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Yi-yang Sun, Peng-fei Wang, Gui-rong Yang, Dong-qing Du, Chun-jing Li, Zi-jun Mu, Yu-xia Ma, Na Zhang Department of Acupuncture-Moxibustion and Tuina, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of ChinaCorrespondence: Yu-xia Ma; Na Zhang, Email phdmayuxia@126.com; zhangna2008zhentui@163.comBackground: Clinical acupuncture decisions are highly operator-dependent and require physician-patient interactions. The Delphi method allows subjective factors such as expert experience and preference of patients to be taken into account in clinical decision making, which is particularly applicable to acupuncture. Currently, the Delphi method is widely used to support clinical decisions in acupuncture. Therefore, it is necessary to provide high-quality and complete descriptions of the Delphi process when making clinical decisions. This study aims to evaluate the quality of the Delphi process in acupuncture, facilitate its standardization and rigor for further clinical decision making in acupuncture.Methods: Articles sourced from six databases were searched systematically to assess the quality of the Delphi consensus process based on the standards for conducting and reporting Delphi studies (CREDES). Descriptive statistics and analysis were presented according to the percentage of each item. Five-score Likert scale was used to evaluate the reporting quality of four domains as well as each item in CREDES by two independent researchers, combined with ICC-value to assess the consistency.Results: A total of 37 qualified articles were included according to eligibility criteria. As for the low reporting rate, the item “External validation” was reported as the lowest positive rate at 32.43% and the item “Prevention of bias” was 48.65%. The item “Adequacy of conclusions”, “Definition and attainment of consensus”, and “Discussion of limitations” were reported at a positive ratio of 62.16%, 64.86%, and 67.57% individually. The average scores of the four domains based on CREDES from highest to lowest were, respectively, as follows: planning and design (68.75%), reporting (66.07%), rationale for the choice of the Delphi technique (65.54%), study conduct (45.10%).Conclusion: The reporting quality of the Delphi consensus process in acupuncture is acceptable currently, but the reporting rate on some items is still low. Further standardization, including either clearer checklists or study reports, should be developed and strengthened to guide clinical decisions in acupuncture.Keywords: delphi, consensus, acupuncture, CREDES, quality assessment

Ting-Yu Hsu,1 Chi-Yung Cheng,1,2,* I-Min Chiu,1,2 Chun-Hung Richard Lin,2 Fu-Jen Cheng,1 Hsiu-Yung Pan,1 Yu-Jih Su,3 Chao-Jui Li1,* 1Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan; 3Department of Internal Medicine, Division of Rheumatology, Allergy and Immunology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan*These authors contributed equally to this workCorrespondence: Chi-Yung Cheng; Chao-Jui Li, Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao-Sung, Kaohsiung, 833, Taiwan, Tel +886-7-7317123 ext. 8415, Email qzsecawsxd@gmail.com; chaojui@cgmh.org.twBackground: The global aging population presents a significant challenge, with older adults experiencing declining physical and cognitive abilities and increased vulnerability to chronic diseases and adverse health outcomes. This study aims to develop an interpretable deep learning (DL) model to predict adverse events in geriatric patients within 72 hours of hospitalization.Methods: The study used retrospective data (2017– 2020) from a major medical center in Taiwan. It included non-trauma geriatric patients who visited the emergency department and were admitted to the general ward. Data preprocessing involved collecting prognostic factors like vital signs, lab results, medical history, and clinical management. A deep feedforward neural network was developed, and performance was evaluated using accuracy, sensitivity, specificity, positive predictive value (PPV), and area under the receiver operating characteristic curve (AUC). Model interpretation utilized the Shapley Additive Explanation (SHAP) technique.Results: The analysis included 127,268 patients, with 2.6% experiencing imminent intensive care unit transfer, respiratory failure, or death during hospitalization. The DL model achieved AUCs of 0.86 and 0.84 in the validation and test sets, respectively, outperforming the Sequential Organ Failure Assessment (SOFA) score. Sensitivity and specificity values ranged from 0.79 to 0.81. The SHAP technique provided insights into feature importance and interactions.Conclusion: The developed DL model demonstrated high accuracy in predicting serious adverse events in geriatric patients within 72 hours of hospitalization. It outperformed the SOFA score and provided valuable insights into the model’s decision-making process. Keywords: explainable machine learning, deep learning algorithm, adverse events, mortality

Long-Fei Xia,1 Jing-Bo Li,2 Guo-Sheng Tian,2 Wei-Ran Jiang,3 Yao-Shuang Li,1 Chen-Ying Lin,1 Hui-Na Qiu,2 Fan Wu,4 Jun-Jia Wang,5 Chun-Jun Li,2 Jing-Na Lin2 1Tianjin Union Medical Center, Tianjin Medical University, Tianjin, 300070, People’s Republic of China; 2Department of Endocrinology, Health Management Center, Tianjin Union Medical Center, Nankai University Affiliated Hospital, Tianjin, 300121, People’s Republic of China; 3Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, NY, USA; 4School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China; 5Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of ChinaCorrespondence: Jing-Na Lin; Chun-Jun Li, Email 13207628978@163.com; li_chunjun@126.comObjective: To investigate the impact of sarcopenia on the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) among individuals with type 2 diabetes mellitus (T2DM).Methods: This study included the clinical, laboratory, and body composition data of 1491 patients with T2DM who were admitted to the Department of Endocrinology and Metabolism at Tianjin Union Medical Center from July 2018 to July 2023. The China-PAR model was utilized to evaluate cardiovascular disease risk. Associations between ASCVD risk and various clinical parameters were analyzed, and the relationship between body composition parameters and ASCVD risk was assessed using logistic regression.Results: The analysis revealed that T2DM patients with sarcopenia had a higher 10-year ASCVD risk compared to those without sarcopenia, with reduced muscle mass independently predicting an increased risk of cardiovascular disease. This association was significant among female T2DM patients, while male T2DM patients with sarcopenia showed a marginally higher median ASCVD risk compared to their non-sarcopenic counterparts. ASCVD risk inversely correlated with body muscle parameters and positively correlated with fat content parameters. Specifically, height- and weight-adjusted fat mass (FM, FM%, FMI) were identified as risk factors for ASCVD. Conversely, muscle parameters adjusted for weight and fat (ASM%, SMM%, FFM%, ASM/FM, SMM/FM, FMM/FM) were protective against ASCVD risk. These findings highlight the critical role of sarcopenia in influencing cardiovascular disease risk among Chinese patients with T2DM, as predicted by the China-PAR model.Conclusion: This study highlights the importance of sarcopenia in T2DM patients, not only as an indicator of ASCVD risk, but possibly as an independent risk factor in this demographics.Keywords: atherosclerotic cardiovascular disease, ASCVD, type 2 diabetes, T2DM, sarcopenia, fat content, muscle mass

