fabry disease was performed using a dry blood test to measure α-galactosidase activity in male patients and blood globotriaosylsphingosine (lyso-Gb3) levels in female patients. For patients with positive screen results, genetic diagnosis of Fabry disease was pursued through Sanger sequencing of the GLA gene, covering all exons and a segment of intron 4., Results: A total of 977 patients (659 male, 68%) were enrolled from seven hospitals across Taiwan. Four patients (0.4%, all male) had positive screening results, and two patients (0.2%) were genetically diagnosed with Fabry disease. Case 1 had the GLA c.658C>T mutation and experienced ischemic stroke in the bilateral occipital regions. Case 2 had the GLA c.640-801G>A mutation and experienced an ischemic stroke in the left superficial watershed area., Conclusion: The prevalence of undiagnosed Fabry disease in this cohort of Taiwanese young adults with ischemic stroke or TIA was 0.3% among the young male population. Understanding the prevalence of undiagnosed Fabry disease in young adults with ischemic stroke could help shape future Fabry disease screening policies., Data Access Statement: The collected data will be available upon reasonable request from the corresponding author., 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.

Background & Aims: Treatment indications for patients with chronic hepatitis B (CHB) remain contentious, particularly for patients with mild alanine aminotransferase (ALT) elevation. We aimed to evaluate treatment effects in this patient population., Methods: This rollover study extended a placebo-controlled trial that enrolled non-cirrhotic patients with CHB and ALT levels below two times the upper limit of normal. Following 3 years of randomized intervention with either tenofovir disoproxil fumarate (TDF) or placebo, participants were rolled over to open-label TDF for 3 years. Liver biopsies were performed before and after the treatment to evaluate histopathological changes. Virological, biochemical, and serological outcomes were also assessed (NCT02463019)., Results: Of 146 enrolled patients (median age 47 years, 80.8% male), 123 completed the study with paired biopsies. Overall, the Ishak fibrosis score decreased in 74 (60.2%), remained unchanged in 32 (26.0%), and increased in 17 (13.8%) patients (p<0.0001). The Knodell necroinflammation score decreased in 58 (47.2%), remained unchanged in 29 (23.6%), and increased in 36 (29.3%) patients (p=0.0038). The proportion of patients with an Ishak score ≥ 3 significantly decreased from 26.8% (n=33) to 9.8% (n=12) (p=0.0002). Histological improvements were more pronounced in patients switching from placebo. Virological and biochemical outcomes also improved in placebo switchers and remained stable in patients who continued TDF. However, serum HBsAg levels did not change and no patient cleared HBsAg., Conclusions: In CHB patients with minimally raised ALT, favorable histopathological, biochemical, and virological outcomes were observed following 3-year TDF treatment, for both treatment-naïve patients and those already on therapy.

Purpose: Postoperative delirium (POD) is a syndrome that often occurs after surgery. Nursing staff are the first-line personnel who have the most time and close contact with postoperative patients. If delirium is not recognized immediately, it will affect the patient's prognosis and increase clinical care requirements and health care costs. This study explores postanesthesia care unit (PACU) nursing staff's knowledge and ability to recognize POD in patients., Design: A cross-sectional study was conducted with purposive sampling to recruit nurses from hospital PACUs in central and southern Taiwan. Data were collected from April to December 2019 using a questionnaire survey on knowledge of POD and videos to test delirium recognition abilities., Methods: A total of 178 nurses from 9 hospitals met the inclusion criteria for participation; 2 participants were unable to attend because of taking leave, resulting in 176 valid questionnaires., Findings: The percentage of correct answers for POD knowledge was 63.84%, and for recognizing POD was 59.1%, both at a moderate level. Nurses' advanced skills significantly influenced their POD knowledge and recognition abilities. There was a positive correlation between PACU nurses' POD knowledge and recognition abilities (r = 0.23, P < .01)., Conclusions: PACU nurses demonstrated a moderate level of knowledge and ability to recognize POD in patients. Those with higher-level nursing skills showed better POD knowledge and recognition abilities. Nurses with better POD knowledge exhibited higher recognition abilities., Competing Interests: Declaration of Competing Interest None to report., (Copyright © 2024 The American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Objectives: Given increasing research suggesting the utility of positron emission tomography/magnetic resonance imaging (PET/MRI) in identifying the pain generator of low back pain, our study aims to assess its effectiveness in evaluating the source of pain in patients with failed back surgery syndrome (FBSS) by comparing the performance of fluorine-18-labeled fluorodeoxyglucose ( 18 F-FDG) PET/MRI with conventional MRI., Methods: We retrospectively analyzed data from patients with FBSS who underwent 18 F-FDG PET and MRI of the lumbar vertebrae and lower extremities for undetermined sources of pain. We assessed 1) The diagnostic reliability and efficacy of MRI and 18 F-FDG PET/MRI according to correct differential diagnosis, affected level, and affected side of the pain source compared to the findings of selective root or peripheral nerve block or revision lumbar spine surgery; and 2) The association between standardized uptake value (SUV) and standardized uptake value ratio (SUVR) threshold and accuracy of the suspected pathology on 18 F-FDG PET/MRI., Results: Among 30 included patients, the diagnostic accuracy of pain source recognition was higher for 18 F-FDG PET/MRI than for MRI alone (1.0 vs. 0.4 in spinal disease and 0.8 vs. 0 in lower extremity disease, both p < 0.05). SUVR values of 1.4-1.5 showed the highest accuracy (0.93), higher than the accuracy obtained using the SUV threshold (0.87)., Conclusion: 18 F-FDG PET/MRI added value to MRI alone in detecting of hypermetabolic activity associated with pain from spinal and non-spinal sources., (© 2024. The Author(s) under exclusive licence to Japan Radiological Society.)

