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Huan Tian,1 Feng Zhao,1 Bao-Sen Yue,1 Bing-Tao Zhai2– 5 1Department of Pharmacy, Xi’an Hospital of Traditional Chinese Medicine, Xi’an, People’s Republic of China; 2College of Pharmacy, Shaanxi University of Chinese Medicine, Xi’an, People’s Republic of China; 3State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Xi’an, People’s Republic of China; 4Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Xi’an, People’s Republic of China; 5Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Xi’an, People’s Republic of ChinaCorrespondence: Bing-Tao Zhai, Email zbp@sntcm.edu.cnAbstract: A multidrug combination strategy is an important mean to improve the treatment of cancer and is the mainstream scheme of clinical cancer treatment. The active ingredients of traditional Chinese medicine, represented by toad skin and toad venom, have the advantages of high efficiency, low toxicity, wide action and multiple targets and have become ideal targets in combined treatment strategies for tumors in recent years. Toad skin and toad venom are traditional Chinese animal medicines derived from Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider that have shown excellent therapeutic effects on the treatment of various cancers and cancer pain as adjuvant antitumor drugs in clinical practice. The involved mechanisms include inducing apoptosis, arresting the cell cycle, inhibiting cell proliferation, migration and invasion, inhibiting tumor angiogenesis, reversing the multidrug resistance of tumor cells, and regulating multiple signaling pathways and targets. Moreover, a multidrug combination strategy based on a nanodelivery system can realize the precise loading of the active ingredients of toad skin or toad venom and other antitumor drugs and carry drugs to overcome physiological and pathological barriers, complete efficient enrichment in tumor tissues, and achieve targeted delivery to tumor cells and the controlled release of drugs, thus enhancing antitumor efficacy and reducing toxicity and side effects. This article reviewed the clinical efficacy and safety of the combination of toad skin and toad venom with chemotherapeutic drugs, targeted drugs, analgesics and other drugs; evaluated the effects and mechanisms of the combination of toad skin and toad venom with chemotherapy, targeted therapy, radiotherapy or hyperthermia, traditional Chinese medicine, signaling pathway inhibitors and other therapies in cell and animal models; and summarized the codelivery strategies for the active ingredients of toad skin and toad venom with chemotherapeutic drugs, small-molecule targeted drugs, monoclonal antibodies, active ingredients of traditional Chinese medicine, and photodynamic and photothermal therapeutic drugs to provide a basis for the rational drug use of toad skin and toad venom in the clinic and the development of novel drug delivery systems.Keywords: toad skin, toad venom, combinational antitumor strategies, codelivery strategies, cancer, cancer pain

Jiajin Feng,1,* Keming Chen,1,* Haifu Tian,1 Al-qaisi Mohammed Abdulkarem,1 Yunshang Tuo,1 Xuehao Wang,1 Bincheng Huang,1 Yu Gao,1 Zhiyong Lv,1 Rui He,2 Guangyong Li1 1General Hospital of Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 2Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangyong Li, Email guangyongli1979@hotmail.comObjective: To explore the effectiveness of prostate biopsy density in predicting prostate cancer under cognitive and systematic biopsy mode in multi-parametric magnetic resonance imaging (mpMRI).Methods: A retrospective analysis was conducted on clinical data of 204 patients who were suspected of having prostate cancer with prostate-specific antigen (PSA) levels less than 50 ng mL− 1 and underwent cognitive and systematic biopsy through the perineal approach in our hospital from 2022 to 2023. Univariate and multivariate logistic regression analyses were used to evaluate the odds ratios of prostate biopsy density and relevant clinical indicators. Logistic regression analysis was performed to establish a predictive model combining indicators with predictive value. The predictive value of each indicator and the new model was evaluated using receiver operating characteristic (ROC) curves and the area under the curve (AUC).Results: The detection rate of prostate cancer in the study population was 32.35%. Multivariate analysis showed that age, PSAD, PI-RADS 2.1 score, and prostate biopsy density were independent predictors of prostate cancer. The ROC curve analysis revealed an AUC of 0.707 (95% CI 0.625– 0.790) for biopsy density, with a cutoff value of approximately 0.22 needle mL− 1. The best predictive model consisted of age, PSAD, PI-RADS 2.1 score, and biopsy density, with an AUC of 0.857.Conclusion: Biopsy density is associated with the detection of prostate cancer, with a critical value of 0.22 needle mL− 1. Combining biopsy density with other clinical indicators can significantly improve the ability to predict prostate cancer and avoid unnecessary prostate biopsy cores.Keywords: prostate biopsy, multi-parametric magnetic resonance imaging, biopsy density, cognitive fusion, cancer prediction

Haoyang Tian,1,* Hui Chen,2,* Xiaochun Yin,2 Meiyi Lv,3 Lingling Wei,1 Yuna Zhang,4 Shuhan Jia,5 Jingyuan Li,1 Hui Song1 1School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, People’s Republic of China; 2Department of Endodontics, Jinan Stomatological Hospital, Jinan, People’s Republic of China; 3Department of Pediatric Dentistry, Jinan Stomatological Hospital, Jinan, People’s Republic of China; 4Department of Stomatology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 5Department of Stomatology, Yancheng NO. 1 People’s Hospital, Yancheng, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Song; Jingyuan Li, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, Jinan, Shandong, 250012, People’s Republic of China, Tel +86-531-88382912, Fax +86-531-88382923, Email songhui@sdu.edu.cn; jingyuan_31@163.comIntroduction: Diabetes has been recognized as an independent risk factor for periodontitis. Increasing evidences indicate that hyperglycemia aggravates inflammatory response of human periodontal ligament cells (hPDLCs). Carbon monoxide-releasing molecule-3 (CORM-3) is a water-soluble compound that can release carbon monoxide (CO) in a controllable manner. CORM-3 has been shown the anti-inflammatory effect in different cell lineages.Methods: We stimulated periodontal ligament cells with LPS and high glucose. The expression of inflammatory cytokine was detected by ELISA. RT-qPCR, Western blot and immunofluorescence were used to detect the expression of TLR2, TLR4, RAGE and the activation of NF-κB pathway. We performed silencing and overexpression treatment of RAGE targeting the role of RAGE. We performed the immunostaining of paraffin sections of the periodontitis model in diabetes rats.Results: The results showed that CORM-3 significantly inhibited the expression of inflammatory cytokine in hPDLCs stimulated with LPS and high glucose. CORM-3 also inhibited LPS and high glucose-induced expression of RAGE/NF-κB pathway and TLR2/TLR4/NF-κB pathway. Silence of RAGE resulted in significantly decreased expression of proteins above. Overexpression of RAGE significantly enhanced the expression of these factors. CORM-3 abrogated the effect of RAGE partially. In animal model, CORM-3 suppressed the inflammatory response of periodontal tissues in experimental periodontitis of diabetic rats.Discussion: Our research proved CORM-3 reduced the inflammatory response via RAGE/NF-κB pathway and TLR2/TLR4/NF-κB pathway in the process of high glucose exacerbated periodontitis. These findings demonstrated the role of RAGE in the process of high glucose exacerbated periodontitis and suggested that CORM3 be a potential therapeutic strategy for the treatment of diabetes patients with periodontitis. Keywords: carbon monoxide-releasing molecules, periodontitis, diabetes, receptor for advanced glycation end products, lipopolysaccharide