Chao-Jen Li,1,* Hung-Wen Tsai,2,* Yi-Li Chen,3 Chun-I Wang,4 Yang-Hsiang Lin,5 Pei-Ming Chu,6,7 Hsiang-Cheng Chi,8,9 Yi-Ching Huang,3 Cheng-Yi Chen3 1Department of General & Gastroenterological Surgery, An Nan Hospital, China Medical University, Tainan, Taiwan; 2Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; 5Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 6Department of Anatomy, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 7Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan; 8Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan; 9Chinese Medicine Research Center, China Medical University, Taichung, Taiwan*These authors contributed equally to this workCorrespondence: Cheng-Yi Chen, Tel/Fax +886-6-2353535#5329, Email cychen@gs.ncku.edu.twIntroduction: Hepatocellular carcinoma (HCC) accounts for 80% of all liver cancers and is the 2nd leading cause of cancer-related death in Taiwan. Various factors, including rapid cell growth, a high recurrence rate and drug resistance, make HCC difficult to cure. Moreover, the survival rate of advanced HCC patients treated with systemic chemotherapy remains unsatisfactory. Hence, the identification of novel molecular targets and the underlying mechanisms of chemoresistance in HCC and the development more effective therapeutic regimens are desperately needed.Methods: An MTT assay was used to determine the cell viability after cisplatin or doxorubicin treatment. Western blotting, qRT‒PCR and immunohistochemistry were utilized to examine the protein tyrosine phosphatase IVA3 (PTP4A3) level and associated signaling pathways. ELISA was utilized to analyze the levels of the inflammatory cytokine IL-6 influenced by cisplatin, doxorubicin and PTP4A3 silencing.Results: In this study, we found that PTP4A3 in the cisplatin/doxorubicin-resistant microarray was closely associated with the overall and recurrence-free survival rates of HCC patients. Cisplatin or doxorubicin significantly reduced cell viability and decreased PTP4A3 expression in hepatoma cells. IL-6 secretion increased with cisplatin or doxorubicin treatment and after PTP4A3 silencing. Furthermore, PTP4A3 was highly expressed in tumor tissues versus adjacent normal tissues from HCC patients. In addition, we evaluated the IL-6-associated signaling pathway involving STAT3 and JAK2, and the levels of p-STAT3, p-JAK2, STAT3 and JAK2 were obviously reduced with cisplatin or doxorubicin treatment in HCC cells using Western blotting and were also decreased after silencing PTP4A3. Collectively, we suggest that cisplatin or doxorubicin decreases HCC cell viability via downregulation of PTP4A3 expression through the IL-6R-JAK2-STAT3 cascade.Discussion: Therefore, emerging evidence provides a deep understanding of the roles of PTP4A3 in HCC cisplatin/doxorubicin chemoresistance, which can be applied to develop early diagnosis strategies and reveal prognostic factors to establish novel targeted therapeutics to specifically treat HCC.Keywords: hepatocellular carcinoma, chemoresistance, cisplatin, doxorubicin, PTP4A3, IL-6

Zhong-Han Fang,1,2 Hong-Lin Liao,1,2 Qing-Feng Tang,1,2 Ya-Jing Liu,1,2 Yan-Yan Zhang,1,2 Jiu Lin,1,2 Hao-Peng Yu,3 Cheng Zhou,4 Chun-Jie Li,1,5 Fei Liu,1,2,* Jie-Fei Shen1,2,* 1State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, National Center for Stomatology, West China School of Stomatology, Sichuan University, Chengdu, People’s Republic of China; 2Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China; 3West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 5Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fei Liu; Jie-Fei Shen, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China, Email liufei.hxkq@scu.edu.cn; shenjiefei@scu.edu.cnBackground: Recent studies have demonstrated the contribution of non-coding RNAs (ncRNAs) to neuropathic pain. However, the expression profile of ncRNAs in the trigeminal ganglion (TG) and their functional mechanism underlying trigeminal neuropathic pain are still unclear.Methods: In the present study, the trigeminal neuropathic pain model induced by chronic constriction injury of the infraorbital nerve (CCI-ION) was used to study the expression profile and potential regulatory mechanism of miRNAs, lncRNAs, circRNAs, and mRNAs in the TG by RNA-sequencing (RNA-seq) and bioinformatics analysis. CCI-ION mice suffered from mechanical allodynia from 3 days to 28 days after surgery.Results: The RNA-seq results discovered 67 miRNAs, 216 lncRNAs, 14 circRNAs, 595 mRNAs, and 421 genes were differentially expressed (DE) in the TG of CCI-ION mice 7 days after surgery. And 39 DEGs were known pain genes. Besides, 5 and 35 pain-related DE mRNAs could be targeted by 6 DE miRNAs and 107 DE lncRNAs, respectively. And 23 pain-related DEGs had protein–protein interactions (PPI) with each other. GO analysis indicated membrane-related cell components and binding-related molecular functions were significantly enriched. KEGG analysis showed that nociception-related signaling pathways were significantly enriched for DE ncRNAs and DEGs. Finally, the competing endogenous RNA (ceRNA) regulatory network of DE lncRNA/DE circRNA-DE miRNA-DE mRNA existed in the TG of mice with trigeminal neuropathic pain.Conclusion: Our findings demonstrate ncRNAs are involved in the development of trigeminal neuropathic pain, possibly through the ceRNA mechanism, which brings a new bright into the study of trigeminal neuropathic pain and the development of novel treatments targeting ncRNAs.Keywords: trigeminal neuropathic pain, non-coding RNAs, RNA-sequencing, trigeminal ganglion, trigeminal nerve injury, bioinformatics

Chuan-Jiang Li,1,* Liang Li2,* 1Department of Surgery, Nanfang Hospital, 2Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, People’s Republic of China *The authors contributed equally to this work Abstract: Tacrolimus is a product of fermentation of Streptomyces, and belongs to the family of calcineurin inhibitors. It is a widely used immunosuppressive drug for preventing solid-organ transplant rejection. Compared to cyclosporine, tacrolimus has greater immunosuppressive potency and a lower incidence of side effects. It has been accepted as first-line treatment after liver and kidney transplantation. Tacrolimus has specific features in Chinese transplant patients; its in vivo pharmacokinetics, treatment regimen, dose and administration, and adverse-effect profile are influenced by multiple factors, such as genetics and the spectrum of primary diseases in the Chinese population. We reviewed the clinical experience of tacrolimus use in Chinese liver- and kidney-transplant patients, including the pharmacology of tacrolimus, the immunosuppressive effects of tacrolimus versus cyclosporine, effects of different factors on tacrolimus metabolism on Chinese patients, personalized medicine, clinical safety profile, and patient satisfaction and adherence. This article provides guidance for the rational and efficient use of tacrolimus in Chinese organ-transplant patients. Keywords: tacrolimus, liver transplantation, kidney transplant, Chinese, personalized medicine

Xinlin Yang, Ching-Ju Li, Yueping Wan, Pinar Smith, Guowei Shang, Quanjun Cui Department of Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, VA, USA Abstract: Antioxidants were implicated as potential reagents to enhance osteogenesis, and nano-fullerenes have been demonstrated to have a great antioxidative capacity by both in vitro and in vivo experiments. In this study, we assessed the impact of a polyhydroxylated fullerene, fullerol, on the osteogenic differentiation of human adipose-derived stem cells (ADSCs). Fullerol was not toxic against human ADSCs at concentrations up to 10 µM. At a concentration of 1 µM, fullerol reduced cellular reactive oxygen species after a 5-day incubation either in the presence or in the absence of osteogenic media. Pretreatment of fullerol for 7 days increased the osteogenic potential of human ADSCs. Furthermore, when incubated together with osteogenic medium, fullerol promoted osteogenic differentiation in a dose-dependent manner. Finally, fullerol proved to promote expression of FoxO1, a major functional isoform of forkhead box O transcription factors that defend against reactive oxygen species in bone. Although further clarification of related mechanisms is required, the findings may help further development of a novel approach for bone repair, using combined treatment of nano-fullerol with ADSCs. Keywords: polyhydroxylated fullerene, bone repair, reactive oxygen species, forkhead box protein O1