Background/Objectives: Luteolin (LUT) is a natural flavonoid with known anti-inflammatory, antioxidant, and anti-cancer properties. Cervical cancer, particularly prevalent in certain regions, remains a significant health challenge due to its high recurrence and poor response to treatment. This study aimed to investigate the anti-tumor effects of LUT on human cervical epidermoid carcinoma cells (Ca Ski), focusing on cell growth inhibition, apoptosis induction, and regulation of mitochondrial membrane potential. Methods: Ca Ski cells were treated with varying concentrations of LUT (0, 25, 50, 100 µM) for different time periods (24, 48, 72 hours). Cell viability was measured using the MTT assay, apoptosis was assessed by flow cytometry with annexin V-FITC/PI staining, and changes in mitochondrial membrane potential were evaluated using JC-1 staining. Caspase-3 activation was examined by flow cytometry, and expression of apoptosis-related proteins (caspase-3, -8, -9, AIF) was analyzed via Western blotting. Results: LUT significantly inhibited the growth of Ca Ski cells in a dose- and time-dependent manner, with the most pronounced effects observed at 100 µM over 72 hours. Flow cytometry confirmed that LUT induced apoptosis without causing necrosis. Mitochondrial membrane potential was reduced after LUT treatment, coinciding with increased caspase-3 activation. Western blot analysis revealed the upregulation of pro-apoptotic proteins caspase-3, -8, -9, and AIF, indicating that LUT induces apoptosis through the intrinsic mitochondrial pathway. Conclusions: Luteolin effectively inhibits cervical cancer cell proliferation and induces apoptosis by disrupting mitochondrial membrane potential and activating caspases. These findings suggest that LUT holds potential as a therapeutic agent for cervical cancer, with further studies needed to explore its in vivo efficacy and broader clinical applications.

Background: The combination of anti-angiogenic therapy and immune checkpoint inhibitors has revolutionized the management of unresectable hepatocellular carcinoma (uHCC). While an early-phase study demonstrated promising outcomes for lenvatinib plus pembrolizumab (L+P) in treating uHCC, the LEAP-002 trial did not meet its primary endpoint. However, the comparative efficacy between L+P and atezolizumab plus bevacizumab (A+B) as first-line treatment remains a topic of uncertainty. This study aimed to assess the effectiveness and safety of L+P in contrast to A+B among patients diagnosed with uHCC., Methods: We conducted a retrospective analysis of enrolled patients with uHCC who received L+P or A+B as initial systemic treatment at Chang Gung Memorial Hospital from June 2019 to December 2022. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) by modified RECIST were compared., Results: 121 patients were recruited, with 37 receiving L+P and 84 receiving A+B. Among them, 95 (78.5%) patients were BCLC stage C, and 99 (81.8%) patients had viral etiology for HCC, predominantly chronic HBV (68.6%). Both the L+P and the A+B groups demonstrated comparable OS (18.2 months versus 14.6 months, p = 0.35) and PFS (7.3 months versus 8.9 months, p = 0.75). The ORR and DCR were similar. After propensity score matching, the results remained consistent between the matched patients. Treatment-related adverse events of any grade occurred in 30 (81.1%) in the L+P group and 62 (73.8%) in the A+B group., Conclusions: Our findings suggest that L+P and A+B exhibit comparable efficacy and safety profiles in real-world settings.

