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Chia-Yu Huang,1,2 Mei-Yao Wu,3– 5 Ming-Cheng Huang,2,3 Teng-Shun Yu,6,7 Peter Karl Mayer,3,8,&ast; Hung-Rong Yen2,3,5,8,9,&ast; 1Department of Family Medicine, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan; 2Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 3Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan; 4School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 5Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; 6Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan; 7College of Medicine, China Medical University, Taichung, Taiwan; 8International Master Program in Acupuncture, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 9Chinese Medicine Research Center, China Medical University, Taichung, Taiwan&ast;These authors contributed equally to this workCorrespondence: Hung-Rong Yen, School of Chinese Medicine, College of Chinese Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung, 404, Taiwan, ext. 3001 Fax +886-4-22365141, Email hungrongyen@mail.cmu.edu.twPurpose: Disability is the comorbidity of dementia for which there is no available preventive measure. The aim of this study was to investigate the association between acupuncture treatment and the risk of disability development in dementia patients.Patients and Methods: A cohort study was performed using a nationwide health database in Taiwan. The included dementia patients were divided into acupuncture and non-acupuncture cohorts based on whether they received acupuncture treatment during the follow-up period. The variables in the two cohorts were controlled by 1:1 propensity-score matching. The difference in disability development in dementia patients between the acupuncture and non-acupuncture cohorts was also analyzed. Subgroup analyses were performed using socioeconomic variables, comorbidities and anti-dementia agents (donepezil, rivastigmine, galantamine and memantine) used for dementia treatment.Results: A total of 9,760 dementia patients met our inclusion criteria, and patients were divided into an equal number (n=2,422) of acupuncture and non-acupuncture groups, respectively, after 1:1 propensity-score matching. The dementia patients had a lower risk of disability development after acupuncture treatment than those who did not receive acupuncture treatment (adjusted hazard ratio 0.65, 95% confidence interval 0.60– 0.70, p < 0.001). The results were independent of basic variables or comorbidities in the two cohorts. Patients who did not use anti-dementia agents had a lower risk of developing disability after receiving acupuncture intervention than those who used anti-dementia agents.Conclusion: Our results revealed the relationship between acupuncture intervention and decreased risk of developing disability in dementia patients. The results are useful for dementia treatment, trial design and further planning of care programs.Keywords: acupuncture, disability, dementia, traditional Chinese medicine

Background: Several assessments have been developed to assess school-aged children's emotional and behavioral problems (EBPs), but none based on the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision. This study aimed to develop the Assessment for Emotional and Behavioral Problems in School-aged children (AEBPS) fitting current knowledge of mental health disorders., Materials and Methods: This study included 2 phases. In Phase I, the assessment construct and its corresponding items were developed. In Phase II, the reliability and validity of the AEBPS were examined., Results: The AEBPS contains 120 items in five subscales. The psychometric results showed that the AEBPS subscales had high internal consistency (Cronbach's alpha = 0.83-0.97) and acceptable to good test-retest reliability (intra-class correlation coefficient = 0.65-0.93). The results of exploratory factor analysis showed that most items within each subscale of the AEBPS significantly contributed to their respective concepts. The AEBPS subscales had small to high correlations with the subscales of the Child Behavior Checklist (r = 0.37-0.87). The AEBPS had good discriminant validity to differentiate children with and without EBPs., Conclusions: The newly-developed AEBPS fits the current knowledge of mental health diagnoses for assessing school-aged children's EBPs and has sound psychometric evidence. The AEBPS can be reliably and validly used in a variety of settings., Competing Interests: Declaration of Competing Interest All authors declare that: (i) no support, financial or otherwise, has been received from any organization that may have an interest in the submitted work; and (ii) there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The prevalence of stroke-related sarcopenia has been noted; however, epidemiological data and interventions that increase or reduce the incidence of stroke-related sarcopenia remain lacking., Methods: Studies on stroke-related sarcopenia were included in association or interventional analyses. All analyses were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two evaluators independently extracted the data., Results: Female stroke patients had a higher preference for sarcopenia than male patients (pooled odds ratio [OR] = 0.670, 95 % CI 0.533-0.842, p = 0.001). Although stroke patients without drug use have improved skeletal muscle mass index (SMI) (MD = 0.272, 95 % CI 0.087-0.457, p = 0.004), handgrip strength (HGS) was not significantly altered (MD = -0.068, 95 % CI -0.221-0.076, p = 0.354). Stroke patients with nutrient interventions have improved SMI (MD = -0.354, 95 % CI -0.635- -0.073, p = 0.014) and HGS (MD = -0.394, 95 % CI -0.678- -0.111, p = 0.006); the synergistic effect of rehabilitation exercise has not been ruled out. Whether a sex difference exists in these interventions remains to be investigated. The underlying pathological mechanisms and potential therapeutic strategies for this disease are discussed., Conclusion: Sex difference, proteostasis, and mitochondrial function may impact the incidence of stroke-related sarcopenia. Understanding the underlying pathological mechanisms and potential therapeutic targets for this disease will provide new insights into disease treatment, prevention, and drug development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oxidative stress is a pivotal factor in the pathogenesis of various cardiovascular diseases. Rhodiola, a traditional Chinese medicine, is recognized for its potent antioxidant properties. Salidroside, a phenylpropanoid glycoside derived from Rhodiola rosea, has shown remarkable antioxidant capabilities. This study aimed to elucidate the potential protective mechanisms of Rhodiola and salidroside against H 2 O 2 -induced cardiac apoptosis in H9c2 cardiomyoblast cells. H9c2 cells were exposed to H 2 O 2 for 4 h, and subsequently treated with Rhodiola or salidroside for 24 h. Cell viability and apoptotic pathways were assessed. The involvement of insulin-like growth factor 1 receptor (IGF1R) and the activation of extracellular regulated protein kinases 1/2 (ERK1/2) were investigated. H 2 O 2 (100 μM) exposure significantly induced cardiac apoptosis in H9c2 cells. However, treatment with Rhodiola (12.5, 25, and 50 μg/mL) and salidroside (0.1, 1, and 10 nM) effectively attenuated H 2 O 2 -induced cytotoxicity and apoptosis. This protective effect was associated with IGF1R-activated phosphorylation of ERK1/2, leading to the inhibition of Fas-dependent proteins, HIF-1α, Bax, and Bak expression in H9c2 cells. The images from hematoxylin and eosin staining and immunofluorescence assays also revealed the protective effects of Rhodiola and salidroside in H9c2 cells against oxidative damage. Our findings suggest that Rhodiola and salidroside possess antioxidative properties that mitigate H 2 O 2 -induced apoptosis in H9c2 cells. The protective mechanisms involve the activation of IGF1R and subsequent phosphorylation of ERK1/2. These results propose Rhodiola and salidroside as potential therapeutic agents for cardiomyocyte cytotoxicity and apoptosis induced by oxidative stress in heart diseases. Future studies may explore their clinical applications in cardiac health., (© 2024 Wiley Periodicals LLC.)

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1β/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding., (© 2024 Wiley Periodicals LLC.)

