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Mei Liu,1,* Sili Guo,1,* Xiaohan Li,1,* Yang Tian,1 Yanjie Yu,2 Lili Tang,1 Qimei Sun,1 Ting Zhang,1 Mingwei Fan,3 Lili Zhang,1 Yingjiang Xu,4 Jiajia An,5 Xiangqian Gao,6 Lei Han,7 Lei Zhang1 1Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 2Department of Ultrasound Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 3Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 4Department of Interventional Vascular Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 5Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 6Department of Pathology, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 7Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lei Zhang, Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China, Email binzhouzhanglei@outlook.comBackground: GLP-1 receptor agonists (GLP-1 RA) have been proven to treat several metabolic diseases; however, the effects of GLP-1 RA on polycystic ovary syndrome (PCOS) remain unclear. Here, we aimed to investigate whether semaglutide, a novel GLP-1 RA, could alleviate ovarian inflammation in PCOS mice.Methods: Female C57BL/6J mice were subcutaneously injected with dehydroepiandrosterone for 21 days to establish the PCOS model. Then the mice were randomly divided into three groups: PCOS group (n = 6), S-0.42 group (semaglutide 0.42 mg/kg/w, n = 6), and S-0.84 group (semaglutide 0.84 mg/kg/w, n = 6). The remaining six mice were used as controls (NC). After 28 days of intervention, serum sex hormones and inflammatory cytokine levels were measured. Hematoxylin and eosin staining was used to observe the ovarian morphology. Immunohistochemical staining was used to detect the relative expression of CYP19A1, TNF-α, IL-6, IL-1β, and NF-κB in ovaries. CYP17A1 and StAR were detected using immunofluorescence staining. Finally, the relative expressions of AMPK, pAMPK, SIRT1, NF-κB, IκBα, pIκBα, TNF-α, IL-6, and IL-1β were measured using Western blotting.Results: First, after intervention with semaglutide, the weight of the mice decreased, insulin resistance improved, and the estrous cycle returned to normal. Serum testosterone and IL-1β levels decreased significantly, whereas estradiol and progestin levels increased significantly. Follicular cystic dilation significantly improved. The expression of TNF-α, IL-6, IL-1β, NF-κB, CYP17A1, and StAR in the ovary was significantly downregulated, whereas CYP19A1 expression was upregulated after the intervention. Finally, we confirmed that semaglutide alleviates ovarian tissue inflammation and improves PCOS through the AMPK/SIRT1/NF-κB signaling pathway.Conclusion: Semaglutide alleviates ovarian inflammation via the AMPK/SIRT1/NF‑κB signaling pathway in PCOS mice.Keywords: GLP-1 receptor agonist, polycystic ovary syndrome, semaglutide, inflammation

Min Zhang,1– 3,* Man Mi,1,2,4,* Zilong Hu,3,4,* Lixian Li,3,4 Zhiping Chen,1– 3 Xiang Gao,5 Di Liu,3,4 Bilian Xu,3 Yanzhi Liu1– 3 1Zhanjiang Key Laboratory of Orthopaedic Technology and Trauma Treatment, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, 524037, People’s Republic of China; 2Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Infectious Diseases, Guangdong Provincial Administration of Traditional Chinese Medicine (Central People’s Hospital of Zhanjiang), Zhanjiang, 524037, People’s Republic of China; 3Marine Medical Research Institute of Zhanjiang, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China; 4Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China; 5Stem Cell Research and Cellular Therapy Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 524001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bilian Xu, Marine Medical Research Institute of Zhanjiang, School of Marine and Tropical Medicine, Guangdong Medical University, Zhanjiang, 524023, People’s Republic of China, Tel +86-0759-2388588, Email 124879846@qq.com Yanzhi Liu, Zhanjiang Key Laboratory of Orthopaedic Technology and Trauma Treatment, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, 524037, People’s Republic of China, Tel +86-0759-3157875, Email liuyanzhi02@163.comAbstract: Polydopamine is a versatile and modifiable polymer, known for its excellent biocompatibility and adhesiveness. It can also be engineered into a variety of nanoparticles and biomaterials for drug delivery, functional modification, making it an excellent choice to enhance the prevention and treatment of orthopedic diseases. Currently, the application of polydopamine biomaterials in orthopedic disease prevention and treatment is in its early stages, despite some initial achievements. This article aims to review these applications to encourage further development of polydopamine for orthopedic therapeutic needs. We detail the properties of polydopamine and its biomaterial types, highlighting its superior performance in functional modification on nanoparticles and materials. Additionally, we also explore the challenges and future prospects in developing optimal polydopamine biomaterials for clinical use in orthopedic disease prevention and treatment.Keywords: polydopamine, biomaterials, nanoparticles, bone, orthopaedics

Wei Zhang,1,* Jiayu Zhang,2,* Dian Jiao,1,* Qisheng Tang,1 Xiaoping Gao,1 Zhenyu Li,1 Fa Yang,3 Zhiguang Zhao,1 Longfei Yang4 1Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710038, People’s Republic of China; 2Department of Urology, Air Force Hospital of Southern Theater Command, Guangzhou, Guangdong, 510062, People’s Republic of China; 3Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710032, People’s Republic of China; 4Department of Transfusion Medicine, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, 710038, People’s Republic of China*These authors contributed equally to this workCorrespondence: Longfei Yang; Zhiguang Zhao, Email y68lf@163.com; zzg13991809889@163.comPurpose: Lichen sclerosus urethral stricture disease (LS USD) is a refractory and progressive disease primarily affecting the anterior urethra in males. Various potential etiological factors, such as genetics, autoimmunity, infection, and exposure to infectious urine, have been suggested. However, the accurate etiology of LS in the male urethra remains unclear.Patients and Methods: In this study, we conducted single-cell RNA sequencing to identify the transcriptional profiles of three patients with LS USD and three patients with non-LS USD. Immunofluorescence was used to confirm the single-cell sequence results.Results: Our study revealed distinct subsets of vein endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts (FBs) with high proportions in LS USD, contributing to the tissue microenvironment primarily involved in proinflammatory and immune responses. In particular, FBs displayed a unique subset, Fib7, which is exclusively present in LS USD, and exhibited high expression levels of SAA1 and SAA2. The accumulation of macrophages, along with the dysregulated ratios of M1/M2-like phenotype macrophages, may be engaged in the pathogenesis of LS USD. Through cell–cell communication analysis, we identified significant interactions involving CXCL8/ACKR1 and CCR7/CCL19 in LS USD. Remarkably, Fib7 exhibited exclusive communication with IL-1B macrophages through the SAA1/FPR2 receptor–ligand pair.Conclusion: Our study provides a profound understanding of the tissue microenvironment in LS USD, which may be valuable for understanding the pathogenesis of LS USD. Keywords: lichen sclerosus, urethral stricture disease, single-cell RNA sequencing, heterogeneity, fibroblasts, macrophages

Song Li,1,* Nandong Hu,2,* Zicheng Wei,2 Jiangchuan Wang,2 Rongzhou Wang,2 Xifa Gao,2 Yingping Qiu,2 Xiao Chen2 1Department of Radiology, The Second Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 230040, People’s Republic of China; 2Department of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao Chen; Yingping Qiu, Department of Radiology, The Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210029, People’s Republic of China, Tel +86 025 86617141, Email chxwin@163.com; ypqiusz@111.comIntroduction: Osteoporosis diagnosis often utilizes quantitative computed tomography (QCT). This study explored the validity of applying lumbar bone mineral density (LBMD) standards to thoracic vertebrae (T8-T10) for osteoporosis detection during CT lung cancer screenings. This study investigated the utility of thoracic BMD (BMD-T8-T10) for detecting osteoporosis in older persons during CT lung cancer screening.Methods: We studied 701 participants who underwent QCT scans for both LBMD and BMD-T8-T10. Osteoporosis was diagnosed using ACR criteria based on LBMD. We determined BMD-T8-T10 thresholds via a receiver operating characteristic (ROC) curve and translated BMD-T8+T9+T10 to LBMD (TTBMD) using linear regression. Kappa test was used to evaluate the accuracy of BMD-T8-T10 thresholds and TTBMD in diagnosing osteoporosis.Results: Raw BMD-T8-T10 poorly identified osteoporosis (kappa = 0.51). ROC curve analysis identified BMD-T8-T10 thresholds for osteopenia (138 mg/cm3) and osteoporosis (97 mg/cm3) with areas under the curve of 0.97 and 0.99, respectively. We normalized BMD-T8-T10 to TTBMD based on the formula: TTBMD = 0.9 × BMD-T8-T10 - 2.56. These thresholds (kappa = 0.74) and TTBMD performed well in detecting osteoporosis/osteopenia (kappa = 0.74).Conclusion: Both calculating BMD-T8-T10 threshold (138.0 mg/cm3 for osteopenia and 97 mg/cm3 for osteoporosis) and normalizing BMD-T8-T10 to LBMD demonstrated good performance in identifying osteoporosis in older adults during CT lung cancer screening.Keywords: quantitative computed tomography, thoracic vertebral bone mineral density, osteoporosis, Computed tomography, lung cancer

Lili Huang,1,* Yesong Liu,2,* Tingting Geng,1,* Nannan Zhang,2 Liang Sun,1 Shouling Wu,3 Xiang Gao1 1Department of Nutrition and Food Hygiene, School of Public Health, Institute of Nutrition, Fudan University, Shanghai, People’s Republic of China; 2Department of Neurology, Kailuan General Hospital, Tangshan, People’s Republic of China; 3Department of Cardiology, Kailuan General Hospital, Tangshan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiang Gao, Department of Nutrition and Food Hygiene, School of Public Health, Institute of Nutrition, Fudan University, 130 Dongan Road, Shanghai, 200032, People’s Republic of China, Email xiang_gao@fudan.edu.cn Shouling Wu, Department of Cardiology, Kailuan General Hospital, 57 Xinhua East Road, Tangshan, 063000, People’s Republic of China, Tel +86 315 3025655, Fax +86 315 3725312, Email drwusl@163.comBackground: Sleep complaints were reported to be associated with stroke, however, the evidence on the association between healthy sleep pattern and stroke risk in Chinese is limited.Objective: The aim of this study was to investigate the association between healthy sleep pattern and stroke in Chinese, and the influence of metabolic diseases on the association.Methods: A total of 11,851 participants from the Kailuan study in China without stroke at baseline were included. We calculated a healthy sleep score according to four sleep factors, and defined the low-risk groups as follows: no insomnia, no excessive daytime sleepiness, no frequent snoring, and sleep 7– 8h/d. Each low-risk sleep factor was assigned a score of 1. Cox proportional hazard models were used to assess the association between healthy sleep score and stroke. Mediation analysis was used to estimate the role of metabolic diseases (obesity, diabetes, and hypertension) in the healthy sleep score-stroke association.Results: During a mean follow-up period of 7.7 years, 504 cases of stroke were identified. A higher healthy sleep score was associated with a lower risk of stroke in a dose-response manner (P-trend=0.03). The adjusted hazard ratio (HR) for participants with a healthy sleep score of 4 versus ≤ 2 was 0.75 (95% confidence interval [CI]: 0.56, 0.96). In addition, obesity, diabetes, and hypertension collectively explained 21.9% (95% CI: 17.2, 26.5) of the association between healthy sleep score and stroke.Conclusion: Adherence to healthy sleep pattern was associated with a lower risk of stroke, and the favorable association was partially mediated by metabolic diseases.Keywords: healthy sleep pattern, metabolic disease, stroke, mediation

Tiantian Guo,1 Yao Wang,1 Dixuan Chen,2 Sifan Cui,2 Shuyue Guo,1 Yixing Feng,1 Jialin Zhu,1 Luchen Chang,1 Jiawei Zhang,2 Xiujun Gao,2 Xi Wei1 1Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, 300060, People’s Republic of China; 2School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, 300070, People’s Republic of ChinaCorrespondence: Xi Wei, Department of Diagnostic and Therapeutic Ultrasonography, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin, 300060, People’s Republic of China, Email weixi@tmu.edu.cn Xiujun Gao, School of Biomedical, Engineering and Technology, Tianjin Medical University, No. 22, Meteorological Station Road, Tianjin, 300070, People’s Republic of China, Email gaoxiujun12242@tmu.edu.cnPurpose: Chemotherapy remains the primary therapeutic approach for advanced Hepatocellular Carcinoma (HCC). The therapeutic effect of chemotherapy is limited and the toxic side effects are serious. The aim of this study is to develop a nanobubble that is ultrasonically responsive to reduce the toxic side effects of direct chemotherapy.Methods: We developed curcumin/doxorubicin-cis-aconitic anhydride-polyethylene glycol nanobubble (C/DCNB) surface modified with acid-sensitive polyethylene glycol (PEG). And it is loaded with curcumin (CUR) and doxorubicin (DOX), as liposomes at the nanoscale for diagnosis and therapy of tumors.Results: In this study, the acid-sensitive PEG on the surface layer of nanobubbles serves to stabilize them in the blood circulatory system and in normal tissues, while peeling off in the acidic tumor microenvironment (pH 6.8). C/DCNB can identify tumor sites through contrast-enhanced ultrasound (CEUS). And ultrasound-mediated nanobubbles promote permeability of the tumor vascular, thus improving the enhanced permeability and retention (EPR) effects in the tumor, leading to the accumulation of nanobubbles in the tumor. After endocytosis of nanobubbles, drugs are released and curcumin generates reactive oxygen species (ROS) under ultrasound conditions. CUR can enhance the sensitivity of tumor cells to DOX by inhibiting the expression of P-glycoprotein. In vitro and vivo experiments demonstrate that C/DCNB can facilitate contrast-enhanced ultrasound imaging while simultaneously delivering drugs, enabling both imaging and treatment.Conclusion: The combination of C/DCNB and ultrasound provides an effective strategy for improving the efficiency of HCC therapy and imaging. Keywords: combination of sonodynamic therapy and chemotherapy, the synergistic effect of two drugs, integration of diagnosis and treatment, ultrasound

