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Pilong Shi,1,* Yuetong Sha,1,* Xinran Wang,1,* Tao Yang,1 Jiawei Wu,1 Jiajun Zhou,1 Kai Liu,1 Xue Guan,2 Song Wang,1 Yongsheng Liu,1 Jingquan Gao,3 Hongli Sun,1 Tao Ban,1 Yonggang Cao1 1Department of Pharmacology, Harbin Medical University, Heilongjiang, 163319, People’s Republic of China; 2Morphological Experiment Center, Harbin Medical University, Heilongjiang, 163319, People’s Republic of China; 3Department of Nursing, School of Medicine, Lishui University, Lishui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yonggang Cao; Hongli Sun, Email 437343482@qq.com; sunhongli@hmudq.edu.cnPurpose: Myocardial ischemia-reperfusion injury (MI/RI) is associated with increased oxidative damage and mitochondrial dysfunction, resulting in an elevated risk of mortality. MI/RI may be alleviated by protecting cardiomyocytes from oxidative stress. Lutein, which belongs to a class of carotenoids, has proven to be effective in cardiovascular disease treatment due to its remarkable antioxidant properties, but its application is limited due to its poor stability and low bioavailability in vivo.Methods: In this study, a delivery system was developed based on distearoyl phosphatidyl ethanolamine (DSPE)-thiol-ketone (TK)-PEG2K (polyethylene glycol 2000) (abbreviated as DTP) and PCM-SH (CWLSEAGPVVTVRALRGTGSW) to deliver lutein (abbreviated as lutein@DTPP) to damaged myocardium. First, lutein, lutein@DTP, or lutein@DTPP were injected through the tail vein once a day for 3 days and then MI/RI model rats were established by exposing rats to ischemia for 45 min and reperfusion for 6 h. We employed a range of experimental techniques including qRT-PCR, Western blotting, transmission electron microscopy, immunohistochemistry, immunofluorescence, flow cytometry, immunoprecipitation, molecular docking, and molecular dynamics simulations.Results: Lutein@DTPP exhibited good myocardial targeting and ROS-responsive release. Our data suggested that lutein@DTPP effectively suppresses ferroptosis in cardiomyocytes. Mechanistically, we observed an upregulation of mouse double minute-2 (MDM2) in the hearts of MI/RI models and cardiomyocytes exposed to hypoxia/reoxygenation (H/R) conditions. In addition, NADH-ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1) translocation from the cytosol to the mitochondria was inhibited by MDM2 upregulation. Notably, no significant variation in the total NDUFS1 expression was observed in H/R-exposed cardiomyocytes following treatment with siMDM2. Further study indicated that lutein facilitates the translocation of NDUFS1 from the cytosol to mitochondria by directly binding and sequestering MDM2, thereby improving mitochondrial function and inhibiting ferroptosis.Conclusion: Lutein@DTPP promoted the mitochondrial translocation of NDUFS1 to restore mitochondrial function and inhibited the ferroptosis of cardiomyocytes by directly binding and sequestering MDM2. Keywords: myocardial ischemia-reperfusion injury, lutein, ROS, MDM2, NDUFS1, ferroptosis

Xiao Wang,1,* Ying Cao,2,* Jing Hu,3 Lian-Cheng Jia,4 Bo Li,3 Baoli Liu,5 Wei-Hai Yao,2 Xiao-Lu Pei,6 Wei Peng,2 Shuang Wang,2 Cun-Zhi Liu,1,7 Jian-Feng Tu,1,7 Zhi-Cheng Qu2 1School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Emergency Department, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 3Evidence Based Medicine Center, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 4Urinary Surgery, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 5Nephrology Department, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 6Nursing Department, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 7International Acupuncture and Moxibustion Innovation Institute, Beijing University of Chinese Medicine, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhi-Cheng Qu, Emergency Department, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 23 Meishuguanhou Street, Dongcheng District, Beijing, 100010, People’s Republic of China, Email qzhch0824@163.com Jian-Feng Tu, School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, People’s Republic of China, Email tujianfeng1@126.comIntroduction: Analgesia is often delayed for suspected acute renal colic due to urinary calculi (ARCUC) even in emergency department. Acupuncture has a rapid onset and is effective for analgesia, however, evidence about early-acupuncture for suspected ARCUC is limited. This trial aims to evaluate the efficacy of early-intervention acupuncture compared with sham acupuncture on pain relief among emergency department suspected ARCUC patients.Methods and Analysis: A total of 84 eligible patients who are suspected diagnosed with ARCUC will be randomly allocated to the acupuncture group or the sham acupuncture group. Each patient will receive 1 session of acupuncture or sham acupuncture before diagnostic imaging. The primary outcome will be the response rate at 10 min after needle manipulation, defined as the proportion of patients whose Numeric Rating Scale (NRS) score decrease by at least 50% from baseline. Secondary outcomes will include pain intensity assessed by NRS, further analgesia requirement, revisit rate, surgical intervention rate, satisfaction evaluation, and adverse events. The final diagnosis rate determined by radiography will be recorded and reported. All patients who receive randomization will be included in the intention-to-treat analysis.Conclusion: This study’s findings are anticipated to evaluate the analgesic effect of early-intervention acupuncture for acute renal colic in emergency department, which could be useful for moving the timing of analgesia forward and aligning pain management for acute renal colic more with the guidelines.Trial Registration Number: ChiCTR2100049069 (https://www.chictr.org.cn/showproj.html?proj=125338).Keywords: acupuncture, complementary medicine, pain management, emergency medicine, renal colic