Objective: Methamphetamine causes considerable short- and long-term adverse health effects. Our aim was to assess the effects of methamphetamine use on pulmonary hypertension and lung diseases at the population level., Methods: This population-based retrospective study used data from the Taiwan National Health Insurance Research Database between 2000 and 2018 that included 18,118 individuals with methamphetamine use disorder (MUD) and 90,590 matched participants of the same age and sex without substance use disorder as the non-exposed group. A conditional logistic regression model was used to estimate associations of methamphetamine use with pulmonary hypertension and lung diseases such as lung abscess, empyema, pneumonia, emphysema, pleurisy, pneumothorax, or pulmonary hemorrhage. Incidence rate ratios (IRRs) of pulmonary hypertension and hospitalization due to lung diseases were determined between the methamphetamine group and non-methamphetamine group using negative binomial regression models., Results: During an 8-year observation period, 32 (0.2%) individuals with MUD and 66 (0.1%) non-methamphetamine participants suffered from pulmonary hypertension, and 2652 (14.6%) individuals with MUD and 6157 (6.8%) non-methamphetamine participants suffered from lung diseases. After adjusting for demographic characteristics and comorbidities, individuals with MUD were 1.78 times (95% confidence interval (CI) = 1.07-2.95) more likely to have pulmonary hypertension and 1.98 times (95% CI = 1.88-2.08) more likely to have a lung disease, especially emphysema, lung abscess, and pneumonia in descending order. Furthermore, compared to the non-methamphetamine group, the methamphetamine group was associated with higher risks of hospitalization caused by pulmonary hypertension and lung diseases. The respective IRRs were 2.79 and 1.67. Individuals with polysubstance use disorder were associated with higher risks of empyema, lung abscess, and pneumonia compared to individuals with MUD alone, with respective adjusted odds ratios of 2.96, 2.21, and 1.67. However, pulmonary hypertension and emphysema did not differ significantly between MUD individuals with or without polysubstance use disorder., Conclusions: Individuals with MUD were associated with higher risks of pulmonary hypertension and lung diseases. Clinicians need to ensure that a methamphetamine exposure history is obtained as part of the workup for these pulmonary diseases and provide timely management for this contributing factor., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2023 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Cardiovascular disease is one of the leading causes of death worldwide and has a high prevalence. Insulin-like growth factor-II receptor α (IGF-IIRα) acts as a stress-inducible negative regulator. This study focused on the substantial impact of heightened expression of IGF-IIRα in cardiac myoblasts and its association with the exacerbation of cardiac dysfunction. Using lipopolysaccharide (LPS)-induced H9c2 cardiac myoblasts as a model for sepsis, we aimed to elucidate the molecular interactions between IGF-IIRα and LPS in exacerbating cardiac injury. Our findings demonstrated a synergistic induction of cardiac inflammation and hypertrophy by LPS stimulation and IGF-IIRα overexpression, leading to decreased cell survival. Excessive calcineurin activity, triggered by this combined condition, was identified as a key factor exacerbating the negative effects on cell survival. Cellular changes such as cell enlargement, disrupted actin filaments, and upregulation of hypertrophy-related and inflammation-related proteins contributed to the overall hypertrophic and inflammatory responses. Overexpression of IGF-IIRα also exacerbated apoptosis induced by LPS in H9c2 cardiac myoblasts. Inhibiting calcineurin in LPS-treated H9c2 cardiac myoblasts with IGF-IIRα overexpression effectively reversed the detrimental effects, reducing cell damage and mitigating apoptosis-related cardiac mechanisms. Our study suggests that under sepsis-like conditions in the heart with IGF-IIRα overexpression, hyperactivation of calcineurin worsens cardiac damage. Suppressing IGF-IIRα and calcineurin expression could be a potential intervention to alleviate the impact of the illness and improve cardiac function., (© 2024 Wiley Periodicals LLC.)

Background: Approximately 7% of the males exhibit reduced fertility; however, the regulatory genes and pathways involved remain largely unknown. TBC1 domain family member 21 (TBC1D21) contains a conserved RabGAP catalytic domain that induces GDP/GTP exchange to inactivate Rabs by interacting with microtubules. We previously reported that Tbc1d21-null mice exhibit severe sperm tail defects with a disrupted axoneme, and that TBC1D21 interacts with RAB10. However, the pathological mechanisms underlying the Tbc1d21 loss-induced sperm tail defects remain unknown., Results: Murine sperm from wild-type and Tbc1d21-null mice were comparatively analyzed using proteomic assays. Over 1600 proteins were identified, of which 15 were significantly up-regulated in Tbc1d21-null sperm. Notably, several tektin (TEKT) family proteins, belonging to a type of intermediate filament critical for stabilizing the microtubular structure of cilia and flagella, were significantly up-regulated in Tbc1d21 -/- sperm. We also found that TBC1D21 interacts with TEKT1. In addition, TEKT1 co-localized with RAB10 during sperm tail formation. Finally, we found Tbc1d21-null sperm exhibited abnormal accumulation of TEKT1 in the midpiece region, accompanied by disrupted axonemal structures., Conclusions: These results reveal that TBC1D21 modulates TEKTs protein localization in the axonemal transport system during sperm tail formation., (© 2024 American Association for Anatomy.)

Purpose: This study aims to investigate the feasibility of the home-based parent- mediated intervention Naturalistic developmental behavioral intervention (HB-NDBI) in underserved Taiwanese families of children with Autism spectrum disorder (ASD) and explore its effects on children's developmental skills and parents' parenting stress., Method: 24 underserved Taiwanese families of children with ASD (mean age = 46.5 months) received 12-week HB-NDBI programs. Social Responsiveness Scale, Second Edition (SRS-2), Mullen Scales of Early Learning (MSEL), Child Behavior Checklist (CBCL/1.5-5), and Parenting Stress Index (PSI) were administered before and after the HB-NDBI programs., Results: Following the HB-NDBI programs, significant improvements in social cognition, social communication subscales, receptive language subscale, internalizing, externalizing, and total behavioral problems scales of children, and release of parenting stress were observed., Conclusion: This study demonstrated the feasibility of home-based parent-mediated intervention for underserved families in Taiwan. These promising results might facilitate the development of such interventions for underserved families., Competing Interests: The authors have no financial relationships relevant to this article to disclose. The authors do not have any potential conflict of interest, real or perceived., (Copyright © 2024 Academy of Pediatric Physical Therapy of the American Physical Therapy Association.)

Background: Round spermatid injection (ROSI) into oocytes offers men with non-obstructive azoospermia (NOA) the opportunity to have biological offspring in cases where mature spermatozoa are not detected. However, the clinical outcomes of ROSI remains poor. This study compares the outcomes of ROSI with intracytoplasmic sperm injection (ICSI) and investigates the effect of hormonal pretreatment., Methods: This retrospective cohort study enrolled infertile couples undergoing either ROSI or ICSI at the reproductive center in Taipei Veterans General Hospital. The administration of selective estrogen receptor modulators, gonadotropins, and aromatase inhibitors in male patients were collected. Relevant hormonal markers and biochemical parameters were determined. The outcomes of ROSI and ICSI were assessed based on fertilization rate, implantation rate, and live birth rate., Results: A total of 36 couples were recruited in the ROSI group, whereas 39 couples were recruited in the ICSI group for the analysis. Patients in each group demonstrated similar characteristics, except for a higher proportion of male patients in the ROSI group who were pretreated with anastrozole. The fertilization rate and implantation rate were similar between ROSI and ICSI groups after adjusting for confounding variable. The live birth rate was significant lower in the ROSI group (8.3%) than in the ICSI group (30.8%) before and after adjusting for confounding variable., Conclusion: ROSI demonstrated fertilization and implantation rates comparable to those of ICSI for male patient with NOA undergoing testicular sperm extraction surgery. Further studies evaluating the effect of anastrozole administration on ROSI outcomes are warrant., Competing Interests: Conflicts of interest: Dr. William J Huang, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

Human skin aging, a complex process influenced by intrinsic aging and extrinsic photoaging, is marked by the accumulation of reactive oxygen species (ROS) that cause DNA damage, impaired dermal fibroblast function, and wrinkle formation. External stressors, such as ultraviolet (UV) radiation, can trigger cellular senescence. Sirtuin-1 (SIRT1), an NAD + -dependent enzyme in the sirtuin family, plays a crucial role in deacetylating p53, thereby inhibiting its nuclear translocation and reducing skin senescence. Galangin, a flavonoid found in honey and Alpinia officinarum root, has antioxidant and anti-inflammatory properties. This study investigates the protective mechanism of galangin against UVB-induced senescence in human dermal fibroblasts (HDFs) by examining its effects on SIRT1 and its target, acetylated-p53. An in vitro model of UVB-induced senescence using HDFs and an in vivo model using nude mice were employed to assess the dermal protective effects of galangin. The results demonstrate that while UVB exposure does not decrease SIRT1 protein levels, it impairs its enzymatic function. However, galangin treatment counteracts these adverse effects. Additionally, UVB exposure significantly reduces cell viability and upregulates senescence markers like p16, p21, and p53 nuclear transactivation. An increase in senescence-associated β-galactosidase (SA-β-gal) positive cells was observed in UVB-exposed dermal fibroblasts. Galangin treatment mitigates UVB-induced cellular senescence by enhancing SIRT1-mediated p53 deacetylation, thereby inhibiting nuclear translocation and reducing dermal senescence. These findings suggest that galangin is a promising agent for alleviating UVB-induced skin aging and could be a potential component in antiaging cosmetic formulations.

Background: Nephroureterectomy with bladder cuff excision is the standard treatment for high-risk upper urinary tract urothelial carcinoma (UTUC). The role of minimally invasive surgery in treating locally advanced UTUC remains controversial. This study aimed to compare the outcomes of open, laparoscopic, and robotic surgeries for managing locally advanced UTUC., Methods: We retrospectively reviewed 705 patients with locally advanced UTUC from multiple institutions throughout Taiwan. Perioperative outcomes and oncological outcomes, such as cancer-specific survival, overall survival, disease-free survival and bladder-free survival, were compared between the open, laparoscopic and robotic groups., Results: The minimally invasive group had better overall and cancer-specific survival (CSS) rates. The 2-year CSS rates of the open, laparoscopic and robotic groups were 71%, 83%, and 77% respectively (p < 0.001). The robotic group had similar outcomes to the laparoscopic group. (p = 0.061, 0.825, 0.341 for OS, CSS, DFS respectively.) More lymph node dissections were performed and more lymph nodes were harvested in the robotic group (p = 0.009)., Conclusions: Our results demonstrated that minimally invasive surgery, including laparoscopic and robotic surgery, for locally advanced UTUC resulted in oncological outcomes that are non-inferior to those of open surgery., (© 2024. The Author(s).)