Intramuscular fat content is one of the most important factors affecting beef quality. However, the role of alternate polyadenylation (APA) in intramuscular fat deposition remains unclear. We compared APA events in muscle samples from high and low intramuscular fat (IMF) cattle, based on RNA-seq data. A total of 363 significant APAs were identified. Notably, the number of shortened 3'UTR events exceeded the number of lengthened 3'UTR events, and genes associated with shortened 3'UTR events were enriched in fatty acid metabolism-related pathways. Most APA events had alternative 3'UTR (aUTR) lengths of 200-300 bp. As the 3'UTR lengthened, the aUTR also lengthened (R2 = 0.79). These findings indicate that genes with longer 3'UTRs are more likely to be regulated by APA in the muscle of cattle with high IMF. To determine whether the identified APA events drove alterations in the expression of fat deposition-related genes, we analyzed the relationship between APA events and differentially expressed genes and identified several genes critical for fat deposition (e.g., PFKL and SLC1A5). Since miRNAs usually bind to the 3'UTR region of protein-coding genes and affect gene expression, we constructed an miRNA-APA network to detect several key miRNAs that may regulate fat deposition. We identified 10 important miRNAs that affect changes in IMF content, which may be gained (gained miRNA-binding sites) or lost (lost miRNA-binding sites) owing to 187 differential APA events. Our study characterized the APA profiles of cattle with high and low intramuscular fat content and provided further insights into the relationship between APA, miRNA, and fat deposition., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society of Animal Science. 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: Advanced maternal age is associated with decreased oocyte quantity and quality and in vitro fertilization (IVF) success rates. This study aimed to investigate whether melatonin supplementation can improve IVF outcomes in women of advanced maternal age by modulating cuproptosis and ferroptosis., Methods: This prospective cohort study included 161 women aged 35-45 years undergoing IVF-frozen embryo transfer cycles. Participants were assigned to either melatonin (n = 86, 2 mg daily for ≥ 8 weeks) or control (n = 75) groups. Cumulus cells were analyzed for cuproptosis and ferroptosis-related gene expression. Additional experiments were conducted on the HGL5 human granulosa cell line to assess mitochondrial function and metabolic reprogramming., Results: Melatonin supplementation significantly improved IVF outcomes in women aged ≥ 38 years, increasing clinical pregnancy rates (46.0% vs. 20.3%, P < 0.01), ongoing pregnancy rates (36.5% vs. 15.3%, P < 0.01), and live birth rates (33.3% vs. 15.3%, P < 0.05). In cumulus cells from patients, gene expression analysis revealed that melatonin modulated cuproptosis and ferroptosis-related genes, including ATP7B and GPX4, with more pronounced effects in the ≥ 38 years group. This suggests melatonin enhances cellular resilience against oxidative stress and metal-induced toxicity in the ovarian microenvironment. In vitro studies using HGL5 cells showed melatonin reduced oxidative stress markers, improved mitochondrial function, restored expression of glycolysis and TCA cycle-related genes and modulated cuproptosis and ferroptosis-related gene expression. These findings provide mechanistic insight into melatonin's protective effects against regulated cell death in ovarian cells, potentially explaining the improved IVF outcomes observed., Conclusions: Melatonin supplementation significantly improved IVF outcomes in women of advanced maternal age, particularly those ≥ 38 years old, likely by modulating cuproptosis and ferroptosis and enhancing mitochondrial function in cumulus and granulosa cells. These results suggest that melatonin could be a promising adjuvant therapy for improving IVF success rates in older women., (© 2024. The Author(s).)

Butyric acid as a short-chain fatty acid (SCFA) is one of the key microbial metabolites of ruminants. Numerous studies indicate that butyrate is crucial in muscle growth and development, and plays an important molecular regulatory role mainly by inhibiting histone deacetylation. DNA methylation, a major epigenetic modification, is involved in cell differentiation. Butyrate, in addition to its role in acetylation modifications, can alter the DNA methylation status of cells. However, the impact of butyrate on the DNA methylation of bovine skeletal muscle satellite cells (SMSCs) remains unclear. In this study, we developed a differentiation model of SMSCs and employed RNA sequencing (RNA-seq) alongside whole genome bisulfite sequencing (WGBS) to explore the effects of butyrate treatment on DNA methylation status and its relationship with gene expression. Treatment of SMSCs with sodium butyrate (NaB) at 1.0 mM for 2 days significantly inhibited the expression of DNA methyltransferases (DNMT1, DNMT2, DNMT3A) at the mRNA and protein levels while promoting the expression of demethylases (TET1, TET2, TET3) at mRNA levels. WGBS identified 4292 differentially methylated regions (DMRs), comprising 2294 hypermethylated and 1998 hypomethylated regions. These DMRs were significantly enriched in the MAPK, cAMP, and Wnt signaling pathways, all of which are implicated in myogenesis and development. Combining RNA-seq and WGBS data revealed a total of 130 overlapping genes, including MDFIC, CREBBP, DMD, LTBP2 and KLF4. These genes are predominantly involved in regulating the FoxO, MAPK, PI3K-Akt, and Wnt signaling pathways. This study provides new insights into the effects of butyrate-mediated DNA methylation on SMSC development and enhances our understanding of butyrate as an epigenetic modifier beyond its role in acetylation., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Our previous studies have revealed a correlation between urinary phthalates (PAE) metabolites and parabens and PM 2.5 exposure and susceptibility to attention-deficit/hyperactivity disorder (ADHD) in school-age children. Our goal was to examine the relationships between urinary organophosphate flame retardants (OPFRs) and their metabolites and the susceptibility to ADHD in the same cohort of children. We recruited 186 school children, including 132 with ADHD and 54 normal controls, living in southern Taiwan to investigate five OPFRs (1,3-dichloro-2-propyl phosphate (TDCPP), tri-n-butyl phosphate (TnBP), tris (2-chloroethyl) phosphate (TCEP), tris(2-butoxyethyl) phosphate (TBEP), and triphenyl phosphate (TPHP)) and five OPFR metabolites (bis(1,3-dichloro-2-propyl) phosphate (BDCPP), di-n-butyl phosphate (DNBP), bis(2-chloroethyl) hydrogen phosphate (BCEP), di-(2-butoxyethyl) phosphate (DBEP), and diphenyl phosphate (DPHP)) in urine. ADHD patients' behavioral symptoms and neuropsychological function were assessed using the Swanson, Nolan, and Pelham Version IV Scale (SNAP-IV) and the Conners' Continuous Performance Test 3rd Edition (Conners CPT3), respectively. BCEP was predominant among urinary OPFRs and the metabolites in both the ADHD and control groups. ADHD children had significantly higher levels of urinary BDCPP, BCEP, DBEP, DPHP, TCEP, TBEP, TNBP, TPHP, and Σ 10 OPFR compared to the controls. After controlling for age, gender, body mass index, PM 2.5 exposure scenarios, and urinary phthalate metabolites, parabens, bisphenol-A and creatinine, levels of urinary BDCPP, TDCPP, and TBEP in ADHD children showed significant and dose-dependent effects on core behavioral symptoms of inattention. DNBP levels were positively correlated with neuropsychological deficits (CPT detectability, omission, and commission), while urinary DPHP in ADHD children were negatively related to CPT detectability and commission. Hyperactivity and impulsivity were not correlated with urinary OPFRs and their metabolites in ADHD children. In conclusion, the ADHD symptom of inattention and CPT performance may be closely associated with certain urinary OPFRs and their metabolites, independent of urinary PAE metabolites, parabens, and bisphenol-A in school-age-ADHD children., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: How-Ran Chao reports financial support was provided by National Science and Technology Council. How-Ran Chao reports a relationship with National Science and Technology Council 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.)