Yongping Cao, Mengyun Zhou, Tianhong Xu Department of Dermatology, Hangzhou Third People’s Hospital, Hangzhou City, Zhejiang Province, People’s Republic of ChinaCorrespondence: Tianhong Xu, Department of Dermatology, Hangzhou Third People’s Hospital, 38 West Lake Road, Hangzhou City, Zhejiang Province, People’s Republic of China, Email tianhongxu2024@163.comBackground: It is well-documented that rheumatoid arthritis (RA), ankylosing spondylitis (AS), and juvenile idiopathic arthritis (JIA) often exhibit skin manifestations, with psoriasis typically occurring around the time of diagnosis. Thus, it is essential to investigate the potential causal relationship between these forms of arthritis and psoriasis.Methods: The OpenGWAS provided traitIDs for exposure factors (RA (bbj-A-74), AS (ebi-A-GCST005529), and JIA (finn-b-JUVEN-ARTHR)) and outcome (psoriasis, finn-b-L12-PSORIASIS). bbj-A-74 had 19,190 samples (9,739,303 SNPs), ebi-A-GCST005529 had 22,647 samples (99,962 SNPs), finn-b-JUVEN-ARTHR had 173,622 samples (16,380,296 SNPs), and psoriasis had 216,752 samples (16,380,464 SNPs). Initially, 57 RA SNPs, 25 AS SNPs, and 5 JIA SNPs were acquired. Causal links were explored via univariate Mendelian Randomization (UVMR) analysis, with sensitivity analyses ensuring reliability. Additionally, multivariate MR (MVMR) analysis was conducted to further estimate the effect of each exposure factor on psoriasis.Results: Significant causal links (P < 0.05, OR > 1) were found between bbj-A-74, ebi-A-GCST005529, finn-b-JUVEN-ARTHR, and finn-b-L12-PSORIASIS, indicating associations of RA, AS, and JIA with psoriasis. Sensitivity analyses ensured the reliability of these finding, showing no heterogeneity, horizontal pleiotropy, or SNP locus oversensitivity in UVMR results. Furthermore, MVMR analysis revealed AS and JIA as psoriasis risk factors, while RA showed non-significant protective effects. This suggests AS and JIA may contribute to psoriasis onset or exacerbation when coexisting.Conclusion: MR analyses were conducted to investigate the causal links between RA, AS, JIA, and psoriasis, enhancing our grasp of the underlying mechanisms of psoriasis.Keywords: causal links, openGWAS, sensitivity analyses, risk factors

Minghui Li,1,&ast; Jiabi Wu,1,&ast; Tao Yang,1 Yuhang Zhao,1 Ping Ren,1 Lingling Chang,2 Pilong Shi,1 Jing Yang,1 Yuhang Liu,2 Xiaolei Li,3 Peng Wang,2 Yonggang Cao1 1Department of Pharmaceutics, Harbin Medical University, Heilongjiang, 163319, People’s Republic of China; 2Department of Physiology, Harbin Medical University, Heilongjiang, 163319, People’s Republic of China; 3Department of Pathology, Jiangsu College of Nursing, Jiangsu, 223003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peng Wang, Department of Physiology, Harbin Medical University, Xinyang Road 39, Gaoxin District, Daqing, Heilongjiang, People’s Republic of China, Email wangpeng810122@126.com Yonggang Cao, Department of Pharmaceutics, Harbin Medical University, Xinyang Road 39, Gaoxin District, Daqing, Heilongjiang, People’s Republic of China, Email caoyonggang@hmudq.edu.cnBackground: Cardiac microvascular damage is substantially related with the onset of myocardial ischaemia-reperfusion (IR) injury. Reportedly, allicin (AL) effectively protects the cardiac microvascular system from IR injury. However, the unsatisfactory therapeutic efficacy of current drugs and insufficient drug delivery to the damaged heart are major concerns. Here, inspired by the natural interaction between neutrophils and inflamed cardiac microvascular endothelial cells (CMECs), a neutrophil membrane-camouflaged nanoparticle for non-invasive active-targeting therapy for IR injury by improving drug delivery to the injured heart is constructed.Methods: In this study, we engineered mesoporous silica nanoparticles (MSNs) coated with a neutrophil membrane to act as a drug delivery system, encapsulating AL. The potential of the nanoparticles (named AL@MSNs@NM) for specific targeting of infarcted myocardium was assessed using small animal vivo imaging system. The cardiac function of AL@MSNs@NM after treatment was evaluated by Animal Ultrasound Imaging system, HE staining, and Laser Speckle Imaging System. The therapeutic mechanism was analyzed by ELISA kits, immunofluorescence, and PCR.Results: We discovered that AL@MSNs@NM significantly improves cardiac function index, reduced infarct size and fibrosis, increased vascular perfusion in ischemic areas, and also promoted the function of CMECs, including migration, tube formation, shear stress adaptation, and nitric oxide production. Further research revealed that AL@MSNs@NM have cardio-protective functions in IR rats by inhibiting CMEC ferroptosis and increasing platelet endothelial cell adhesion molecule-1 (PECAM-1) expression.Conclusion: Our results indicated that AL@MSNs@NM significantly reversed CMEC ferroptosis and increased PECAM-1 expression, enhanced cardiac function, and reduced myocardial infarction size. Therefore, this strategy demonstrates that engineered biomimetic nanotechnology effectively delivers AL for targeted therapy of myocardial infarction.Keywords: neutrophil membrane, ischemia-reperfusion, allicin, cardiac microvascular endothelial cells, ferroptosis