Juan Li,1,* Ziqing Gao,1,* Ning Li,1 Ling Yao,1 Chao Liu,1 Che Xu,1 Xiaohui Ren,1 Aiqin Wang,1 Siqi Gao,2 Miao Wang,2 Xiang Gao,2 Kun Li,3 Jianfeng Wang1 1Department of Ophthalmology, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, People’s Republic of China; 2School of Clinical Medicine, Bengbu Medical University, Bengbu, Anhui, 233004, People’s Republic of China; 3School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, 233100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kun Li; Jianfeng Wang, Email liangliang2419@126.com; wangjianfeng1969@163.comBackground: Drug therapy for eye diseases has been limited by multiple protective mechanisms of the eye, which can be improved using well-designed drug delivery systems. Mesoporous silica nanoparticles (MSNs) had been used in many studies as carriers of therapeutic agents for ocular diseases treatment. However, no studies have focused on ocular biosafety. Considering that MSNs containing tetrasulfur bonds have unique advantages and have drawn increasing attention in drug delivery systems, it is necessary to explore the ocular biosafety of tetrasulfur bonds before their widespread application as ophthalmic drug carriers.Methods: In this study, hollow mesoporous silica nanoparticles (HMSNs) with different tetrasulfur bond contents were prepared and characterized. The ocular biosafety of HMSN-E was evaluated in vitro on the three selected ocular cell lines, including corneal epithelial cells, lens epithelial cells and retinal endothelial cells (HREC), and in vivo by using topical eye drops and intravitreal injections.Results: In cellular experiments, HMSNs caused obvious S content-dependent cytotoxic effect. HMSNs with the highest tetrasulfur bond content (HMSN-E), showed the highest cytotoxicity among all the HMSNs, and HREC was the most vulnerable cell to HMSN-E. It was shown that HMSN-E could react with intracellular GSH to generate H2S and decrease intracellular GSH concentration. Treatment of HREC with HMSN-E increased intracellular ROS, decreased mitochondrial membrane potential, and induced cell cycle arrest at the G1/S checkpoint, finally caused apoptosis and necrosis of HREC. Topical eye drops of HMSN-E could cause corneal damage. The intravitreal injection of HMSN-E could induce inflammation in the vitreum and ganglion cell layers, resulting in vitreous opacities and retinal abnormalities.Conclusion: The incorporation of tetrasulfur bonds into HMSN can have toxic effects on ocular tissues. Therefore, when mesoporous silica nanocarriers are designed for ophthalmic pharmaceuticals, the ocular toxicity of the tetrasulfur bonds should be considered.Keywords: ophthalmic safety, hollow mesoporous silica nanoparticles, ophthalmic drug delivery, tetrasulfur bond

Kaiyue Zhang, Chunnan Li, Peitong Wu, Xiaochen Gao, Xueqin Feng, Jiaming Shen, Nanxi Zhang, Xuesheng Hu, Shuo Wang, Hui Zhang, Jingwei Lv, Jiaming Sun Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, People’s Republic of ChinaCorrespondence: Jiaming Sun; Jingwei Lv, Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Nanguan District, Changchun, 130117, People’s Republic of China, Tel +0431-86763809, Fax + 8676 3968, Email Sun_jiaming2000@163.com; jingwei-lv@hotmail.comPurpose: Zhixiao Tang (ZXT), a traditional Chinese compound prescription, has been used clinically to treat pneumonia in China. However, the underlying mechanism of ZXT treatment in pneumonia is still unclear. The present study aimed to reveal the potential mechanism of ZXT in pneumonia using a strategy combining metabolomics and network pharmacology.Methods: Initially, the chemical compositions were identified by UPLC-QE-Orbitrap-MS, while the prediction of potential signal pathways was performed through network pharmacology. To assess the anti-inflammatory properties of ZXT in the context of pneumonia, models of 16HBE cells induced by LPS and zebrafish induced by CuSO4 were established to measure levels of inflammatory markers and apoptosis. Subsequently, the differential changes of endogenous metabolites in cells caused by ZXT were examined using metabolomics technology, and the molecular docking analysis of key targets was carried out using Autodock Vina software. Ultimately, the validation of the primary pathways and targets was conducted through quantitative RT-PCR and Western blot techniques.Results: A total of 75 compounds were identified through UPLC-QE-Orbitrap-MS analyses. Network pharmacological analysis shows that it plays an anti-inflammatory role in C-type lectin receptor signaling pathway. After ZXT intervention, the inflammatory factors and apoptosis in cells were significantly reduced. Metabonomics analysis showed that 18 metabolites changed significantly. Four key genes were identified, which exhibited partial compatibility with the findings of network pharmacology. Molecular docking analysis confirmed the substantial affinity of the primary targets for ZXT. Furthermore, ZXT exerted a suppressive effect on neutrophil migration, down-regulated the expression of pro-inflammatory cytokine genes, and inhibited the up-regulation of the Dectin-1/SYK/NF-κB signaling pathway. In vivo cell experiments also yielded consistent experimental outcomes.Conclusion: This study enhances comprehension of the pharmacological mechanism underlying ZXT’s efficacy in pneumonia treatment, thereby establishing a scholarly basis for future research and clinical utilization of ZXT in pneumonia management. Keywords: Zhixiao Tang, pneumonia, network pharmacology, integrated metabolomics, 16HBE, Zebrafish

Zheng Zhang,1,2,* Binbin Shao,3,* Hongzhou Liu,2,4 Ben Huang,2,5 Xuechen Gao,1 Jun Qiu,1 Chen Wang1,2 1Center of Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, People’s Republic of China; 2Center for Gene Diagnosis, Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China; 3Department of Prenatal Diagnosis, Women’s Hospital of Nanjing Medical University, Nanjing Women and Children’s Healthcare Hospital, Nanjing, Jiangsu Province, People’s Republic of China; 4School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuang Province, People’s Republic of China; 5Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chen Wang; Jun Qiu, Center of Clinical Laboratory, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou, Jiangsu Province, 215006, People’s Republic of China, Email 1617657224@qq.com; 13606136542@126.comPurpose: Early recognition of coronary artery disease (CAD) could delay its progress and significantly reduce mortality. Sensitive, specific, cost-efficient and non-invasive indicators for assessing individual CAD risk in community population screening are urgently needed.Patients and Methods: 3112 patients with CAD and 3182 controls were recruited from three clinical centers in China, and differences in baseline and clinical characteristics were compared. For the discovery cohort, the least absolute shrinkage and selection operator (LASSO) regression was used to identify significant features and four machine learning algorithms (logistic regression, support vector machine (SVM), random forest (RF) and extreme gradient boosting (XGBoost)) were applied to construct models for CAD risk assessment, the receiver operating characteristics (ROC) curve and precision-recall (PR) curve were conducted to evaluate their predictive accuracy. The optimal model was interpreted by Shapley additive explanations (SHAP) analysis and assessed by the ROC curve, calibration curve, and decision curve analysis (DCA) and validated by two external cohorts.Results: Using LASSO filtration, all included variables were considered to be statistically significant. Four machine learning models were constructed based on these features and the results of ROC and PR curve implied that the XGBoost model exhibited the highest predictive performance, which yielded a high area of ROC curve (AUC) of 0.988 (95% CI: 0.986– 0.991) to distinguish CAD patients from controls with a sensitivity of 94.6% and a specificity of 94.6%. The calibration curve showed that the predicted results were in good agreement with actual observations, and DCA exhibited a better net benefit across a wide range of threshold probabilities. External validation of the model also exhibited favorable discriminatory performance, with an AUC, sensitivity, and specificity of 0.953 (95% CI: 0.945– 0.960), 89.9%, and 87.1% in the validation cohort, and 0.935 (95% CI: 0.915– 0.955), 82.0%, and 90.3% in the replication cohort.Conclusion: Our model is highly informative for clinical practice and will be conducive to primary prevention and tailoring the precise management for CAD patients. Keywords: coronary artery disease, predictive model, machine learning, XGBoost, primary prevention

Xingyue Gao,1 Sihao Shen,1 Wenzhong Xiang,2 Xiuzu Song2 1The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou Third People’s Hospital, Hangzhou, People’s Republic of China; 2Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou, People’s Republic of ChinaCorrespondence: Wenzhong Xiang, Department of Dermatology, Hangzhou Third People’s Hospital, Westlake Ave 38, Hangzhou, 310002, People’s Republic of China, Email xiangwenzhong@126.comPurpose: Coronavirus disease (COVID-19) may trigger the reactivation of the latent varicella-zoster virus and may be a risk factor for herpes zoster (HZ). However, the causal relationship between COVID-19 and varicella-zoster infections remains controversial. This study aimed to estimate the causal inferences between COVID-19 and HZ.Methods: This study used a two-sample Mendelian randomization (MR) design. The inverse variance-weighted method was used as the primary method and sensitivity analyses were conducted, including the MR-Egger regression, weighted median and weighted mode. We searched at https://gwas.mrcieu.ac.uk/ using the keywords “COVID-19” for exposure data and “zoster” for outcome datasets.Results: We got 26 COVID-19 datasets and five zoster datasets. We used 26 COVID-19 datasets as exposure data corresponding to each zoster dataset for the MR analysis. There were nine datasets of COVID-19 where the number of SNPs was fewer than three in the MR analysis of the risk of HZ, varicella zoster virus (VZV) glycoprotein E and I antibody levels, anti-VZV IgG seropositivity, and post-zoster neuralgia. In addition, there were 10 datasets of COVID-19 where the number of SNPs was less than three in the MR analysis of anti-VZV IgG levels. The results of the MR analysis showed that all p-values were greater than 0.05. Sensitivity analysis revealed no evidence of horizontal pleiotropy in most two sample MR analyses.Conclusion: Our results indicate that there is no causal relationship between COVID-19 and varicella-zoster infection, HZ progression, and postherpetic neuralgia.Keywords: COVID-19, herpes zoster, varicella-zoster virus, chronic pain

Min Yu,1– 3 Zeliang Hao,1– 3 Liyue Xu,4 Long Zhao,4 Yongfei Wen,4 Fang Han,4,&ast; Xuemei Gao1– 3,&ast; 1Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, People’s Republic of China; 2Center for Oral Therapy of Sleep Apnea, Peking University Hospital of Stomatology, Beijing, People’s Republic of China; 3National Center for Stomatology, Beijing, 100081, People’s Republic of China; 4Sleep Division, Peking University People’s Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang Han, Sleep Division, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People’s Republic of China, Tel +86-010-88324204, Email hanfang1@hotmail.com Xuemei Gao, Department of Orthodontics, Peking University School and Hospital of Stomatology, No. 22 Zhongguancun South Avenue, Haidian District, Beijing, 100081, People’s Republic of China, Tel/Fax +86-010-82195350, Email xmgao@263.netPurpose: Catathrenia is a rare sleeping disorder characterized by repetitive nocturnal groaning during prolonged expirations. Patients with catathrenia had heterogeneous polysomnographic, comorbidity, craniofacial characteristics, and responses to treatment. Identifying phenotypes of catathrenia might benefit the exploration of etiology and personalized therapy.Patients and Methods: Sixty-six patients diagnosed with catathrenia by full-night audio/video polysomnography seeking treatment with mandibular advancement devices (MAD) or continuous positive airway pressure (CPAP) were included in the cohort. Polysomnographic characteristics including sleep architecture, respiratory, groaning, and arousal events were analyzed. Three-dimensional (3D) and 2D craniofacial hard tissue and upper airway structures were evaluated with cone-beam computed tomography and lateral cephalometry. Phenotypes of catathrenia were identified by K-mean cluster analysis, and inter-group comparisons were assessed.Results: Two distinct clusters of catathrenia were identified: cluster 1 (n=17) was characterized to have more males (71%), a longer average duration of groaning events (18.5± 4.8 and 12.8± 5.7s, p=0.005), and broader upper airway (volume 41,386± 10,543 and 26,661± 6700 mm3, p< 0.001); cluster 2 (n=49) was characterized to have more females (73%), higher respiratory disturbance index (RDI) (median 1.0 [0.3, 2.0] and 5.2 [1.2, 13.3]/h, p=0.009), more respiratory effort-related arousals (RERA)(1 [1, 109] and 32 [13, 57)], p=0.005), smaller upper airway (cross-sectional area of velopharynx 512± 87 and 339± 84 mm2, p< 0.001) and better response to treatment (41.2% and 82.6%, p=0.004).Conclusion: Two distinct phenotypes were identified in patients with catathrenia, primary catathrenia, and catathrenia associated with upper airway obstruction, suggesting respiratory events and upper airway structures might be related to the etiology of catathrenia, with implications for its treatment.Keywords: subtype, groaning, upper airway, treatment, OSA, sleep-disordered breathing

Pengzhu Huang,1,2,&ast; Rongrong Wu,1,2,&ast; Xin Guo,1,2,&ast; Xiaoli Gao,1,2 Ye Yan,1,2 Cha Han,1,2 Fengxia Xue1,2 1Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fengxia Xue; Cha Han, Department of Gynecology and Obstetrics, Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China, Tel +86-22-60363769, Fax +86-22-27813550, Email xuefengxia@tmu.edu.cn; tjhancha@tmu.edu.cnObjective: This study aimed to evaluate the impact of twin pregnancies with antiphospholipid antibody (aPL) positivity, a rare and complex clinical condition that remains a huge challenge for management.Methods: This study enrolled twin-pregnant women at our hospital between January 2018 and August 2023. Women with and without aPL positivity were selected using propensity score matching (PSM). Clinical features and pregnancy outcomes were compared between the two groups in the PSM cohort. To analyze the effect of aPL positivity on pregnancy outcomes, multivariate logistic models were used to obtain adjusted odds ratios (aOR) with 95% confidence intervals (CI).Results: Among the 773 women with twin pregnancies, aPL positivity was found in 26 women (3.36%). In the PSM cohort, there were 24 twin-pregnant women with positive aPL, and 48 women without aPL were selected as controls. Twin-pregnant women with aPL positivity had a higher proportion of abortion (8.33% vs 0, P = 0.043), preterm birth < 34 weeks (33.33% vs 8.33%, P = 0.007) and very low birthweight (< 1500 g) (20.83% vs 4.17%, P = 0.016) than the control group. In addition, stillbirth of one fetus was observed in one twin-pregnant woman with positive aPL. Multivariate logistic regression analysis revealed that twin pregnancy with aPL positivity was associated with preterm birth < 34 weeks (aOR = 2.76, 95% CI: 0.83– 4.70, P = 0.005), very low birthweight (< 1500 g) (OR = 2.40, 95% CI: 0.18– 4.67, P = 0.034) and small for gestational age (SGA) (aOR = 1.66, 95% CI: 0.22– 3.10, P =0.024).Conclusion: Twin pregnancies with aPL positivity were correlated with obstetric complications, including abortion, preterm birth < 34 weeks and very low birthweight (< 1500 g). The detection of aPL may be of clinical significance for women with twin pregnancies and should be considered in future studies.Keywords: twin pregnancy, antiphospholipid antibody, pregnancy outcomes, propensity score matching