Background: Percutaneous left atrial appendage occlusion (LAAO) is indicated in patients with atrial fibrillation for whom long-term oral anticoagulation is contraindicated. Whether outcomes are different based on operator certification [interventional cardiology (IC) versus electrophysiology (EP)] is unclear., Objectives: To compare LAAO outcomes by physician certification (EP versus IC) in the NCDR LAAO Registry., Methods: We identified patients from 2020-2022 undergoing implantation of a Watchman FLX or Amulet LAAO device and stratified patients by primary operator certification. Outcomes of interest included: (1) any major adverse event (MAE), 2) mortality, 3) ischemic stroke, and 4) major bleeding during the initial hospitalization and at 45 days. We performed multivariable Cox proportional hazards regression analysis to determine the risk of adverse events by physician certification., Results: A total of 1,638 physicians (57% electrophysiologists) performing 91,711 procedures during the study period were included. EPs were more likely to use intracardiac echocardiography (25.2% vs 9.7%, p<0.001) and had lower radiation total (235 mGy vs 305 mGy, p<0.001). EPs were more likely than ICs to discharge patients on DOAC+aspirin, whereas ICs were more likely to discharge patients on single or dual antiplatelet therapy (all p<0.001). In-hospital death (0.1% vs. 0.1%, p=0.46) and MAE (1.5% vs 1.6%, p=0.42) were similar by physician certification. At 45 days, there was no difference in death [HR death 1.03, 95% CI (0.89-1.2)] or MAE [HR MAE 0.97, 95% CI (0.91-1.03)] after multivariable regression., Conclusions: Contemporary LAAO is safe with low rates of procedural complications and no significant differences in procedural outcomes by operator subspecialty after multivariable adjustment. Continued utilization of technology by EPs and ICs is necessary to allow for broad access to this treatment for eligible patients., (Copyright © 2024. Published by Elsevier Inc.)

The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.

Background: The aim of this study was to validate and compare the performance of statistical (Utstein-Based Return of Spontaneous Circulation and Shockable Rhythm-Witness-Age-pH) and machine learning-based (Prehospital Return of Spontaneous Circulation and Swedish Cardiac Arrest Risk Score) models in predicting the outcomes following out-of-hospital cardiac arrest and to assess the impact of the COVID-19 pandemic on the models' performance., Methods and Results: This retrospective analysis included adult patients with out-of-hospital cardiac arrest treated at 3 academic hospitals between 2015 and 2023. The primary outcome was neurological outcomes at hospital discharge. Patients were divided into pre- (2015-2019) and post-2020 (2020-2023) subgroups to examine the effect of the COVID-19 pandemic on out-of-hospital cardiac arrest outcome prediction. The models' performance was evaluated using the area under the receiver operating characteristic curve and compared by the DeLong test. The analysis included 2161 patients, 1241 (57.4%) of whom were resuscitated after 2020. The cohort had a median age of 69.2 years, and 1399 patients (64.7%) were men. Overall, 69 patients (3.2%) had neurologically intact survival. The area under the receiver operating characteristic curves for predicting neurological outcomes were 0.85 (95% CI, 0.83-0.87) for the Utstein-Based Return of Spontaneous Circulation score, 0.82 (95% CI, 0.81-0.84) for the Shockable Rhythm-Witness-Age-pH score, 0.79 (95% CI, 0.78-0.81) for the Prehospital Return of Spontaneous Circulation score, and 0.79 (95% CI, 0.77-0.81) for the Swedish Cardiac Arrest Risk Score model. The Utstein-Based Return of Spontaneous Circulation score significantly outperformed both the Prehospital Return of Spontaneous Circulation score ( P <0.001) and the Swedish Cardiac Arrest Risk Score model ( P =0.007). Subgroup analysis indicated no significant difference in predictive performance for patients resuscitated before versus after 2020., Conclusions: In this external validation, both statistical and machine learning-based models demonstrated excellent and fair performance, respectively, in predicting neurological outcomes despite different model architectures. The predictive performance of all evaluated clinical scoring systems was not significantly influenced by the COVID-19 pandemic.

The predatory gall midge, Aphidoletes aphidimyza (Rondani), and tobacco aphid cocoon wasp, Aphidius gifuensis Ashmead, are important natural enemies of Myzus persicae (Sulzer) (Hemiptera: Aphididae). Predation by A. aphidimyza and A. gifuensis can regulate M. persicae; however, how interspecific interference competition affects their foraging efficiency is unknown. Here, we investigated the consumption and parasitization abilities of A. aphidimyza 3rd instar larva and A. gifuensis adults under various conditions. Consumption of parasitized aphids by A. aphidimyza 3rd instar larvae was significantly lower than that of nonparasitized controls, with a substantial increase in handling time. The presence of A. gifuensis adults did not significantly affect the predation capacity of A. aphidimyza larvae. Relative to controls, A. aphidimyza larvae predation trace (PT) and imago activity significantly decreased A. gifuensis parasitism rates at different aphid densities. Further, A. aphidimyza larvae PT increased the A. gifuensis handling time of M. persicae, whereas the presence of A. aphidimyza adults had the opposite effect. Coexistence with heterospecific natural enemies reduced the parasitic capacity of A. gifuensis, whereas A. aphidimyza larvae predation capability was influenced to a lesser extent. Our results demonstrate that intraguild interactions strongly influence the predatory and parasitic efficacy of A. aphidimyza and A. gifuensis, although the effect on A. gifuensis was more pronounced. For effective biological control of M. persicae using A. aphidimyza and A. gifuensis, we recommend releasing A. aphidimyza first to mitigate intraguild predation and enhance the overall success of the pest control program., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. 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.)

Background/Objectives: Patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and high-risk features frequently have progression to life-threatening metastasis without second-generation antiandrogens. This study investigated nmCRPC patients for the survival and prognostic factors from a cohort before the approved use of second-generation antiandrogens. Methods: From March 2016 to January 2021, 326 patients treated with second-generation antiandrogens for metastatic castration-resistant prostate cancer (mCRPC) or metastatic castration-sensitive prostate cancer were retrieved. Forty-four patients experiencing nmCRPC with no use of second-generation antiandrogens were reviewed. The prognostic factors, at initial diagnosis or at nmCRPC, associated with metastasis-free survival (MFS) and overall survival (OS) were analyzed. Results: The median follow-up time after nmCRPC was 46 months. The median PSA level at nmCRPC was 2.7 ng/mL. Thirty-eight of forty-four patients with nmCRPC had a PSA doubling time (PSADT) of 10 months or shorter, and the median PSADT was 4 months. The median OS from nmCRPC was 53 months, and the median interval for nmCRPC patients progressing to mCRPC was 20 months. Upon univariate analysis, PSADT < 10 months ( p = 0.049) and the very-high-risk group at the initial diagnosis ( p = 0.043) were associated with significantly shorter post-nmCRPC MFS. The very-high-risk group ( p = 0.031) was associated with significantly worse post-nmCRPC OS. In terms of survivals from the initial diagnosis of prostate cancer, Gleason grade ≥ 8 was the only independent factor with MFS and OS. Conclusions: Without second-generation antiandrogens, nmCRPC patients with PSADT <10 months and in the initial very-high-risk group developed subsequent mCRPC in a significantly faster fashion. Patients of the very-high-risk group had shorter survival rates after nmCRPC.