Yongkang Zhang,&ast; Jiarui Liu,&ast; Yuzhen Wang, Yuan Zong, Kangli Yin, Fang Cao, Xinyu Liang, Yemin Cao Diagnosis and Treatment Center of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yemin Cao; Yongkang Zhang, Diagnosis and Treatment Center of Vascular Disease, Shanghai TCM-Integrated Hospital, No. 230 Baoding Road, Hongkou District, Shanghai, People’s Republic of China, Tel +8613361831119 ; +8613761921568, Email caoyemin@shutcm.edu.cn; zhangyongkang_tcm@163.comPurpose: Peripheral arterial disease (PAD) is a chronic ischemic disease caused by atherosclerosis of the lower extremities, with early clinical symptoms manifesting mainly as intermittent claudication. Current treatment of PAD is based on the control of cardiovascular risk factors. However, even vasoactive drugs are not ideal for improving ischemic symptoms in the lower limbs of PAD patients. Ruanjian Qingmai granules, derived from the classic formula of the late Professor Jiuyi Xi, a famous traditional Chinese medicine doctor in Shanghai, have good clinical efficacy in the treatment of the pattern of blood vessel stasis and obstruction of PAD and have been used by more than 600,000 PAD patients over the past three decades. This study aims to evaluate the efficacy and safety of Ruanjian Qingmai granules in patients with symptomatic PAD.Patients and methods: A prospective, center-randomized, double-blind, placebo-controlled clinical trial will be conducted at 9 grade A tertiary hospitals in Shanghai. It is anticipated that 250 patients with early symptomatic PAD will be recruited and randomized to the control and intervention groups (1:1 ratio of central randomization). Subjects will be treated with Ruanjian Qingmai granules or placebo at 6 g twice daily for 16 weeks. The primary efficacy indicators are the pain-free walking distance and maximum walking distance. The secondary efficacy indicators are the ankle-brachial index, walking impairment questionnaire, quality of life score, and Chinese medicine syndrome score.Conclusion: Positive results from this study will demonstrate the efficacy and safety of Ruanjian Qingmai granules in improving ischemic symptoms in patients with symptomatic PAD.Clinical Registration: This study has been registered with the Chinese Clinical Trials Registry (ChiCTR2200056109, Date: 02/01/2022, https://www.chictr.org.cn/showproj.html?proj=150982).Keywords: peripheral arterial disease, Ruanjian Qingmai granules, intermittent claudication, efficacy, randomized controlled trial, protocol

Tiansu Lv,1,2,&ast; Jie Tian,1,3,&ast; Yaohuan Sun,1,3 Yujuan Zhang,1,2 Fang Qi,1,2 Liulan Xiang,1,2 Yutian Cao,1,2 Wenhui Zhang,1,2 Jiaxuan Huai,1,2 Yinfeng Dong,4 Xiqiao Zhou1,2 1Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 3School of Nursing, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 4Department of Pathology and Pathophysiology, School of Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiqiao Zhou; Yinfeng Dong, Email zhouxiqiao@njucm.edu.cn; dongyf@njucm.edu.cnBackground: Metabolic Associated Fatty Liver Disease (MAFLD) poses a significant threat to human health, as it can result in hepatic fibrosis and potentially progress to cirrhosis, in addition to causing a range of extrahepatic complications. The early detection of MAFLD is crucial, particularly during the initial stages when the condition may be amenable to reversal and the body composition could be vital importance.Methods: Data from participants at the Jiangsu Province Hospital of Traditional Chinese Medicine, covering the period from January 1 to December 31, 2022, were collected and subsequently randomized into training and validation cohorts. Independent risk factors for MAFLD were identified using statistical methodologies in conjunction with clinical relevance, and these factors were ultimately utilized to develop the nomogram.Results: In the training cohort, there were 356 cases of MAFLD out of a total of 513 patients, representing 71.2%, while in the validation cohort, 161 cases of MAFLD were identified out of 220 patients, accounting for 73.2%. In terms of statistical outcomes and clinical relevance, we identified a total of 12 closely related or significant variables. To enhance our understanding of the critical role of body composition parameters in predicting the incidence of MAFLD, we developed two distinct nomograms, one of which included body composition data. Notably, the nomogram that incorporated body composition demonstrated superior predictive performance, as evidenced by a well-fitted calibration curve and a C-index of 0.893 (with a range of 0.8625 to 0.9242). Furthermore, the decision curve analysis indicated that utilizing the nomogram that included body composition would yield greater benefits.Conclusion: The nomogram serves as an effective tool for predicting MAFLD. Its utility in early risk identification of MAFLD is of significant importance, as it facilitates timely intervention and treatment for patients affected by this condition.Keywords: Metabolic Associated Fatty Liver Disease, Body Composition, Nomogram