Lu Hou,1,&ast; Jing Zhang,2,&ast; Jing Liu,3 Chang Chen,1 Xuezheng Gao,4 Limin Chen,4 Zhenhe Zhou,1,3 Hongliang Zhou5 1Department of Psychiatry, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi City, 214151, People’s Republic of China; 2Department of Psychiatry, Huaian Third People’s Hospital, Huaian City, 223021, People’s Republic of China; 3School of Humanities and Management Science, Wannan Medical College, Wuhu City, 241000, People’s Republic of China; 4Department of Psychiatry, The Affiliated Mental Health Center of Jiangnan University, Wuxi City, 214151, People’s Republic of China; 5Department of Psychology, The Affiliated Hospital of Jiangnan University, Wuxi City, 214151, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenhe Zhou, Department of Psychiatry, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi City, 214151, People’s Republic of China, Tel +86-1-335-811-8986, Fax +86-510-83219366, Email zhouzh@njmu.edu.cn Hongliang Zhou, Department of Psychology, the Affiliated Hospital of Jiangnan University, Wuxi City, 214151, People’s Republic of China, Tel +86-1-536-525-1126, Fax +86-510-85808820, Email Hongliangzh2022@hotmail.comPurpose: Nicotine withdrawal is a multifaceted physiological and psychological process that can induce a spectrum of mood disturbances. Gaining a more nuanced understanding of how pure nicotine withdrawal influences cognitive control functions may provide valuable insights for the enhancement of smoking cessation programs. This study investigated changes in inhibitory control function in smokers after 2-hour nicotine withdrawal using the event-related potential (ERP) technique.Participants and Methods: 28 nicotine dependence (ND) patients and 28 health controls (HCs) completed a smoking-cued Go/No-go task containing two different types of picture stimuli, smoking-cued and neutral picture stimuli. We analyzed the behavioral and ERP data using a mixed model Repeated Measure Analysis of Variance (ANOVA).Results: No-go trials accuracy rate (ACC) at baseline (time 1) was lower in the ND group compared to HCs with smoking-cued stimuli, and No-go trials ACC after 2-hour nicotine withdrawal (time 2) was not lower in the ND group compared to HCs. When confronted with smoking-cued stimuli, the No-go trials ACC was higher in time 2 than in time 1 in the ND group. For the ERP component, the No-go N2 amplitudes in the ND group with smoking-cued stimuli were lower than that of HCs, whereas after 2-hour nicotine withdrawal, the ND group’s No-go N2 amplitudes higher than that at time 1, and did not differ from that of HCs. No-go P3 amplitudes were not significantly different between the two groups.Conclusion: Evidenced from ERP data, ND patients have an inhibitory control dysfunction in the face of smoking cues, which is mainly manifested in the early stage of response inhibition rather than in the late stage. Two-hour nicotine withdrawal improves inhibitory control dysfunction in ND patients. The No-go N2 component is an important and sensitive neuroelectrophysiological indicator of inhibitory control function in ND patients.Keywords: nicotine dependence, inhibitory control, 2-hour nicotine withdrawal, event-related potentials, Go/No-go task

Zhuoyuan Zhang,1,2,&ast; Dan Liu,1,2,&ast; Rui Lv,1,2,&ast; Haoyan Zhao,1,2,&ast; Tianjing Li,1,2 Yutao Huang,2 Zhicheng Tian,2 Xiangyu Gao,2 Peng Luo,2 Xin Li3 1Biochemistry and Molecular Biology, College of Life Science, Northwest University, Xi’an, 710127, People’s Republic of China; 2Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China; 3Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peng Luo; Xin Li, Email pengluo@fmmu.edu.cn; li_xin_mail@126.comPurpose: Neuroinflammation occurs in response to central nervous system (CNS) injury, infection, stimulation by toxins, or autoimmunity. We previously analyzed the downstream molecular changes in HT22 cells (mouse hippocampal neurons) upon lipopolysaccharide (LPS) stimulation. We detected elevated expression of Fibrillarin (FBL), a nucleolar methyltransferase, but the associated proinflammatory mechanism was not systematically elucidated. The aim of this study was to investigate the underlying mechanisms by which FBL affects neuroinflammation.Methods: RT-real-time PCR, Western blotting and immunofluorescence were used to assess the mRNA and protein expression of FBL in HT22 cells stimulated with LPS, as well as the cellular localization and fluorescence intensity of FBL. BAY-293 (a son of sevenless homolog 1 (SOS1) inhibitor), SR11302 (an activator protein-1 (AP-1) inhibitor) and KRA-533 (a KRAS agonist) were used to determine the molecular mechanisms underlying the effect of FBL. AP-1 was predicted to be the target protein of FBL by molecular docking analysis, and validation was performed with T-5224 (an AP-1 inhibitor). In addition, the downstream signaling pathways of FBL were identified by transcriptome sequencing and verified by RT-real-time PCR.Results: LPS induced FBL mRNA and protein expression in HT22 cells. In-depth mechanistic studies revealed that when we inhibited c-Fos, AP-1, and SOS1, FBL expression decreased, whereas FBL expression increased when KRAS agonists were used. In addition, the transcript levels of inflammatory genes in the NF-kB signaling pathway (including CD14, MYD88, TNF, TRADD, and NFKB1) were elevated after the overexpression of FBL.Conclusion: LPS induced the expression of FBL in HT22 cells through the RAS/MAPK signaling pathway, and FBL further activated the NF-kB signaling pathway, which promoted the expression of relevant inflammatory genes and the release of cytokines. The present study reveals the mechanism by which FBL promotes neuroinflammation and offers a potential target for the treatment of neuroinflammation.Keywords: FBL, neuroinflammation, LPS, molecular docking, transcriptome sequencing

Xusheng Gao, Caihong Ding, Dan Xie, Qing Wang, Peipei Jiang, Yuyu Wang, Yu Xiong Department of Tuberculosis, Shandong Public Health Clinical Center, Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Yu Xiong, Department of Tuberculosis, Shandong Public Health Clinical Center, Shandong University, No. 11, Lieshishan East Road, Licheng District, Jinan, Shandong, People’s Republic of China, Tel +8615589995880, Email yiyiruguo1@163.comBackground: In recent decades, there has been a substantial surge in the incidence of non-tuberculous Mycobacteria (NTM) infections. However, the diagnosis and management of NTM globally present significant challenges, particularly in cases involving Mycobacterium abscessus complex (MABC) infection where effective therapeutic options are limited.Case Presentation: We reported a 38-year-old female patient who was infected with MABC of skin due to “beauty needle” at a beauty salon, with mass on both cheeks, accompanied by redness, and pain, and some of them was ulcered and effused. Puncture pumping pus from bilateral cheek mass for many times, rinsed with “metronidazole”, and oral “cephalosporin” treatment did not work. Therefore, she came to our hospital. MABC was detected in abscess paracentesis pus by nucleic acid mass spectrometry, and was proved by the cultured result of the pus. Thus, the patient was diagnosed as skin MABC infection, and anti-NTM treatment was taken. However, adverse reactions such as tinnitus, hepatotoxicity and neurovirulence occurred during the initial treatment. After adjusting to the contezolid-containing regimen, these adverse reactions improved. After nearly 6 months of treatment, the cheek mass was gradually reduced and the skin ruptures were gradually healed. Follow-up for 10 months showed that the patient’s facial symptoms were significantly improved, and no drug-related adverse reactions happened.Conclusion: This was the first successful case of multiple drug resistance MABC infection of skin treated with contezolid-containing antibiotic management strategies, which exhibited remarkable efficacy and good safety in this intractable disease.Keywords: Mycobacterium abscessus complex, antibiotic therapy, contezolid, Case report

Qingxia Lin,1 Jinrong Zhu,2 Xuelei Gao3 1Department of Dermatology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, People’s Republic of China; 2Department of Central Pharmacy, Zhucheng People’s Hospital, Weifang, Shandong, People’s Republic of China; 3Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, People’s Republic of ChinaCorrespondence: Xuelei Gao, Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, People’s Republic of China, Email gaoxuelei17@163.comAbstract: Vitiligo is a skin depigmentation disease resulting from melanocyte destruction and often co-occurring with autoimmune disorders like hyperthyroidism, alopecia areata, pernicious anemia, and systemic lupus erythematosus (SLE). Although various traditional treatments exist for vitiligo, their effectiveness varies considerably. This report presents a unique case of a vitiligo patient with concomitant systemic lupus erythematosus. Remarkably, after a 30-day course of treatment with tofacitinib, complete repigmentation of the white macular rash was achieved, and there were no adverse drug reactions. These findings provide compelling evidence for the efficacy and safety of oral JAK inhibitors, such as tofacitinib, in vitiligo treatment. Additionally, JAK inhibitors can yet be regarded as a promising new treatment option for vitiligo patients with concurrent autoimmune diseases.Keywords: vitiligo, systemic lupus erythematosus, tofacitinib, JAK inhibitors

Yinghong Li,1,&ast; Fanwu Wu,1,&ast; Jianbo Zhang,1 Ye Xu,1 Hong Chang,1 Yueyue Yu,1 Chunhua Jiang,1 Xiujuan Gao,1 Huijuan Liu,1 Zhen Chen,2 Chenxi Wu,1 Ji-An Li1,3 1Hebei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, People’s Republic of China; 2Oriental Herbs KFT, Budapest, Hungary; 3School of Public Health, North China University of Science and Technology, Tangshan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chenxi Wu; Ji-An Li, Tel +86-15930951086, Fax +86-03158805765, Email chenxi.wu@ncst.edu.cn; JianLi@ncst.edu.cnPurpose: Type 2 diabetes mellitus (T2DM) is associated with reduced insulin uptake and glucose metabolic capacity. Potentilla discolor Bunge (PDB) has been used to treat T2DM; however, the fundamental biological mechanisms remain unclear. This study aimed to understand the active ingredients, potential targets, and underlying mechanisms through which PDB treats T2DM.Methods: Components and action targets were predicted using network pharmacology and molecular docking analyses. PDB extracts were prepared and validated through pharmacological intervention in a Cg>InRK1409A diabetes Drosophila model. Network pharmacology and molecular docking analyses were used to identify the key components and core targets of PDB in the treatment of T2DM, which were subsequently verified in animal experiments.Results: Network pharmacology analysis revealed five effective compounds made up of 107 T2DM-related therapeutic targets and seven protein–protein interaction network core molecules. Molecular docking results showed that quercetin has a strong preference for interleukin-1 beta (IL1B), IL6, RAC-alpha serine/threonine-protein kinase 1 (AKT1), and cellular tumor antigen p53; kaempferol exhibited superior binding to tumor necrosis factor and AKT1; β-sitosterol demonstrated pronounced binding to Caspase-3 (CASP3). High-performance liquid chromatography data quantified quercetin, kaempferol, and β-sitosterol at proportions of 0.030%, 0.025%, and 0.076%, respectively. The animal experiments revealed that PDB had no effect on the development, viability, or fertility of Drosophila and it ameliorated glycolipid metabolism disorders in the diabetes Cg>InRK1409A fly. Furthermore, PDB improved the body size and weight of Drosophila, suggesting its potential to alleviate insulin resistance. Moreover, PDB improved Akt phosphorylation and suppressed CASP3 activity to improve insulin resistance in Drosophila with T2DM.Conclusion: Our findings suggest that PDB ameliorates diabetes metabolism disorders in the fly model by enhancing Akt activity and suppressing CASP3 expression. This will facilitate the development of key drug targets and a potential therapeutic strategy for the clinical treatment of T2DM and related metabolic diseases. Keywords: Potentilla discolor Bunge, T2DM, network pharmacology, molecular docking, Drosophila

Chang Chen,1 Qian Mei,2 Qi Liu,3 Meichen Lu,4 Lu Hou,1 Xiaohong Liu,3 Xuezheng Gao,3 Limin Chen,3 Zhenhe Zhou,1– 4 Hongliang Zhou5 1Department of Psychiatry, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi City, People’s Republic of China; 2School of Humanities and Management Science, Wannan Medical College, Wuhu City, People’s Republic of China; 3Grade 2021 Class 3, First Clinical Medical College of Jinzhou Medical University, Jinzhou City, People’s Republic of China; 4Department of Psychiatry, The Affiliated Mental Health Center of Jiangnan University, Wuxi City, People’s Republic of China; 5Department of Psychology, The Affiliated Hospital of Jiangnan University, Wuxi City, People’s Republic of ChinaCorrespondence: Zhenhe Zhou, Wuxi Mental Health Center, No. 156, Qianrong Road, Binhu District, Wuxi City, Jiangsu Province, People’s Republic of China, Tel +86-1-335-811-8986, Fax +86-510-83219366, Email zhouzh@njmu.edu.cn Hongliang Zhou, The Affiliated Hospital of Jiangnan University, No. 200, Huihe Road, Binhu District, Wuxi City, Jiangsu Province, People’s Republic of China, Tel +86-1-536-525-1126, Fax +86-510-85808820, Email Hongliangzh2022@hotmail.comPurpose: Schizophrenia patients show impaired conditional reasoning. This study was to investigate event-related potential (ERP) characteristics of the conditional reasoning in schizophrenia.Patients and methods: Participants included 24 schizophrenia patients and 30 normal controls (NCs), and the measurements of ERPs were conducted during the Wason selection task.Results: Results showed that NCs consistently outperformed schizophrenia patients in terms of accuracy. Among the different rule types of the task, the precautionary type experiment yielded the highest accuracy rates. In contrast, both the descriptive and abstract type experiments resulted in lower accuracy. The RTs of the abstract type experiment were the shortest among the four experiments. In the abstract type of the Wason selection task, the NCs exhibited higher amplitudes for both the N1 and P2 components compared to the schizophrenia patients. At the parietal lobe, the N2 amplitudes were higher for the social contract type of the task compared to the precautionary version. At the frontal lobe, the N2 amplitudes were highest for the abstract type of the task. In the abstract type, the N2 amplitude at the parietal lobe was higher than that at the central lobe. The NCs displayed lower amplitudes for both the P3 and slow wave compared to the schizophrenia patients. Differences were observed between the NC and schizophrenia groups in terms of the latencies for N1, P2, N2, P3 and slow wave components across different experiment types and regions of interest.Conclusion: In conclusion, the observed ERP patterns provide valuable insights into the neural mechanisms underlying the Wason selection task, highlighting the differences between NCs and patients with schizophrenia.Keywords: event-related potential, wason selection task, schizophrenia, conditional reasoning, neural mechanism