Background: The impact of nucleos(t)ide analogues on intrahepatic viral burden and immune microenvironment in patients with chronic hepatitis B (CHB) is not clear., Objective: We aimed to characterise the effects of tenofovir disoproxil fumarate (TDF) on intrahepatic viral burden and the liver immune microenvironment in patients with CHB., Design: Core liver biopsies were collected at baseline and year 3 from patients with CHB with minimally raised serum alanine aminotransferase in a double-blind placebo-controlled trial (NCT01522625). Paired biopsies were analysed by RNA-sequencing (n=119 pairs), a custom multiplex immunofluorescence assay (n=30 pairs), and HBV-targeted long-read DNA sequencing (n=49 pairs)., Results: Both non-integrated and integrated HBV DNA were present in all patients at baseline, with >65% having interchromosomal translocations. Treatment significantly reduced the frequency of HBV core+ hepatocytes and intrahepatic (integrated and non-integrated) HBV DNA, but had no effect on HBsAg+ hepatocytes. Clonally expanded integrations were enriched for HBsAg coding regions and showed dysregulation of nearby genes. At baseline, there was significant enrichment of intrahepatic CD8+ T cell proximity to HBV core+ hepatocytes, but not to HBsAg+ cells. The densities of T cells and B cells were significantly reduced by TDF. Transcriptomic analyses found TDF induced widespread downregulation of immune-related genes including inhibitory and regulatory genes., Conclusion: TDF significantly reduced intrahepatic integrated and non-integrated HBV DNA, exerting disparate effects on HBV core+ and HBsAg+ cells and on different immune cell subsets. Our data suggest there may be differential cytotoxic T cell-mediated killing of HBV core+ versus HBsAg+ hepatocytes, providing insights for HBV cure strategies., Competing Interests: Competing interests: DZP, CMS, AA, DH, NvB, PW, BF, BD, LL, LD, HM, SPF, SB, RR and VS were employees and stockholders of Gilead Sciences, Inc. J-TL, C-HT and Y-CH have research support from Gilead Sciences. C-HT and Y-CH are paid lecturers for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme and Novartis. Y-CH is an advisory committee member for Gilead Sciences., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Less differentiated thyroid cancer may upregulate the expression of glucose transporter 1 (GLUT1) and increase glycolytic activity. However, it is uncertain whether GLUT1 can be used as a target for therapy., Methods: Thyroid cancer cell lines were treated with two different GLUT1 inhibitors, STF-31 and BAY-876. Functional assays were conducted to evaluate the effects of these inhibitors on cell biology., Results: GLUT1 inhibitors dose-dependently decreased cell growth and clonogenicity of thyroid cancer cells. Cell cycle analysis showed that these inhibitors caused G2/M arrest instead of apoptosis. Additionally, treatment with GLUT1 inhibitors led to the activation of autophagy. In both the Transwell and spheroid models, GLUT1 inhibitors significantly suppressed cell invasiveness. Moreover, GLUT1 inhibitors demonstrated synergistic interactions when combined with lenvatinib., Conclusions: Treatment with GLUT1 inhibitors activates autophagy and provokes cell cycle arrest, accompanied by a decrease in colony formation and invasive capacity in thyroid cancer cells., (© 2024 Wiley Periodicals LLC.)

Context: Dysregulation of circadian rhythms has been linked to cancer susceptibility. Thyroid cancer cells demonstrate altered circadian oscillations in endogenous clock transcripts., Objective: Our previous research identified NR1D1, a component of the circadian clock, as one of the recurrence-associated genes in papillary thyroid cancer. The objective of this study was to investigate the expression pattern of NR1D1 in thyroid cancer and explore its prognostic and translational implications., Methods: We assessed NR1D1 expression using immunohistochemical analysis and examined its correlation with clinicopathological parameters. In vitro and in vivo experiments were performed to elucidate the oncogenic roles of NR1D1 and potential mechanisms., Results: Nuclear NR1D1 expression was present in thyroid follicular epithelial-derived cancers, whereas normal thyroid tissue and benign nodular goiter showed no detectable NR1D1 immunoreactivity. Patients with high expression of NR1D1 had more advanced disease stages, extrathyroidal extension, lymphovascular invasion, and shorter recurrence-free survival compared to those with low levels of NR1D1. Through gain- and loss-of-function studies, we demonstrated that NR1D1 modulation affected the growth of organoids, resistance to anoikis, and the invasive and migratory capacity of thyroid cancer cells. The invasion-promoting effect of NR1D1 was regulated by the β-catenin/ZEB1 axis. Moreover, the overexpression of NR1D1 accelerated xenograft growth and lung metastasis in vivo., Conclusion: NR1D1 is overexpressed in malignant thyroid tumors and has prognostic significance. Our findings suggest therapeutic potential in targeting NR1D1 for thyroid cancer., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objective: Although some serious games have been developed for physical therapy, little work has been conducted through a participatory design approach. Therefore, a game prototype was developed, which involved related stakeholders in the design process. Materials and Methods: The iterative participatory design process was adopted with the input of 18 patients with frozen shoulder symptoms, 4 health professionals, 2 game designers, and 5 researchers in an iterative process to design, test, and evaluate the game prototype. In total, 17 patients participated in the interviews to explore their needs and desires for a serious game. The health professionals participated in the interviews to understand the medical requirement and experience pertaining to frozen shoulder and were included in the workshop to give feedback on the game prototype. At the conclusion of the iterative design process, a Kinect-based prototype game with three levels was used for a case study with one patient who was diagnosed with frozen shoulder and has been receiving medical treatment in the hospital. Results: Based on the outcomes derived from data collected among diverse stakeholders, the prototype game underwent iterative development by the team and was assessed by a participant with frozen shoulder symptoms. Findings revealed that the participant demonstrated enhanced shoulder mobility and a reduction in pain intensity, despite the lack of significant improvement for health-related quality of life. Nevertheless, the participant reported a positive experience with the prototype game. Conclusion: This study underscores the importance of involving diverse stakeholders in the development process to create more effective and user-centric serious games for rehabilitation. The participatory approach, exemplified by the prototype game, demonstrates potential improvements in both user experience and overall effectiveness during the rehabilitation process.