Zelan Xiao,1 Shengfang Long,2 Zhiqiang Yan,1 Zhen Chen,1 Lihui Lin,1 Yawen Cao1 1Department of Gynecology, Hainan Western Central Hospital, Danzhou City, Hainan Province, People’s Republic of China; 2Department of Obstetrics and Gynecology, Yangpu Economic Development Zone Hospital, Danzhou City, Hainan Province, People’s Republic of ChinaCorrespondence: Yawen Cao, Department of Gynecology, Hainan Western Central Hospital, No. 5, Wuxiang, Xinshijie Garden Community, Danzhou City, Hainan Province, 571700, People’s Republic of China, Tel +86 18876098257, Email caoyw2024yw@163.comAbstract: Abdominal pregnancy is a rare and life-threatening form of ectopic pregnancy. Although the underlying mechanism of this abnormal disorder is unknown, a number of risk factors have been identified, including pelvic inflammatory disease, history of pelvic surgery, intrauterine device use and previous ectopic pregnancy. Diaphragmatic rupture due to ectopic pregnancy is a rare and life-threatening condition that can lead to massive intraperitoneal haemorrhage and haemorrhagic shock. This report presents the case of a 21-year-old woman who presented with 7 weeks and 4 days of amenorrhoea and 14 hours of acute abdominal pain. On examination, she was in haemorrhagic shock with signs of acute abdomen. Emergency exploratory laparotomy revealed a haemoperitoneum of 1500 mL and active bleeding from a 3× 2 cm rupture in the right hemidiaphragm. Haemostasis was achieved and the patient recovered well post-operatively. This case highlights the importance of considering diaphragmatic rupture in the differential diagnosis of acute abdomen and haemorrhagic shock, especially in patients with ectopic pregnancy.Keywords: abdominal pregnancy, ectopic pregnancy, diaphragmatic pregnancy

Jiong Li,1 Dongqin Lei,1 Yanbing Cao,2,3 Fuli Xin,2,3 Zhenxi Zhang,1 Xiaolong Liu,2,3 Ming Wu,2,3 Cuiping Yao1 1Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Photonics and Sensing, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049, People’s Republic of China; 2The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China; 3Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, People’s Republic of ChinaCorrespondence: Ming Wu, Mengchao Hepatobiliary Hospital of Fujian Medical University, 312 Xi Hong Road, Fuzhou, 350025, People’s Republic of China, Email wmmj0419@163.com Cuiping Yao, School of Life Science and Technology, Xi’an Jiaotong University, 28 Xian Ning West Road, Xi’an, 710049, People’s Republic of China, Email zsycp@xjtu.edu.cnIntroduction: Photodynamic therapy (PDT) has attracted increasing attention in the clinical treatment of epidermal and luminal tumors. However, the PDT efficacy in practice is severely impeded by tumor hypoxia and the adverse factors associated with hydrophobic photosensitizers (PSs), including low delivery capacity, poor photoactivity and limited ROS diffusion. In this study, Pt nanozymes decorated two-dimensional (2D) porphyrin metal-organic framework (MOF) nanosheets (PMOF@HA) were fabricated and investigated to conquer the obstacles of PDT against hypoxic tumors.Materials and Methods: PMOF@HA was synthesized by the coordination of transition metal iron (Zr4+) and PS (TCPP), in situ generation of Pt nanozyme and surface modification with hyaluronic acid (HA). The abilities of hypoxic relief and ROS generation were evaluated by detecting the changes of O2 and 1O2 concentration. The cellular uptake was investigated using flow cytometry and confocal laser scanning microscopy. The SMMC-7721 cells and the subcutaneous tumor-bearing mice were used to demonstrate the PDT efficacy of PMOF@HA in vitro and in vivo, respectively.Results: Benefiting from the 2D structure and inherent properties of MOF materials, the prepared PMOF@HA could not only serve as nano-PS with high PS loading but also ensure the rational distance between PS molecules to avoid aggregation-induced quenching, enhance the photosensitive activity and promote the rapid diffusion of generated radical oxide species (ROS). Meanwhile, Pt nanozymes with catalase-like activity effectively catalyzed intratumoral overproduced H2O2 into O2 to alleviate tumor hypoxia. Additionally, PMOF@HA, with the help of externally coated HA, significantly improved the stability and increased the cell uptake by CD44 overexpressed tumor cells to strengthen O2 self-supply and PDT efficacy.Conclusion: This study provided a new strategy of integrating 2D porphyrin MOF nanosheets with nanozymes to conquer the obstacles of PDT against hypoxic tumors.Keywords: 2D porphyrin MOF, hypoxic relief, Pt nanozyme, photodynamic therapy