Wenrong Zhang,1,2,&ast; Haining Wang,1,&ast; Tong Wu,1 Xintao Gao,1 Yuting Shang,1 Zhifang Zhang,1 Xingjian Liu,1 Yinü Li1 1National Key Laboratory of Agricultural Microbiology, Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, People’s Republic of China; 2College of Life Sciences, Capital Normal University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xingjian Liu; Yinü Li, Tel/Fax +861082109854 ; +861082105495, Email liuxingjian@caas.cn; liyinv@caas.cnPurpose: COVID-19 is rampant throughout the world, which has caused great damage to human lives and seriously hindered the development of the global economy. Aiming at the treatment of SARS-CoV-2, in this study, we proposed a novel fenobody strategy based on ferritin (Fe) self-assembly technology.Methods: The neutralizing nanobody H11-D4 of SARS-CoV-2 fused to the C-terminus of end-modified human ferritin was expressed in E. coli and silkworm baculovirus expression systems. A large number of nanoparticles were successfully self-assembled in silkworms, while relatively few nanoparticles can be observed in the treated products from E. coli by electron microscopy. Subsequently, the fenobody’s expression level and neutralizing activity were then evaluated.Results: The results showed that the IC50 of H11-D4 and fenobody Fe-H11-D4 expressed in E. coli were 171.1 nmol L− 1 and 20.87 nmol L− 1, respectively. However, the IC50 of Fe-HD11-D4 expressed in silkworms was 1.46 nmol L− 1 showing better neutralization activity.Conclusion: Therefore, fenobodies can be well self-assembled in silkworm baculovirus expression system, and ferritin self-assembly technology can effectively improve nanobody neutralization activity.Keywords: COVID-19, ferritin, fenobody, baculovirus expression system, silkworm

Lihe Ma,1 Rui Yan,1 Xiang Wang,2 Xiaohong Gao,1 Na Fan,1 Linmei Liu,3 Haifen Kang3 1Nursing College of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Department of Foreign Language, Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of General Surgery, First Affiliated Hospital of Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Rui Yan, Nursing College of Shanxi Medical University, No. 56 of Xinjian Road, Yingze District, Taiyuan, Shanxi, 030001, People’s Republic of China, Tel +86 13934168679, Email yanruifl29@outlook.comBackground: Surgical nursing is a high-risk, high-pressure, and complex field. Nurses need extensive knowledge, skills, and abilities. Problem-Based Learning (PBL) and Simulation-Based Learning (SBL) are effective student-centered methods. Which method is better for surgical nurse training? More research is needed to determine the best approach for undergraduate surgical nurse education.Purpose: To compare the impact of PBL and SBL on undergraduate nursing students’ performance and improve learning outcomes in surgical nursing education.Methods: We used a pretest/post-test design with 318 nursing undergraduates randomly assigned to two groups. Participants completed three progressive scenarios focused on surgical nursing cases. Experts blindly reviewed video recordings using the 70-item Korean Nurses’ Core Competence Scale (KNCCS) to assess performance. The 13-item Satisfaction and Self-confidence in learning Scale (SSS) measured learning confidence and satisfaction. SBL participants also completed the 16-item Educational Practices in Simulation Scale (EPSS) and 20-item Simulation Design Scale (SDS).Results: The study found significant positive effects on both groups, with noticeable improvements in post-test, retention, and follow-up test results (P < 0.001). The SBL group showed higher competency levels in nurses (P < 0.001). The Cohen’s d and effect size (r) for various skills were as follows: clinical performance (0.84767 and 6.39023), critical thinking (0.31017 and 0.15325), professional attitude (0.85868 and 0.39452), and communication skills (1.55149 and 0.61294). The satisfaction and self-confidence of nurses were higher in the SBL group (4.53± 0.596; 4.47± 0.611) compared to the PBL group (4.32± 0.689; 4.25± 0.632) in all dimensions of SSS (all P < 0.05). The SBL group also scored high in simulation design and EPSS. However, improvements are needed in fidelity, objectives, information, and students’ expectations.Conclusion: SBL and PBL improve nurses’ core competence, satisfaction, and self-confidence. SBL is superior. This study promotes student-centered education, enhancing surgical nursing professionals’ quality and ensuring future patient safety.Keywords: baccalaureate nursing, education, problem-based learning, simulation training, surgical nursing

Dexiu Chen,1 Zhangjing Shi,1 Xiaolan Gao,1 Yuxiang Yang,1 Xianying Lei,1,&ast; Yingchun Hu2,&ast; 1Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2Department of Emergency Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingchun Hu, Department of Emergency Medicine, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel +86-830-3165851, Email huyingchun913@swmu.edu.cn Xianying Lei, Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel +86-830-3165527, Email leixianying310@swmu.edu.cnPurpose: There are no satisfactory diagnostic biomarkers for sepsis. Accordingly, this study screened biomarkers valuable for sepsis diagnosis and prognosis using data-independent acquisition (DIA) combined with clinical data analysis.Patients and Methods: Serine protease inhibitor Kazal-type 1 (SPINK1) is a differentially expressed protein that was screened using DIA and bioinformatics in sepsis patients (n = 22) and healthy controls (n = 10). The plasma SPINK1 levels were detected using an enzyme-linked immunosorbent assay (ELISA) in an expanded population (sepsis patients, n = 52; healthy controls, n = 10). The diagnostic value of SPINK1 in sepsis was evaluated using receiver operating characteristic (ROC) curve analysis based on clinical data. The prognostic value of SPINK1 for sepsis was evaluated using correlation and survival analyses.Results: DIA quality control identified 78 differential proteins (72 upregulated and six downregulated), among which SPINK1 was highly expressed in sepsis. The ELISA results suggested that SPINK1 expression was significantly elevated in the sepsis group (P < 0.05). ROC analysis of SPINK1 yielded an area under the curve (AUC) of 0.9096. Combining SPINK1 with procalcitonin (PCT) for ROC analysis yielded an AUC of 1. SPINK1 expression was positively correlated with the Sequential Organ Failure Assessment (SOFA) score (r = 3497, P = 0.0053) and APACHE II score (r = 3223, P = 0.0106). High plasma SPINK1 protein expression was negatively correlated with the 28-day survival rate of patients with sepsis (P = 0.0149).Conclusion: The plasma of sepsis patients contained increased SPINK1 protein expression. Combining SPINK1 with PCT might have a high diagnostic value for sepsis. SPINK1 was associated with the SOFA score, APACHE II score, and the 28-day survival rate in patients with sepsis.Keywords: serine protease inhibitor Kazal-type 1, sepsis, DIA, PCT, biomarker

Xiaojing Chen,1– 3,&ast; Qilin Yang,4,&ast; Li Gao,1– 3 Weinan Chen,1 Xiaoyu Gao,1– 3 Yameng Li,1– 3 Liying Ao,5 Dejun Sun1– 3 1Department of Respiratory and Critical Care Medicine, Inner Mongolia People’s Hospital, Hohhot, 010017, People’s Republic of China; 2NHC Key Laboratory of Diagnosis & Treatment of COPD, Inner Mongolia People’s Hospital, Hohhot, 010017, People’s Republic of China; 3Inner Mongolia Key Laboratory of Respiratory Diseases, Inner Mongolia People’s Hospital, Hohhot, 010017, People’s Republic of China; 4Department of Critical Care, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 5Department of Otolaryngology, Inner Mongolia People’s Hospital, Hohhot, 010017, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dejun Sun, Department of Respiratory and Critical Care Medicine, Inner Mongolia People’s Hospital, No. 26 Zhaowuda Road, Saihan District, Hohhot, 010017, People’s Republic of China, Email nmg_sdj@163.comBackground: Serum anion gap (AG) has been proven to be associated with prognosis in critically ill patients. However, few studies have investigated the association between AG and all-cause mortality in critically ill patients with chronic obstructive pulmonary disease (COPD).Objective: We hypothesized that the initial AG level would predict the mortality risk in critically ill patients with COPD.Methods: This retrospective cohort study was based on the Medical Information Mart for Intensive Care (MIMIC) IV database. We extracted demographics, vital signs, laboratory tests, comorbidity, and scoring systems from the first 24 hours after patient ICU admission. Multivariable logistic regression analysis models were used to explore the association between serum AG levels and mortality. Interaction and stratified analyses were conducted including age, gender and comorbidity.Results: A total of 5531 critically ill patients with COPD were enrolled, composed of 53.6% male and 46.4% female with a median age of 73 years. The all-cause mortality of these patients during ICU hospitalization was 13.7%. The risk of all-cause mortality increased as the AG level increased in the univariate logistic regression analysis (OR=1.13, 95% CI: 1.11– 1.15, p< 0.01). After adjusting for all the covariates in multivariate logistic regression analysis, the odds ratio was 1.06 (95% CI: 1.04– 1.09, p< 0.01). Compared with the lowest AG group Q1 (≤ 11mmol/L), the adjusted OR value for AG and mortality in Q2 (12– 13mmol/L) was 0.89 (95% CI: 0.63– 1.25, p=0.502), Q3 (14– 15mmol/L) was 0.95 (95% CI: 0.68– 1.34, p=0.788), and Q4 (≥ 16mmol/L) was 1.49 (95% CI: 1.10– 2.02, p=0.009) respectively. In addition, the results of the subgroup and stratified analyses were robust.Conclusion: AG is positively related to all-cause mortality in critically ill patients with COPD.Keywords: AG, COPD, mortality, MIMIC IV

Jiwen Hou,1,2,&ast; Hua Jiang,1,&ast; Yan Han,1 Rong Huang,1 Xiang Gao,1 Wei Feng,1 Zongjun Guo2 1Department of Geriatrics, Affiliated Hospital of Chengdu University, Chengdu, People’s Republic of China; 2Department of Geriatrics, Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zongjun Guo, Department of Geriatrics, Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, Shandong Province, People’s Republic of China, Tel +8618661808736, Email guozjj@163.comPurpose: This study assessed the influences of different lifestyle on mild cognitive impairment (MCI) progression and established a decision tree prediction model to analyse their predictive significance on MCI progression incidence.Patients and Methods: From October 2015 to February 2020,330 patients with MCI were recruited, and demographic and lifestyle information collected. They were followed up for 19.04 ± 10.227 months. Cognitive function was assessed using the Mini-Mental State Examination Scale every 6 months, and they were divided into MCI stable group and MCI progression group.Results: The Kaplan Meier survival analysis showed an overall cohort survival rate of 33.2%; the annual conversion rate of MCI progression was 20%. Physical exercise, social engagement, high-fat diet, age, napping, and tea drinking were decision tree prediction model nodes. Hobbies were the most important factor for predicting MCI progression. The MCI progression probability rates were: with hobbies 26.829% (44 cases), without hobbies 57.831% (96 cases); for those withot hobbies, with physical exercise 43.077% (28 cases) without physical exercise 72.340% (68 cases); for those without hobbies with physical exercise and social engagement 20.000% (4 cases), without social engagement 53.333% (24 cases); for those without hobbies, physical exercises and social engagement and with nap habits 48.485% (16 cases), without nap habits 66.667% (8 cases). The decision tree prediction model AUC for predicting the MCI progression receiver operating characteristic curve was 0.737 (95% confidence interval: 0.685– 0.785) (75.71% sensitivity, 71.75% specificity, P < 0.001.Conclusion: Hobbies, physical exercise, social engagement, napping, and drinking tea can help prevent MCI progression, while a high-fat diet may exacerbate MCI progression. In this study the rule with the lowest MCI progress probability for those who had hobbies, high-fat diet, and social engagement. And the decision tree model had good prediction efficiency.Keywords: lifestyle, mild cognitive impairment progression, survival analysis, decision tree prediction model

Xin Gao,1 Jiale Xu,2 Musen Xu,2 Pengzhe Han,2 Jingchao Sun,2 Ruifeng Liang,1 Shaojian Mo,2,&ast; Yanzhang Tian2,&ast; 1School of Public Health, Shanxi Medical University, Taiyuan, People’s Republic of China; 2Department of Biliary and Pancreatic Surgery, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Shanxi Bethune Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaojian Mo; Yanzhang Tian, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China, Tel +8619834514208 ; +8613903512030, Email 1009184648@qq.com; tyz2030@163.comPurpose: Acute pancreatitis is a common gastrointestinal emergency. Approximately 20% of patients with acute pancreatitis develop organ failure, which is significantly associated with adverse outcomes. This study aimed to establish an early prediction model for persistent organ failure in acute pancreatitis patients using 24-hour admission indicators.Patients and Methods: Clinical data and 24-h laboratory indicators of patients diagnosed with acute pancreatitis from January 1, 2017 to January 1, 2022 in Shanxi Bethune Hospital were collected. Patients from 2017 to 2021 were used as the training cohort to establish the prediction model, and patients from 2021 to 2022 were used as the validation cohort. Univariate logistic regression and LASSO regression were used to establish prediction models. The performance of the model was evaluated using area under the curve (AUC), calibration curves, and decision curve analysis (DCA), and subsequently validated in the validation group.Results: A total of 1166 patients with acute pancreatitis were included, a total of 145 patients suffered from persistent organ failure from 2017 to 2021. Data were initially selected for 100 variables, and after inclusion and exclusion, 46 variables were used for further analysis. Two prediction models were established and nomogram was drawn respectively. After comparison, the prediction values of the two models were similar (The univariate model AUC was 0.867, 95% CI (0.834– 0.9). The LASSO model AUC was 0.864, 95% CI (0.828– 0.895)), and the model established by LASSO regression was more parsimonious. A web calculator was developed using the model established by LASSO.Conclusion: Predictive model including 6 risk indicators can be used to predict the risk of persistent organ failure in patients with acute pancreatitis.Keywords: prediction model, LASSO regression, acute pancreatitis, nomogram, organ failure