Qiang-qiang Fan,1 Bing-tao Zhai,1 Dan Zhang,1 Xiao-fei Zhang,1 Jiang-xue Cheng,1 Dong-yan Guo,1– 3 Huan Tian4 1School of Pharmacy, Shaanxi University of Chinese Medicine, Xi’an, 712046, People’s Republic of China; 2Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, Shaanxi University of Chinese Medicine, Xi’an, 712046, People’s Republic of China; 3State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xi’an, 712046, People’s Republic of China; 4Xi’an Hospital of Traditional Chinese Medicine, Xi’an, 712046, People’s Republic of ChinaCorrespondence: Dong-yan Guo; Huan Tian, Email 2051080@sntcm.edu.cn; 18149412681@163.comPurpose: Yinhua Gout Granules (YGG) is a traditional Chinese medicine preparation with a variety of pharmacological effects, and its clinical efficacy in the treatment of gouty arthritis (GA) has been fully confirmed. However, the pharmacodynamic basis of YGG and its anti-inflammatory mechanism of action in GA are unknown. The objective of this study was to identify the active components and molecular mechanisms of YGG in the treatment of GA.Methods: Ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) and network pharmacology were used to identify and predict the potential active ingredients and related signaling pathways. Then, we revealed the anti-GA effects of YGG based on pharmacodynamic experiments in GA rats. Finally, we integrated transcriptomics and network pharmacology to elucidate the potential mechanism of action and verified the putative mechanism by molecular docking, immunohistochemical (IHC) and Western blot.Results: We have identified 10 major active components of YGG that may have anti-GA effects, such as ferulic acid, rutin, luteolin, etc. Using molecular docking, we found that 10 major compounds could bind well to TNF, PTGS2, IL-6, IL1β, NOS2 and PTGS1, and the binding energies were all less than − 5 kcal/mol. Animal studies have shown that YGG can improve joint inflammation and inflammatory cell infiltration, reduce serum UA, BUN and Cr levels (p

Qi Qi,* Jun Yang,* Linhui Yang, Huohuan Tian, Chun Wan, Dan Liu Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dan Liu; Chun Wan, Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China, Email liudan10965@wchscu.cn; wanchun66@wchscu.cnAbstract: Lemierre syndrome (LS) is a rare and life-threatening condition predominantly caused by Fusobacterium necrophorum. Currently, there are no standardized clinical guidelines for LS management. Here, we describe the case of a 40-year-old male with fever, productive cough, and dyspnea but no sore throat. Diagnostic radiological examinations revealed multiple pulmonary cavitary nodules and an internal jugular vein occlusion. Metagenomic Next-Generation Sequencing (mNGS) of the alveolar lavage fluid identified Fusobacterium necrophorum, thereby confirming the diagnosis of LS. Intriguingly, the patient exhibited a delayed clinical response despite receiving the appropriate antibiotic. After integrating tigecycline into the treatment to address potential co-infecting bacteria, we observed a marked improvement in his clinical symptoms. Subsequent follow-up over 12 weeks post-discharge revealed complete alleviation of symptoms, and a chest CT scan showed marked regression of the lung lesions.Keywords: Lemierre syndrome, Fusobacterium necrophorum, septic thrombophlebitis, antibiotic therapy, anticoagulation

Hefeng Tian, Haiou Qi Nursing Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Haiou Qi, Nursing Department, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China, Email sea7312@163.comBackground: Shoulder pain is one of the most common symptoms after laparoscopic surgery, which seriously affects people’s health and quality of life. Many clinical studies have shown that noninvasive physiotherapy is the most beneficial treatment for patients, but the best approach for various noninvasive physiotherapy is unclear. The purpose of this study protocol is to compare the effectiveness of different noninvasive physiotherapy in relieving postlaparoscopic shoulder pain (PLSP).Methods: We will search ten electronic databases including PubMed, Web of Science, Medline, Scopus, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, WanFang Data and VIP databases from their inception to November 2023. We will select randomized controlled trials (RCTs) to evaluate the effectiveness of noninvasive physiotherapy on PLSP. Our primary outcome will be to measure the intensity of shoulder pain at 24 and 48 hours after the end of the noninvasive intervention in the included study. Secondary outcomes include incidence of shoulder pain at 24 and 48 hours, postoperative nausea / vomiting and incidence of other complications after noninvasive intervention. Then, standard network meta-analysis will be conducted using Review Manager 5.4 and STATA 18.Results: Our systematic review and network meta-analysis will identify the best noninvasive physiotherapy for PLSP patients.Conclusion: This systematic review will address the existing knowledge gap regarding best practice for relieving PLSP with noninvasive physiotherapy. The results of this network meta-analysis will help medical staff and patients choose the best method to relieve the PLSP. Furthermore, we hope that the results of this study will provide evidence-based for the improvement of guidelines and facilitate the decision sharing process.Systematic review registration: PROSPERO CRD42023481829.Keywords: physiotherapy, shoulder pain, protocol, systematic review, network meta-analysis