Purpose: To improve the quality of community health nursing practice, the learning outcomes of nursing students in community health nursing courses must be enhanced. Although the flipped classroom is considered an effective innovative teaching strategy, evidence of its application in community health nursing courses is limited. Therefore, this study aimed to examine the effects of a flipped classroom approach on community nursing competence, academic performance, course engagement, and learning satisfaction for a community health nursing course., Design: A quasi-experimental study design was adopted between September 2021 and January 2022., Methods: Two classes of nursing students ( n  = 92) from a 2-year nursing program at a university in Taiwan were recruited. The classes were randomly assigned to the intervention group ( n  = 50) that attended a flipped classroom and the control group ( n  = 42) that received traditional lecture-based instruction., Findings: Compared with the control group, the intervention group demonstrated significantly greater improvements in community nursing competence ( p = .012) and significantly higher academic performance ( p = .005). In addition, the course engagement and learning satisfaction of the two groups were high, but not significantly different., Conclusions: A flipped classroom can be an important strategy to enhance community nursing competence and academic performance., Clinical Evidence: The flipped classroom strategy can enhance community nursing competence of nursing students, which may improve the quality of population-based healthcare.

Two novel sulfated polysaccharides (SPs), N10 and K5 were isolated from ammonium sulfate or potassium sulfate at concentrations of 10 mM and 5 mM in liquid cultures of Antrodia cinnamomea, respectively. N10 and K5 were galactoglucans with a galactose:glucose molar ratio of approximately 1:3. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, N10 and K5 exhibited strong anti-inflammatory potential, of 56 % and 23 % maximal inhibition of IL-6 and TNF-α production, respectively. Mechanical analysis revealed differences between N10 and K5, with N10 inhibiting the LPS-stimulated phosphorylation of ERK and p38 in RAW264.7 cells. K5 inhibited the LPS-stimulated phosphorylation of AKT and TGFβR-II. N10 and K5 were fragmented into F1, F2, and F3, the molecular weights of which were 455, 24, 0.9, and 327, 36, 1.9 kDa, respectively. K5 F2 and K5 F3 exhibited high degrees of sulfation of 1:3 and 1:8, resulting in strong anti-inflammation, of 83 % and 37 % highest inhibition of IL-6 and TNF-α production, respectively. Therefore, low-molecular-weight and high-sulfation-degree SPs exhibited strong anti-inflammatory activity. Specifically, K5 F2 inhibited the phosphorylation of p38, and K5 F3 suppressed the signaling pathway of p38/JNK. Overall, the sulfation degree of SPs is concluded to affect the anti-inflammatory responses., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: While the opioid crisis has been a significant concern in North America, Taiwan has not encountered a similar crisis. This study investigated medical students' perceptions of opioid therapy for chronic pain management in Taiwan., Methods: A cross-sectional questionnaire survey was conducted among third- and fourth-year medical students who had completed an 18-hour pain medicine curriculum, in comparison with those who did not take the course in Mar 2022 and May 2023. The survey assessed their knowledge, attitude, and perceptions of the opioid crisis in the United States and Taiwan., Results: In total, 135 (88.2%) of 153 senior medical students who had completed the curriculum responded to the survey. They exhibited a better understanding of opioids (P < 0.001) and held a more negative attitude toward opioid use (P = 0.011) compared with 105 students who did not take the course. Additionally, out of 240 respondents, 177 (73.8%) acknowledged the ongoing opioid crisis in the United States, while only 70 (29.2%) disagreed with the notion of an ongoing opioid crisis in Taiwan. Furthermore, 90% of all students expressed agreement with the need for further education on chronic pain management after graduation., Conclusion: Among senior medical students in Taiwan, those who completed an elective pain medicine curriculum demonstrated enhanced knowledge of opioids, a more cautious attitude toward opioid use, and a willingness to receive further education on chronic pain management. Over 70% of students remained uncertain or incorrectly believed that there was an opioid crisis in Taiwan., (© 2024. The Author(s).)

Background/Objectives : Uvulopalatopharyngoplasty (UPPP), palatal plus nasal surgery (PNS), and continuous positive airway pressure (CPAP) are widely implemented treatments for obstructive sleep apnea (OSA). This study aims to explore the long-term effects on objective sleep parameters and patient-reported outcomes (PROs) following different therapeutic interventions for OSA. Methods : Data from patients with moderate-to-severe OSA were retrospectively collected from a medical center and a regional hospital, spanning from December 2011 to August 2018. Objective evaluations included the Apnea-Hypopnea Index (AHI), minimum O 2 saturation, and sleep efficiency. The PROs consisted of the Snore Outcomes Survey and Epworth Sleepiness Scale. Using mixed-effects models, we evaluated longitudinal changes in sleep parameters and PROs, accounting for repeated measures and variations within individuals over time. Results : Among 448 patients with moderate-to-severe OSA, follow-up data were collected for 42 patients undergoing UPPP surgery, 171 undergoing PNS, 127 using CPAP, and 108 in the non-treated group. The mean follow-up was 16.7 months (SD = 11.9, range: 1.6-77.3). Significant improvements were observed in AHI, minimum O 2 saturation, and hypersomnia immediately following interventions with UPPP, PNS, and CPAP therapy ( p < 0.05). Moreover, the analysis revealed no significant rate of change in these parameters over time, suggesting that the benefits of these treatments were sustained in the long term. Furthermore, all interventions exhibited a significant short-term effect on self-reported snoring when compared to the control group, with a p -value of less than 0.001. However, the magnitude of this improvement gradually decreased over time. The snore scores seemed to return to pre-treatment levels among the UPPP, PNS, and CPAP groups after averages of 46.4, 63.5, and 74.4 months, respectively (all p < 0.05). Conclusions : Surgical interventions and CPAP therapy showed potential long-term effectiveness in managing OSA. Snoring symptoms reappeared about 3.9-5.3 years after surgical treatments, which seemed earlier than the average of 6.2 years in patients receiving CPAP and should be considered in patient-participatory decision-making processes.