Jiaxu Lu,1,2,&ast; Jiaxian Chen,2,&ast; Junhong Ye,2 Zhen Shi,2 Xiang Gao,1 Peicong Chen,2 Yanzhou Chang,2 Hao Lin,2 Peng Li1 1Stem Cell Research and Cellular Therapy Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China; 2Orthopedic Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Lin, Orthopedic Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China, Email linhao@gdmu.edu.cn Peng Li, Stem Cell Research and Cellular Therapy Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China, Email 13763086273@163.comIntroduction: Osteosarcoma is a prevalent and highly malignant primary bone tumor. However, current clinical therapeutic drugs for osteosarcoma are not suitable for long-term use due to significant side effects. Therefore, there is an urgent need to develop new drugs with fewer side effects. Dipsacus asperoides C. Y. Cheng et T. M. Ai, a traditional Chinese medicine, is commonly used for its anti-inflammatory, anti-pain, bone fracture healing, and anti-tumor effects. In this study, we investigated the effects of exosome-like nanoparticles derived from Dipsacus asperoides (DAELNs) on osteosarcoma cells in vitro and in vivo.Methods: DAELNs were isolated and purified from Dipsacus asperoides and their physical and chemical properties were characterized using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The cellular uptake of DAELNs in osteosarcoma cells was analyzed by PKH26 staining. The proliferation, invasion, migration, and apoptosis of osteosarcoma cells were assessed using CCK8 assay, EdU assay, colony-formation assay, transwell assay, wound healing assay, and mitochondrial membrane potential measurement, respectively. The regulatory mechanism of DAELNs inhibiting the progression of osteosarcoma via activating P38/JNK signaling pathway was investigated using Western blotting and immunohistochemistry. Moreover, the therapeutic effects of DAELNs were evaluated using in vivo small animal imaging assay, HE staining, and immunohistochemistry.Results: Our results showed that DAELNs inhibited the proliferation, invasion, migration, and fostered the apoptosis of osteosarcoma cells in vitro and suppressed the tumor growth of osteosarcoma cells in a xenograft nude mouse model. Furthermore, the bio-distribution of DiD-labeled DAELNs showed preferential targeting of osteosarcoma tumors and excellent biosafety in histological analysis of the liver and kidney. Mechanistically, DAELNs activated the P38/JNK signaling pathway-induced apoptosis.Conclusion: Taken together, DAELNs are novel, natural, and osteosarcoma-targeted agents that can serve as safe and effective therapeutic approaches for the treatment of osteosarcoma.Keywords: osteosarcoma, Dipsacus asperoides-derived exosomes-like nanoparticles, P38/JNK signaling pathway

Mei Liu,1,&ast; Xiangqian Gao,2,&ast; Yang Tian,1 Huiwei Li,3 Ziqi Yin,1 Lei Han,4 Lei Zhang1 1Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 2Department of Pathology, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China; 3Department of Intensive Care Unit, the Fifth People’s Hospital of Jinan, Jinan, Shandong, People’s Republic of China; 4Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Zhang, Department of Endocrinology and Metabolism, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China, Email binzhouzhanglei@outlook.com Lei Han, Department of Reproductive Medicine, Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of China, Email hanleimm@126.comContext: Metrnl is a novel adipokine mainly produced by white adipose tissue, which plays important roles in insulin sensitization, and energy homeostasis. However, information about the function of Metrnl in Metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear.Methods: This is a control study, which enrolled 176 adults with MAFLD and 176 normal controls. They were matched in body mass index (BMI), age, and sex. Serum Metrnl was determined by ELISA. Other biochemical data were also collected.Results: Compared to the controls, circulating Metrnl was prominently decreased in the MAFLD adults (P< 0.001). Next, binary logistic regression model indicated that sex, waist circumference (WC), triglyceride, γ-gamma glutamyl transferase(γ-GGT), and Metrnl was independently associated with MAFLD. Further, as Metrnl levels elevated across its tertiles, the rate of MAFLD decreased (67.52, 66.95, and 15.38%; P value for trend< 0.001). Data from multivariate logistic regression models evidenced that compared with the lowest tertile of Metrnl, the odds ratio of MAFLD was 0.023(95% CI 0.006– 0.086, P< 0.001) for the highest tertile after adjusting for potential confounders. Besides, area under ROC curve of Metrnl for diagnosis MAFLD was 0.755(95% CI 0.705– 0.805). Metrnl was positively correlated with diastolic blood pressure, WC, BMI, systolic blood pressure, γ-GGT, and Creatinine in MAFLD. Finally, we found systolic blood pressure and Creatinine were independently related to serum Metrnl in MAFLD.Conclusion: Serum Metrnl is reduced in adult with MAFLD. The results suggest that Metrnl may be a protective factor associated with the pathogenesis of MAFLD.Keywords: metabolic dysfunction-associated fatty liver disease, metrnl, adipokine, adipose tissue

Rongcui Sui,1– 3 Jie Li,4 Yunhan Shi,1– 3 Shizhen Yuan,1– 3 Huijun Wang,1– 3 Jianhong Liao,1– 3 Xiang Gao,1– 3 Demin Han,1– 3 Yanru Li,1– 3 Xingjun Wang4 1Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Obstructive Sleep Apnea-Hypopnea Syndrome Clinical Diagnosis and Therapy and Research Centre, Capital Medical University, Beijing, People’s Republic of China; 3Key Laboratory of Otolaryngology-Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, People’s Republic of China; 4Department of Electronic Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, People’s Republic of ChinaCorrespondence: Demin Han; Yanru Li, Beijing Tongren Hospital, Capital Medical University, 1 Dongjiaominxiang, Dongcheng District, Beijing, People’s Republic of China, Email deminhan_ent@hotmail.com; liyanruru@aliyun.comPurpose: This study aimed to investigate the association between sleep spindle metrics and executive function in individuals with obstructive sleep apnea (OSA). Furthermore, we examined the association of age and education on executive function.Patients and Methods: A total of 230 (40.90 ± 8.83 years, F/M = 45/185) participants were enrolled. Overnight electroencephalogram (C3-M2) recording detected sleep spindles by a novel U-Net-type neural network that integrates temporal information with time-frequency images. Sleep spindle metrics, including frequency (Hz), overall density (events/min), fast density (events/min), slow density (events/min), duration (sec) and amplitude (μV), were measured. Executive function was assessed using standardized neuropsychological tests. Associations between sleep spindle metrics, executive function, and demographic factors were analyzed using multivariate linear regression.Results: In fully adjusted linear regression models, higher overall sleep spindle density (TMT-A, B=− 1.279, p=0.009; TMT-B, B=− 1.813, p=0.008), fast sleep spindle density (TMT-A, B=− 1.542, p=0.048; TMT-B, B=− 2.187, p=0.036) and slow sleep spindle density (TMT-A, B=− 1.731, p=0.037; TMT-B, B=− 2.449, p=0.034) were associated with better executive function. And the sleep spindle duration both during N2 sleep time (TMT-A, B=− 13.932, p=0.027; TMT-B, B=− 19.001, p=0.034) and N3 sleep time (TMT-B, B=− 29.916, p=0.009; Stroop-incongruous, B=− 21.303, p=0.035) was independently associated with better executive function in this population. Additionally, age and education were found to be highly associated with executive function.Conclusion: Specific sleep spindle metrics, higher overall density, fast density and slow density during N2 sleep time, and longer duration during N2 and N3 sleep time, are independent and sensitive indicators of better executive function in young adult and middle-aged patients with OSA. Further research is needed to explore the underlying mechanisms and clinical implications of these findings.Keywords: sleep spindle metrics, executive function, obstructive sleep apnea, young adults, middle-aged adults

Yiwei Zhao,&ast; Zechao Qu,&ast; Songchuan Zhao, Yong Zhang, Yining Gong, Bo Zhang, Xiangcheng Gao, Dong Wang, Liang Yan Department of Spine Surgery, Honghui Hospital, Xi’an Jiao Tong University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liang Yan, Department of Spine Surgery, Honghui Hospital, Xi’an Jiao Tong University, Xi’an, People’s Republic of China, Email yanliangdr5583@163.comAbstract: The maintenance of bone homeostasis is dynamically regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Abnormal differentiation of osteoclast and insufficient osteoblast production can cause bone diseases such as osteoporosis. As one of the highly conserved catabolic pathways in eukaryotic cells, autophagy plays an important role in maintaining cell homeostasis, stress injury repair, proliferation and differentiation. Numerous studies have found that autophagy activity is essential for the survival, differentiation and function of bone cells, and that regulation of autophagy can affect the metabolism of osteoblasts and osteoclasts, thus affecting bone homeostasis. Therefore, using autophagy as a theme, this review outlines the basic process of autophagy, the relationship between autophagy and osteoblasts and osteoclasts, and summarizes the latest research progress of common autophagic signaling pathways in osteoblasts and osteoclasts. The regulatory effects of protein molecules and natural compounds on the autophagy pathway of osteoblasts and osteoclasts discovered in current research are summarized and discussed. This will help to further clarify the mechanism of osteoporosis, understand the relationship between autophagy and osteoporosis, and propose new therapeutic strategies and new ideas for anti-osteoporosis.Keywords: osteoporosis, osteoblast, osteoclast, autophagy signaling pathway, natural compounds

Xiangjin Gao,1,2,&ast; Xiuqi Zhang,1,&ast; Le Kuai,3,&ast; Qing Yang,4 Huan Li,4 Rui Zhang,1 Bin Li,1 Ruiping Wang1,2 1Clinical Research Center, Shanghai Skin Diseases Hospital, Medical School of Tongji University, Shanghai, People’s Republic of China; 2School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Obstetrics and Gynecology Department, Songjiang Maternal and Child Health-Care Hospital, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruiping Wang, Clinical Research Center, Shanghai Skin Diseases Hospital, Medical School of Tongji University, 1278 Baode Road, Jing’an District, Shanghai, 200443, People’s Republic of China, Tel +86-189 1879 1651, Fax +86-21-3680 3000, Email w19830901@126.comObjective: This study was based on a gestational diabetes mellitus (GDM) cohort in Shanghai to examine the association between physical exercise and plasma glucose control among GDM women with and determine what the effects of pre-pregnancy body mass index (BMI).Methods: In this study, GDM was diagnosed if the plasma glucose values at any of the following time points reached the diagnostic threshold: fasting blood glucose (5.1 mmol/L), 1-hour blood glucose (10.0 mmol/L), and 2-hour blood glucose (8.5 mmol/L) by 75 g oral glucose tolerance test (OGTT). Information on GDM women was extracted from the hospital’s health records and prenatal examination forms and was obtained through face-to-face interviews after delivery. A restricted cubic spline curve with four knots was used to flexibly model the relationship between the duration of moderate-intensity physical exercise and the percentage of abnormal plasma glucose among GDM patients with different BMI values. In this study, a P-value less than 0.05 (two-tailed) was considered as statistical significance.Results: Among 1139 GDM women with GDM, the median percentage of abnormal plasma glucose (PG) was 40.0% (interquartile range (IQR): 20.0– 66.7%), and the difference between overweight-obese group and underweight-normal group was statistically significant (50.0% vs 40.0%, P < 0.001). In this study, engaging in more physical exercise during pregnancy contributed to a higher prevalence of satisfactory glycemic control, and women with BMI < 25 kg/m2 should engage in no less than 90 minutes of moderate-intensity physical activity per day to achieve satisfactory glycemic control (prevalence of abnormal PG < 35%). However, over 120 minutes of daily moderate-intensity physical activity is required for GDM women with a BMI ≥ 25 kg/m2 to achieve satisfactory glycemic control.Conclusion: Overweight or obese women with GDM have a higher risk of poor glycemic control and require a longer duration of physical exercise to achieve the same level of blood glucose control.Keywords: gestational diabetes mellitus, plasma glucose control, physical exercise, overweight and obesity

Yifan Sun,1 Zixuan Huang,2 Xuezheng Gao,1 Limin Chen,3 Jun Wang,1,3 Zhenhe Zhou,1,3 Hongliang Zhou4 1Department of Psychiatry, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi City, 214151, People’s Republic of China; 2Department of Music and Wellbeing, School of Music, University of Leeds, Leeds City, UK; 3Department of Psychiatry, The Affiliated Mental Health Center of Jiangnan University, Wuxi City, 214151, People’s Republic of China; 4Department of Psychology, The Affiliated Hospital of Jiangnan University, Wuxi City, 214151, People’s Republic of ChinaCorrespondence: Jun Wang, Department of Clinical Psychology, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi City, 214151, People’s Republic of China, Tel +86 13358119628, Fax +86 51083219366, Email woodfish2@126.com; Zhenhe Zhou, Department of Psychiatry, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi City, 214151, People’s Republic of China, Tel +86 13358118986, Fax +86 51083219366, Email zhouzh@njmu.edu.cnPurpose: Anhedonia, a core symptom of major depressive disorder (MDD), is explored in this study, focusing on the neural underpinnings through the examination of two event-related potential (ERP) components: feedback-related negativity (FRN) and stimulus-preceding negativity (SPN).Patients and Methods: This cross-sectional study was conducted in China from March 2022 to March 2023. It involved 35 MDD patients and 31 healthy controls (HC) participating in a modified 2-door task with simultaneous EEG recordings. Depression severity and anhedonia were assessed using the Hamilton Depression Scale (HAMD) and the Temporal Experience of Pleasure Scale (TEPS-CV), respectively. FRN and SPN metrics, along with correlations with each other and clinical assessments, were examined.Results: In comparison to the HC group, the MDD group exhibited significantly lower scores in TEPS-CV (t = 2.854, p = 0.006) and its subscales (t = − 3.596, p = 0.001 and t = 2.434, p = 0.018, respectively), along with consistently reduced amplitudes of FRN (F 1.64= 4.726, p = 0.033) and SPN (F 1.64= 4.195, p = 0.045) across all conditions. Limited correlations were observed between ERP metrics and clinical indicators, except for positive correlations between FRN amplitudes (loss minus win) and HAMD scores (r = 0.392, p = 0.020), and SPN amplitudes after losing (SPN-L) and TEPS-CV consumption subscale scores (r = 0.357, p = 0.035). Notably, while the HC group displayed no significant FRN-SPN correlations, the MDD group exhibited positive FRN-SPN correlations under distinct conditions (r = 0.376, p = 0.026 and r = 0.355, p = 0.037, respectively).Conclusion: Our data reveal subjective and objective anhedonia in both consumption and anticipation, suggesting a shared impairment in reward feedback processing and anticipatory neural mechanisms in individuals with MDD. These findings deepen our understanding of anhedonia’s neural foundations and may guide targeted interventions for this core symptom.Keywords: major depressive disorder, anhedonia, event-related potential, reward processing, feedback-related negativity, stimulus-preceding negativity