Objective: This study aimed to test different AI-based face-swapping models applied to videos of epileptic seizures, with the goal of protecting patient privacy while retaining clinically useful seizure semiology. We hypothesized that specific models would show differences in semiologic fidelity compared to the original clinical videos., Methods: Three open-source models, SimSwap, MobileFaceSwap and GHOST were adopted for face-swapping. For every model, an AI generated male and female image were used to replace the original faces. One representative seizure per patient from three patients with epilepsy was chosen (3 seizure videos x 3 AI models x 2 M/F swap) and remade to 18 transformed video clips. To evaluate the performance of the three models, we used both objective (AI-based) and subjective (expert clinician) evaluation. The objective assessment included four metrics for facial appearance and four metrics for facial expression changes. Four experienced epileptologists reviewed the clips and scoring according to deidentification and preservation of semiology. Kruskal-Wallis H test was used for statistical analysis among the models., Results: In the reproduced videos, the swapped face cannot be recognized as the original face, with no significant difference in scores of deidentification either by objective or subjective assessment. Regarding semiology preservation, no significant differences between models were observed in the objective evaluations. The subjective evaluations revealed that the GHOST model outperformed the other two models (p=0.028)., Conclusion: This is the first study evaluating AI face swapping models in epileptic seizure video clips. Optimization of AI face-swapping models could enhance the accessibility of seizure videos for education and research while protecting patient privacy and maintaining semiology., Competing Interests: Declaration of Competing Interest The authors report no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer research is continuously exploring new avenues to improve treatments, and ferroptosis induction has emerged as a promising approach. However, the lack of comprehensive analysis of the ferroptosis sensitivity in different cancer types has limited its clinical application. Moreover, identifying the key regulator that influences the ferroptosis sensitivity during cancer progression remains a major challenge. In this study, we shed light on the role of ferroptosis in colorectal cancer and identified a novel ferroptosis repressor, NUDT16L1, that contributes to the ferroptosis insensitivity in this cancer type. Mechanistically, NUDT16L1 promotes ferroptosis insensitivity in colon cancer by enhancing the expression of key ferroptosis repressor and mitochondrial genes through direct binding to NAD-capped RNAs and the indirect action of MALAT1. Our findings also reveal that NUDT16L1 localizes to the mitochondria to maintain its proper function by preventing mitochondrial DNA leakage after treatment of ferroptosis inducer in colon cancer cells. Importantly, our orthotopic injection and Nudt16l1 transgenic mouse models of colon cancer demonstrated the critical role of NUDT16L1 in promoting tumor growth. Moreover, clinical specimens revealed that NUDT16L1 was overexpressed in colorectal cancer, indicating its potential as a therapeutic target. Finally, our study shows the therapeutic potential of a NUDT16L1 inhibitor in vitro, in vivo and ex vivo. Taken together, these findings provide new insights into the crucial role of NUDT16L1 in colorectal cancer and highlight its potential as a promising therapeutic target., 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 B.V. All rights reserved.)

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Aims: The recent approval of enzalutamide for metastatic castration-sensitive prostate cancer underscores its growing clinical significance, raising concerns about emerging resistance and limited treatment options. While the reactivation of the androgen receptor (AR) and other genes plays a role in enzalutamide resistance, identifications of novel underlying mechanism with therapeutic potential in enzalutamide-resistant (EnzaR) cells remain largely elusive., Methods: Drug-resistant prostate cancer cell lines, animal models, and organoids were utilized to examine NUDT21 function by transcriptomic and metabolomic analyses through loss-of-function and gain-of-function assays. Notably, a mono-methylation monoclonal antibody and conditional-knockin transgenic mouse model of NUDT21 were generated for evaluating its function., Results: NUDT21 overexpression acts as a crucial alternative polyadenylation (APA) mediator, supported by its oncogenic role in prostate cancer. PRMT7-mediated mono-methylation of NUDT21 induces a shift in 3'UTR usage, reducing oncogenicity. In contrast, its un-methylation promotes cancer growth and cuproptosis insensitivity in EnzaR cells by exporting toxic copper and suppressing docosahexaenoic acid (DHA) biosynthesis. Crucially, NUDT21 inhibition or DHA supplementation with copper ionophore holds therapeutic promise for EnzaR cells., Conclusions: The un-methylation of NUDT21-mediated 3'UTR shortening unveils a novel mechanism for enzalutamide resistance, and our findings offer innovative strategies for advancing the treatment of prostate cancer patients experiencing enzalutamide resistance., 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.)

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignant tumor, and it ranks 2nd in terms of mortality rate among all malignancies in Taiwan. Sorafenib is a multiple tyrosine kinase inhibitor that suppresses tumor cell proliferation and angiogenesis around tumors via different pathways. However, the survival outcome of advanced HCC patients treated with sorafenib is still unsatisfactory. Unfortunately, there are no clinically applicable biomarkers to predict sorafenib therapeutic efficiency in HCC thus far. We found that serpin peptidase inhibitor, clade G, member 1 (SERPING1) is highly associated with overall and recurrence-free survival rates in HCC patients and is also highly correlated with several clinical parameters. SERPING1 expression was increased with sorafenib in both the HCC cell extract and conditioned medium, which was also observed in sorafenib-resistant HepG2 and Huh7 cells. Sorafenib decreased cell viability and migration, which was similar to the effect of SERPING1 in HCC progression. Moreover, sorafenib inhibited both MMP-2 and MMP-9 activity and enhanced the expression of p-ERK in HCC cells. In summary, sorafenib reduces HCC cancer progression might through the p-ERK-MMP-2-MMP-9 cascade via upregulation of SERPING1. In the present study, the roles and molecular mechanisms of SERPING1 and its value as a marker for predicting sorafenib resistance and progression in HCC patients were examined. The results of the present study provide a deep understanding of the roles of SERPING1 in HCC sorafenib resistance, which can be applied to develop early diagnosis and prognosis evaluation methods and establish novel therapeutic targets for specifically treating HCC., (© 2024 The Author(s). Environmental Toxicology published by Wiley Periodicals LLC.)

Introduction: Patients with advanced-stage or intermediate-stage hepatocellular carcinoma (HCC) unsuitable for transarterial chemoembolization (TACE) had poor prognoses. Recent advancements in hepatic arterial infusion chemotherapy (HAIC) and immune checkpoint inhibitors (ICIs) have demonstrated higher tumor response rates, which improved overall survival (OS). HAIC achieves an OS rate of approximately 14.5-15.3 months with a 39.1-42.5% tumor response rate. In comparison, ICIs have a 12-14 month OS rate with a 26-33% tumor response rate. Given these promising responses, this study evaluates the efficacy of conversion therapy with curative intent following HAIC or ICIs, focusing on survival outcomes., Methods: We retrospectively analyzed 80 patients with advanced or TACE-unsuitable intermediate HCC. Patients completed two HAIC or four ICI cycles, followed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria imaging. Based on demographics, cirrhosis status, Barcelona Clinic Liver Cancer classification (BCLC) stage, treatment responses, and treatment modality, survival impacts were analyzed. OS was compared between HAIC and immunotherapy groups. The effect of conversion therapy with curative intent on survival outcomes was analyzed using a Cox regression model., Results: Among the 80 patients, 26 achieved positive response (CR/PR) with HAIC or ICIs, and 9 of them subsequently underwent conversion therapy with curative intent. Key prognostic factors included Child-Pugh stage B vs. A (HR=2.21, p=0.041), BCLC stage C vs. B (HR=4.38, p=0.011), and elevated AFP levels (HR=5.02, p&lt;0.001). Positive responders saw substantial survival benefits (HR=0.26, p=0.001). Patients undergoing conversion therapy exhibited significantly enhanced survival. Median OS was 13.58 months with standard therapy, while the curative intent surgery group did not reach the median OS (p=0.002). For CR/PR patients, 48-month survival was 75.0% for the curative surgery group versus 38.0% for standard treatment., Conclusion: Conversion therapy with curative intent following HAIC or ICIs might enhances survival in patients with advanced or TACE-unsuitable intermediate-stage HCC., (S. Karger AG, Basel.)