KaiMing Wei,1,2,&ast; Yuan Cao,1,3,&ast; XiangJin Kong,1,2 ChuanZhen Liu,1,2 XingHua Gu1,2 1Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Cardiovascular Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 3National Key Laboratory for Innovation and Transformation of Luobing Theory; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: XingHua Gu, Email guxinghua@email.sdu.edu.cnBackground: Cardiovascular diseases, such as aortic valve calcification (AVC) and carotid atherosclerosis (CAS), impose substantial health challenges on a global scale. Both disorders have overlapping risk factors, which might trigger similar immune-inflammatory reactions in both diseases.Methods: Shared differentially expressed genes (DEGs) were identified in the AVC and CAS datasets from the Gene Expression Omnibus (GEO). Candidate hub genes associated with immunity were identified using LASSO and immune cell infiltration analysis, and single gene set enrichment analysis (GSEA) was performed on the datasets. Subsequently, the hub genes were confirmed by qRT‒PCR validation in tissue samples.Results: A total of 140 upregulated and 65 downregulated common genes were screened. Enrichment analyses highlighted immune system processes, response to stress, and cytokine pathways among the identified CEGs. LASSO identified candidate hub genes, including ANGPTL1, CX3CR1, and CCL4. Immune cell infiltration analysis emphasized the participation of immune cells, including macrophages, γδ T cells, and resting NK cells. The three hub genes were validated by qRT‒PCR analysis.Conclusion: Our study explored immunological processes, including immune-related genes and cells, involved in the development of AVC and CAS. In particular, the identified hub genes ANGPTL1, CX3CR1, and CCL4 play crucial roles in mediating immune-inflammatory responses, which are central to the pathogenesis of these cardiovascular diseases, and the involvement of these genes in key immune pathways suggests that they could serve as potential biomarkers for early diagnosis or as targets for therapeutic strategies.Keywords: aortic valve calcification, carotid atherosclerosis, immune-related genes

Yue Li,1,2,&ast; Yuhui Wang,2,3,&ast; Yonghong Cao,1,2 Xinxiu Zhang,1,2 Wu Dai,1,2 Yiran Zhao,1,2 Lei Zhang,1,2 Xiaofang Han1,2 1Department of Endocrinology, Hefei Hospital Affiliated to Anhui Medical University, Hefei, People’s Republic of China; 2The Fifth Clinical College of Anhui Medical University, Hefei, People’s Republic of China; 3Department of Cardiology, Hefei Hospital Affiliated to Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaofang Han, Email hxfanghf@sina.comPurpose: To inquire into the relationship between diabetic peripheral neuropathy (DPN) and serum levels of growth differentiation factor-15 (GDF-15) in individuals with type 2 diabetes mellitus (T2DM).Patients and Methods: Out of 162 T2DM patients classified according to the diagnostic criteria of DPN, 75 were allocated to the non-DPN group and 87 to the DPN group. In turn, based on serum GDF-15 quartiles, all patients were additionally divided (GDF-15 low to high) into group A (40 cases), group B (41 cases), group C (41 cases), and group D (40 cases). General data and laboratory indexes of patients were collected, and enzyme-linked immunosorbent assay (ELISA) was used to determine serum GDF-15 levels.Results: Compared to the non-DPN group, in the DPN group GDF-15 levels were noticeably greater (P < 0.001). Using serum GDF-15 as a grouping variable, DPN prevalence and body mass index were gradually increased, motor and sensory nerve latencies were gradually lengthened, and amplitude (Amp) and nerve conduction velocity (NCV) were gradually decreased with increasing GDF-15 levels (P < 0.05). Linear regression modeling revealed that GDF-15 levels correlated positively with the latencies of sensory and motor nerves, and negatively with their corresponding NCV (P < 0.05). Binary logistic regression results indicated GDF-15 as an independent predictor for DPN (P < 0.05), whereas restricted cubic spline analysis indicated a dose-response, nonlinear relationship between GDF-15 and DPN.Conclusion: Serum GDF-15 level strongly correlates with DPN, and may represent an independent predictor and a biological marker for the disease.Keywords: growth differentiation factor 15, diabetic neuropathy, nerve conduction study, type 2 diabetes mellitus