Background and Aims: Diagnosis code classification is a common method for cohort identification in cirrhosis research, but it is often inaccurate and augmented by labor-intensive chart review. Natural language processing using large language models (LLMs) is a potentially more accurate method. To assess LLMs' potential for cirrhosis cohort identification, we compared code-based versus LLM-based classification with chart review as a "gold standard.", Approach and Results: We extracted and conducted a limited chart review of 3788 discharge summaries of cirrhosis admissions. We engineered zero-shot prompts using a Generative Pre-trained Transformer 4 to determine whether cirrhosis and its complications were active hospitalization problems. We calculated positive predictive values (PPVs) of LLM-based classification versus limited chart review and PPVs of code-based versus LLM-based classification as a "silver standard" in all 3788 summaries. Compared to gold standard chart review, code-based classification achieved PPVs of 82.2% for identifying cirrhosis, 41.7% for HE, 72.8% for ascites, 59.8% for gastrointestinal bleeding, and 48.8% for spontaneous bacterial peritonitis. Compared to the chart review, Generative Pre-trained Transformer 4 achieved 87.8%-98.8% accuracies for identifying cirrhosis and its complications. Using LLM as a silver standard, code-based classification achieved PPVs of 79.8% for identifying cirrhosis, 53.9% for HE, 55.3% for ascites, 67.6% for gastrointestinal bleeding, and 65.5% for spontaneous bacterial peritonitis., Conclusions: LLM-based classification was highly accurate versus manual chart review in identifying cirrhosis and its complications. This allowed us to assess the performance of code-based classification at scale using LLMs as a silver standard. These results suggest LLMs could augment or replace code-based cohort classification and raise questions regarding the necessity of chart review., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Coronavirus disease 2019 (COVID-19) has a considerable impact on the global healthcare system. Individuals who have recovered from COVID often experience chronic respiratory symptoms that affect their daily lives. This study aimed to assess respiratory dynamics such as airway hyperresponsiveness (AHR) and bronchodilator response in post-COVID patients., Methods: This study included 282 adults with respiratory symptoms who underwent provocation tests. The demographic details, clinical symptoms and medical histories were recorded. Baseline spirometry, methacholine challenge tests (MCT) and post-bronchodilator spirometry were performed. Patients were divided into the following four groups: Group 1: non-COVID-19 and negative MCT; Group 2: post-COVID-19 and negative MCT; Group 3: non-COVID-19 and positive MCT; and Group 4: post-COVID-19 and positive MCT., Results: Most post-COVID-19 patients (43.7%) experienced AHR, and wheezing was more common. Patients in Group 4 exhibited increased intensities of dyspnoea, cough and wheezing with the lowest pulmonary function test (PFT) parameters at baseline. Moreover, significant decreases in PFT parameters after the MCT were observed in these patients. Although the prevalence of a low forced expiratory volume in 1 s to forced vital capacity ratio (<70%) was initially 2% in Group 4, it increased to 29% after MCT. No significant differences in allergic history or underlying diseases were observed between the groups., Conclusions: These findings provide comprehensive insights into the AHR and respiratory symptoms of post-COVID-19 individuals, highlighting the characteristics and potential exacerbations in patients with positive MCT results. This emphasises the need of MCT to address respiratory dynamics in post-COVID-19 individuals., Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to declare., (Copyright ©The authors 2024.)

Doxorubicin (DOX) is mostly utilized as a wide range of antitumor anthracycline to treat different cancers. The severe antagonistic impacts of DOX on cardiotoxicity constrain its clinical application. Many mechanisms are involved in cardiac toxicity induced by DOX in the human body. Mitochondria is a central part of fatty acid and glucose metabolism. Thus, impaired mitochondrial metabolism can increase heart failure risk, which can play a vital role in cardiomyocyte mitochondrial dysfunction. This study aimed to assess the possible cardioprotective effect of water-extracted Artemisia argyi (AA) against the side effect of DOX in H9c2 cells and whether these protective effects are mediated through IGF-IIR/Drp1/GATA4 signaling pathways. Although several studies proved that AA extract has benefits for various diseases, its cardiac effects have not yet been identified. The H9c2 cells were exposed to 1 μM to establish a model of cardiac toxicity. The results revealed that water-extracted AA could block the expression of IGF-IIR/calcineurin signaling pathways induced by DOX. Notably, our results also showed that AA treatment markedly attenuated Akt phosphorylation and cleaved caspase 3, and the nuclear translocation markers NFATC3 and p-GATA4. Using actin staining for hypertrophy, we determined that AA can reduce the effect of mitochondrial reactive oxygen species and cell size. These findings suggest that water-extracted AA could be a suitable candidate for preventing DOX-induced cardiac damage., (© 2024 International Union of Biochemistry and Molecular Biology, Inc.)

Background: Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear., Methods: We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome., Results: Stratifying patients based on %Notch4 + Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4 + Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection., Conclusions: The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4 + Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Justice motivation has been considered one cause of celebrity infidelity scandals becoming flaming incidents. Nevertheless, few studies have examined how the belief in a just world (BJW), one motivation for justice, affects people's attitudes toward these incidents. This study was conducted to identify the relations among BJW, negative emotions toward infidelity (NE), and celebrity infidelity blaming (CIB). Data were collected from 1186 Japanese adults (mean age = 44.9 years, SD = 13.8; 49.4% male). The results of structural equation modeling revealed that NE positively relates to CIB and plays a mediating role between BJW and CIB. However, BJW neither facilitates NE nor positively predicts CIB; on the contrary, it suppresses both NE and CIB. The findings indicate that BJW decreases people's blame on celebrity infidelity and suggest future directions for mitigating the issues posed by casting blame on celebrities' cheating scandals.

Objective: To explore the application value of reticulocyte hemoglobin equivalent (Ret-He) for diagnosing latent iron deficiency in female plateletpheresis donors., Methods: A total of 230 female plateletpheresis donors in Fujian Blood Center from January to February 2022 were selected as the research group and divided into three groups: normal group, iron depletion (ID) group and iron deficient erythropoiesis (IDE) group, according to the severity of iron deficiency. The level of hemoglobin (HGB), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), coefficient of variation of red cell distribution width (RDW-CV) and Ret-He were measured by using the Sysmex XN automated hematology analyzer. Chemiluminescence immunoassay was used to detect iron biochemical indexes. Receiver operating characteristic(ROC) curve analysis was performed to evaluate the diagnosic value of relevant indicators in female blood donors with latent iron deficiency., Results: Ret-He in ID group was 32.55 (31.15,33.10)pg, which was significantly lower than that in the normal group ［33.80(32.73，34.70)pg］ （ P <0.05）, and significantly higher than that in IDE group ［30.40(28.70,31.50)pg］ （ P <0.05）. ROC analysis in diagnosis of IDE demonstrated that the area under the curves (AUCs) of HGB, MCV, MCH, RDW-CV and Ret-He were 0.892, 0.843, 0.909, 0.890, 0.931, respectively. When the critical value of Ret-He was 32.05 pg, its sensitivity and specificity were 85.90% and 92.60%, respectively. However, all red blood cell parameters had poor diagnostic value for ID., Conclusion: Ret-He is a perfect predictor for latent iron deficiency in female blood donors. Detection of Ret-He can advance the diagnosis of iron deficiency in female blood donors to the IDE stage.

Sea level rise and climate change are shaping present societies, particularly those on oceanic islands. Few historical examples could serve as references for these changes. One such potential model is the Saudeleur Dynasty with its capital Nan Madol on the Pacific Island of Pohnpei. However, the timing of its construction, as well as the dynasty's fluctuations and potential environmental influences, has remained unresolved. Through the analyses of 230 Th ages on 171 dates on corals fragments used as building materials and charcoal 14 C ages from excavations, 2 major construction phases spanning from the 10th to the 15th century CE can be discerned. The results show that the first phase of the site's construction, spanning the 10th-12th century, marked the dynasty's rise. The second period, spanning from the late 12th to the early 15th century, provides the most substantial evidence for the demise of the island-scale chiefdom and a significant societal reorganization. The phases are centuries earlier than previously believed. With this new evidence, we propose the hypothesis that variations in the El Niño-Southern Oscillation and subsidence-related sea level rise presented major challenges for building and maintaining Nan Madol, and thus, influenced the course of the island's history. This case serves as a compelling example of how adverse climatic conditions can spur investments-in this case, in seawater defense under high sea levels-yet ultimately may contribute to abandonment. It offers lessons for island nations, showcasing coastal resilience in the face of worsening catastrophic events that unfolded over generations., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Recent studies have shown that high dietary fructose intake enhances intestinal tumor growth in mice. Our previous work indicated that glucose enables hypoxic colorectal cancer (CRC) cells to resist receptor-interacting protein (RIP)-dependent necroptosis. Despite having the same chemical formula, glucose and fructose are absorbed through different transporters yet both can enter the glycolytic metabolic pathway. The excessive intake of dietary fructose, leading to its overflow into the colon, allows colonic cells to absorb fructose apically. This study explores the mechanisms behind apical fructose-mediated death resistance in CRC cells under hypoxic stress. Utilizing three CRC cell lines (Caco-2, HT29, and T84) under normoxic and hypoxic conditions with varying fructose concentrations, we assessed lactate dehydrogenase (LDH) activity, RIP1/3 complex formation (a necroptosis marker), and cell integrity. We investigated the role of fructose in glycolytic-mediated death resistance using glycolytic inhibitors iodoacetate (IA, a glycolytic inhibitor to glyceraldehyde 3-phosphate dehydrogenase), and UK5099 (UK, an inhibitor to mitochondrial pyruvate carrier). Our findings reveal that apical fructose prevents the hypoxia-induced RIP-dependent necroptosis in Caco-2 and HT29 cells. Fructose exposure under hypoxia also preserved epithelial integrity. IA, but not UK, blocked fructose-mediated glycolytic metabolite production and necrosis, indicating that anaerobic glycolytic metabolites facilitate death resistance. Notably, fructose treatment upregulated pyruvate kinase (PK)-M1 mRNA in hypoxic Caco-2 and HT29 cells, while PKM2 upregulation was exclusive to HT29 cells. In conclusion, apical fructose utilization through glycolysis effectively inhibits hypoxia-induced RIP-dependent necroptosis in CRC cells, shedding light on potential metabolic adaptation mechanisms in the tumor microenvironment and suggesting novel targets for therapeutic intervention., (© 2024. The Author(s).)