Background: The purpose of this study was to estimate the effect of remote nursing guidance based on WeChat platform for female patients receiving subcutaneous anticoagulation during the COVID-19 epidemic., Methods: Retrospective analysis of clinical data, including demographic data and anticoagulation complications, of 126 female patients who received subcutaneous anticoagulation therapy and received remote nursing guidance using WeChat platform in our hospital from January 2022 to December 2022. The Anti-Clot Treatment Scale (ACTS) and the World Health Organization Quality of Life-BREF (WHOQOL-BREF) scale were used to evaluate patients' satisfaction with anticoagulation and quality of life at the beginning of anticoagulation, half a month after anticoagulation, and after three months of anticoagulation., Results: In total, 126 patients were involved in this study, all of them were female, 115 cases were natural pregnancy, 11 cases were assisted reproduction. This study included seven cases of lower extremity deep vein thrombosis, 100 cases of hypercoagulable state, 10 cases of antiphospholipid syndrome, and eight cases of protein S deficiency, one case of hyperhomocysteinemia. During the follow-up period, four patients (3.17%) had subcutaneous injection complications, including three cases of subcutaneous hemorrhage and one case of liquid leakage. A total of 123 patients had completed the planned anticoagulation therapy or were receiving anticoagulation therapy as planned, and three patients did not receive anticoagulation therapy as planned (zero cases lost contact, two cases changed treatment units, and one case refused treatment). ACTS score (55.03 ± 1.73) and WHOQOL-BREF score (62.18 ± 3.17) after three months of anticoagulation, ACTS score (54.18 ± 1.20) and WHOQOL-BREF score (60.37 ± 2.25) after half a month of anticoagulation was significantly higher than the ACTS score (47.81 ± 1.69) and WHOQOL-BREF score (55.25 ± 1.85) at the beginning of anticoagulation, and the difference was statistically significant ( P value < 0.01)., Conclusions: During the COVID-19 pandemic, remote nursing instruction via the WeChat platform for female patients receiving subcutaneous anticoagulation can increase anticoagulation compliance, satisfaction, and quality of life., Competing Interests: The authors declare there are no competing interests., (©2024 Jiang et al.)

Selective functionalisation of synthetically useful vinyl epoxides via carbon-carbon (C-C) bond formation has been a major challenge for many years due to its unique inherent chemical reactivity. Non-stabilised carbanions in the form of organometallic reagents have been shown to be robust and versatile reagents in C-C bond formation; however, they are employed in superstoichiometric quantities, require the protection of active functional groups, and generate copious amounts of metallic waste. Therefore, the development of mild carbanion sources as simple alternatives is highly desired. In this work, we report a highly chemo- and regioselective palladium-catalysed vinyl epoxide cross-coupling utilising hydrazones as organometallic equivalents (HOME). Hydrazones, generated from carbonyl-containing renewable feedstocks, enable a more sustainable reaction, and provide an alternative to highly reactive and sensitive unstabilized organometallic reagents. A broad substrate scope, with high functional group tolerance, is demonstrated along with the late-stage functionalisation of natural product derivatives., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Our previous study has found that monoclonal antibodies targeting a conserved epitope peptide spanning from residues 1144 to 1156 of SARS-CoV-2 spike (S) protein, namely S(1144-1156), can broadly neutralize all of the prevalent SARS-CoV-2 strains, including the wild type, Alpha, Epsilon, Delta, and Gamma variants. In the study, S(1144-1156) was conjugated with bovine serum albumin (BSA) and formulated with Montanide ISA 51 adjuvant for inoculation in BALB/c mice to study its potential as a vaccine candidate. Results showed that the titers of S protein-specific IgGs and the neutralizing antibodies in mouse sera against various SARS-CoV-2 variants, including the Omicron sublineages, were largely induced along with three doses of immunization. The significant release of IFN-γ and IL-2 was also observed by ELISpot assays through stimulating vaccinated mouse splenocytes with the S(1144-1156) peptide. Furthermore, the vaccination of the S(1143-1157)- and S(1142-1158)-EGFP fusion proteins can elicit more SARS-CoV-2 neutralizing antibodies in mouse sera than the S(1144-1156)-EGFP fusion protein. Interestingly, the antisera collected from mice inoculated with the S(1144-1156) peptide vaccine exhibited better efficacy for neutralizing Omicron BA.2.86 and JN.1 subvariants than Omicron BA.1, BA.2, and XBB subvariants. Since the amino acid sequences of the S(1144-1156) are highly conserved among various SARS-CoV-2 variants, the immunogen containing the S(1144-1156) core epitope can be designed as a broadly effective COVID-19 vaccine. KEY POINTS: • Inoculation of mice with the S(1144-1156) peptide vaccine can induce bnAbs against various SARS-CoV-2 variants. • The S(1144-1156) peptide stimulated significant release of IFN-γ and IL-2 in vaccinated mouse splenocytes. • The S(1143-1157) and S(1142-1158) peptide vaccines can elicit more SARS-CoV-2 nAbs in mice., (© 2024. The Author(s).)

The homolysis of chemical bonds represents one of the most fundamental reactivities of excited molecules. Historically, it has been exploited to generate radicals under ultraviolet (UV) light irradiation. However, unlike most contemporary radical-generating mechanisms, the direct excitation to homolyze chemical bonds and produce aliphatic carbon-centered radicals under visible light remains rare, especially in metallaphotoredox cross couplings. Herein, we present our design of the dihydropyrimidoquinolinone (DHPQ) reagents derived from ketones, which can undergo formal deacylation and homolytic C-C bond cleavage to release alkyl radicals without external photocatalysts. Spectroscopic and computational analysis reveal unique optical and structural features of DHPQs, rationalizing their faster kinetics in alkyl radical generation than a structurally similar but visible-light transparent radical precursor. Such a capability allows DHPQ to facilitate a wide range of Ni-metallaphotoredox cross couplings with aryl, alkynyl and acyl halides. Other catalytic and non-catalyzed alkylative transformations of DHPQs are also feasible with various radical acceptors. We believe this work would be of broad interest, aiding the synthetic planning with simplified operation and expanding the synthetic reach of photocatalyst-free approaches in cutting-edge research., (© 2024 Wiley-VCH GmbH.)