Tingting Zhang,1,&ast; Lan Yao,1,&ast; Tao Li,2 Haoxin Tian,3 Guirong Song4 1Nursing Department, the First Hospital Affiliated to Dalian Medical University, Dalian, People’s Republic of China; 2Department of Neurology, the First Hospital Affiliated to Dalian Medical University, Dalian, People’s Republic of China; 3The First Clinical College, Dalian Medical University, Dalian, People’s Republic of China; 4Department of Health Statistics, School of Public Health, Dalian Medical University, Dalian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guirong Song, Email songsara2016@dmu.edu.cnBackground: Promoting participation and autonomy (PA) in society has been highlighted as an ultimate goal of rehabilitation for people with chronic diseases by the World Health Organization, but few studies have focused on PA in people with Parkinson’s disease (PD). Therefore, this study aimed to determine the level of PA in PD patients and investigate the associated psychological and behavioural factors.Methods: PD patients were recruited from the Department of Neurology of the First Hospital Affiliated with Dalian Medical University using convenience sampling for this cross-sectional study. A questionnaire covering social-demographic and disease-related characteristics, Chinese version of Impact on Participation and Autonomy (IPA) Questionnaire, Connor-Davidson Resilience Scale (CD-RISC), Self-rating Depression Scale (SDS), Self-rating Anxiety Scale (SAS), Medical Coping Modes Questionnaire (MCMQ), Social Support Rating Scale (SSRS), Hoehn-Yahr Staging System and Unified Parkinson’s Disease Rating Scale (UPDRS) were used for investigation. A multivariate stepwise linear regression analysis was used to determine the factors that influence IPA.Results: A total of 326 PD patients responded to all the questionnaires. The patients had a mean IPA score of 46.6 (SD 21.79). Multiple linear regression analyses revealed that UPDRS II (β = 0.35, p < 0.001) had the strongest correlation with IPA, followed by tenacity, which was the second strongest factor (β = − 0.25, p < 0.001). Hoehn-Yahr stage (β = 0.19, p < 0.001) and availability of social support (β =− 0.12, p =0.001) were also strong factors.Conclusion: The average level of PA among PD patients was at the lower middle-level. Among PD patients, physical function, psychological resilience and social support were the strongest factors associated with PA. These findings provide valuable insights into PD patients’ PA and can help medical professionals identify the early risks of restricted PA among PD patients, implement interventions to promote PA and ultimately achieve rehabilitation.Keywords: participation and autonomy, psychological resilience, social support, Parkinson’s disease, medical coping modes

Chunyan Yang,&ast; Hao Tian,&ast; Guixing Xu, Qin Luo, Mingsheng Sun, Fanrong Liang Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fanrong Liang, Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, No. 37 Shi’er Qiao Road, Chengdu, Sichuan, 610075, People’s Republic of China, Email acuresearch@126.comPurpose: The effect of acupuncture as adjunctive therapy for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) was controversial. Thus, we aimed to evaluate the effects of acupuncture for treating AECOPD.Methods: Eight databases were searched from database inception to July 30, 2023. All RCTs compared acupuncture plus conventional western medicine with conventional western medicine alone were included. Outcomes were quality of life, lung function, blood oxygen condition, exercise capacity, daily symptoms, duration of hospitalization, and adverse events. The statistical analyses were conducted using Stata 17.0, and methodological quality was measured by the Cochrane bias risk assessment tool. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the quality of evidence.Results: Twelve studies including 915 patients were included. Compared with conventional western medicine alone, acupuncture combined with conventional western therapy significantly improved quality of life (CAT: MD: − 3.25; 95% CI: − 3.73 to − 2.78, P< 0.001) and arterial blood gas (PaCO2: MD: − 1.85; 95% CI: − 2.74 to − 0.95, P< 0.001; PaO2: MD: 5.15; 95% CI: 1.22 to 9.07, P = 0.01). And for lung function, statistical benefits were found in FEV1/FVC (MD: 4.66; 95% CI: 2.21 to 7.12, P< 0.001), but no difference was seen for FEV1% (MD: 1.83; 95% CI: − 0.17 to 3.83, P = 0.073). There was no significant improvement in exercise capacity (6MWD: MD: 96.69; 95% CI: − 0.60 to 193.98, P = 0.051), hospitalization duration (MD: − 5.70; 95% CI: − 11.97 to 0.58, P = 0.075), and dyspnea (mMRC: MD: − 0.19; 95% CI: − 0.61 to 0.63, P = 0.376) between two groups. Overall bias for CAT and mMRC was in “high” risk, FEV1%, FEV1/FVC, PaCO2, and PaO2 was in “some concern” and 1 RCT assessing hospitalization duration was in “low” risk. And the overall assessments were either moderate, low or very low certainty. Seven trials performed safety assessment of acupuncture, and no serious adverse events were reported.Conclusion: Acupuncture might have auxiliary effects on AECOPD. However, the quality of the evidence is limited, and more high-quality RCTs are needed to be performed in the future.Keywords: acute exacerbation of chronic obstructive pulmonary disease, acupuncture, systematic review, meta-analysis

Qing-rui Qi,1 Huan Tian,2 Bao-sen Yue,2 Bing-tao Zhai,1 Feng Zhao2 1State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Key Laboratory of Chinese Medicine Fundamentals and New Drugs Research, and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Shaanxi University of Chinese Medicine, Xi’an, 712046, People’s Republic of China; 2Xi’an Hospital of Traditional Chinese Medicine, Xi’an, 710021, People’s Republic of ChinaCorrespondence: Bing-tao Zhai; Feng Zhao, Email zbp@sntcm.edu.cn; zf6369@126.comAbstract: The active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxycamptothecin (SN38), is 100– 1000 times more active than CPT-11 and has shown inhibitory effects on a range of cancer cells, including those from the rectal, small cell lung, breast, esophageal, uterine, and ovarian malignancies. Despite SN38’s potent anticancer properties, its hydrophobicity and pH instability have caused substantial side effects and anticancer activity loss, which make it difficult to use in clinical settings. To solve the above problems, the construction of SN38-based drug delivery systems is one of the most feasible methods to improve drug solubility, enhance drug stability, increase drug targeting ability, improve drug bioavailability, enhance therapeutic efficacy and reduce adverse drug reactions. Therefore, based on the targeting mechanism of drug delivery systems, this paper reviews SN38 drug delivery systems, including polymeric micelles, liposomal nanoparticles, polymeric nanoparticles, protein nanoparticles, conjugated drug delivery systems targeted by aptamers and ligands, antibody-drug couplings, magnetic targeting, photosensitive targeting, redox-sensitive and multi-stimulus-responsive drug delivery systems, and co-loaded drug delivery systems. The focus of this review is on nanocarrier-based SN38 drug delivery systems. We hope to provide a reference for the clinical translation and application of novel SN38 medications.Keywords: SN38, drug delivery system, cancer