Objectives: To stratify the severity of cricoarytenoid joint fixation (CAJF) by surgery and understand the role of it played in the bilateral vocal fold immobility (BVFI). The second objective emphasizes on the significance of the preoperative differential diagnosis from neurogenic immobility with medical history and endoscopic findings., Methods: A retrospective review was conducted of 74 patients between 2005 and 2022. Careful medical history inquiry, and videolaryngoscopy are conducted to recruit the appropriate surgical candidates. All patients underwent arytenoid remobilization (AR) followed by vocal fold medialization with arytenoid adduction (AA) or lateralization with suture lateralization (SL). The severity of CAJF is graded during the operation or inferred based on the period from operation to recurrence., Result: A total of 18 patients, aged between 18 and 76 years, were analyzed. Among them, 14 cases were classified as the adducted type with ventilation problems, with three presenting with dyspnea, and 11 requiring artificial airways. Additionally, four patients presented with the abducted type, characterized by aphonia. Meanwhile, two additional cases were considered for comparison but were not included in this cohort of 18 subjects due to incorrect diagnosis and inappropriate management. Using AR procedure, the AA procedure offered three aphonia subjects a voiced sound without airway impairment and the SL procedure decannulated 100% (11/11) of the artificial airways and improved the airway patency in 100% (3/3) of the non-tracheostomized subjects despite the severity of CAJF. The severity of joint ankylosis was distributed as follows: In the aphonia group, there were three subjects with grade I, one subject with grade II, and 0 subjects with grade III. In the ventilation group, there was one subject with grade I, seven subjects with grade II, and six subjects with grade III. In contrast, the two cases used for comparison experienced recurrent dyspnea and failed decannulation because the AR procedure was not performed. The follow-up period was averaged in 58 and 14 months at least., Conclusion: From this experience, it is the accurate preoperative diagnosis instead of the severity of CAJF that determines the successful rate in airway patency and voiced phonation if the AR procedure is utilized. Careful medical history inquiry and videolaryngoscopic examination can correctly differentiate the mechanical from neurogenic origin without the help of EMG. Evidence of level: 4., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase-both of which are vital for maintaining cellular redox balance-combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury., (© 2024. The Author(s).)

Aims: Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer., Main Methods: We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan., Key Findings: Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan., Significance: Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients., Competing Interests: Declaration of competing interest The authors declare there are no competing interests, and all authors consent to publish the data., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Study Design: The study included 2 fresh-frozen cadavers., Objective: To elucidate the positional relationship between surgical instruments and nerve roots during full endoscopic facet-sparing (FE fs-TLIF) and full endoscopic facet-resecting (FE fr-TLIF) transforaminal lumbar interbody fusion and propose safe instrumentation insertion procedures and recommend cage glider designs aimed at protecting nerve roots., Background: Endoscopic surgical techniques are increasingly used for minimally invasive lumbar fusion surgery, with FE fr-TLIF and FE fs-TLIF being common approaches. However, the risk of nerve root injury remains a significant concern during these procedures., Patients and Methods: Eight experienced endoscopic spine surgeons performed uniportal FE fr-TLIF and FE fs-TLIF on cadaveric lumbar spines, totaling 16 surgeries. Postoperation, soft tissues were removed to assess the positional relationship between the cage entry point and nerve roots. Distances between the cage entry point, traversing nerve root, and exiting nerve root were measured. Safe instrumentation design and insertion procedures were determined., Results: In FE fr-TLIF, the mean distance between the cage entry point and traversing nerve root was significantly shorter compared with FE fs-TLIF (3.30 ± 1.35 vs . 8.58 ± 2.47 mm, respectively; P < 0.0001). Conversely, the mean distance between the cage entry point and the exiting nerve root was significantly shorter in FE fs-TLIF compared with FE fr-TLIF (3.73 ± 1.97 vs . 6.90 ± 1.36 mm, respectively; P < 0.0001). For FE fr-TLIF, prioritizing the protection of the traversing root using a 2-bevel tip cage glider was crucial. In contrast, for FE fs-TLIF, a single-bevel tip cage glider placed in the caudal location was recommended., Conclusion: This study elucidates the anatomic relationship between cage entry points and nerve roots in uniportal endoscopic lumbar fusion surgery. Protection strategies should prioritize the traversing root in FE fr-TLIF and the exiting root in FE fs-TLIF, with corresponding variations in surgical techniques., Level of Evidence: Level V., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