SARS-CoV-2 vaccination has reduced hospitalization and mortality for nursing home residents (NHRs) but emerging variants and waning immunity challenge vaccine effectiveness. This study assesses the immunogenicity of the most recent XBB.1.5 monovalent vaccine to variant strains among NHRs. Participants were subset of a longitudinal study of consented NHRs and Healthcare workers (HCWs) who have received serial blood draws to assess immunogenicity with each SARS-CoV-2 mRNA vaccine dose. We report data on participants who received the XBB.1.5 monovalent vaccine post-FDA approval in Fall 2023. NHRs were categorized by whether they had an interval SARS-CoV-2 infection between their first bivalent vaccine dose and their XBB.1.5 monovalent vaccination. The sample included 61 NHRs [median age 76 (IQR 68-86), 51% female] and 28 HCWs [median age 45 (IQR 31-58), 46% female). After XBB.1.5 vaccination, a robust geometric mean fold rise (GMFR) in XBB.1.5-specific neutralizing antibody titers was observed:17.3 (95% confidence interval [CI] 9.3, 32.4) and NHRs with interval infection and 11.3 (95% CI 5, 25.4) in those without and 13.6 (95% CI 8.4,22) in HCWs. For JN.1-specific titers, GMFRs were 14.9 (95% CI 7.9, 28) and 6.5 (95% CI 3.3, 13.1) in NHRs with and without interval infection, and 11.4 (95% CI 6.2, 20.9) in HCWs. NHRs with interval SARS-CoV-2 infection had higher titers across all analyzed strains analyzed. The XBB.1.5 vaccine significantly elevates Omicron-specific neutralizing antibody titers to XBB.1.5 and JN.1 strains in both NHRs and HCWs with more pronounced in those previously infected with SARS-CoV-2 since bivalent vaccination., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Butyric acid, a pivotal short-chain fatty acid in rumen digestion, profoundly influences animal digestive and locomotor systems. Extensive research indicates its direct or indirect involvement in the growth and development of muscle and fat cells. However, the impact of butyric acid on the proliferation and differentiation of bovine skeletal muscle satellite cells (SMSCs) remains unclear. This study aimed to elucidate the effects of butyrate on SMSCs proliferation and differentiation. After isolating, SMSCs were subjected to varying concentrations of sodium butyrate (NaB) during the proliferation and differentiation stages. Optimal treatment conditions (1 mM NaB for 2 days) were determined based on proliferative force, cell viability, and mRNA expression of proliferation and differentiation marker genes. Transcriptome sequencing was employed to screen for differential gene expression between 1 mM NaB-treated and untreated groups during SMSCs differentiation. Results indicated that lower NaB concentrations (≤1.0 mM) inhibited proliferation while promoting differentiation and apoptosis after a 2-day treatment. Conversely, higher NaB concentrations (≥2.0 mM) suppressed proliferation and differentiation and induced apoptosis. Transcriptome sequencing revealed differential expression of genes(ND1, ND3, CYTB, COX2, ATP6, MYOZ2, MYOZ3, MYBPC1 and ATP6V0A4,etc.) were associated with SMSCs differentiation and energy metabolism, enriching pathways such as Oxidative phosphorylation, MAPK, and Wnt signaling. These findings offer valuable insights into the molecular mechanisms underlying butyrate regulation of bovine SMSCs proliferation and differentiation, as well as muscle fiber type conversion in the future study., Competing Interests: Declaration of competing interest The authors confirm that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Aim: This study aimed to develop a theory to guide family members caring for young people with depressive disorders and suicidal ideations., Design: Strauss and Corbin's Grounded Theory., Methods: Theoretical sampling was used to recruit primary family caregivers (aged 22-60) of young people experiencing depressive disorders and suicidal ideations from hospitals and psychiatric clinics in Taiwan. Data were collected using interviews (n = 23) in 2023. Data were analysed using Corbin & Strauss' analytical framework, including open, axial and selective coding until theoretical saturation was reached., Results: A paradigm model was used to link the 13 categories and develop a substantive theory to help guide family members in the care of their young persons with depressive disorders and suicidal ideations. The core category that emerged was 'Struggling to contain the young person's life by adjusting, assisting, and protecting them from diving into depression'. Other key categories interconnected with this core category were-creating a nurturing environment, adjusting to changes, protecting the young person's safety and assisting with their medical treatment., Conclusion: Family caregivers could use this theory as a guide to enhance the care of young persons experiencing depressive disorders and suicidal ideations and accompany them alongside the healing process., Implications for the Profession: Nursing professionals could provide psychoeducation to family caregivers on how to hold the young person gently and acquire compassion for the young persons' lived experience, thoughts and emotions, by creating a nurturing environment, adjusting to changes, protecting their safety and assisting with their medical treatment., Impact: This theory provides valuable guidance for future intervention research aimed at improving family caregivers' ability to care for young persons with depressive disorders and suicidal ideations., Reporting Method: The COREQ guidelines were utilised., Patient or Public Contribution: No patient or public contribution., (© 2024 John Wiley & Sons Ltd.)

Study Objective: To assess the association of intraoperative hypotension with long-term survivals in older patients after major noncardiac surgery mainly for cancer., Design: A secondary analysis of databases from three randomized trials with long-term follow-up., Setting: The underlying trials were conducted in 17 tertiary hospitals in China., Patients: Patients aged 60 to 90 years who underwent major noncardiac thoracic or abdominal surgeries (≥ 2 h) in a single center were included in this analysis., Exposures: Restricted cubic spline models were employed to determine the lowest mean arterial pressure (MAP) threshold that was potentially harmful for long-term survivals. Patients were arbitrarily divided into three groups according to the cumulative duration or area under the MAP threshold. The association between intraoperative hypotension exposure and long-term survivals were analyzed with the Cox proportional hazard regression models., Measurements: Our primary endpoint was overall survival. Secondary endpoints included recurrence-free and event-free survivals., Main Results: A total of 2664 patients (mean age 69.0 years, 34.9% female sex, 92.5% cancer surgery) were included in the final analysis. MAP < 60 mmHg was adopted as the threshold of intraoperative hypotension. Patients were divided into three groups according to duration under MAP < 60 mmHg (<1 min, 1-10 min, and > 10 min) or area under MAP <60 mmHg (< 1 mmHg⋅min, 1-30 mmHg⋅min, and > 30 mmHg⋅min). After adjusting confounders, duration under MAP < 60 mmHg for > 10 min was associated with a shortened overall survival when compared with the < 1 min patients (adjusted hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.09 to 1.57, P = 0.004); area under MAP < 60 mmHg for > 30 mmHg⋅min was associated with a shortened overall survival when compared with the < 1 mmHg⋅min patients (adjusted HR 1.40, 95% CI 1.16 to 1.68, P < 0.001). Similar associations exist between duration under MAP < 60 mmHg for > 10 min or area under MAP < 60 mmHg for > 30 mmHg⋅min and recurrence-free or event-free survivals., Conclusions: In older patients who underwent major noncardiac surgery mainly for cancer, intraoperative hypotension was associated with worse overall, recurrence-free, and event-free survivals., 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 Inc. All rights reserved.)

The condensation of amino acids into peptides plays a crucial role in protein synthesis and is thus essential for understanding the origins of life. However, the spontaneous formation of peptides from amino acids in bulk aqueous media is energetically unfavorable, posing a challenge for elucidating plausible abiotic mechanisms. In this study, we investigate the formation of amide bonds between amino acids within highly supersaturated aerosol droplets containing dicyandiamide (DCD), a cyanide derivative potentially present on primordial Earth. Metastable states, i.e. supersaturation, within individual micron-sized droplets are studied using both an optical trap and a linear quadrupole electrodynamic balance. When irradiated with intense visible light, amide bond formation is observed to occur and can be monitored using vibrational bands in Raman spectra. The reaction rate is found to be strongly influenced by droplet size and kinetic modelling suggests that it is driven by the photochemical product of a DCD self-reaction. Our results highlight the potential of atmospheric aerosol particles as reaction environments for peptide synthesis and have potential implications for the prebiotic chemistry of early Earth., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Competing Interests: Conflicts of interest: Dr. Ming-Chih Hou, 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.