Objectives: To develop an intrinsic capacity (IC) score and to investigate the association between IC transition with overall and cause-specific mortality, incident disability and healthcare utilization., Design: Retrospective cohort study SETTING AND PARTICIPANTS: Data from 1852 respondents aged ≥ 65 years who completed the 1999 and 2003 surveys of the Taiwan Longitudinal Study on Aging were analyzed., Measurements: Transitions of IC score were categorized into three groups: (1) Improved IC (IC 2003-1999 >0), (2) Stable IC (IC 2003-1999 = 0), (3) Worsened IC (IC 2003-1999 <0). Cox regression and subdistribution hazard models were used to investigate IC transitions and 4-year overall and cause-specific mortality, respectively. Logistic regression were employed to develop weighted IC score (wIC, 0-16) and assess its association with incident disability and healthcare utilization. Similar analysis were repeated using non-weighted IC (nIC, 0-8) to ensure robustness., Results: Comparing to decreased wIC group, stable or increased wIC participants had significantly lower 4-year all-cause mortality, and death from infection, cardiometabolic/cerebrovascular diseases, organ failure and other causes. (Hazard ratio (HR) ranged from 0.36 to 0.56, 95% CI ranged from 0.15 to 1.00, p ≤ 0.049 in the stable wIC group; HR ranged from 0.41 to 0.51, 95% CI ranged from 0.22 to 0.94, p ≤ 0.034 in the increased wIC group). Moreover, individuals with stable or increased wIC demonstrated lower risk of incident disability and hospitalization. (Odds ratio (OR) = ranged from 0.34 to 0.70, 95% CI ranged from 0.19 to 1.00, p ≤ 0.048). Participants with stable wIC also exhibited reduced risk of emergency department visits (OR = 0.58, 95% CI = 0.41 to 0.82, p = 0.002). These results were generally consistent in the nIC model., Conclusion: Participants with stable or increased IC experienced significantly lower all-cause and most cause-specific mortality, incident disability, and healthcare utilization, which was independent of baseline IC and comorbidities. The findings remained consistent across weighted and non-weighted IC model., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Double-atom site catalysts (DASs) have emerged as a recent trend in the oxygen reduction reaction (ORR), thereby modifying the intermediate adsorption energies and increasing the activity. However, the lack of an efficient dual atom site to improve activity and durability has limited these catalysts from widespread application. Herein, the nitrogen-coordinated iron and tin-based DASs (Fe-Sn-N/C) catalyst are synthesized for ORR. This catalyst has a high activity with ORR half-wave potentials (E 1/2 ) of 0.92 V in alkaline, which is higher than those of the state-of-the-art Pt/C (E 1/2  = 0.83 V), Fe-N/C (E 1/2  = 0.83 V), and Sn-N/C (E 1/2  = 0.77 V). Scanning electron transmission microscopy analysis confirmed the atomically distributed Fe and Sn sites on the N-doped carbon network. X-ray absorption spectroscopy analysis revealed the charge transfer between Fe and Sn. Both experimental and theoretical results indicate that the Sn with Fe-NC (Fe-Sn-N/C) induces charge redistribution, weakening the binding strength of oxygenated intermediates and leading to improved ORR activity. This study provides the synergistic effects of DASs catalysts and addresses the impacts of P-block elements on d-block transition metals in ORR., (© 2024 Wiley‐VCH GmbH.)

Several life-prolonging therapies for metastatic castration-resistant prostate cancer (mCRPC) are available, including radium-223 dichloride ( 223 Ra), which was approved based on phase 3 data demonstrating improved overall survival (OS) and a favorable safety profile. To date, real-world evidence for 223 Ra use in Taiwan is from three studies of <50 patients. This observational study (NCT04232761) enrolled male patients with histologically/cytologically confirmed mCRPC with bone metastases from centers across Taiwan. 223 Ra was prescribed as part of routine practice by investigators. Patients with prior 223 Ra treatment were excluded. The primary objective was to assess 223 Ra safety; secondary objectives evaluated efficacy parameters, including OS. Overall, 224 patients were enrolled. Most patients had an Eastern Cooperative Oncology Group performance status of 0/1 (79.0%) and ≤20 bone metastases (69.2%); no patients had visceral metastases. 223 Ra was first- or second-line therapy in 23.2% and 47.7% of patients, respectively. The total proportion of patients who received 5-6 223 Ra cycles was 68.8%; this proportion was greater with first-line use (84.3%) than second- (65.7%) or third-/fourth-line use (64.1%). More chemotherapy-naïve patients (61.9%) completed the 6-cycle 223 Ra treatment than chemotherapy-exposed patients (56.7%). Any-grade treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 54.0% and 28.6% of patients, respectively, while 12% experienced 223 Ra-related adverse events. Median OS was 15.7 months (95% confidence interval 12.13-19.51); patients receiving 5-6 223 Ra injections and earlier 223 Ra use had longer OS than those receiving fewer injections and later 223 Ra use. 223 Ra provides a well-tolerated and effective treatment for Taiwanese patients with mCRPC and bone metastases., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Pseudorabies virus (PRV), an α-herpesvirus, induces immunosuppression and can lead to severe neurological diseases. N-methyl-D-aspartate receptor (NMDAR), an important excitatory nerve receptor in the central nervous system, is linked to various nervous system pathologies. The link between NMDAR and PRV-induced neurological diseases has not been studied. In vivo studies revealed that PRV infection triggers a reduction in hippocampal NMDAR expression, mediated by inflammatory processes. Extensive hippocampal neuronal degeneration was found in mice on the 6th day by hematoxylin-eosin staining, which was strongly correlated with increased NMDAR protein expression. In vitro studies utilizing the CCK-8 assay demonstrated that treatment with an NMDAR antagonist significantly heightened the cytotoxic effects of PRV on T lymphocytes. Notably, NMDAR inhibition did not affect the replication ability of PRV. However, it facilitated the accumulation of pro-inflammatory cytokines in PRV-infected T cells and enhanced the transcription of the CD25 gene through the secretion of interleukin-2 (IL-2), consequently exacerbating immunosuppression. In this study, we found that NMDAR has functional activity in T lymphocytes and is crucial for the inflammatory and immune responses triggered by PRV infection. These discoveries highlight the significant role of NMDAR in PRV-induced neurological disease pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The most effective drug, doxorubicin (DOX), is widely used worldwide for clinical application as an anticancer drug. DOX-induced cytotoxicity is characterized by mitochondrial dysfunction. There is no alternative treatment against DOX-induced cardiac damage despite intensive research in the present decades. Ohwia caudata has emerged as a potential herbal remedy that prevents from DOX-induced cytotoxicity owing to its pharmacological action of sustaining mitochondrial dynamics by attenuating oxidative stress and inducing cellular longevity. However, its underlying mechanisms are unknown. The novel treatment provided here depends on new evidence from DOX-treated H9c2 cells, which significantly enhanced insulin-like growth factor (IGF) II receptor (IGF-IIR) pathways that activated calcineurin and phosphorylated dynamin-related protein 1 (p-Drp1) at ser616 (p-Drp1[ser616]); cells undergo apoptosis due to these factors, which translocate to mitochondria and disrupt their function and integrity, and in terms of herbal medicine treatment, which significantly blocked these phenomena. Thus, our findings indicate that maintaining integrity of mitochondria is an essential element in lowering DOX-induced cytotoxicity, which further emphasizes that our herbal medicine can successfully block IGF-IIR pathways and could potentially act as an alternative mechanism in terms of cardioprotective against doxorubicin., (© 2024 International Union of Biochemistry and Molecular Biology, Inc.)