Yuxiang Xu, Xiaonan Gao, Yunfang Zhu, Qi Zhang, Hongxin Qie, Haopeng Zhao, Jinglin Gao, Mingxia Wang Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of ChinaCorrespondence: Mingxia Wang, Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, People’s Republic of China, Tel +86-311-66696233, Email mxia_wang@163.comPurpose: To develop an UPLC-MS/MS method for the quantitative analysis of pentoxifylline in beagle dog plasma and apply it to a pharmacokinetic study of food effect.Methods: Sample separation was achieved using a Kinetex Phenyl-Hexyl column (50 × 2.1 mm, 1.7 μm) with a gradient elution program in 5.5 min after a simple protein precipitation with methanol. Using the mobile phase that made up by 0.2% formic acid and 5mM ammonium formate water (A) and methanol (B). Quantitation was carried out using the positive ionization mode with multiple reaction monitoring (MRM). A randomized, single-dose, two-period crossover study was conducted in six fasted or fed beagles that received 400 mg pentoxifylline sustained-release tablets (Brand name: Shuanling™, CSPC Pharmaceutical Group). WinNonlin® software was used to calculate pharmacokinetic parameters.Results: The linear calibration range was 2– 1000 ng/mL (r2> 0.99). Both intra- and inter-batch precision were less than 6.27%, and the accuracy ranged from 88.65% to 97.18%. Pentoxifylline was readily absorbed in fasted and fed dogs administered a dose of 400 mg (tmax:1.54h vs 1.83h). Compared to the fasted group, the AUC0→t and Cmax in the fed group increased by 1.71-fold and 1.30-fold, respectively. In the fasted group, the AUC0→t and Cmax values were 4684.08 h•ng/mL and 2402.33 ng/mL, respectively. In the fed group, these values were 8027.75 h•ng/mL and 3119.67 ng/mL. The difference in AUC0-t between the fed and fasted group was statistically significant.Conclusion: The novel optimized UPLC-MS/MS assay is an effective tool for the determination of pentoxifylline and has been successfully applied in pharmacokinetic studies of pentoxifylline in beagle dogs. The administration of pentoxifylline sustained-release tablets with food significantly increased the area under the time curve, and it is recommended that they should be administered during or shortly after feeding.Keywords: pentoxifylline, sustained-release tablets, food effect, UPLC-MS/MS, pharmacokinetics

Zhou Zhu,1,2,&ast; Na Zhou,1,&ast; Shuangni Yu,3 Xin Gao,4 Xin Cheng,5 Yingyi Wang,1 Chunmei Bai1 1Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 3The Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 4The Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 5The Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingyi Wang, Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China, Email wangyingyi@pumch.cnBackground: Co-occurrence of breast cancer and non-Hodgkin’s lymphoma is a rare condition with diagnostic and therapeutic challenges. The coexistence of follicular lymphoma (FL) and triple-negative breast cancer (TNBC) has not been described previously.Case Presentation: A 46-year-old woman, already suffering a history of untreated, advanced-stage, high tumor burden FL, was admitted for a rapidly progressing right breast mass. Ultrasonography showed an 8.3 × 3.6 × 4.1 cm fungating mass in the right breast with enlarged lymph nodes (LNs) in bilateral axillae. PET-CT demonstrated increased 18F- FDG activity in right breast mass, LNs on both sides of the diaphragm, enlarged spleen, and bone marrow. Biopsy of the right breast mass revealed TNBC. The patient underwent neoadjuvant therapy with R-CHOP and achieved partial response of breast tumor. However, TNBC progressed after three cycles of R-CHOP. According to the next-generation sequencing (NGS) assay on breast mass showing a homologous recombination repair (HRR) deficiency (HRD) score of 72, the neoadjuvant regimen was changed to rituximab plus nab-paclitaxel and cisplatin (R-TP) and resulted in significant tumor regression. The patient then underwent right mastectomy with an axillary LN dissection. After the surgery, she was regularly monitored and given adjuvant therapy with R-TP and radiotherapy.Conclusion: The coexistence of FL and HRD-positive TNBC poses diagnostic and treatment challenges. Well-founded neoadjuvant strategy based on multidisciplinary team (MDT) discussion and NGS warranted a good outcome in this case.Keywords: multiple primary malignancies, follicular lymphoma, triple-negative breast cancer, HRD, neoadjuvant therapy, MDT, case report

Zaiwen Fan,1 Xiaonan Gao,2 Mingxia Wang,2 Ziqiang Tian1 1Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Ziqiang Tian, Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, People’s Republic of China, Email dr_tianzq@126.com Mingxia Wang, Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, People’s Republic of China, Email mxia_wang@163.comAim: The goal of our study was to investigate the effects of single-dose simvastatin and itraconazole application on the pharmacokinetics of erlotinib in rats.Methods: Twenty-one male Sprague-Dawley rats were randomly divided into 3 groups, including erlotinib combined with simvastatin, erlotinib combined with itraconazole and erlotinib alone groups. The rats were given a single dose of 2 mg/kg simvastatin, 15 mg/kg itraconazole or 0.5% sodium carboxymethyl cellulose followed by 12 mg/kg erlotinib. The concentration of erlotinib in rat plasma was determined by UPLC-MS/MS. As internal standard, tinidazole was used for chromatographic analysis on the Kinetex C18 column (100× 2.1 mm, 2.6 μm).Results: Erlotinib was validated in the calibration range of 5– 1000 ng/mL. The lower limit of quantification (LLOQ) was 5 ng/mL. The inter- and intra-day precisions for erlotinib were less than 10.56%, and the accuracies were in the range of 98.61– 104.99%. The validated UPLC-MS/MS method was successfully applied to this study. Compared with the erlotinib alone group, the values of AUC0-t, AUC0-∞, Cmax, Vz/F and t1/2 in the simvastatin group showed no statistical differences among pharmacokinetic parameters (P> 0.05). However, the values of AUC0-t, AUC0-∞ and Cmax, in the itraconazole group were approximately 1.32-fold, 1.32-fold and 1.34-fold higher, and the CL/F was lower than those in the erlotinib alone group; the difference was statistically significant (P< 0.05).Conclusion: Simvastatin had no significant effect on the pharmacokinetics of erlotinib, whereas co-administration of itraconazole considerably increased the exposure of erlotinib. Therefore, we should pay more attention to the potential drug-drug interaction to ensure safety in cancer patient treatment.Keywords: erlotinib, simvastatin, itraconazole, drug–drug interaction, UPLC-MS/MS, pharmacokinetic

Jiawei Qian,1,2 Xiulan Shen,3 Xin Gao,3 Qiuhua Sun2 1Department of Nursing, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2School of Nursing, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Emergency and Trauma Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Qiuhua Sun, Email sqh807@163.comBackground: Delirium is common in older patients during the postoperative period, increasing the number of adverse events, and grip strength is associated with delirium. Subsyndromal delirium (SSD) is a prostate of clinical delirium; nevertheless, the relationship between grip strength and SSD has not been elucidated. This study aimed to examine the association between grip strength and SSD in the elderly after arthroplasty.Methods: A total of 181 patients were recruited from two Chinese hospitals. SSD and delirium were evaluated before the surgery and the first week after surgery using the confusion assessment method. The Mini-mental State Examination was used to assess patients’ cognitive function, and their grip strength was evaluated with an electronic hand dynamometer before surgery. Logistic regression and ROC curve analysis were conducted to determine the odds ratio and predictive value of grip strength for SSD.Results: The incidence of SSD and postoperative delirium (POD) was 41.44% and 14.36% for the elderly following arthroplasty respectively, and approximately 1/3 of SSD progressed into POD. Older age, declined cognitive function, fall history, and lower grip strength were risk factors for SSD (P< 0.05). The area under the ROC curve of grip strength was 0.863 and 0.900 for males and females respectively, and the cut-off point of it was determined to be 22.050 kg for men and 18.050 kg for women.Conclusion: SSD and POD are common among older people. Decreased grip strength, advanced age, lower cognitive function, and fall history were independent risk factors for SSD, and grip strength was a significant predictor for SSD in aged patients after the arthroplasty.Keywords: subsyndromal delirium, delirium, grip strength, risk factor, joint replacement

Xiang Cui,1 Ziyi Zhang,1,2 Hanqing Xi,1 Kun Liu,1 Bing Zhu,1 Xinyan Gao1 1Department of Physiology, Institute of Acupuncture and Moxibustion, Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China; 2College of Acupuncture and Tuina, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi Province, 712046, People’s Republic of ChinaCorrespondence: Xiang Cui; Xinyan Gao, Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China, Tel +86-10-64089422 ; +86-10-64089420, Email drcuixiang@163.com; xinyangao2001@msn.comAbstract: A series of studies have demonstrated acupoint sensitization, in which acupoints can be activated in combination with sensory hypersensitivity and functional plasticity during visceral disorders. However, the mechanisms of acupoint sensitization remain unclear. Neuroanatomy evidence showed nociceptors innervated in acupoints contribute to the mechanism of acupoint sensitization. Increasing studies suggested sympathetic nerve plays a key role in modulating sensory transmission by sprouting or coupling with sensory neuron/nociceptor in the peripheral, forming the functional structure of the sympathetic-sensory coupling. Notably, the sensory inputs of the disease-induced sensitized acupoint contribute to the homeostatic regulation and also involve in delivering therapeutic information under acupuncture, hence, the role of sprouted sympathetic in acupoint function should be given attention. We herein reviewed the current knowledge of sympathetic and its sprouting in pain modulation, then discussed and highlighted the potential value of sympathetic-sensory coupling in acupoint functional plasticity.Keywords: referred pain, hyperalgesia, acupuncture, nociceptor, Somato-sympathetic-viscera reflex

Xuezheng Gao,1 Zixuan Huang,2 Jiangjuan Li,3 Zhenhe Zhou,1,3 Hongliang Zhou4 1Department of Psychiatry, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi City, 214151, People’s Republic of China; 2Department of Music and Wellbeing, School of Music, University of Leeds, Leeds City, UK; 3Department of Psychiatry, The Affiliated Mental Health Center of Jiangnan University, Wuxi City, 214151, People’s Republic of China; 4Department of Psychology, The Affiliated Hospital of Jiangnan University, Wuxi City, 214151, People’s Republic of ChinaCorrespondence: Zhenhe Zhou, Department of Psychiatry, The Affiliated Wuxi Mental Health Center of Nanjing Medical University, Wuxi City, 214151, People’s Republic of China, Tel +86-13358118986, Fax +86-510-83219366, Email zhouzh@njmu.edu.cn Hongliang Zhou, Department of Psychology, The Affiliated Hospital of Jiangnan University, Wuxi City, 214151, People’s Republic of China, Tel +86-18341654302, Fax +86-510-85808820, Email Hongliangzh2022@hotmail.comPurpose: Patients with schizophrenia show deficits in facial emotion recognition and emotional intensity assessment, and also exhibit structural and functional irregularities in specific brain regions. In this study, we aimed to examine differences in active brain regions involved in processing the Emotion Intensity Recognition Task (EIRT), which can serve as an indicator of emotion recognition and ability to perceive intensity, between patients with schizophrenia and healthy controls (HCs). The purpose of this study was to investigate dysfunctional brain regions and investigate the role of the amygdala in social cognition deficits in patients with schizophrenia by focusing on alterations in amygdala activity linked to facial emotion recognition.Participants and Methods: Twenty-two patients who met a diagnostic criteria for schizophrenia according to DSM-IV and 27 HCs participated in an MRI scan while completing the EIRT. Behavioral and MRI data were collected and analyzed.Results: Behavioral results showed that patients with schizophrenia made significantly more errors in recognizing surprise, happiness, sadness, fear, and neutral expressions, and patients with schizophrenia exhibited significantly slower response times in recognizing happy facial expressions. Imaging results showed that schizophrenia patients found hypoactivation in several inferior parietal and temporal regions, in the cerebrum and anterior cingulate; and decreased amygdala activation in individuals with schizophrenia was associated with impaired recognition of fear in facial expressions.Conclusion: Facial emotion processing deficits are emotion-specific (surprise, happiness, sadness, fear, and neutral expressions) in schizophrenia. Hypoactivation in several inferior parietal and temporal regions, in the cerebrum and anterior cingulate, was thought to contribute to symptom formation in schizophrenia. Reduction in amygdala activation in schizophrenia patients was associated with impairment of the fear-emotional process.Keywords: schizophrenia, social cognition, functional magnetic resonance imaging, emotion, facial affect recognition, amygdala

Xin Xiong,1,2,&ast; Xinlin Gao,1,&ast; Jiawei Zhong,1 Shoushan Hu,1 Yijun Li,1 Yunhao Zheng,1 Yang Liu2 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China; 2State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Temporomandibular Joint, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Liu, State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Temporomandibular Joint, West China Hospital of Stomatology, Sichuan University, No. 14, 3rd Section, Renmin South Road, Chengdu, 610041, People’s Republic of China, Tel +86 028-85503898, Fax +86 018-85503898, Email liu@scu.edu.cnPurpose: This study conducted a bibliometric analysis that comprehensively described publications on temporomandibular joint and occlusion from 1 January 2000 to 31 October 2022, aiming to reveal hotspots and predict future research trends.Methods: A total of 2985 articles and reviews were retrieved from Web of Science Core Collection (WoSCC). Excel 2019, VOSviewer and CiteSpace software were used for visualizing analysis of research trends, authors, journals, institutions, countries, keywords and cited references.Results: Both the annual publication counts and citation times increased significantly. Wang MQ was the most active author. Moreover, Manfredini D and Okeson JP were the most influential two. Journal of Oral Rehabilitation was the core journal. University of Sao Paulo was the most productive institutions. “Temporomandibular disorders” (TMDs), “temporomandibular joint” and “occlusion” were the top 3 keywords with the most frequencies. Keywords and references with burst showed that the causes of TMDs, diagnosis and treatments for TMDs as well as bruxism may be hotspots currently and in the future.Conclusion: In this study, the research trends, the most productive and influential authors, journals, institutions, countries, in addition to keywords and cited references with burst in the field of temporomandibular joint and occlusion were revealed by a bibliometric analysis, which could help scholars to understand recent hotspots and future trends.Keywords: bibliometric analysis, temporomandibular joint, occlusion, keywords analysis