Huimin Tian, Haitao Shang, Yichi Chen, Bolin Wu, Chunyue Wang, Xiaodong Wang, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel +86 13313677182, Fax +86 451 85718392, Email hrbchengwen@163.comBackground: Apoptosis resistance of hepatocellular carcinoma (HCC) often leads to treatment failure. Nonetheless, overcoming the resistance of HCC to apoptosis by inducing necroptosis of tumor cells to bypass the apoptotic pathway may be a promising treatment strategy. Sonodynamic therapy (SDT) has broad prospects in disease treatment because of its noninvasive characteristic and spatiotemporal control. The combination of SDT and shikonin in the treatment of HCC is expected to be a new tumor treatment method that can overcome apoptosis resistance.Methods: In this study, the antitumor effect was evaluated using normal liver cell line WRL68, HCC cell line HepG2 and HepG2 xenograft mouse models. Indocyanine green (ICG) was loaded on nanobubbles (NBs) to construct ICG-loaded nanobubbles (ICG-NBs). Combined sonosensitizer nanoplatforms with ultrasound (US) to achieve efficient SDT, the combination of SDT and shikonin in treating HCC can activate shikonin-induced necroptosis. As a result, tumor cells that produced apoptosis resistance were destroyed by necroptosis.Results: The results indicated a successful preparation of ICG-NBs with a uniform particle size of 273.0 ± 118.9 nm spherical structures. ICG-NB-mediated SDT, in combination with shikonin treatment, inhibited the viability, invasion, and migration of tumor cells. SDT + shikonin treatment group caused a substantial increase in necroptotic cells. The increased degree of tumor necrosis and the upregulated expression of receptor-interacting protein 3 kinase were observed in vivo studies, which indicated that the antitumor effect was accompanied by enhanced necroptosis in the SDT + shikonin treatment group.Conclusion: ICG-NB-mediated SDT combined with shikonin inhibits the growth of HCC by increasing the necroptosis of tumor cells. Therefore, this combination therapy is a promising treatment strategy against the specific cancer.Keywords: sonodynamic therapy, hepatocellular carcinoma, necroptosis, shikonin, sonosensitizer

Yu Hu,1– 3 Hui Guo,1– 3 Shuai Cheng,1– 3 Junpeng Sun,2,4 Jiaqun Du,2,4 Xiaobang Liu,2,4 Ying Xiong,5 Liqing Chen,6 Chang Liu,3,6 Chao Wu,2,4 He Tian1– 3 1School of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People’s Republic of China; 2Liaoning Provincial Collaborative Innovation Center for Medical Testing and Drug Research, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People’s Republic of China; 3Key Laboratory of Medical Tissue Engineering of Liaoning Province, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People’s Republic of China; 4Pharmacy School, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People’s Republic of China; 5Laboratoire Catalyse et Spectrochimie (LCS), Normandie Université, ENSICAEN, UNICAEN, CNRS, Caen, 14050, France; 6Department of Endocrinology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People’s Republic of ChinaCorrespondence: He Tian; Chao Wu, Email tianhe@jzmu.edu.cn; wuchao@jzmu.edu.cnBackground: Oxidative stress induced reactive oxygen species (ROS) and aggregation of amyloid β (Aβ) in the nervous system are significant contributors to Alzheimer’s disease (AD). Cerium dioxide and manganese oxide are known as to be effective and recyclable ROS scavengers with high efficiency in neuroprotection.Methods: A hollow-structured manganese-doped cerium dioxide nanoparticle (LMC) was synthesized for loading Resveratrol (LMC-RES). The LMC-RES were characterized by TEM, DLS, Zeta potential, and X-ray energy spectrum analysis. We also tested the biocompatibility of LMC-RES and the ability of LMC-RES to cross the blood-brain barrier (BBB). The antioxidant effects of LMC-RES were detected by SH-SY5Y cells. Small animal live imaging was used to detect the distribution of LMC-RES in the brain tissue of AD mice. The cognitive abilities of mice were tested by water maze and nesting experiments. The effects of LMC-RES in reducing oxidative stress and protecting neurons was also explored by histological analysis.Results: The results showed that LMC-RES had good sustained release effect and biocompatibility. The drug release rate of LMC-RES at 24 hours was 80.9 ± 2.25%. Meanwhile, LMC-RES could cross the BBB and enrich in neurons to exert antioxidant effects. In Aβ-induced SH-SY5Y cells, LMC-RES could inhibits oxidative stress through the Nrf-2/HO-1 signaling pathway. In AD model mice, LMC-RES was able to reduce ROS levels, inhibit Aβ-induced neurotoxicity, and protect neurons and significantly improve cognitive deficits of AD mice after drug administration.Conclusion: LMC-RES can effectively across the BBB, reduce oxidative stress, inhibit Aβ aggregation, and promote the recovery of neurological function.Keywords: cerium dioxide nanoparticles, manganese, oxidative stress, resveratrol, Alzheimer’s disease

Xiaodong Wang, Chunyue Wang, Huimin Tian, Yichi Chen, Bolin Wu, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng; Bolin Wu, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, People’s Republic of China, Tel +86 13313677182 ; +86 15663615088, Email chengwen@hrbmu.edu.cn; wubolin@hrbmu.edu.cnPurpose: Sonodynamic therapy (SDT) is a promising and significant measure for the treatment of tumors. However, the internal situation of hepatocellular carcinoma (HCC) is complex, separate SDT treatment is difficult to play a good therapeutic effect. Here, we used SDT combined with MG-132 to mediate apoptosis and autophagy of HCC cells to achieve the purpose of treatment of cancer.Methods: To determine the generated reactive oxygen species (ROS) and the change of mitochondrial membrane potential (ΔΨm), HepG2 cells were stained by 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) and 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1) staining to determine the IR-820@NBs-mediated SDT to achieve HCC therapy through the mitochondrial pathway. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to detect cell viability and apoptosis rate of HepG2 cells. Autophagy was detected by mCherry-GFP-LC3B fluorescence labeling. Chloroquine (Cq) pretreatment was used to explore the relationship between autophagy and apoptosis. To detect the ability of HepG2 cells migration and invasion, cell scratch assay and transwell assay were used.Results: The successfully prepared IR-820@NBs could effectively overcome the shortcomings of IR-820 and induce lethal levels of ROS by ultrasound irradiation. As a dual agonist of apoptosis and autophagy, MG-132 could effectively enhance the efficacy of SDT in the process of treating HCC. After pre-treatment with Cq, the cell activity increased and the level of apoptosis decreased, which proved that apoptosis and autophagy were induced by combined therapy, autophagy, and apoptosis have the synergistic anti-tumor effect, and part of apoptosis was autophagy-dependent. After combined therapy, the activity and invasive ability of HCC cells decreased significantly.Conclusion: SDT combined with MG-132 in the process of treating liver cancer could effectively induce apoptosis and autophagy anti-tumor therapy, which is helpful to the research of new methods to treat liver cancer.Keywords: sonodynamic therapy, MG-132, apoptosis, autophagy, hepatocellular carcinoma