Background: QL1701 is a proposed biosimilar to the reference trastuzumab (Herceptin®). This trial compared the efficacy and safety of QL1701 with the reference trastuzumab in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer., Materials and Methods: This randomized, double-blinded, parallel-controlled, phase III equivalence trial was conducted in 73 centers in China. Eligible patients with histologically or cytologically diagnosed HER2-positive metastatic breast cancer were randomly assigned (1 : 1) to receive either QL1701 or reference trastuzumab in combination with docetaxel (every 3 weeks) for eight cycles as the first-line treatment. Then, in patients with objective responses or stable disease, the QL1701 or reference trastuzumab with or without docetaxel was maintained for totally up to 12 months if tolerated. The primary endpoint was 24-week objective response rate (ORR) assessed by an independent review committee (IRC). The equivalence margin was 0.80-1.25 with a 90% confidence interval (CI) for the ORR ratio (QL1701 to reference trastuzumab)., Results: Between 29 April 2020 and 15 March 2022, 474 patients were randomized, and 473 received either QL1701 (n = 236) or reference trastuzumab (n = 237). The risk ratio for 24-week ORR was 1.07 (90% CI 0.94-1.21). The 90% CI fell within the pre-specified equivalence margin of 0.80-1.25. The 24-week ORR assessed by IRC was 59.7% (95% CI 53.2% to 66.1%) versus 56.1% (95% CI 49.5% to 62.5%) in QL1701 and the reference trastuzumab, respectively. As of 12 April 2023, there were no notable differences in progression-free survival (median: 8.3 versus 8.4 months) and overall survival (1-year rate: 95.1% versus 93.3%) between the two groups. Safety, pharmacokinetic (PK), and immunogenicity profiles were similar between the two groups., Conclusion: QL1701 demonstrated equivalent efficacy and similar safety to the reference trastuzumab when combined with docetaxel in the first-line treatment of patients with HER2-positive metastatic breast cancer, with similar PK and immunogenicity profiles., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Surgical resection (SR) is the main treatment for small bowel adenocarcinoma (SBA), but it increases metabolic demand, systemic inflammation, and digestive dysfunction, resulting in major impacts on the postoperative outcomes of patients. In this study, we aimed to investigate the role of the postoperative prognostic nutritional index (PNI), a surrogate marker of inflammation and nutrition, in patients with SBA after resection., Methods: From June 2014 to March 2022, 44 consecutive patients who underwent SR for SBA in Taipei Veterans General Hospital were retrospectively reviewed. Factors associated with survival including PNI were analyzed., Results: PNI decreased in patients after SR for SBA (median change: -1.82), particularly in those who underwent Whipple operation or developed postoperative pancreatic fistula. Postoperative PNI <45.2 best predicted overall survival (OS) (area under the receiver operating characteristic curve [AUROC]: 0.826, p = 0.001). Patients with lower postoperative PNI had significantly worse OS compared to those with higher postoperative values (median OS: 19.3 months vs not reached, p < 0.001). Low postoperative PNI (hazard ratio [HR]: 11.404, p = 0.002), tumoral lymphovascular invasion (HR: 8.023, p = 0.012), and adjuvant chemotherapy (HR: 0.055, p = 0.002) were independent risk factors for OS. Postoperative PNI also significantly predicted recurrence-free survival independent of lymphovascular invasion and adjuvant chemotherapy (HR: 6.705, p = 0.001)., Conclusion: PNI commonly decreases in patients with SBA who undergo Whipple surgery or develop postoperative pancreatic fistula. Postoperative PNI independently predicts survival and may serve as a clinical marker to optimize patient outcomes., Competing Interests: Conflicts of interest: The 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.)

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.

Temporomandibular joint inflammatory diseases are a significant subtype of temporomandibular disorders (TMD) characterized by inflammatory pain in the orofacial area. The N-methyl-D-aspartate receptor (NMDAR), specifically the NR2A subtype, was crucial in neuropathic pain. However, the exact role of NR2A in inflammatory pain in the TMJ and the molecular and cellular mechanisms mediating peripheral sensitization in the trigeminal ganglion (TG) remain unclear. This study utilized male and female mice to induce the TMJOA model by injecting Complete Freund's adjuvant (CFA) into the TMJ and achieve conditional knockout (CKO) of NR2A in the TG using Cre/Loxp technology. The Von-Frey filament test results showed that CFA-induced orofacial pain with reduced mechanical withdrawal threshold (MWT), which was not developed in NR2A CKO mice. Additionally, the up-regulation of interleukin (IL)-1β, IL-6, and nerve growth factor (NGF) in the TG induced by CFA did not occur by NR2A deficiency. In vitro, NMDA activated satellite glial cells (SGCs) with high expression of glial fibrillary acidic protein (GFAP), and both NMDA and LPS led to increased IL-1β, IL-6, and NGF in SGCs. NR2A deficiency reduced these stimulating effects of NMDA and LPS. The regulation of IL-1β involved the p38, Protein Kinase A (PKA), and Protein Kinase C (PKC) pathways, while IL-6 signaling relied on PKA and PKC pathways. NGF regulation was primarily through the p38 pathway. This study highlighted NR2A's crucial role in the TG peripheral sensitization during TMJ inflammation by mediating ILs and NGF, suggesting potential targets for orofacial inflammatory pain management., Competing Interests: Declaration of competing interest We confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Appetite hormones may play a significant role in neuronal excitability and synaptic plasticity and may also affect brain function development. This study aimed to explore the role of appetite hormones in attention deficit/hyperactivity disorder (ADHD), including aspects of pathophysiology, pharmacotherapy, and side effects. We recruited 119 patients with ADHD who were undergoing methylphenidate treatment (ADHD+MPH), 77 unmedicated ADHD patients (ADHD-MPH), and 87 healthy controls. Blood samples were collected from all participants to examine serum levels of orexin A, ghrelin, leptin, and adiponectin. Behavioral symptoms were assessed using the Swanson, Nolan, and Pelham Rating Scale, and visual and auditory attention were evaluated using computerized neuropsychological tests. The side effects of methylphenidate treatment were measured using Barkley's Side Effects Rating Scale. Orexin levels in the control group were significantly higher than in the ADHD-MPH (p=0.037) and ADHD+MPH (p<0.001) groups; additionally, orexin levels in the ADHD-MPH group were significantly higher than in the ADHD+MPH group (p=0.032). Leptin levels in both the ADHD+MPH (p=0.011) and ADHD-MPH (p=0.011) groups were significantly lower than in the control group. Ghrelin levels were positively associated with auditory attention across all ADHD groups (p=0.015). Furthermore, ghrelin levels were positively correlated with methylphenidate dosage (p=0.024), and negatively correlated with methylphenidate side effects (p=0.044) in the ADHD+MPH group. These findings provide further insight into the relationships between appetite hormones, pharmacotherapy, and ADHD. Orexin A and leptin are associated with the etiology of ADHD, while orexin A and ghrelin play important roles in attention deficits and methylphenidate usage in ADHD., Competing Interests: Declaration of Competing Interest All authors disclose that they have no financial interests or potential conflicts of interest related to this research in the biomedical field., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is the most common form of age-related dementia worldwide. Although the neuropathology of AD is clear, its pathogenesis remains unclear. Recently, conceptualising AD as brain-centred has reoriented many scientists because the close functional relationship between the peripheral and central nerves is increasingly recognised. Recently, various studies have focused on the crosstalk between peripherals and centrals. A new hotspot of research and new therapeutic strategies have emerged from this great progress. This mini-review is an overview of the potential molecular mechanism in AD via the bidirectional lung-brain axis, providing a new perspective for the systemic understanding of AD onset., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lu, Li, Wang and Wang.)