Chemical-inducible gene expression systems are commonly used to regulate gene expression for functional genomics in various plant species. However, a convenient system that can tightly regulate transgene expression in Nicotiana benthamiana is still lacking. In this study, we developed a tightly regulated copper-inducible system that can control transgene expression and conduct cell death assays in N. benthamiana. We tested several chemical-inducible systems using Agrobacterium-mediated transient expression and found that the copper-inducible system exhibited the least concerns regarding leakiness in N. benthamiana. Although the copper-inducible system can control the expression of some tested reporters, it is not sufficiently tight to regulate certain tested hypersensitive cell death responses. Using the MoClo-based synthetic biology approach, we incorporated the suicide exon HyP5SM/OsL5 and Cre/LoxP as additional regulatory elements to enhance the tightness of the regulation. This new design allowed us to tightly control the hypersensitive cell death induced by several tested leucine-rich repeat-containing proteins and their matching avirulence factors, and it can be easily applied to regulate the expression of other transgenes in transient expression assays. Our findings offer new approaches for both fundamental and translational studies in plant functional genomics., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Background: There are limited studies that explored the preparation and challenges faced by standardized patients (SPs) in portraying characters in difficult communication scenarios, and the strategies used to overcome these challenges. The purpose of this study was to understand the experience of SPs in interpreting difficult communication situations and the learning needs of performing similar scenarios. And it allows the researchers to explore the meaning, beliefs, values, and aspiration associated with their role as SPs. The findings could shade light on the significance of their experiences and provide valuable insights for the development of future SP training programs., Methods: The design of this study is framed by a narrative inquiry, using semi-structured guidelines to conduct in-depth interviews with 11 SPs who have participated in the performances of difficult communication situations. Research data were analyzed by Polkinghorne narrative analysis, and Riessman's four criteria were used to establish rigor., Results: Analysis revealed the following five themes: scenarios to real life connections, process of preparing for a performance, methods to detach from character, obtaining unexpected rewards, and needs for performance training. There are two to three subthemes that are subsumed under each theme., Conclusions: To strengthen training in difficult communication for healthcare professionals, the use of SPs to interpret challenging difficult communication scenarios will continue to increase. Educators need to ensure that SPs are fully prepared physically and emotionally before, during and after their performance. Offering of continuing education and training in feedback techniques are crucial to extend the tenure of SPs, reduce their frustration, prevent attrition, and ultimately, reduce training costs. In the future, SP training should also include detachment and feedback techniques to alleviate SPs' stress.

Physical frailty is a critical determinant of mortality in patients with cirrhosis and can be objectively measured using the Liver Frailty Index (LFI), which is potentially modifiable. We aimed to identify LFI cut-points associated with waitlist mortality. Ambulatory adults with cirrhosis without HCC awaiting liver transplantation from 9 centers from 2012 to 2021 for ≥3 months with ≥2 pre-liver transplantation LFI assessments were included. The primary explanatory variable was the change in LFI from first to second assessments per 3 months (∆LFI); we evaluated clinically relevant ∆LFI cut-points at 0.1, 0.2, 0.3, and 0.5. The primary outcome was waitlist mortality (death or delisting for being too sick), with transplant considered as a competing event. Among 1029 patients, the median (IQR) age was 58 (51-63) years; 42% were female; and the median lab Model for End-Stage Liver Disease-Sodium at first assessment was 18 (15-22). For each 0.1 improvement in ∆LFI, the risk of overall mortality decreased by 6% (cause-specific hazard ratio: 0.94, 95% CI: 0.92-0.97, p < 0.001). ∆LFI was associated with waitlist mortality at cut-points as low as 0.1 (cause-specific hazard ratio: 0.63, 95% CI: 0.46-0.87) and 0.2 (HR: 0.61, 95% CI: 0.42-0.87). An improvement in LFI per 3 months as small as 0.1 in the pre-liver transplantation period is associated with a clinically meaningful reduction in waitlist mortality. These data provide estimates of the reduction in mortality risk associated with improvements in LFI that can be used to assess the effectiveness of interventions targeting physical frailty in patients with cirrhosis., (Copyright © 2024 American Association for the Study of Liver Diseases.)

In this review, we explore the intricate relationship between glucose metabolism and mechanotransduction pathways, with a specific focus on the role of the Hippo signaling pathway in chondrocyte pathophysiology. Glucose metabolism is a vital element in maintaining proper chondrocyte function, but it has also been implicated in the pathogenesis of osteoarthritis (OA) via the induction of pro-inflammatory signaling pathways and the establishment of an intracellular environment conducive to OA. Alternatively, mechanotransduction pathways such as the Hippo pathway possess the capacity to respond to mechanical stimuli and have an integral role in maintaining chondrocyte homeostasis. However, these mechanotransduction pathways can be dysregulated and potentially contribute to the progression of OA. We discussed how alterations in glucose levels may modulate the Hippo pathway components via a variety of mechanisms. Characterizing the interaction between glucose metabolism and the Hippo pathway highlights the necessity of balancing both metabolic and mechanical signaling to maintain chondrocyte health and optimal functionality. Furthermore, this review demonstrates the scarcity of the literature on the relationship between glucose metabolism and mechanotransduction and provides a summary of current research dedicated to this specific area of study. Ultimately, increased research into this topic may elucidate novel mechanisms and relationships integrating mechanotransduction and glucose metabolism. Through this review we hope to inspire future research into this topic to develop innovative treatments for addressing the clinical challenges of OA.

Background: Existing prognostic scoring systems for intensive care unit (ICU) trauma patients require extensive data collection. The Geriatric Trauma Outcome Score (GTOS), which is based on age, injury severity, and transfusion need, has been validated for predicting mortality in elderly patients with trauma; however, its utility in the general ICU trauma population remains unexplored., Methods: This retrospective study included 2952 adult ICU trauma patients admitted between 2016 and 2021. The GTOS was calculated as follows: age + (Injury Severity Score × 2.5) + 22 (if transfused within 24 h). The area under the receiver operating characteristic curve (AUROC) was used to assess GTOS's ability to predict mortality. The optimal GTOS cutoff was determined using Youden's index. Mortality rates were compared between the high and low GTOS groups, including a propensity score-matched analysis adjusted for baseline characteristics., Results: This study included 2952 ICU trauma patients, with an overall mortality rate of 11.0% ( n = 325). GTOS demonstrated good predictive accuracy for mortality (AUROC 0.80). The optimal cutoff was 121.8 (sensitivity, 0.791; specificity, 0.685). Despite adjustments, patients with GTOS ≥ 121.8 had significantly higher mortality (17.4% vs. 6.2%, p < 0.001) and longer hospital stays (20.3 vs. 15.3 days, p < 0.001) compared to GTOS < 121.8., Conclusions: GTOS showed a reasonable ability to predict mortality in ICU trauma patients across all ages, although not as accurately as more complex ICU-specific models. With its simplicity, the GTOS may serve as a rapid screening tool for risk stratification in acute ICU trauma settings when combined with other data.

Background and Aims: Small-for-gestational-age (SGA) newborns have a higher risk of morbidity and mortality. Recognizing the risk factors for SGA helps raise early awareness of the issue and provides valuable insights for both healthcare providers and pregnant women. We aimed to identify determinants of SGA using population-based databases in Taiwan., Methods: Data were retrieved from the National Health Insurance, Birth Reporting, and Maternal and Child Health databases for this nationwide case-control study. Live births between 20 and 44 weeks of gestation from 2005 to 2014 were enrolled and linked to their mothers to determine maternal conditions during pregnancy. For every SGA newborn, four controls matched by gestational age and birth year were randomly selected. Multivariable logistic regression was used to identify risk factors for SGA, with adjusted odds ratios (aORs) and 95% confidence intervals (CIs) accounting for potential confounders and interaction terms., Results: A total of 158,405 live SGA births were identified, with 623,584 controls randomly selected. Independent risk factors for SGA included maternal age <20 years (aOR 1.68, 95% CI 1.62, 1.75); female sex in newborns (aOR 1.28, 95% CI 1.27, 1.30); socioeconomic deprivation (aOR 1.29, 95% CI 1.21, 1.38); hypertension (aOR 1.6, 95% CI 1.52, 1.67); kidney disorders (aOR 1.29, 95% CI 1.16, 1.44); thyroid disorders (aOR 1.13, 95% CI 1.09, 1.17); systemic lupus erythematosus (aOR 2.59, 95% CI 2.33, 2.89); antiphospholipid syndrome (aOR 2.08, 95% CI 1.64, 2.64); gestational hypertension (aOR 1.69, 95% CI 1.61, 1.76); pre-eclampsia (aOR 3.12, 95% CI 3.01, 3.25); and antepartum hemorrhage (aOR 1.05, 95% CI 1.03, 1.07) after adjustment for other covariates., Conclusions: SGA was associated with younger maternal age, female newborns, underlying comorbidities, and obstetric conditions. Gestational hypertension and pre-eclampsia were significant risk factors affecting infants of both sexes and all age groups and could mask the effects of maternal age and infant sex., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Health Science Reports published by Wiley Periodicals LLC.)