Yichi Chen,1– 3 Bolin Wu,1– 3 Haitao Shang,1– 3 Yucao Sun,1– 3 Huimin Tian,1– 3 Huajing Yang,1– 3 Chunyue Wang,1– 3 Xiaodong Wang,1– 3 Wen Cheng1– 3 1Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 2Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 3Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin, 150081, People’s Republic of ChinaCorrespondence: Wen Cheng, Department of Ultrasound, Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel +86 13313677182, Fax +86 451 85718392, Email chengwen@hrbmu.edu.cnBackground: Despite the clinical efficacy of immunotherapy in treating malignant tumors, its effectiveness is often hampered by the immunosuppressive nature of the tumor microenvironment (TME). In this study, we propose the design of a nanoscale ultrasound contrast agent capable of triggering macrophage polarization and immunogenic cell death (ICD) for the treatment of hepatocellular carcinoma (HCC) through sonodynamic treatment (SDT) and immunotherapy.Methods: The re-educator (designated as ICG@C3F8-R848 NBs) is composed of the Toll-like receptor agonist resiquimod (R848) and the sonosensitizer Indocyanine green (ICG), utilizing nanobubbles (NBs) as carriers. The technique known as ultrasound-targeted nanobubble destruction (UTND) employs nanosized microbubbles and low-frequency ultrasound (LFUS) to ensure accurate drug delivery and enhance safety.Results: Following intravenous delivery, ICG@C3F8-R848 NBs have the potential to selectively target and treat primary tumors using SDT in conjunction with ultrasonography. Importantly, R848 can enhance antitumor immunity by inducing the polarization of macrophages from an M2 to an M1 phenotype.Conclusion: The SDT-initiated immunotherapy utilizing ICG@C3F8-R848 NBs demonstrates significant tumor suppression effects with minimal risk of systemic toxicity. The utilization of this self-delivery re-education technique would contribute to advancing the development of nanomedicine for the treatment of hepatocellular carcinoma.Keywords: hepatocellular carcinoma, synergistic sono-immunotherapy strategy, tumor-associated-macrophage

Huakai Tian,1,&ast; Zitao Liu,2,&ast; Zuo Zhang,3,&ast; Lipeng Zhang,2,&ast; Zhen Zong,2 Jiang Liu,2 Houqun Ying,4 Hui Li5 1Department of General Surgery, First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 2Department of Gastrointestinal Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 3Department of Obstetrics and Gynecology, Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 4Department of Nuclear Medicine, Jiangxi Province Key Laboratory of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 5Department of Rheumatology and Immunology, First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Li, Department of Rheumatology and Immunology, First Affiliated Hospital of Nanchang University, 17 Yongwai Main Street, Nanchang, 330006, People’s Republic of China, Tel +86-15079108591, Email lihui0791nc@126.com Houqun Ying, Department of Nuclear Medicine, Jiangxi province Key Laboratory of Laboratory Medicine, the Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, People’s Republic of China, Tel/Fax +86 791-86300410, Email yinghouqun2013@163.comObjective: The aim of this study was to investigate the clinical significance of Fibrinogen and Platelet to Pre-albumin Ratio(FPAR) in predicting the prognosis of patients with advanced gastric cancer(AGC) and to construct a predictive model.Methods: We collected clinical data from 489 postoperative patients with AGC. FPAR was divided into high and low groups according to the receiver operating characteristic (ROC) curve. The value of FPAR in predicting the prognosis of progressive gastric cancer was analysed using univariate and multivariable Cox regression analysis and its relationship with clinicopathological features. Finally, the Overall Survival(OS) and recurrence-free survival(RFS) prediction models were constructed and validated using FPAR.Results: Univariate and multifactorial cox regression analysis showed that grade (P< 0.001), TNM-stage (P< 0.001), chemotherapy (P< 0.001), and FPAR (OR=3.054,95% CI:2.088– 4.467, P< 0.001) were independent risk factors for OS; grade (P=0.021), N-stage (P=0.024), TNM-stage (P=0.033), and FPAR (OR=2.215,95% CI:1.634– 3.003, P< 0.001) were independent risk factors for RFS. Subgroup analysis showed that the FPAR-low group had higher OS and RFS than the FPAR-high group, regardless of the patient’s TNM stage (p< 0.05). However, OS was instead higher in the the stage III-FPAR-low group than in the the stage II-FPAR-high group (p< 0.05), while RFS was not significantly different. Predictive models incorporating FPAR had better predictive performance than those without FPAR, showing wide range of net benefit and AUC. After correction, the 2-year AUC, 3-year AUC and C-index of the OS model were 0.737, 0.756, and 0.746; the 2-year AUC, 3-year AUC, and C-index of the RFS model were 0.738, 0.758, and 0.711.Conclusion: FPAR levels were associated with prognosis in patients with AGC and could independently predict RFS and OS.Keywords: advanced gastric cancer, FPAR, overall survival, recurrence-free survival, prognosis

Qingsen Ran,1 He Tian,1 Jian Lin,1 Han Wang,2 Bo Wang,1 Zhixin Chen,1 Da Song,1 Chunzhu Gong1 1Department of Science and Education, Shenzhen Pingle Orthopedic Hospital (Shenzhen Pingshan Traditional Chinese Medicine Hospital), Shenzhen, Guangzhou Province, 518118, People’s Republic of China; 2Department of Gastroenterology, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin Province, 130021, People’s Republic of ChinaCorrespondence: Chunzhu Gong, Email gczq_82@126.comAbstract: The progression of diabetes frequently results in a myriad of neurological disorders, including ischemic stroke, depression, blood-brain barrier impairment, and cognitive dysfunction. Notably, diabetes-associated cognitive impairment, a prevalent comorbidity during the course of diabetes, progressively affects patients’ cognitive abilities and may reciprocally influence diabetes management, thereby severely impacting patients’ quality of life. Extracellular vesicles, particularly nanoscale exosomes, have garnered considerable attention in recent years. These exosomes carry and transfer various functional molecules, such as proteins, lipids, and diverse non-coding RNAs, serving as novel regulators and communicators in intercellular interactions. Of particular interest, mesenchymal stem cell-derived exosomes (MSC-Exos) have been reported to traverse the blood-brain barrier and ameliorate intracerebral pathologies. This review elucidates the role of MSC-Exos in diabetes-related cognitive impairment, with a focus on their applications as biomarkers, modulation of neuronal regeneration and synaptic plasticity, anti-inflammatory properties, antioxidative effects, and their involvement in regulating the functionality of β-amyloid proteins during the course of cognitive impairment. The immense therapeutic potential of MSC-Exos in the treatment of diabetes-induced cognitive dysfunction is emphasized.Keywords: diabetes-associated cognitive impairment, mesenchymal stem cell-derived exosomes, blood-brain barrier, neuronal regeneration, synaptic plasticity