Xinjing Gao,1– 4 Wenjiao Wang1– 4 1Department of Critical Care Medicine, The Third Central Hospital of Tianjin, Tianjin, People’s Republic of China; 2Nankai University Affiliated Third Central Hospital, Nankai University, Tianjin, People’s Republic of China; 3Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, The Third Central Hospital of Tianjin, Tianjin, People’s Republic of China; 4Artificial Cell Engineering Technology Research Center, The Third Central Hospital of Tianjin, Tianjin, People’s Republic of ChinaCorrespondence: Wenjiao Wang, Tel +86-22-84112109, Fax +86-22-84112095, Email wangwenjiao_tj3zx@163.comPurpose: Infections induced by multidrug-resistant (MDR) pathogens are one of the most common and serious complications in extracorporeal membrane oxygenation (ECMO) patients. However, there is currently little research about “ECMO and MDR bacteria”. The purpose of our study was to clarify the epidemiological characteristics of MDR bacteria and provide references for empiric antibiotic treatments according to the drug susceptibility tests for ECMO patients.Patients and Methods: There were 104 patients admitted to our department and receiving ECMO treatments between January 2014 and December 2022. Altogether, 61 veno-arterial ECMO (VA-ECMO) and 29 veno-venous ECMO (VV-ECMO) patients enrolled. The data on other intensive care unit (ICU) patients in our department in the same period are summarized.Results: A total of 82 MDR bacteria were detected from ECMO patients, and most of these were MDR Gram-negative bacteria (MDR-GNB). There were also 5559 MDR-GNB collected from other patients in our department in the same period. We found that the distribution of MDR-GNB in ECMO patients was different from other critical patients. The proportion of Klebsiella pneumoniae (MDR-KP) in VV-ECMO patients was higher than other critical patients (35.1% and 21.3%, respectively). Moreover, the proportions of MDR Acinetobacter baumannii (MDR-AB) of VA-ECMO and VV-ECMO were higher than other critical patients (54.6%, 43.2% and 30.5%, respectively). In addition, MDR-AB and MDR-KP in ECMO patients exhibited higher percentages of drug resistance to possibly appropriate antibiotics for other critical patients, but showed better sensitivity to colistin.Conclusion: Infections induced by MDR-GNB in ECMO patients were serious and exhibited higher degrees of drug resistance compared with other ICU patients. Colistin might be an option to consider if there is no medical contraindication. However, widespread use of broad spectrum antibiotics is something that should be discouraged, and alternative options are being explored.Keywords: multidrug-resistant Gram-negative bacteria, MDR-GNB, multidrug-resistant Klebsiella pneumoniae, MDR-KP, multidrug-resistant Acinetobacter baumannii, MDR-AB, colistin

Xiaoyun Gao,&ast; Moxi Chen,&ast; Penghao Liu, Shenyuan Zhou, Sai Kong, Junfeng Zhang, Jun Cao Department of Anesthesiology, Shanghai Sixth People’s Hospital, Shanghai, 200233, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Cao, Department of Anesthesiology, Shanghai Sixth People’s Hospital, No. 600, Yishan Road, Shanghai, 200233, People’s Republic of China, Tel +86 18930173661, Email dr_caojun@sina.comBackground: A novel ultrasound-guided paravertebral block, the edge laminar block (ELB) was reported recently. However, it was unclear how effective ELB was in comparison with traditional blocking methods. We conducted a trial to compare the analgesic efficacy of ELB with the thoracic paravertebral block (TPVB) and the retrolaminar block (RLB) in patients undergoing video-assisted thoracic surgery (VATS).Methods: We identified 90 patients who were scheduled for VATS and randomly assigned them to three groups: ELB group (Group E), TPVB group (Group T), and RLB group (Group R). Each group underwent ELB, TPVB, and RLB, respectively, under ultrasound guidance before general anesthesia induction. All patients received post-operative routine analgesia protocol. Our primary outcome was the extent of dermatomal sensory loss on the midclavicular, midaxillary, and scapular lines, measured using a pinprick 15 minutes after the nerve block. Secondary outcomes included the intraoperative dose of sufentanil, the numerical rating scale (NRS) scores assessed in the post-anesthesia care unit (PACU) and at 6, 12, and 24 hours post-operatively, and pethidine administrated as analgesic rescue dose.Results: The percentages of nerve block range reaching the midclavicular line, midaxillary line, and scapular line in Group E were 96.7%, 93.3%, 93.3%, and 60% in Group T and 30%, 56.7%, and 96.7% in Group R, respectively. Group E had wider dermatomal sensory loss on the midclavicular line and midaxillary line compared to Group R (P

Shirong Li,1,&ast; Wene Wei,1,&ast; Zhaorong Feng,1,&ast; Yingzhen Bian,1 Jinmiao Pan,1 Jinling Mai,1 Shufang Ning,1,2 Jinglei Huang,1 Xiangyang Gao,3,&ast; Litu Zhang1,2,&ast; 1Department of Research, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China; 2Department of Research, Guangxi Cancer Molecular Medicine Engineering Research Center, Nanning, People’s Republic of China; 3Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangyang Gao; Litu Zhang, Email 13811130808@126.com; zhanglitu@gmail.comPurpose: In current studies, the role of serum Cytokeratin-19 fragments (CYFRA 21-1) in colorectal cancer (CRC) remains unclear. This study aimed to clarify the diagnostic and prognostic value of CYFRA 21-1 in CRC.Patients and Methods: Data were collected for 196 stage I–III CRC patients and 50 colorectal liver metastases (CRLM) patients between January 2018 and December 2019. The serum CYFRA 21-1 levels were measured using the chemiluminescent particle immunoassay (CMIA) kit in all objects and common biomarkers such as CA19-9, CEA, HSP90α, and AFP were measured in all colorectal cancer patients. We investigated the association between CYFRA 21-1 level and clinicopathological features. In addition, we evaluated the ability of serum CRFRA21-1 to differentiate CRLM from CRC. To assess the potential prognostic value, we used Cox proportional hazard model for univariate or multivariate analyses.Results: Serum CYFRA 21-1 was significantly elevated in CRLM patients compared to stage I–III CRC patients (5.85 ng/mL vs 2.29 ng/mL, p < 0.001). For all CRC patients cohort, stage I–III CRC patients cohort and CRLM patients cohort, the optimal cutoff levels of CYFRA 21-1 for overall survival (OS) were 3.47 ng/mL, 2.14 ng/mL and 7.63 ng/mL, respectively, and the optimal cutoff levels for progression-free survival (PFS) were 3.47 ng/mL, 2.56 ng/mL and 7.63 ng/mL, respectively. For CRLM patients, Kaplan–Meier analysis showed that patients with high CYFRA 21-1 level had poor OS. Multivariate analysis indicated that the CYFRA 21-1 level was an independent prognostic factor for PFS in stage I–III patients. And CYFRA 21-1 levels and age were independent prognostic factors for OS and PFS in CRLM patients.Conclusion: CYFRA 21-1 can better differentiate CRLM patients from the whole CRC patients and has unique prognostic value for CRLM patients.Keywords: colorectal cancer, colorectal liver metastases, CRLM, prognosis, cytokeratin-19 fragments, CYFRA21-1, overall survival, progression-free survival

Xiangyu Gao,&ast; Hongmei Li,&ast; Yuan Yu, Xiaoyuan Huai, Bo Feng, Jun Song Department of Endocrinology, East Hospital, Tongji University School of Medicine, Shanghai, 200120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Song; Bo Feng, Department of Endocrinology, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, People’s Republic of China, Tel/Fax +86 021-38804518, Email songjuntj@tongji.edu.cn; fengbodfyy@tongji.edu.cnPurpose: The dusk phenomenon refers to a spontaneous and transient pre-dinner hyperglycemia that affects glucose fluctuation and glycemic control, and the increasing use of continuous glucose monitoring (CGM) has facilitated its diagnosis. We investigated the frequency of the dusk phenomenon and its relationship with the time in range (TIR) in patients with type 2 diabetes mellitus (T2DM).Patients and Methods: This study involved 102 patients with T2DM who underwent CGM for 14 days. CGM-derived metrics and clinical characteristics were evaluated. A consecutive dusk blood glucose difference (pre-dinner glucose minus 2-hour post-lunch glucose) of ≥ 0 or once-only dusk blood glucose difference of < 0 was diagnosed as the clinical dusk phenomenon (CLDP).Results: We found that the percentage of CLDP was 11.76% (10.34% in men, 13.64% in women). Compared with the non-CLDP group, the CLDP group tended to be younger and have a lower percentage of TIR (%TIR3.9-10) and higher percentage of time above range (%TAR> 10 and %TAR> 13.9) (P ≤ 0.05). Adjusted for confounding factors, the binary logistic regression analysis showed a negative association of CLDP with %TIR (odds ratio < 1, P < 0.05). We repeated the correlation analysis based on 70%TIR and found significant differences in hemoglobin A1c, fasting blood glucose, mean blood glucose, standard deviation of the sensor glucose values, glucose coefficient of variation, largest amplitude of glycemic excursions, mean amplitude of glycemic excursions, glucose management indicator, and percentage of CLDP between the two subgroups of TIR ≤ 70% and TIR > 70% (P < 0.05). The negative association between TIR and CLDP still remained after adjustment by the binary logistic regression analysis.Conclusion: The CLDP was frequently present in patients with T2DM. The TIR was significantly correlated with the CLDP and could serve as an independent negative predictor.Keywords: time in range, dusk phenomenon, type 2 diabetes, continuous glucose monitoring

Bijun Lian,1,2,&ast; Min Qu,1,&ast; Wenhui Zhang,1,&ast; Zhenyang Dong,1 Huan Chen,1 Zepeng Jia,1 Yan Wang,1 Jing Li,3 Xu Gao1 1Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Urology, the 903rd PLA Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China; 3Centre for Translational Medicine, Naval Medical University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xu Gao, Department of Urology, Changhai Hospital, NO. 168 Changhai Road, Yangpu District, Shanghai, 200438, People’s Republic of China, Tel +86 21-31161717, Email gaoxu.changhai@foxmail.com Jing Li, Center for Translational Medicine, Navy Medical University, No. 800 Xiangyin Road, Yangpu District, Shanghai, 200438, People’s Republic of China, Tel +86 21-31161718, Email ljing@smmu.edu.cnObjective: Based on post-operative PSA at 6th week (PSA6w) after radical prostatectomy to establish an optimal model for predicting natural biochemical recurrence (BCR).Methods: A total of 742 patients with post-operative PSA6w from PC-follow database, between January 2003 and October 2022, were included. All the patients had not received any hormone therapy and radiotherapy before operation and BCR. Of these patients, 588 cases operated by one surgeon were enrolled for modelling and another 154 cases operated by other surgeons were for external validation. After screened by Cox regression, the post-operative PSA6w, pathological stage, Gleason Grade and positive surgical margins were adopted for modelling. The R software was used to plot the nomogram of the prediction model for BCR. C-index and calibration curve were calculated to evaluate the new model. Finally, integrated discrimination improvement was adopted to evaluate the prediction performances of the new nomogram model and the classical Kattan nomogram.Results: The C-index of the new model was 0.871 (95% CI: 0.830– 0.912). The calibration curve of the new model demonstrated superior consistency between the predicted and actual value. The C-index of the external validation group was 0.850 (95% CI: 0.742– 0.958), which demonstrated perfect universality. The integrated discrimination improvement showed a 12.61% improvement in prediction performance over that of the classical Kattan nomogram (P < 0.01). Based on the new nomogram, patients were divided to high and low BCR group with a 3 year BCR-free cutoff probability as 74.72%. Low-risk patients, accounting for 77.89% of the patients, have no need to follow up frequently with a false-negative rate only 5.24%, which will save medical resources to a large extent.Conclusion: Post-operative PSA6w is a sensitive risk biomarker for early natural BCR. The new nomogram model could predict BCR probability with a higher accuracy and will further simplify the clinical follow-up strategies.Keywords: prostate cancer, biochemical recurrence, post-operative PSA, prediction model, nomogram

Xiaoli Gao, Zhiqiang Liu, Zuomin Wang Department of Stomatology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of ChinaCorrespondence: Zuomin Wang; Zhiqiang Liu, Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongti South Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86 10 85231492, Email wzuomin@sina.cn; kokorora@sina.comBackground: Dental pulp stem cells (DPSCs) are considered excellent candidates for stem cell-based tissue regeneration. In this study, we aimed to evaluate the therapeutic effect of DPSCs in a mouse chronic obstructive pulmonary disease (COPD) model and to explore whether DPSCs reduce lung inflammation and oxidative stress by regulating the nuclear factor erythroid‐2 related factor‐2 (Nrf2) signaling pathway.Methods: DPSCs were isolated from dental pulp tissue by the tissue block method. Emphysema of C57BL/6 mice was induced by endotracheal administration of porcine pancreatic elastase (PPE). Then, the DPSCs were injected into the lungs through the trachea, and after 3 weeks of stem cell treatment, various efficacy tests were performed. The AniRes2005 animal lung function analytic system was used to detect lung function. Hematoxylin-eosin staining (H&E) and Victoria blue staining was used to assess emphysema severity. The animal tissues were detected by Western blot, RT‒qPCR, ELISA and oxidative stress related detection.Results: In experimental COPD models, DPSCs transplantation improved lung function, body weight, and emphysema-like changes better than bone marrow mesenchyml stem cells (BM-MSCs). Compared with the COPD group, the levels of IL-1β, TNF-α and IL-6 in lung tissue and bronchoalveolar lavage fluid (BALF) were decreased after transplantation of DPSCs. DPSCs may be associated with lower malondialdehyde (MDA) levels, and higher catalase (CAT) and glutathione (GSH) levels. Western blot results showed that the expression of Nrf2 and its downstream factors increased after transplantation of DPSCs.Conclusion: The current study showed that DPSCs had good performance in the treatment of a mouse COPD model and could be a promising option for stem cell therapy. DPSCs may play antioxidant and anti-inflammatory roles in COPD by activating the Nrf2 signaling pathway.Keywords: chronic obstructive pulmonary disease, dental pulp stem cells, Nrf2, inflammation, oxidative stress