Bone loss leading to osteoporosis is a well-known feature in patients with ankylosing spondylitis (AS), with the prevalence of osteoporosis varying widely across different studies. However, there is still no consensus on the treatment of osteoporosis in AS patients. A 67-year-old male, a case of AS under medication control, had taken oral bisphosphonate for about seven years for suspected osteoporosis due to compression fracture at T12 and discontinued for disproportionately high dual-energy X-ray absorptiometry T-score (11.0 SD). He had been well until his right hip painful disability developed after a fall at home with a resultant right subtrochanteric transverse fracture with medial cortical spike, fulfilling features of atypical femoral fractures five months later. Open reduction and internal fixation with a cephalomedullary femoral nail were performed smoothly on the same day, and the fracture healed slowly and eventually one year later with only supplementation of calcium with vitamin D., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Huang et al.)

Heroin dependence (HD) is a complex disease with a substantial genetic contribution and is associated with traits of impulsivity and specific personality traits. The neurotrophic factor nerve growth factor (NGF) may mediate the reward processes in HD. This study aims to investigate whether NGF gene polymorphisms are associated with the co-occurrence of HD and impulsivity/specific personality traits in HD patients. To minimize the potential confounding effects of population stratification, we selected a homogeneous Han Chinese population and recruited 1364 participants (831 HD patients and 533 healthy controls). In addition, 163 female HD patients completed the Chinese version of the Barratt Impulsiveness Scale Version 11 (BIS-11), and 440 HD patients completed the Chinese version of the Tridimensional Personality Questionnaire (TPQ) for subsequent analysis. We identified three polymorphisms with altered allele and genotype frequency in HD patients versus controls (p = 0.035 for rs2254527; p = 0.005 for rs6678788; p = 0.006 for rs7523654), especially in the female subgroup. Four associations identified via haplotype analysis were significant in the female subgroup (p = 0.003 for T-T-A haplotype and p = 0.002 for C-C-A haplotype in block 1; p = 0.011 for T-T haplotype and p = 0.009 for C-T haplotypes in block 2), but not in the male subgroup. Male HD patients had higher novelty-seeking (NS) scores, and female HD patients had higher harm avoidance (HA) scores. However, there was no significant association between the selected NGF polymorphisms and BIS or TPQ scores in HD patients. NGF variants may contribute to the risk of HD development in females but do not mediate the relationship between impulsivity and specific personality traits in the female population., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by widespread inflammation and multi-organ damage. Toll-like receptor 7 (TLR-7) and autophagy have been implicated in SLE pathogenesis. Rice husk silica liquid (RHSL) has shown potential for modulating inflammatory responses, but its effects on SLE have not been thoroughly investigated. This study aims to evaluate the impact of RHSL on immune responses and autophagy in cell culture experiments, focusing on its effects on TLR-7 signaling, cytokine production, and autophagy modulation. RAW264.7 cells and human peripheral blood mononuclear cells (PBMCs) from healthy donors and SLE patients were used. Cells were stimulated with LPS or TLR-7 agonists and treated with RHSL. Cell viability was assessed, and cytokine levels (TNF-α and IL-6) were measured by ELISA. Autophagy-related proteins (LC3II, ATG5-ATG12) were analyzed by Western blotting. The effect of autophagy inhibition was studied using 3-methyladenine (3-MA). A concentration of 100 μg/mL RHSL did not affect cell viability but significantly reduced the TNF-α production in TLR-7 agonist-stimulated RAW264.7 cells (compared to TLR-7 alone, 3.41 ± 0.54 vs. 6.72 ± 0.07 folds) and PBMCs (compared to TLR-7 alone, 0.97 ± 0.19 vs. 1.40 ± 0.33 folds). RHSL enhanced autophagy, as evidenced by increased LC3II (4.35 ± 1.08 folds) and ATG5-ATG12 (7.07 ± 1.30 folds) conjugation in both RAW264.7 cells and SLE patient-derived PBMCs. The reduction in TNF-α production by RHSL was attenuated by 3-MA, indicating that autophagy plays a role in this process. RHSL also inhibited the translocation of phosphorylated NF-κB into the nucleus, suggesting a mechanism for its anti-inflammatory effects. RHSL exhibits potential as an immunomodulatory agent in SLE by enhancing autophagy and modulating TLR-7 signaling pathways. These findings suggest that RHSL could offer therapeutic benefits for managing inflammatory responses in SLE and warrant further investigation into its clinical applications.

Introduction: Early identification of high-risk traumatic brain injury (TBI) patients is crucial for optimizing treatment strategies and improving outcomes. The C-reactive protein-to-lymphocyte ratio (CLR) reflects systemic immunology and inflammation function and serves as a new biomarker for patient stratification. This study aimed to assess the predictive value of the CLR for mortality in patients with isolated moderate to severe TBI. Methods: A retrospective analysis of trauma registry data from 2009 to 2022 was conducted, including 1641 adult patients with isolated moderate to severe TBI. Patient demographics, the CLR, injury characteristics, and outcomes were compared between deceased and surviving patients. Univariate and multivariate analyses were performed to identify mortality risk factors. The optimal CLR cut-off value for predicting mortality was determined using receiver operating characteristic (ROC) curve analysis. Results: The CLR was significantly higher in deceased patients compared to survivors (60.1 vs. 33.9, p < 0.001). The optimal CLR cut-off value for predicting mortality was 54.5, with a sensitivity of 0.328 and a specificity of 0.812. The area under the ROC curve was 0.566, indicating poor discriminative ability. In the multivariate analysis, the CLR was not a significant independent predictor of mortality (OR 1.03, p = 0.051). After propensity score matching to attenuate the difference in baseline characteristics, including sex, age, comorbidities, conscious level, and injury severity, the high-CLR group (CLR ≥ 54.5) did not have significantly higher mortality compared to the low-CLR group (CLR < 54.5). Conclusion: While the CLR was associated with mortality in TBI patients, it demonstrated poor discriminative ability as a standalone predictor. The association between a high CLR and worse outcomes may be primarily due to other baseline patient and injury characteristics, rather than the CLR itself.

In dairy farming, the uncertainty of cow calving date often imposes waiting costs for days on farmers. Improving the accuracy of calving date prediction would mitigate these costs, specifically before a few days of the event. We monitored and analyzed the heart rate patterns of eight pregnant cows in the days leading up to calving using a dedicated monitoring device. We decomposed the heart rate data into three distinct components: trend, daily cycle, and the remainder, and discovered that the heart rate trend exhibited a sharp decline more than 40 h before the calving event via the trend turning point. To detect the turning point, we applied common financial technical indicators traditionally used to identify turning points of asset prices in trading markets for the extracted heart rate trend. This study remains a feasibility study because of the limited observations, but it indicates that these indicators can effectively capture the trend's turning point in real time, offering a promising approach for enhanced calving prediction. In addition to discussing the practical implications for cow management, we also contemplate the broader utility of these technical indicators in the context of various dynamic scientific data analyses., (© 2024. The Author(s).)

While Asian American parents are key contributors in racially socializing their children, past research indicates that issues of race are not frequently discussed among Asian American families. Moreover, there is limited research on how Asian American parents' sociocultural factors predict the amount and ways they talk about race to their children. We conducted latent profile analyses among 150 Asian American parents' (M age  = 42.36, range = 26-65 years) racial discussions, and the profiles' association with parents' sociocultural factors (i.e., enculturation, acculturation, internalized racism, collectivism, and loss of face) were examined. Four distinct profiles were identified with distinct levels of awareness of discrimination, avoidance of outgroups, minimization of race, and promotion of equality messages. Findings underscore the importance of Asian American parents engaging in nuanced racial discussions with their children, highlighting the need for culturally responsive interventions, educational programs, and policy initiatives to support families in navigating complex racial landscapes and fostering positive youth outcomes., (© 2024 Family Process Institute.)