Jin Sun,1– 3 Yingnan Li,1– 3 Mengjiao Shi,1,2 Hongwei Tian,1– 3 Jun Li,1– 3 Kai Zhu,1– 3 Ying Guo,1– 3 Yanhua Mu,1– 3 Jing Geng,1– 3 Zongfang Li1– 4 1National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Center for Tumor and Immunology, the Precision Medical Institute, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 4Department of Geriatric General Surgery, the Second Affiliated Hospital of Xi’ an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Jing Geng; Zongfang Li, National & Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, the second affiliated hospital, Xi’an Jiaotong University, No. 157 West 5th Road, Xi’an, 710004, People’s Republic of China, Tel +86-29-87679700 ; Tel/Fax +86-29-87679508, Email jgeng18@xjtu.edu.cn; lzf2568@xjtu.edu.cnPurpose: HOX cluster-embedded long noncoding RNAs (HOX-lncRNAs) have been shown to be tightly related to hepatocellular carcinoma (HCC). However, the potential biological roles and underlying molecular mechanism of HOX-lncRNAs in HCC largely remains to be elucidated.Methods: The expression signature of eighteen HOX-lncRNAs in HCC cell lines were measured by qRT-PCR. HOXD-AS2 expression and its clinical significance in HCC was investigated by bioinformatics analysis utilizing the TCGA data. Subcellular localization of HOXD‐AS2 in HCC cells was observed by RNA-FISH. Loss‑of‑function experiments in vitro and in vivo were conducted to probe the roles of HOXD-AS2 in HCC. Potential HOXD-AS2-controlled genes and signaling pathways were revealed by RNA-seq. Rescue experiments were performed to validate that SMYD3 mediates HOXD-AS2 promoting HCC progression. The positive feedback loop of HOXD-AS2 and SMYD3 was identified by luciferase reporter assay and ChIP-qPCR.Results: HOXD-AS2 was dramatically elevated in HCC, and its up-regulation exhibited a positive association with aggressive clinical features (T stage, pathologic stage, histologic grade, AFP level, and vascular invasion) and unfavorable prognosis of HCC patients. HOXD-AS2 was distributed both in the nucleus and the cytoplasm of HCC cells. Knockdown of HOXD-AS2 restrained the proliferation, migration, invasion of HCC cells in vitro, as well as tumor growth in subcutaneous mouse model. Transcriptome analysis demonstrated that SMYD3 expression and activity of MEK/ERK pathway were impaired by silencing HOXD-AS2 in HCC cells. Rescue experiments revealed that SMYD3 as downstream target mediated oncogenic functions of HOXD-AS2 in HCC cells through altering the expression of cyclin B1, cyclin E1, MMP2 as well as the activity of MEK/ERK pathway. Additionally, HOXD-AS2 was uncovered to be positively regulated at transcriptional level by its downstream gene of SMYD3.Conclusion: HOXD-AS2, a novel oncogenic HOX-lncRNA, facilitates HCC progression by forming a positive feedback loop with SMYD3 and activating the MEK/ERK pathway.Keywords: hepatocellular carcinoma, HOXD-AS2, SMYD3, MEK/ERK signaling

Zitao Liu,1 Huakai Tian,2 Zhengming Zhu1 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Gastrointestinal Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of ChinaCorrespondence: Zhengming Zhu, Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, 1 MinDe Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +8613970880051, Email zhengmingzhu28@126.comBackground: The purpose of this study was to explore the clinical significance of circulating tumor cells (CTCs) and cytokines in peripheral blood in preoperative prediction of peritoneal metastasis (PM) in advanced gastric cancer (AGC).Methods: The clinicopathological characteristics of 282 patients with AGC were retrospectively analyzed. The patients were divided into training and validation groups according to the time of receiving treatment. We used univariate analysis and multivariate logistic regression analysis to screen out the independent risk factors of PM in AGC. Then, we incorporated independent risk factors into the nomogram, and evaluated the discriminative ability.Results: The levels of CTCs and interleukin-6 (IL-6) of AGC patients with PM were higher than those without PM (P< 0.05). Moreover, the levels of CTCs and IL-6 in the occult peritoneal metastasis (OPM) group and the CT-positive PM group were higher than those in the negative PM (P< 0.05). Multivariate logistic regression analysis showed that IL-6 > 12.22 pg/mL, CTCs > 4/5mL, CA724 > 6 IU/mL, CA125 > 35 U/mL and tumor size > 5 cm were independent risk factors for PM of AGC. The area under the ROC curve of the nomogram were 0.898 and 0.926 in the training and validation sets, respectively. The clinical decision curve showed that the nomogram had good clinical utility.Conclusion: CTCs and IL-6 in peripheral blood are promising biomarkers for predicting the risk of PM in AGC. The nomogram constructed from five risk factors can effectively assess the risk of PM in AGC patients individually.Keywords: circulating tumor cell counts, interleukin-6, advanced gastric cancer, peritoneal metastasis, occult peritoneal metastasis

Qing Wang,1 Hongyan Wang,2 Haitao Tian,2 Shaoli Niu,2 Ruyi Xu1 1Department of the Sixth Health Care, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100048, People’s Republic of China; 2Department of Geriatrics, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, 100048, People’s Republic of ChinaCorrespondence: Hongyan Wang, Department of Geriatrics, The Sixth Medical Center, Chinese PLA General Hospital, No. 6 Fucheng Road, Haidian District, Beijing, 100048, People’s Republic of China, Tel +86-10-66957726, Email dlyxzxwanghongyan@163.comBackground: Frailty affects the prognosis and management of patients with heart failure, and is often related with sarcopenia. Also, the serum myostatin (MSTN) involved in the development of sarcopenia and frailty. This study aimed to determine the connection between MSTN level and frailty in older adults with chronic heart failure (CHF).Methods: This prospective case-control study enrolled older adult patients with CHF between May 2019 and May 2021, and analyzed their clinical data.Results: In this study 75 older adults with CHF were included, 29 of whom were frail. The B-type natriuretic peptide (BNP) levels were significantly higher in frail older adults with CHF than in older adults with CHF who were not frail (316.82 ± 235.64 pg/mL vs 198.61 ± 112.58 pg/mL; P = 0.016). The MSTN levels were significantly higher in frail participants than in participants who were not frail (2.93 ± 1.35 ng/mL vs 2.24 ± 0.84 ng/mL; P = 0.018). Based on multivariable analysis the BNP (odds ratio [OR] = 1.004, 95% confidence interval [CI] = 1 0.001– 1.008; P = 0.018) and MSTN (OR = 1.772, 95% CI = 1.079– 2.912; P =0 0.024) levels were independently associated with frailty in older adults with CHF.Conclusion: MSTN is a promising biomarker of frailty in elderly patients with CHF.Keywords: myostatin, B-type natriuretic peptide, frailty, chronic heart failure