Zhiqiang Liu,1,&ast; Xiaoli Gao,1,&ast; Lirong Liang,2 Xuan Zhou,1 Xiaozhe Han,3 Ting Yang,4– 7 Kewu Huang,8 Yingxiang Lin,8 Shu Deng,9 Zuomin Wang,1 Chen Wang4– 7,10 1Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Clinical Epidemiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Oral Science and Translational Research, Nova Southeastern University College of Dental Medicine, Fort Lauderdale, FL, USA; 4Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 5National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 6Institute of Respiratory Medicine, Peking Union Medical College, Beijing, People’s Republic of China; 7Department of Respiratory Medicine, Capital Medical University, Beijing, People’s Republic of China; 8Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Beijing, People’s Republic of China; 9Department of Immunology and Infectious Diseases, The Forsyth Institute, Harvard School of Dental Medicine Affiliate, Cambridge, MA, USA; 10WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zuomin Wang, Department of Stomatology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongti South Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86 10 85231492, Email wzuomin@sina.cn Chen Wang, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, 2 Yinghuayuan Dongjie, Chaoyang District, Beijing, 100029, People’s Republic of China, Tel +86 10 65105565, Email wangchen@pumc.edu.cnPurpose: There is insufficient information about the prevalence and risk factors of gastroesophageal reflux disease (GERD) in the Chinese adult population. We aimed to assess the prevalence and identify the risk factors of GERD in China.Methods: We collected data from a nationally representative sample (50,991 subjects) of Chinese adults from a large nation-wide cross-sectional survey. GERD was diagnosed by a standardized Chinese-language GERD questionnaire with a score of ≥ 8. The demographic characteristics, comorbidities and periodontal factors of all participants were collected.Results: Fifty-thousands-one-hundred-eighty-three participants were finally included in this study. The overall prevalence of GERD was 5.6% (95% CI, 5.4– 5.8%) among the general Chinese population aged 20 years or older. Women, smokers, and people with older age, BMI ≥ 25.0 kg/m2, urban residence, lower education level or comorbidities were more prevalent with GERD (p < 0.001). Symptoms of severe periodontitis (OR = 1.40, 95% CI 1.28– 1.52, p < 0.001) and lower frequency of tooth brushing (OR = 2.01, 95% CI 1.76– 2.29, p < 0.001) were significantly associated with risk of GERD.Conclusion: Symptom-based GERD is highly prevalent in the Chinese population. Overweight and smoking are major preventable risk factors for GERD. Periodontal factors are novel potential risk factors for GERD and should be given more attention in GERD prevention.Keywords: gastroesophageal reflux disease, prevalence, risk factor, periodontitis, epidemiology

Poyu Chen1– 3&ast;, Chuangwei Zhang1– 3&ast;, Ping He,4 Shengyuan Pan,1– 3 Wenjie Zhong,1– 3 Yue Wang,1– 3 Qingyue Xiao,1– 3 Xinyan Wang,1– 3 Wenliang Yu,1– 3 Zhangmin He,1– 3 Xiang Gao,1– 3 Jinlin Song1– 3 1College of Stomatology, Chongqing Medical University, Chongqing, 401147, People’s Republic of China; 2Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, People’s Republic of China; 3Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, People’s Republic of China; 4Department of Stomatology, Dazhou Central Hospital, Dazhou, SiChuan, 635000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiang Gao; Jinlin Song, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, 401147, People’s Republic of China, Tel/Fax +86 23 88860105 ; Tel/Fax +86 23 88860026, Email xiangg@hospital.cqmu.edu.cn; songjinlin@hospital.cqmu.edu.cnIntroduction: The functional reconstruction of periodontal tissue defects remains a clinical challenge due to excessive and prolonged host response to various endogenous and exogenous pro-inflammatory stimuli. Thus, a biomimetic nanoplatform with the capability of modulating inflammatory response in a microenvironment-responsive manner is attractive for regenerative therapy of periodontal tissue.Methods: Herein, a facile and green design of engineered bone graft materials was developed by integrating a biomimetic apatite nanocomposite with a smart-release coating, which could realize inflammatory modulation by “on-demand” delivery of the anti-inflammatory agent through a pH-sensing mechanism.Results: In vitro and in vivo experiments demonstrated that this biocompatible nanoplatform could facilitate the clearance of reactive oxygen species in human periodontal ligament stem cells under inflammatory conditions via inhibiting the production of endogenous proinflammatory mediators, in turn contributing to the enhanced healing efficacy of periodontal tissue. Moreover, this system exhibited effective antimicrobial activity against common pathogenic bacteria in the oral cavity, which is beneficial for the elimination of exogenous pro-inflammatory factors from bacterial infection during healing of periodontal tissue.Conclusion: The proposed strategy provides a versatile apatite nanocomposite as a promising “inflammation scavenger” and propels the development of intelligent bone graft materials for periodontal and orthopedic applications.Graphical Abstract: Keywords: periodontal bone regeneration, pH-responsive, inflammatory modulation, antibacterial activity, biomimetic nanoplatform

Binyan Liu,1 Xun Xin,2 Xueyuan Gao,3 Lili Gao2 1School of Psychological and Cognitive Sciences, Peking University, Beijing, People’s Republic of China; 2Business School, Southwest University of Political Science and Law, Chongqing, People’s Republic of China; 3Department of Economics and Management, China University of Labor Relations, Beijing, People’s Republic of ChinaCorrespondence: Xun Xin, Business School, Southwest University of Political Science and Law, No. 301 Baosheng Road, Yubei Distrct, Chongqing, 401120, People’s Republic of China, Tel + 86− 18911302529, Email xinxun0629@163.comPurpose: This study investigates how challenge–hindrance stressors influence employability through the energy–motivation mechanism and explores the moderating role of pay satisfaction and perceived career opportunity based on the JD-R model.Methods: Three-wave time-lagged longitudinal data of 206 employees are analyzed using latent structural equation modelling.Results: First, challenge stressors have an indirect positive effect on employability, mainly through intrinsic motivation, while hindrance stressors have an indirect negative effect on employability, mainly through emotional exhaustion. Second, perceived career opportunity strengthens the positive effect of challenge stressors on intrinsic motivation, which further promotes employability. Third, pay satisfaction alleviates the negative effect of hindrance stressors on emotional exhaustion, which, in turn, inhibits the decline in employability.Conclusion: The paper clarifies the specific mediating effects of the energy and motivation mechanisms in the association between challenge–hindrance stressors and employability and the moderating effects of pay satisfaction and perceived career opportunity, thus extending studies on the challenge–hindrance stressors to career field and filling the gap in the knowledge of the boundary conditions of the energy–motivation mechanism.Keywords: challenge–hindrance stressors, employability, dual mechanism of energy and motivation, pay satisfaction, perceived career opportunity

Qingqing Li,1,&ast; Tong Su,2,&ast; Xu Zhang,3,&ast; Yanfeng Pan,1,&ast; Shengli Ma,4 Lu Zhang,4 Xianqiang Zhang,1 Xiaojuan Gao1 1Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China; 2Department of Medical, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou city, People’s Republic of China; 4Department of Infectious Diseases, The People’s Hospital of Yongcheng, Yongcheng city, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanfeng Pan, Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Jinshui District, Zhengzhou city, 450000, People’s Republic of China, Tel +8613938448759, Email panfirstfeng@163.comPurpose: To observe the efficacy and safety of anlotinib as a first-line treatment for patients with advanced hepatocellular carcinoma (aHCC) in a real-word environment, explore the optimal treatment regimen for patients with aHCC using anlotinib as a first-line treatment.Patients and Methods: Data from 62 patients with aHCC who received anlotinib single-drug first-line therapy between February 2019 and November 2021. Patients received anlotinib monotherapy, which may be interrupted or discontinued or changed in the event of unacceptable or severe adverse events (AEs) or failure to inhibit tumor progression. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate(ORR), disease control rate (DCR), overall survival (OS), and safety.Results: Among the 62 patients, in the best overall response assessment, there were 12 with complete response (CR; 19.4%), 17 with partial response (PR; 27.4%), 25 with stable disease (SD; 40.3%), and 8 with progressive disease (PD; 14.5%). The ORR and DCR were 46.8% and 87.1%, respectively. Among the 11 patients who received tyrosine kinase inhibitors (TKIs) combined with programmed death 1 (PD-1) inhibitors after disease progression, three (27.3%) had CR, one (9.1%) had PR, three (27.3%) had SD, and four (36.4%) had PD. Therefore, the ORR and DCR were 36.4% and 63.6%, respectively. The median PFS for anlotinib monotherapy was 7.37 months (95% confidence interval [CI]: 5.88– 8.86) and the median OS did not reach. AEs occurred in 95.2% of patients during anlotinib monotherapy, with the most common being thrombocytopenia (51.6%). The incidence of grade ≥ 3 AEs was 38.7%.Conclusion: Anlotinib is effective and well-tolerated as a first-line treatment for patients with aHCC. Treatment with TKIs and PD-1 inhibitors after disease progression has also shown preliminary efficacy and safety; therefore, sequential therapy with anlotinib-TKIs and PD-1 inhibitors may be an effective treatment for patients with aHCC.Keywords: hepatocellular carcinoma, anlotinib, sequential therapy, real world

Guiping Li,1 Kamran Ali,2 Xiujun Gao,1 Sha Lu,1 Weiqin xu,1 Xiaoying Zhu1 1Mental Health Center Affiliated Hangzhou Seventh People’s Hospital Zhejiang University School of Medicine, Hangzhou, 310013, People’s Republic of China; 2Department of Dermatology, International Education College of Zhejiang Chinese Medical University, Hangzhou, 310006, People’s Republic of ChinaCorrespondence: Xiaoying Zhu, Mental Health Center Affiliated Hangzhou Seventh People’s Hospital Zhejiang University School of Medicine, Hangzhou, 310013, People’s Republic of China, Email m18957118053_2@163.comBackground/Objectives: Neurosyphilis is a disease caused by Treponema pallidum when it invades the central nervous system. Asymptomatic neurosyphilis (ANS) is one of the most common types of neurosyphilis, however it is often misdiagnosed. This study aimed to explore the impact of ANS on patient’s quality of life and social stigma.Methods: A total of 159 ANS patients were diagnosed by their serology and cerebrospinal fluid. These patients’ stigma and quality of life were assessed separately through the Social Impact Scale (SIS) and the Easy Response Questionnaire.Results: The average age was 36.25± 8.36 years old, and 114 patients were males (71.69%). The serum syphilis test of 159 selected patients was positive, and the indicators of nucleus cells, protein quantification, and syphilis antibodies in the cerebrospinal fluid met the criteria for ANS. The total stigma score was (40.23 ± 10.12), with the scores of the different entries being clearly differentiated, with the highest being the 15th entry (I feel I need to keep my illness a secret), with an average score of 3.15/4.Conclusion: Patients with asymptomatic neurosyphilis may feel social stigma and are more negative when facing their disease. Health-care workers should be aware of the particular aspects of their condition and pay special attention to the need for patient privacy.Keywords: neurosyphilis, asymptomatic neurosyphilis, social stigma, quality of life, social impact scale, sexually transmitted diseases

Zhuohui Luo,1 Yongcheng Wang,2 Shuo Pang,1 Shan Gao,1 Ning Liu,1 Xiang Gao,1 Li Zhang,1,3 Xiaolong Qi,1,3 Yajun Yang,2 Lianfeng Zhang1,3 1Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100021, People’s Republic of China; 2Beijing Key Laboratory of Active Substance Discovery and Drug Ability Evaluation, Institute of Material Medical, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050, People’s Republic of China; 3Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of ChinaCorrespondence: Yajun Yang, Institute of Material Medical, Peking Union Medical College, Chinese Academy of Medical Sciences, Nanwei Road, Xicheng District, Beijing, 100050, People’s Republic of China, Email yangyajun@imm.ac.cn Lianfeng Zhang, Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Panjiayuan Nanli, Chaoyang District, Beijing, 100021, People’s Republic of China, Tel +86 10-87778442, Fax +86 10-67776394, Email zhanglf@cnilas.orgAim: Alzheimer’s disease (AD) is the most common neurodegenerative disease whose patients suffered from cognitive impairments. In our study, a novel 1,2,4-Oxadiazole derivative wyc-7-20 was synthesized, which showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, β-amyloid (Aβ) clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected. The results demonstrated wyc-7-20 was potent in AD therapy.Purpose: The pathological complexity of AD increased difficulties in medical research. To explore a new potential medical treatment for AD, a novel 1,2,4-Oxadiazole derivative (wyc-7-20) was designed, synthesized to explore the application in this study.Materials and Methods: Human neuroblastoma (SH-SY5Y) cells and human hepatocellular carcinoma (HepG2) cells were used to detect median lethal dose (LD50). H2O2 and Aβ1– 42 oligomers (AβOs) were respectively, added into SH-SY5Y cells to detect anti-ROS (reactive oxygen species) and anti-AβOs effects of wyc-7-20. 3×Tg mice were administered with wyc-7-20, and then Y maze test and Morris water maze (MWM) test were applied to detect cognitive improvements. Brain tissue samples were subsequently collected and analyzed using different techniques.Results: wyc-7-20 showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, Aβ clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected.Conclusion: wyc-7-20 was potent in AD therapy.Graphical abstract: Keywords: 1,2,4-oxadiazole, Alzheimer’s disease, animal model, neuroprotective effect

Xuemei He, Xin Gao, Panpan Xie, Yuan Liu, Wenjing Bai, Yue Liu, Aixin Shi Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Aixin Shi, Clinical Trial Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 Dahua Road, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86 10 85133632, Email aixins0302@126.comBackground: Sotagliflozin (LX4211) is a dual inhibitor of sodium-glucose cotransporter (SGLT)1 and SGLT2 being investigated to improve glycemic control in adults with diabetes. This study was firstly conducted to assess the pharmacokinetic (PK), pharmacodynamic (PD) profiles, safety and tolerability in Chinese healthy subjects after administration of sotagliflozin.Methods: This was a Phase I, randomized, double-blind, placebo-controlled, ascending multiple-dose study. Healthy subjects received 200mg or 400mg of sotagliflozin or placebo once daily for 8 days, respectively. PK parameters of sotagliflozin and LX4211-GLU (main metabolite), as measured by blood samples collected pre/postdose on Day 1/predose on Day 2-Day 8/postdose on Day 8, and PD parameters of absolute urinary glucose excretion (UGE) were determined. Treatment-emergent adverse events (TEAEs) were evaluated.Results: Overall, 24 subjects were enrolled and randomized to sotagliflozin 200 mg (N = 9), sotagliflozin 400 mg (N = 9), or placebo (N = 6) group, and all subjects completed the study. Sotagliflozin was rapidly absorbed with dose-proportional systemic exposure and a moderate degree (less than 2-fold) of accumulation. Sotagliflozin plasma concentrations peaked at 1.0 h post dose. On Day 8, the estimated increases for Cmax and AUCtau were 1.89-fold and 1.70-fold. The pooled accumulation ratio of sotagliflozin was 1.57 for Cmax and 1.84 for AUCtau. LX4211-GLU had similar PK features. UGE was significantly elevated in both sotagliflozin groups relative to the placebo group. All TEAEs were mild and resolved without sequelae. There were no serious AEs or other significant TEAEs.Conclusion: Sotagliflozin was rapidly absorbed with dose-proportional systemic exposure and a moderate degree of accumulation. Both 200 mg and 400 mg sotagliflozin per day were well tolerated in Chinese healthy subjects.Keywords: diabetes mellitus, sotagliflozin/LX4211, sodium-glucose cotransporter, pharmacokinetics, pharmacodynamics, safety