Introduction: This study examined the prevalence and correlates of probable mental health disorders, including psychological distress, somatization, depression, anxiety, phobic anxiety (PHO), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and insomnia among Chinese primary health care (PHC) physicians and nurses amid the post-pandemic period in 2022., Method: Region-stratified sampling was conducted to recruit a national sample of 4,246 respondents from 31 July 2022 to 12 August 2022. A total of 692 primary healthcare institutions were identified in 30 provincial-level administrative regions of China. An online questionnaire was used for assessing probable mental health disorders using Symptoms Checklist-90-Revised (SCL-90-R) and PTSD Checklist for DSM-5 (PCL-5), and sleeping problems using Insomnia Severity Index (ISI). Data on demographics and work were also collected. Bivariate analysis and multiple logistic regression were conducted to identify significant correlates of probable mental health disorders., Results: A total of 4,246 valid questionnaires were identified. Results showed that relative to the prevalence of probable mental health disorders among health care workers at the early stage of the pandemic in China, there was an overall decreased prevalence except for somatization, PHO, and OCD among the current PHC physicians and nurses. Multiple logistic regressions showed that significant risk factors of common probable mental health disorders, namely psychological distress, SOM, DEP, ANX, PHO, OCD, PTSD, and insomnia, were female gender, multimorbidity, history of psychiatric disorders, quarantine experience, never asking anyone for help, and overtime work., Conclusion: Attention should be given to preexisting psychiatric and multimorbid conditions, social support, and work-related stressors. Regular assessment and psychological interventions are needed to enhance the mental health of PHC professionals even after public health crisis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Li, Zheng, Gan, Du, Cai, Li, Wang, Jiang, Zhang, Niu, Tao and Hou.)

Cisplatin is a widely used drug for the clinical treatment of tumors. However, nephrotoxicity limits its widespread use. A series of compounds including eight analogs ( G3-G10 ) and 40 simplifiers ( G11-G50 ) were synthesized based on the total synthesis of Psiguamer A and B, which were novel meroterpenoids with unusual skeletons from the leaves of Psidium guajava . Among these compounds, ( d )-G8 showed the strongest protective effect on cisplatin-induced acute kidney injury (AKI) in vitro and vivo , and slightly enhanced the antitumor efficacy of cisplatin. A mechanistic study showed that ( d )-G8 promoted the efflux of cisplatin via upregulating the copper transporting efflux proteins ATP7A and ATP7B. It enhanced autophagy through the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. ( d )-G8 showed no acute toxicity or apparent pathological damage in the healthy mice at a single dose of 1 g/kg. This study provides a promising lead against cisplatin-induced AKI.

Background: The diagnosis of tuberculous pleurisy (TP) presents a significant challenge due to the low bacterial load in pleural effusion (PE) samples. Cell-free Mycobacterium tuberculosis DNA (cf-TB) in PE samples is considered an optimal biomarker for diagnosing TP. This study aimed to evaluate the applicability of cf-TB testing across diverse research sites with a relatively large sample size., Methods: Patients suspected of TP and presenting with clinical symptoms and radiological evidence of PE were consecutively enrolled by treating physicians from 11 research sites across 6 provinces in China between April 2020 and August 2022. Following centrifugation, sediments obtained from PE were used for Xpert MTB/RIF (Xpert) and mycobacterial culture, while the supernatants were subjected to cf-TB testing. This study employed a composite reference standard to definite TP, which was characterized by any positive result for Mycobacterium tuberculosis (MTB) through either PE culture, PE Xpert, or pleural biopsy., Results: A total of 1412 participants underwent screening, and 1344 (95.2%) were subsequently enrolled in this study. Data from 1241 (92.3%) participants were included, comprising 284 with definite TP, 677 with clinically diagnosed TP, and 280 without TP. The sensitivity of cf-TB testing in definite TP was 73.6% (95% CI 68.2-78.4), significantly higher than both Xpert (40.8%, 95% CI 35.3-46.7, P < 0.001) and mycobacterial culture (54.2%, 95% CI 48.4-59.9, P < 0.001). When clinically diagnosed TP was incorporated into the composite reference standard for sensitivity analysis, cf-TB testing showed a sensitivity of 46.8% (450/961, 95% CI 43.7-50.0), significantly higher than both Xpert (116/961, 12.1%, 95% CI 10.2-14.3, P < 0.001) and mycobacterial culture (154/961, 16.0%, 95% CI 13.8-18.5, P < 0.001). The specificities of cf-TB testing, Xpert, and mycobacterial culture were all 100.0%., Conclusions: The performance of cf-TB testing is significantly superior to that of Xpert and mycobacterial culture methods, indicating that it can be considered as the primary diagnostic approach for improving TP detection. Trial registration The trial was registered on Chictr.org.cn (ChiCTR2000031680, https://www.chictr.org.cn/showproj.html?proj=49316 )., (© 2024. The Author(s).)

Polycystic ovarian syndrome (PCOS) is a common heterogeneous reproductive endocrine metabolic disorder in women of reproductive age characterized by clinical and biochemical hyperandrogenemia, ovulation disorders, and polycystic ovarian morphology. Ferroptosis is a novel type of cell death driven by iron accumulation and lipid peroxidation. Ferroptosis plays a role in maintaining redox balance, iron metabolism, lipid metabolism, amino acid metabolism, mitochondrial activity, and many other signaling pathways linked to diseases. Iron overload is closely related to insulin resistance, decreased glucose tolerance, and the occurrence of diabetes mellitus. There is limited research on the role of ferroptosis in PCOS. Patients with PCOS have elevated levels of ferritin and increased reactive oxygen species in ovarian GCs. Studying ferroptosis in PCOS patients is highly important for achieving personalized treatment. This article reviews the progress of research on ferroptosis in PCOS, introduces the potential connections between iron metabolism abnormalities and oxidative stress-mediated PCOS, and provides a theoretical basis for diagnosing and treating PCOS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Zhang, Ma, Xu, Zhao, Zhang, Li, Zhou and Zheng.)

Deoxygenation of epoxides into alkenes is one of the most important strategies in organic synthesis, biomass conversions, and medicinal chemistry. Although metal-catalyzed direct deoxygenation provides one of the most commonly encountered protocols for the conversion of epoxides to alkenes, the requirement of expensive catalysts and extra reductants has largely limited their universal applicability. Herein, we report an efficient PPh 3 -promoted metal-free strategy for deoxygenation of epoxides to generate alkene derivatives. The success of deoxyalkenylation of epoxides bearing a wide range of functional groups to give terminal, 1,1-disubstituted, and 1,2-disubstituted alkenes manifests the powerfulness and versatility of this strategy. Moreover, gram-scale synthesis with excellent yield and modification of biologically active molecules exemplifies its generality and practicability.