Gaili Wang,1 Huizi Tian,2 Kai Kang,2 Shixian Feng,2 Weihao Shao,1 Xiaorui Chen,1 Caifang Zheng,1 Bowen Zhang,1 Pei Pei,3 Weidong Zhang1 1Department of Epidemiology, School of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, People’s Republic of China; 2Henan Provincial Center for Disease Control and Prevention, Zhengzhou, Henan, 450016, People’s Republic of China; 3Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, 100191, People’s Republic of ChinaCorrespondence: Weidong Zhang, Department of Epidemiology, School of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, People’s Republic of China, Tel +86-0371-67781964, Email imooni@163.comObjective: Little is known about the effect of age at first childbirth on lung function. We aimed to investigate the association between age at first childbirth and lung function in Chinese women and further test whether this association is mediated by body mass index (BMI).Methods: This cross-sectional study is a partial survey of the China Kadoorie Biobank (CKB) which was conducted in Xinxiang City, Henan Province between 2004 and 2008. A total of 16,584 postmenopausal women aged 30– 79 years were enrolled. Multiple linear and logistic regression were used to investigate the association between age at first childbirth and lung function and overweight/obesity. The mediation analysis was performed using the PROCESS procedure for SPSS.Results: The mean (SD) age at first childbirth was 23.1 (2.7) years. Women with first childbirth aged ≤ 19 years and 20– 22 years had lower lung function than women who gave first childbirth aged 23– 25 years. Per 1-year increase in the age at first childbirth was associated with a 3.31 mL increase in FEV1 (95% CI = 1.27– 5.35), 3.91 mL increase in FVC (95% CI = 1.63– 6.18), 0.15% increase in FEV1, % predicted (95% CI = 0.05– 0.24) and 0.14% increase in FVC, % predicted (95% CI = 0.05– 0.22). There was no clear association between age at first childbirth and FEV1/FVC ratio. BMI played a contribution to the association between age at first childbirth and FEV1 and the proportion was 16.4% (indirect effect: β = 0.65, 95% CI = 0.46– 0.89; total effect: β = 3.96, 95% CI = 1.92– 5.99). Similarly, the proportion to FVC, FEV1, % predicted, and FVC, % predicted was 25.0%, 16.6%, and 25.0%, respectively.Conclusion: Early age at first childbirth was associated with lower lung function and BMI mediated the association. It is important to test lung function and popularize the knowledge of weight control in women who gave first childbirth at an early age.Keywords: first childbirth, lung function, body mass index, mediation, postmenopausal women

Jihong Gu,1,&ast; Shucheng Shen,1,&ast; Mengyuan Xiong,1,2 Jin Zhao,1,2 Hongpan Tian,1 Xiao Xiao,1,3 Yirong Li1– 3 1Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Wuhan Research Center for Infectious Diseases and Tumors of the Chinese Academy of Medical Sciences, Wuhan, People’s Republic of China; 3Hubei Engineering Center for Infectious Disease Prevention, Control and Treatment, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yirong Li, Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430061, People’s Republic of China, Tel +8618602718052, Email liyirong838@163.comBackground: Staphylococcus aureus (S. aureus) was able to rapidly evolve and adapt under the pressure of antibiotics, host immune and environmental change. After Corona Virus Disease 2019 (COVID-19) epidemic in Wuhan, China, a large number of disinfectants were used, which might result in rapid evolution of S. aureus.Methods: A total of 619 S. aureus isolates were collected from Zhongnan Hospital, Wuhan University from 2018 to 2021, including group BEFORE (309 strains collected before COVID-19 pandemic) and group AFTER (310 strains collected after COVID-19 pandemic), for comparing the changes of molecular epidemiology. The molecular characteristics of isolates were analyzed by Multi-locus sequence typing (MLST), spa, chromosomal cassette mec (SCCmec) typing, virulence genes were screened by the PCR, antibiotic susceptibility test was carried out by the VITEK system.Results: Thirty-six sequence types (STs) belonging to 14 clone complexes (CCs) were identified. ST5 was the most prevalent clone in both groups, and ST7, ranking the sixth in group BEFORE, became the second dominant clone in group AFTER (6.5% vs 10.0%), whereas ST239 decreased from the seventh to the fourteenth (5.8% vs 1.9%). ST7 in group AFTER had a higher positive rate of virulence genes, including hlb, fnbB, seb, lukDE, sdrE and the proportion of ST7-t091 MRSA strains increased from 19.1% to 50% compared with group BEFORE. Though no significant difference of MRSA proportion was found between two groups, SCCmec type-III in group AFTER decreased (p< 0.01). Though the rate of multidrug-resistance (MDR) decreased, the virulence genes hlb, hlg, fnbB, seb and pvl carrying rates were significantly elevated in MRSA strains of group AFTER.Conclusion: After COVID-19 pandemic, ST7 becomes one of the predominant S. aureus clones in Wuhan and the carrying rate of SCCmec and virulence genes is on the rise. Therefore, it is essential to strengthen the surveillance of ST7 S. aureus clone.Keywords: Staphylococcus aureus, molecular characterization, antimicrobial resistance, virulence gene, disinfectant