To comprehensively investigate the risk factors associated with depression, traditional Chinese medicine constitution (TCMC) has been found to be related to depression. However, the underlying mechanism remains unclear. This study examined the association between the concept of unbalanced TCMCs and major depressive disorder (MDD), investigated the overlapping polygenic risks between unbalanced TCMC and MDD, and performed a mediation test to establish potential pathways. In total, 11,030 individuals were recruited from the Taiwan Biobank, and the polygenic risk score (PRS) for MDD for each participant was calculated using the data from the Psychiatric Genomics Consortium. Unbalanced TCMC were classified as yang-deficiency, yin-deficiency, and stasis. The MDD PRS was associated with yang-deficiency odds ratio [OR] per standard deviation increase in standardized (PRS = 1.07, p = 0.0080), yin-deficiency (OR = 1.07, p = 0.0030), and stasis constitution (OR = 1.06, p = 0.0331). Yang-deficiency (OR = 2.07, p < 0.0001) and stasis constitutions (OR = 1.65, p = 0.0015) were associated with an increased risk of MDD. A higher number of unbalanced constitutions was associated with MDD (p < 0.0001). The effect of MDD PRS on MDD was partly mediated by yang-deficiency (10.21%) and stasis (8.41%) constitutions. This study provides evidence for the shared polygenic risk mechanism underlying depression and TCMC and the potential mediating role of TCMC in the polygenic liability for MDD., (© 2024 Wiley Periodicals LLC.)

This study introduces a new approach to optimizing graphene oxide (GO) properties using liquid-phase plasma treatment in a microenvironment. Our innovation exploits atomic force microscopy (AFM) cantilever frequency tracking to monitor mass variations in GO, which are indicative of surface oxidation-reduction processes or substituent doping (boron/nitrogen). Complementary in situ Raman spectroscopy has observed D/G band shifts, and X-ray photoelectron spectroscopy (XPS) determined the C/O ratio and B/N doping levels pre- and post-treatment, confirming chemical tuning to GO. We can achieve femtogram-level precision in detecting nanomaterial mass changes by correlating elemental ratios with AFM cantilever frequency measurements. This multifaceted approach not only enhances our understanding of the chemical properties of GO but also establishes a new, versatile method for monitoring, modifying, and optimizing the properties of nanomaterials.

Purpose: To determine if an explainable artificial intelligence (XAI) model enhances the accuracy and transparency of predicting embryo ploidy status based on embryonic characteristics and clinical data., Methods: This retrospective study utilized a dataset of 1908 blastocyst embryos. The dataset includes ploidy status, morphokinetic features, morphology grades, and 11 clinical variables. Six machine learning (ML) models including Random Forest (RF), Linear Discriminant Analysis (LDA), Logistic Regression (LR), Support Vector Machine (SVM), AdaBoost (ADA), and Light Gradient-Boosting Machine (LGBM) were trained to predict ploidy status probabilities across three distinct datasets: high-grade embryos (HGE, n = 1107), low-grade embryos (LGE, n = 364), and all-grade embryos (AGE, n = 1471). The model's performance was interpreted using XAI, including SHapley Additive exPlanations (SHAP) and Local Interpretable Model-agnostic Explanations (LIME) techniques., Results: The mean maternal age was 38.5 ± 3.85 years. The Random Forest (RF) model exhibited superior performance compared to the other five ML models, achieving an accuracy of 0.749 and an AUC of 0.808 for AGE. In the external test set, the RF model achieved an accuracy of 0.714 and an AUC of 0.750 (95% CI, 0.702-0.796). SHAP's feature impact analysis highlighted that maternal age, paternal age, time to blastocyst (tB), and day 5 morphology grade significantly impacted the predictive model. In addition, LIME offered specific case-ploidy prediction probabilities, revealing the model's assigned values for each variable within a finite range., Conclusion: The model highlights the potential of using XAI algorithms to enhance ploidy prediction, optimize embryo selection as patient-centric consultation, and provides reliability and transparent insights into the decision-making process., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/aim: Patients diagnosed with advanced metastatic colorectal cancer (CRC) confront a bleak prognosis characterized by low survival rates. Anoikis, the programmed apoptosis resistance exhibited by metastatic cancer cells, is a crucial factor in this scenario., Materials and Methods: We employed bulk flow cytometry and RT-qPCR assays, conducted in vivo experiments with mice and zebrafish, and analyzed patient tissues to examine the effects of the B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1)-midkine (MDK) axis on the cellular response to anoikis. Bmi1 is pivotal in tumorigenesis. This study elucidated the involvement of Bmi1 in conferring anoikis resistance in CRC and explored its downstream targets associated with metastasis., Results: Elevated levels of Bmi1 expression correlated with distant metastasis in CRC. Suppression of Bmi1 significantly diminished the metastatic potential of CRC cells. Inhibition of Bmi1 led to an increase in the proportion of apoptotic SW620 cells detached from the matrix. This effect was further enhanced by the addition of irinotecan, a topoisomerase I inhibitor. Furthermore, Bmi1 was found to synergize with MDK in modulating CRC viability, with consistent expression patterns observed in in vivo models and clinical tissue specimens. In summary, Bmi1 acted as a regulator of CRC metastatic capability by conferring anoikis resistance. Additionally, it collaborated with MDK to facilitate invasion and distant metastasis., Conclusion: Targeting Bmi1 may offer a promising adjunctive therapeutic strategy when administering traditional chemotherapy regimens to patients with advanced CRC., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Triboelectric nanogenerators (TENGs) have become reliable green energy harvesters by converting biomechanical motions into electricity. However, the inevitable charge leakage and poor electric field (EF) of conventional TENG result in inferior tribo-charge density on the active layer. In this paper, TiO 2 -MXene incorporated polystyrene (PS) nanofiber membrane (PTMx NFM) charge trapping interlayer is introduced into single electrode mode TENG (S-TENG) to prevent electron loss at the electrode interface. Surprisingly, this charge-trapping mechanism augments the surface charge density and electric output performance of TENGs. Polyvinylidene difluoride (PVDF) mixed polyurethane (PU) NFM is used as tribo-active layer, which improves the crystallinity and mechanical property of PVDF to prevent delamination during long cycle tests. Herein, the effect of this double-layer capacitive model is explained experimentally and theoretically. With optimization of the PTMx interlayer thickness, S-TENG exhibits a maximum open-circuit voltage of (280 V), short-circuit current of (20 µA) transfer charge of (120 nC), and power density of (25.2 µW cm -2 ). Then, this energy is utilized to charge electrical appliances. In addition, the influence of AC/DC EF simulation in wound healing management (vitro L929 cell migration, vivo tissue regeneration) is also investigated by changing the polarity of trans-epithelial potential (TEP) distribution in the wounded area., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Key Points: We proposed a hierarchical framework including an unsupervised candidate image selection and a weakly supervised patch image detection based on multiple instance learning (MIL) to effectively estimate eosinophil quantities in tissue samples from whole slide images. MIL is an innovative approach that can help deal with the variability in cell distribution detection and enable automated eosinophil quantification from sinonasal histopathological images with a high degree of accuracy. The study lays the foundation for further research and development in the field of automated histopathological image analysis, and validation on more extensive and diverse datasets will contribute to real-world application., (© 2024 ARS‐AAOA, LLC.)