Yin Cao,1– 4 Qingrong Xia,1– 4 Jun Liang,1– 4 Jiequan Wang,1– 4 Feng Shan,1– 4 Biao Dai1– 4 1Department of Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei, People’s Republic of China; 3Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, People’s Republic of China; 4Department of Clinical Pharmacy, Anhui Clinical Research Center for Mental Disorders, Hefei, People’s Republic of ChinaCorrespondence: Jun Liang, Department of Pharmacy, Hefei Fourth People’s Hospital, 316 Huangshan Road, Hefei, 230000, People’s Republic of China, Email amhcliangj@163.comObjective: The present study aims to investigate the effect of common cold on the serum clozapine concentrations in hospitalized patients with schizophrenia.Methods: A total of 65 schizophrenic patients with common cold receiving clozapine treatment were retrospectively enrolled. The demographic data, medication situation, clozapine concentration, and parameters of routine haematological and biochemical laboratory tests were obtained from the medical record system. The serum clozapine concentration and clozapine concentration/dose (C/D) ratios between the baseline period and cold period were compared by paired-sample t tests. Association between the changes in serum concentration and C/D ratios of clozapine and changes in white blood cell (WBC) and neutrophil (NE) counts was evaluated using Pearson correlation analysis.Results: The serum clozapine concentration (t = − 9.856, P < 0.001) and clozapine C/D ratios (t = − 10.071, P < 0.001) were found to be significantly elevated in the cold period compared to the baseline period. Moreover, the changes in the serum clozapine concentration were found to be significantly elevated in female patients compared to male patients (t = − 2.483, P = 0.017). Furthermore, changes in the serum clozapine concentration were positively correlated to the changes in WBC (r = 0.303, P = 0.014) and NE (r = 0.315, P = 0.011) counts. Similarly, changes in clozapine C/D ratios were positively correlated to the changes in WBC (r = 0.275, P = 0.027) and NE (r = 0.328, P = 0.008) counts.Conclusion: The serum clozapine concentrations in patients with schizophrenia during the common cold period were increased, which might by related to the elevated WBC and NE counts.Keywords: clozapine, blood drug concentration, schizophrenia, white blood cell count, neutrophil count, common cold

Fujie Jiang,1,&ast; Shuling Liu,1,&ast; Lu Wang,1 Huifang Chen,1 Yao Huang,2 Ying Cao,2 Xiaoxia Wang,1 Meng Lin,1 Jiuquan Zhang1 1Department of Radiology, Chongqing University Cancer Hospital, Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing, 400030, People’s Republic of China; 2School of Medicine, Chongqing University, Chongqing, 400030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiuquan Zhang; Meng Lin, Department of Radiology Chongqing University Cancer Hospital, No. 181 Hanyu Road, Shapingba District, Chongqing, 400030, People’s Republic of China, Tel/Fax +86-23-65079339, Email zhangjq_radiol@foxmail.com; 15823113338@139.comPurpose: Chemotherapy mediated by Reactive oxygen species (ROS)-responsive drug delivery systems can potentially mitigate the toxic side effects of chemotherapeutic drugs and significantly enhance their therapeutic efficacy. However, achieving precise targeted drug delivery and real-time control of ROS-responsive drug release at tumor sites remains a formidable challenge. Therefore, this study aimed to describe a ROS-responsive drug delivery system with specific tumor targeting capabilities for mitigating chemotherapy-induced toxicity while enhancing therapeutic efficacy under guidance of Fluorescence (FL) and Magnetic resonance (MR) bimodal imaging.Methods: Indocyanine green (ICG), Doxorubicin (DOX) prodrug pB-DOX and Superparamagnetic iron oxide (SPIO, Fe3O4) were encapsulated in poly(lactic-co-glycolic acid) (PLGA) by double emulsification method to prepare ICG/ pB-DOX/ Fe3O4/ PLGA nanoparticles (IBFP NPs). The surface of IBFP NPs was functionalized with mammaglobin antibodies (mAbs) by carbodiimide method to construct the breast cancer-targeting mAbs/ IBFP NPs (MIBFP NPs). Thereafter, FL and MR bimodal imaging ability of MIBFP NPs was evaluated in vitro and in vivo. Finally, the combined photodynamic therapy (PDT) and chemotherapy efficacy evaluation based on MIBFP NPs was studied.Results: The multifunctional MIBFP NPs exhibited significant targeting efficacy for breast cancer. FL and MR bimodal imaging clearly displayed the distribution of the targeting MIBFP NPs in vivo. Upon near-infrared laser irradiation, the MIBFP NPs loaded with ICG effectively generated ROS for PDT, enabling precise tumor ablation. Simultaneously, it triggered activation of the pB-DOX by cleaving its sensitive moiety, thereby restoring DOX activity and achieving ROS-responsive targeted chemotherapy. Furthermore, the MIBFP NPs combined PDT and chemotherapy to enhance the efficiency of tumor ablation under guidance of bimodal imaging.Conclusion: MIBFP NPs constitute a novel dual-modality imaging-guided drug delivery system for targeted breast cancer therapy and offer precise and controlled combined treatment options.Keywords: targeted drug delivery, photodynamic therapy, ROS-responsive chemotherapy, bimodal imaging