Weipeng Shi,1,2 Yaping Jiang,3 Hua Tian,4 Yingzhen Wang,1 Yingze Zhang,5 Tengbo Yu,1 Tao Li1 1Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Medical Department of Qingdao University, Qingdao, Shandong, People’s Republic of China; 3Department of Oral Implantology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 4Department of Neurological Rehabilitation, Qingdao Special Servicemen Recuperation Center of PLA Navy, Qingdao, People’s Republic of China; 5Key Laboratory of Biomechanics of Hebei Province, Department of Trauma Emergency Center, The Third Hospital of Hebei Medical University, Orthopaedics Research Institution of Hebei Province, Shijiazhuang, People’s Republic of ChinaCorrespondence: Tao Li; Tengbo Yu, Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, Shandong Province, People’s Republic of China, Email qdult@qdu.edu.cn; ytb8912@163.comBackground: Periprosthetic joint infection (PJI) is a catastrophic complication after total joint arthroplasty (TJA). Timely and accurate diagnosis is important for the management of PJI. Currently, many biomarkers are available for the diagnosis of PJI, but which inflammatory biomarker combination has the best diagnostic value has not been reported.Materials and Methods: We retrospectively analyzed 244 patients who underwent revision knee or hip arthroplasty in our institution. They were divided into two groups: 87 in the PJI group and 157 in the aseptic failure (AF) group. The preoperative C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), CRP-to-albumin ratio (CAR), CRP-to-lymphocyte ratio (CLR), neutrophil-to-albumin ratio (NAR) and platelet-to-albumin ratio (PAR) were determined and compared between the two groups. Receiver operating characteristic curve (ROC) and area under the curve (AUC) were used to assess the diagnostic value of all biomarkers, and the optimal cut-off value, positive predictive value (PPV) and negative predictive value (NPV) were further calculated by the Youden index.Results: The NLR, PLR, CAR, CLR, NAR and PAR of the PJI group were significantly higher than those of the AF group (P< 0.001). According to the ROC and AUC results, the diagnostic value of CAR and CLR was considered excellent with AUCs of 0.931 and 0.935, respectively. The diagnostic value of NAR (0.739) and PAR (0.785) were fair, the diagnostic value of NLR (0.694) was poor, and PLR (0.535) had no diagnostic ability. Subgroup analysis showed no significant differences in combined inflammatory biomarkers between the two groups.Conclusion: CAR and CLR are valuable combined inflammatory biomarkers for diagnosing PJI, while other markers were of limited value for the diagnosis of PJI.Keywords: C-reactive protein-to-albumin ratio, C-reactive protein-to-lymphocyte ratio, biomarkers, periprosthetic joint infection

A carbon dioxide (CO2) based mixture was investigated as a promising solution to improve system performance and expand the condensation temperature range of a CO2 transcritical Rankine cycle (C-TRC). An experimental study of TRC using CO2/R134a mixtures was performed to recover waste heat of engine coolant and exhaust gas from a heavy-duty diesel engine. The main purpose of this study was to investigate experimentally the effect of the composition ratio of CO2/R134a mixtures on system performance. Four CO2/R134a mixtures with mass composition ratios of 0.85/0.15, 0.7/0.3, 0.6/0.4 and 0.4/0.6 were selected. The high temperature working fluid was expanded through an expansion valve and then no power was produced. Thus, current research focused on the analysis of measured operating parameters and heat exchanger performance. Heat transfer coefficients of various heat exchangers using supercritical CO2/R134a mixtures were provided and discussed. These data may provide useful reference for cycle optimization and heat exchanger design in application of CO2 mixtures. Finally, the potential of power output was estimated numerically. Assuming an expander efficiency of 0.7, the maximum estimations of net power output using CO2/R134a (0.85/0.15), CO2/R134a (0.7/0.3), CO2/R134a (0.6/0.4) and CO2/R134a (0.4/0.6) are 5.07 kW, 5.45 kW, 5.30 kW, and 4.41 kW, respectively. Along with the increase of R134a composition, the estimation of net power output, thermal efficiency and exergy efficiency increased at first and then decreased. CO2/R134a (0.7/0.3) achieved the maximum net power output at a high expansion inlet pressure, while CO2/R134a (0.6/0.4) behaves better at low pressure.

This paper presents results of a preliminary experimental study of the Organic Rankine Cycle (ORC) using CO2/R134a mixture based on an expansion valve. The goal of the research was to examine the feasibility and effectiveness of using CO2 mixtures to improve system performance and expand the range of condensation temperature for ORC system. The mixture of CO2/R134a (0.6/0.4) on a mass basis was selected for comparison with pure CO2 in both the preheating ORC (P-ORC) and the preheating regenerative ORC (PR-ORC). Then, the feasibility and application potential of CO2/R134a (0.6/0.4) mixture for waste heat recovery from engines was tested under ambient cooling conditions. Preliminary experimental results using an expansion valve indicate that CO2/R134a (0.6/0.4) mixture exhibits better system performance than pure CO2. For PR-ORC using CO2/R134a (0.6/0.4) mixture, assuming a turbine isentropic efficiency of 0.7, the net power output estimation, thermal efficiency and exergy efficiency reached up to 5.30 kW, 10.14% and 24.34%, respectively. For the fitting value at an expansion inlet pressure of 10 MPa, the net power output estimation, thermal efficiency and exergy efficiency using CO2/R134a (0.6/0.4) mixture achieved increases of 23.3%, 16.4% and 23.7%, respectively, versus results using pure CO2 as the working fluid. Finally, experiments showed that the ORC system using CO2/R134a (0.6/0.4) mixture is capable of operating stably under ambient cooling conditions (25.2–31.5 °C), demonstrating that CO2/R134a mixture can expand the range of condensation temperature and alleviate the low-temperature condensation issue encountered with CO2. Under the ambient cooling source, it is expected that ORC using CO2/R134a (0.6/0.4) mixture will improve the thermal efficiency of a diesel engine by 1.9%.

Clarifying how increased atmospheric CO2 concentration (eCO2) contributes to accelerated land carbon sequestration remains important since this process is the largest negative feedback in the coupled carbon–climate system. Here, we constrain the sensitivity of the terrestrial carbon sink to eCO2 over the temperate Northern Hemisphere for the past five decades, using 12 terrestrial ecosystem models and data from seven CO2 enrichment experiments. This constraint uses the heuristic finding that the northern temperate carbon sink sensitivity to eCO2 is linearly related to the site-scale sensitivity across the models. The emerging data-constrained eCO2 sensitivity is 0.64 ± 0.28 PgC yr−1 per hundred ppm of eCO2. Extrapolating worldwide, this northern temperate sensitivity projects the global terrestrial carbon sink to increase by 3.5 ± 1.9 PgC yr−1 for an increase in CO2 of 100 ppm. This value suggests that CO2 fertilization alone explains most of the observed increase in global land carbon sink since the 1960s. More CO2 enrichment experiments, particularly in boreal, arctic and tropical ecosystems, are required to explain further the responsible processes.