To plant crops (especially dry crops such as water spinach) with concomitant electricity recovery, a hanging-submerged-plant-pot system (HSPP) is developed. The HSPP consists of a soil pot (anodic) partially submerged under the water surface of a cathode tank. The microbial communities changed with conditions were also investigated. It was found that with chemical fertilizers the closed-circuit voltage (CCV, with 1 kΩ) was stable (approximately 250 mV) within 28 d; however, without fertilizer, the water spinach could adjust to the environment to obtain a better power output (approximately 3 mW m -2 ) at day 28. The microbial-community analyses revealed that the Pseudomonas sp. was the only exoeletrogens found in the anode pots. Using a secondary design of HSPP, for a better water-level adjustment, the maximum power output of each plant was found to be approximately 27.1 mW m -2 . During operation, high temperature resulted in low oxygen solubility, and low CCV as well. At this time, it is yet to be concluded whether the submerged water level significantly affects electricity generation., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Background: The Menstrual Distress Questionnaire (MDQ) is a commonly used questionnaire that assesses various symptoms and distress associated with the menstrual cycle in women. However, the questionnaire has not been completely translated into Chinese with rigorous reliability and validity testing., Methods: This study translated the Menstrual Distress Questionnaire Form Cycle (MDQC) from English into Chinese: MDQCC in two stages. First, it was translated forward and backward using Jones' model; second, to test the validity and reliability, 210 Chinese-speaking women were recruited through online announcements and posters posted between June 2019 and May 2020. Expert validity, construct validity, convergent validity, and factorial validity were determined using content validity index (CVI), intraclass correlation coefficient (ICC), composite reliability (CR), and exploratory factor analysis, respectively. For concurrent criterion validity, MDQCC score was compared with three existing pain scales. Reliability was evaluated using internal consistency across items and two-week test-retest reliability over time., Results: The CVI for content validity was .92. Item-CVI for expert validities among the 46 items ranged from .50 - 1; scale-CVI for the eight subscales, from .87 - 1; ICC, from .650 - .897; and CRs, from .303 - .881. Pearson correlation coefficients between MDQCC and short-form McGill pain questionnaire, present pain intensity, and visual analog scale scores were .640, .519, and .575, respectively. Cronbach's α for internal consistency was satisfactory (.932). ICC for test-retest reliability was .852 for the entire MDQCC., Conclusion: MDQCC was valid and reliable for Mandarin Chinese-speaking women. It can be used to evaluate female psychiatric symptoms related to the menstrual cycle in future work.

Klebsiella pneumoniae is a common causative pathogen of intra-abdominal infection with concomitant bacteraemia, leading to a significant mortality risk. The time to positivity (TTP) of blood culture is postulated to be a prognostic factor in bacteraemia caused by other species. Therefore, this study aimed to investigate the prognostic value of TTP in these patients. The single-centred, retrospective, observational cohort study was conducted between 1 July 2016 and 30 June 2021. All adult emergency department patients with diagnosis of intra-abdominal infection and underwent blood culture collection which yield K. pneumoniae during this period were enrolled. A total of 196 patients were included in the study. The overall 30-day mortality rate was 12.2% (24/196), and the median TTP of the studied cohort was 12.3 h (10.5-15.8 h). TTP revealed a moderate 30-day mortality discriminative ability (area under the curve 0.73, p  < 0.001). Compared with the late TTP group (>12 h, N  = 109), patients in the early TTP (≤12 h, N  = 87) group had a significantly higher risk of 30-day morality (21.8% vs. 4.6%, p  < 0.01) and other adverse outcomes. Furthermore, TTP (odds ratio [OR] = 0.79, p  = 0.02), Pitt bacteraemia score (OR = 1.30, p  = 0.03), and implementation of source control (OR = 0.06, p  < 0.01) were identified as independent factors related to 30-day mortality risk in patients with intra-abdominal infection and K. pneumoniae bacteraemia. Therefore, physicians can use TTP for prognosis stratification in these patients.