Pengfeng Gong,1,&ast; Jie Shen,1 Yu Yang,2,&ast; Dong Xue,1 Hao Lu,1 Qianfeng Zhuang,1 Xiaogang Wang,1 Zinong Tian,1 Yiming Chen,1 Cheng Chen,1 Yunjie Cao1 1Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, 213000, People’s Republic of China; 2Department of Hepato-Pancreato-Biliary Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunjie Cao, Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, 213000, People’s Republic of China, Tel +86-13775188220, Email caoyunjie1847@163.comObjective: To explore patients’ knowledge, attitude, and practice (KAP) toward varicocele in China and the relationship between treatment selection and KAP.Methods: This cross-sectional study enrolled varicocele patients at the Third Affiliated Hospital of Soochow University (September to October 2023). Structural equation modeling (SEM) was used to explore the relationship between clinical factors and KAP. A score >mean score for each dimension was defined as adequate knowledge, positive attitude, and proactive practice. The patients were grouped according to varicocelectomy vs no surgery. Univariable and multivariable logistic regression analyses were used to identify the factors independently associated with KAP. A structural equation modeling (SEM) analysis was performed to examine how the KAP dimensions influenced each other.Results: Among 502 patients, 44.02%, 35.86%, and 20.12% were ≤ 30, 31– 40, and > 40 years old, respectively. Those who underwent varicocelectomy (n=407) had significantly higher knowledge (20 (15– 22) vs 0 (0– 6), P< 0.001), attitude (26 (24– 26) vs 14 (10– 18), P< 0.001), and practice (20 (17– 24) vs 8 (6– 16), P< 0.001) than those who did not. A higher proportion of patients with varicocelectomy were < 40 years old, more educated, had higher income, and were unmarried compared with those without surgery (all P< 0.001). High school or higher education level and varicocelectomy (irrespective of type) were independently associated with adequate knowledge (all P< 0.001). Knowledge, college/bachelor’s degree education, and varicocelectomy type (irrespective of type) were associated with positive attitudes (all P< 0.05). In the SEM, knowledge directly influenced attitude, knowledge directly influenced practice, and attitude directly influenced practice (all P< 0.001). Having knowledge of the subject may direct varicocele patients to varicocelectomy.Conclusion: Chinese patients who underwent varicocelectomy exhibit appropriate KAP regarding varicocele, while non-surgery patients have poorer KAP. These results suggest that patients who did not undergo surgery should nevertheless be properly informed about their disease.Keywords: knowledge, attitude, practice, varicocele, varicocelectomy, cross-sectional study

Yongsheng Cao,1 Jianqin Zhao,2 Yanjuan Ma,2 Shujie Cao,2 Ying Liu2 1Department of Neurology, Sunshine Union Hospital, Weifang, Shandong, People’s Republic of China; 2Department of Endocrinology, Sunshine Union Hospital, Weifang, Shandong, People’s Republic of ChinaCorrespondence: Ying Liu, Department of Endocrinology, Sunshine Union Hospital, 9000 Yingqian Street, Weifang City, Shandong, 261000, People’s Republic of China, Email 175198989@qq.comBackground: Cardiovascular outcome trials indicate renal benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs); however, real-world efficacy and safety studies in Diabetic kidney disease (DKD) are scarce.Methods: This retrospective, single-arm real-world trial involved adults with DKD treated with GLP-1RA for at least 6 months. The primary endpoint was hemoglobin A1c (HbA1c) levels after 6 months.Results: This study included a total of 364 patients with DKD, 153 (42.0%) of whom were female. The median disease duration was 8.0 years, and the mean values of age, HbA1c level, body mass index, and the urinary albumin-to-creatinine ratio (UACR) were 52.1 years, 8.6%, 27.8 kg/m2, and 88.0 mg/g, respectively. Additionally, 73.6% and 26.4% of patients had mild and moderate DKD, respectively. Following 6 months of GLP-1RA treatment, the mean HbA1c level and UACR declined by 1.77% and 40.3%, respectively (both p < 0.001). Compared to their baseline values, patients exhibited significant improvements in 24-h urinary protein, estimated glomerular filtration rate (eGFR), fasting blood glucose, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (all p < 0.001). Patients with a disease duration of < 10 years had more pronounced changes in the HbA1c level, UACR, and eGFR (all p < 0.001) than those with a disease duration of ≥ 10 years. Changes in SBP and DBP were more pronounced in patients also taking angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEis/ARBs) than in those not taking ACEis/ARBs, whereas the changes in UACR and eGFR did not significantly differ.Conclusion: Six-month GLP-1RA treatment improves glucose, blood pressure, lipids, and body weight in patients with mild-to-moderate DKD while slowing down kidney disease progression. It independently reduces proteinuria beyond ACEi/ARB impact, with early use yielding faster outcomes, supporting evidence-based practice.Keywords: diabetic kidney disease, type 2 diabetes, GLP-1RA, HbA1C, UACR