Nucleotide-binding domain and leucine-rich repeat (NLR) proteins play crucial roles in immunity against pathogens in both animals and plants. In solanaceous plants, activation of several sensor NLRs triggers their helper NLRs, known as NLR-required for cell death (NRC), to form resistosome complexes to initiate immune responses. While the sensor NLRs and downstream NRC helpers display diverse genetic compatibility, molecular evolutionary events leading to the complex network architecture remained elusive. Here, we showed that solanaceous NRC3 variants underwent subfunctionalization after the divergence of Solanum and Nicotiana, altering the genetic architecture of the NRC network in Nicotiana. Natural solanaceous NRC3 variants form three allelic groups displaying distinct compatibilities with the sensor NLR Rpi-blb2. Ancestral sequence reconstruction and analyses of natural and chimeric variants identified six key amino acids involved in sensor-helper compatibility. These residues are positioned on multiple surfaces of the resting NRC3 homodimer, collectively contributing to their compatibility with Rpi-blb2. Upon activation, Rpi-blb2-compatible NRC3 variants form membrane-associated punctate and high molecular weight complexes, and confer resistance to the late blight pathogen Phytophthora infestans. Our findings revealed how mutations in NRC alleles lead to subfunctionalization, altering sensor-helper compatibility and contributing to the increased complexity of the NRC network., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JK received funding from industry on NLR biology at the time of the study. JK has filed patents on NLR biology. Other authors have declared that no competing interests exist., (Copyright: © 2024 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Graphene oxide (GO) is a two-dimensional metastable nanomaterial. Interestingly, GO formed oxygen clusterings in addition to oxidized and graphitic phases during the low-temperature thermal annealing process, which could be further used for biomolecule bonding. By harnessing this property of GO, we created a bio-interface with patterned structures with a common laboratory hot plate that could tune cellular behavior by physical contact. Due to the regional distribution of oxygen clustering at the interface, we refer to it as patterned annealed graphene oxide (paGO). In addition, since the paGO was a heterogeneous interface and bonded biomolecules to varying degrees, arginine-glycine-aspartic acid (RGD) was modified on it and successfully regulated cellular-directed growth and migration. Finally, we investigated the FRET phenomenon of this heterogeneous interface and found that it has potential as a biosensor. The paGO interface has the advantages of easy regulation and fabrication, and the one-step thermal reduction method is suitable for biological applications. We believe that this low-temperature thermal annealing method would make GO interfaces more accessible, especially for the development of nano-interfacial modifications for biological applications, revealing its potential for biomedical applications.

Length mismatch between aspiration catheters and microcatheters can hinder optimal thrombus engagement, particularly in tortuous vessels and cases of vascular stenosis. We present a case in which a side puncture technique was used to deploy the stent retriever when exchangeable devices were unavailable. A man in his seventies with basilar artery occlusion underwent mechanical thrombectomy. The aspiration catheter failed to advance because of the tortuosity of the vertebral artery, preventing the microcatheter from delivering the stent retriever distal to the thrombus. By puncturing the aspiration catheter, additional microcatheter length was obtained, allowing the stent to be deployed at the targeted site. Thrombus extraction was then successfully performed using the Solumbra technique. This approach is advantageous for its simplicity and eliminates the need for additional devices. However, it also has specific drawbacks, such as damaging the aspiration catheters., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Macrophages, pivotal components of the immune system, orchestrate host defense mechanisms in humans and mammals. Their polarization into classically activated macrophages (CAMs or M1) and alternatively activated macrophages (AAMs or M2) dictates distinct functional roles in immunity and tissue homeostasis. While the negative regulatory role of CD32b within the FC gamma receptor (FCγR) family is recognized across various immune cell types, its influence on macrophage polarization remains elusive. This study aimed to elucidate the regulatory role of CD32b in macrophage polarization and discern the differential expression markers between the M1 and M2 phenotypes following CD32b siRNA transfection. The results revealed a decrease in the CD32b levels in lipopolysaccharide (LPS)-treated M1 and an increase in interleukin-4 (IL-4)-treated M2 macrophages, as observed in macrophage Raw264.7 cells. Furthermore, CD32b siRNA transfection significantly downregulated the M2 markers (IL-10, VEGF, Arg-1, and STAT6), while upregulating the M1 markers (IL-6, NF-κB, NOS2, and STAT1) in the Raw264.7 cells. Similar findings were recapitulated in macrophage-rich adherent cells isolated from mouse spleens. Additionally, the cytopathological analysis of pleural effusions and ascitic fluids from patients with cancer revealed a positive correlation between advanced tumor stages, metastasis, and elevated CD32b levels. In conclusion, this study highlights the regulatory influence of CD32b in suppressing M1 expression and promoting M2 polarization. Moreover, heightened M2 activation and CD32b levels appear to correlate with tumor progression. A targeted CD32b blockade may serve as a novel therapeutic strategy to inhibit M2 macrophage polarization and is promising for anti-tumor intervention.

Three previously undescribed pyrrolizidinone alkaloids, penicipyrrolizidinones A and B (1 and 2), possessing an unprecedented 2-methyl-2-(oct-6-enoyl)pyrrolizidin-3-one skeleton, and penicipyrrolizidinone C (3), featuring a rare 1-alkenyl-2-methyl-pyrrolizidin-3,7-dione skeleton, together with four known pyrrolidine derivatives (4-7) were isolated from the mangrove-derived fungus Penicillium sp. DM27. Their structures were elucidated through comprehensive spectroscopic analysis, theoretical calculations of ECD spectra, and the modified Mosher's method. A plausible biosynthetic pathway for penicipyrrolizidinones A-C (1-3) was proposed. Compounds 4 and 5 exhibited moderate cytotoxicity against B16-F10 melanoma cells with IC 50 values of 10.5 μM and 15.5 μM, respectively., 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. Published by Elsevier Ltd.)

Background: This retrospective study analyzed tumor tissue profiling data to assess the potential of comprehensive genomic profiling (CGP) for patient care across diverse solid tumors., Material and Methods: Patients with newly diagnosed or recurrent stage IIIB or IV lung adenocarcinoma with a null immunophenotype and esophageal, gastric, pancreatic, or bile duct cancer between January 2020 and July 2023 at two medical centers in Taiwan were included. One cohort was a part of the National Biobank Consortium of Taiwan project, whereas the other consisted of patients undergoing routine clinical practice. Tumor samples were subjected to CGP using FoundationOne®CDx, with therapeutic implications determined using OncoKB classification., Results: FoundationOne®CDx testing of 574 patients was successful in 456 (79.4%) patients. Clinically actionable genomic alterations were detected in 21.1% (96/456) of the patients, including 17.5%, 2.9%, and 0.7% of patients with evidence levels 1, 2, and 3, respectively. Lung adenocarcinoma accounted for the largest proportion of samples with at least one actionable gene alteration (63.2%), followed by bile duct (26.9%), gastric (17.6%), esophageal (4.0%), and pancreatic (3.1%) cancers. Based on CGP results, 43 patients (9.4%) received matched targeted therapy. The median overall survival of patients who received matched therapy or not was 26.1 months (95% confidence interval (CI), 16.7-35.5 months) and 10.6 months (95% CI, 8.1-13.1 months; hazard ratio, 0.28, 95% CI, 0.14-0.55, p < 0.001), respectively., Conclusions: This study provides comprehensive insights into the genomic profiles of diverse cancers in Taiwan, highlighting the crucial role of CGP in identifying actionable genomic alterations and guiding effective therapeutic strategies in real-world practice., Competing Interests: Declaration of competing interest A conflict of interest occurs when an individual's objectivity is potentially compromised by a desire for financial gain, prominence, professional advancement or a successful outcome. JFMA Editors strive to ensure that what is published in the Journal is as balanced, objective and evidence-based as possible. Since it can be difficult to distinguish between an actual conflict of interest and a perceived conflict of interest, the Journal requires authors to disclose all and any potential conflicts of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Inflammation is an intrinsic protective mechanism against various forms of cellular injuries in humans; however, its undesired activation results in tissue damage and cell death. The onset of chronic inflammation and oxidative stress are the key characteristics of autoimmune inflammatory diseases such as rheumatoid arthritis (RA), for which an effective treatment is yet to be developed. Therefore, in this study, we investigated the protective effects and molecular mechanisms of a novel herbal preparation, Jing-Si herbal tea (JS), against H 2 O 2 -induced inflammation and cellular damage in HIG-82 synoviocytes. We found that JS did not show any significant alterations in cell viability at <188 μg/mL; however, a cytotoxic effect was observed at 188-1883 μg/mL concentrations tested. We found that expressions of inflammation associated extracellular matrix (ECM)-degrading proteases MMP-13, ADAMTS-2, -8, and -17 were abnormally enhanced under H 2 O 2 -induced pathological oxidative stress (ROS) in HIG-82 cells. Interestingly, JS treatment not only reduced the ROS levels but also significantly repressed the protein expressions of collagen degrading proteases in a dose-dependent manner. Treatment with JS showed enhanced cell viability against H 2 O 2 -induced toxic ROS levels. The expressions of cell protective aggrecan, Collagen II, and Bcl-2 were increased, whereas MMP-13, ADAMTS-2, Cytochrome C, and cleaved Caspase 3 were decreased by JS under inflammatory agents H 2 O 2 , MIA, LPS, and TNF-α treatment, respectively, in HIG-82 cells. Interestingly, the cytoprotective effect of JS treatment was attributed to a decreased mitochondrial localization of Bax and a reduction of Cytochrome C release into the cytoplasm of H 2 O 2 -treated HIG-82 cells. Collectively, our results suggest a novel protective mechanism of JS for RA treatment, which could be potentially applied as a complementary treatment or as an alternative therapeutic approach to mitigate inflammatory diseases., (© 2024 Wiley Periodicals LLC.)