Diabetic nephropathy, a leading cause of end-stage renal disease, accounts for significant morbidity and mortality. It is characterized by microinflammation in the glomeruli and myofibroblast activation in the tubulointerstitium. Salvia miltiorrhiza Bunge, a traditional Chinese medicine, is shown to possess anti-inflammatory and anti-fibrotic properties, implying its renal-protective potential. This study investigates which type of component can reduce the damage caused by diabetic nephropathy in a single setting. The ethyl acetate (EtOAc) layer was demonstrated to provoke peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ activities in renal mesangial cells by dual luciferase reporter assay. In a high glucose (HG)-cultured mesangial cell model, the EtOAc layer substantially inhibited HG-induced elevations of interleukin-1β, transforming growth factor-β1 (TGF-β1), and fibronectin, whereas down-regulated PPAR-γ was restored. In addition, among the extracts of S. miltiorrhiza , the EtOAc layer effectively mitigated TGF-β1-stimulated myofibroblast activation. The EtOAc layer also showed a potent ability to attenuate renal hypertrophy, proteinuria, and fibrotic severity by repressing diabetes-induced proinflammatory factor, extracellular matrix accumulation, and PPAR-γ reduction in the STZ-induced diabetes mouse model. Our findings, both in vitro and in vivo, indicate the potential of the EtOAc layer from S. miltiorrhiza for future drug development targeting diabetic nephropathy.

Globally, nearly half of deaths from cirrhosis and chronic liver diseases (CLD) and three-quarters of deaths from hepatocellular carcinoma (HCC) occur in the Asia-Pacific region. Chronic hepatitis B is responsible for the vast majority of liver-related deaths in the region. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common form of CLD, affecting an estimated 30% of the adult population. Compared with people of European descent, people from the Asia-Pacific region carry more genetic variants associated with MASLD and its progression. Alcohol is a fast-growing cause of CLD and HCC in Asia as a result of the rising per-capita consumption of alcohol. Drug-induced liver injury is under-recognized and probably has a high prevalence in this region. The epidemiological and outcome data of acute-on-chronic liver failure are heterogeneous, and non-unified definitions across regions contribute to this heterogeneity. CLDs are severely underdiagnosed, and effective treatments and vaccinations are underutilized. In this Review, we highlight trends in the burden of CLD and HCC in the Asia-Pacific region and discuss the rapidly changing aetiologies of liver disease. We examine the multiple gaps in the care cascade and propose mitigating strategies and future directions., (© 2024. Springer Nature Limited.)

Perivascular cerebrospinal fluid (pCSF) flow is a key component of the glymphatic system. Arterial pulsation has been proposed as the main driving force of pCSF influx along the superficial and penetrating arteries; however, evidence of this mechanism in humans is limited. We proposed an experimental framework of dynamic diffusion tensor imaging with low b-values and ultra-long echo time (dynDTI low-b ) to capture pCSF flow properties during the cardiac cycle in human brains. Healthy adult volunteers (aged 17-28 years; seven men, one woman) underwent dynDTI low-b using a 3T scanner (MAGNETOM Prisma, Siemens Healthcare, Erlangen, Germany) with simultaneously recorded cardiac output. The results showed that diffusion tensors reconstructed from pCSF were mainly oriented in the direction of the neighboring arterial flow. When switching from vasoconstriction to vasodilation, the axial and radial diffusivities of the pCSF increased by 5.7 % and 4.94 %, respectively, suggesting that arterial pulsation alters the pCSF flow both parallel and perpendicular to the arterial wall. DynDTI low-b signal intensity at b=0 s/mm 2 (i.e., T2-weighted, [S(b=0 s/mm 2 )]) decreased in systole, but this change was ∼7.5 % of a cardiac cycle slower than the changes in apparent diffusivity, suggesting that changes in S(b=0 s/mm 2 ) and apparent diffusivity arise from distinct physiological processes and potential biomarkers associated with perivascular space volume and pCSF flow, respectively. Additionally, the mean diffusivities of white matter showed cardiac-cycle dependencies similar to pCSF, although a delay relative to the peak time of apparent diffusivity in pCSF was present, suggesting that dynDTI low-b could potentially reveal the dynamics of magnetic resonance imaging-invisible pCSF surrounding small arteries and arterioles in white matter; this delay may result from pulse wave propagation along penetrating arteries. In conclusion, the vasodilation-induced increases in axial and radial diffusivities of pCSF and mean diffusivities of white matter are consistent with the notion that arterial pulsation can accelerate pCSF flow in human brain. Furthermore, the proposed dynDTI low-b technique can capture various pCSF dynamics in artery pulsation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)