Juan Li,1,&ast; Ting Zhou,1,&ast; Pei Wang,1,&ast; Ruian Yin,1 Shengqi Zhang,1 Yile Cao,1 Lijuan Zong,1 Ming Xiao,2 Yongjie Zhang,3 Wentao Liu,4 Lingxiao Deng,5 Fei Huang,6 Jianfei Sun,7,&ast; Hongxing Wang1,&ast; 1Department of Rehabilitation Medicine, Zhongda Hospital Southeast University, Nanjing, 210024, People’s Republic of China; 2Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, People’s Republic of China; 3Department of Human Anatomy, Nanjing Medical University, Nanjing, 211166, People’s Republic of China; 4Department of Pharmacology, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, People’s Republic of China; 5Department of Neurological Surgery, Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indianapolis, IN, 46202-2266, USA; 6Institute of Neurobiology, Binzhou Medical University, Yantai, 264003, People’s Republic of China; 7State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory of Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianfei Sun, State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory of Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210009, People’s Republic of China, Email sunzaghi@seu.edu.cn Hongxing Wang, Department of Rehabilitation Medicine, Southeast University Zhongda Hospital, Nanjing, 210024, People’s Republic of China, Email 101012648@seu.edu.cnBackground: Gigantocellular reticular nucleus (GRNs) executes a vital role in locomotor recovery after spinal cord injury. However, due to its unique anatomical location deep within the brainstem, intervening in GRNs for spinal cord injury research is challenging. To address this problem, this study adopted an extracorporeal magnetic stimulation system to observe the effects of selective magnetic stimulation of GRNs with iron oxide nanoparticles combined treadmill training on locomotor recovery after spinal cord injury, and explored the possible mechanisms.Methods: Superparamagnetic iron oxide (SPIO) nanoparticles were stereotactically injected into bilateral GRNs of mice with moderate T10 spinal cord contusion. Eight-week selective magnetic stimulation produced by extracorporeal magnetic stimulation system (MSS) combined with treadmill training was adopted for the animals from one week after surgery. Locomotor function of mice was evaluated by the Basso Mouse Scale, Grid-walking test and Treadscan analysis. Brain MRI, anterograde virus tracer and immunofluorescence staining were applied to observe the tissue compatibility of SPIO in GRNs, trace GRNs’ projections and evaluate neurotransmitters’ expression in spinal cord respectively. Motor-evoked potentials and H reflex were collected for assessing the integrity of cortical spinal tract and the excitation of motor neurons in anterior horn.Results: (1) SPIO persisted in GRNs for a minimum of 24 weeks without inducing apoptosis of GRN cells, and degraded slowly over time. (2) MSS-enabled treadmill training dramatically improved locomotor performances of injured mice, and promoted cortico-reticulo-spinal circuit reorganization. (3) MSS-enabled treadmill training took superimposed roles through both activating GRNs to drive more projections of GRNs across lesion site and rebalancing neurotransmitters’ expression in anterior horn of lumbar spinal cord.Conclusion: These results indicate that selective MSS intervention of GRNs potentially serves as an innovative strategy to promote more spared fibers of GRNs across lesion site and rebalance neurotransmitters’ expression after spinal cord injury, paving the way for the structural remodeling of neural systems collaborating with exercise training, thus ultimately contributing to the reconstruction of cortico-reticulo-spinal circuit. Keywords: gigantocellular reticular nucleus, locomotion, magnetic stimulation, spinal cord injury, superparamagnetic iron oxide nanoparticles, treadmill training

Panpan Xu,1– 3 Yu Cao,1– 3 Ruiqing Ren,1– 3 Shuai Zhang,1– 3 Cheng Zhang,1– 3 Panpan Hao,1– 3 Meng Zhang1– 3 1State Key Laboratory for Innovation and Transformation of Luobing Theory, Jinan, People’s Republic of China; 2Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, People’s Republic of China; 3Department of Cardiology, Qilu Hospital of Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Meng Zhang; Panpan Hao, Department of Cardiology, Qilu Hospital of Shandong University, No. 107, Wenhuaxi Road, Jinan, Shandong, 250012, People’s Republic of China, Email zhangmeng@sdu.edu.cn; panda.how@sdu.edu.cnPurpose: The systemic inflammation response index (SIRI) and the systemic immune inflammation index (SII) are indicators that reflect the body’s overall systemic inflammatory response. Inflammation plays an important role in the pathogenesis of in-stent restenosis (ISR). The aim of this study was to investigate the predictive value of preoperative SIRI and SII for the occurrence of ISR in patients undergoing coronary stent implantation.Materials and Methods: We retrospectively analyzed the clinical, hematological, and angiographic data of 387 patients who underwent coronary angiography for recurrent angina after coronary stent implantation at Qilu Hospital of Shandong University. Receiver operating characteristic curve (ROC) analysis was used to determine the optimal cutoff values for SIRI and SII to predict ISR. Based on the optimal cutoff values for SIRI and SII, patients were categorized into high-SIRI, low-SIRI, high-SII, and low-SII groups. Multivariate logistic regression models were constructed to assess the predictive value of SIRI and SII for ISR > 50% and ISR > 70%.Results: This study included a total of 387 patients who underwent coronary angiography and follow-up at Qilu Hospital of Shandong University. Patients in the high-SIRI group had a higher incidence of ISR than those in the low-SIRI group (ISR > 50%: 44.8% vs 30.7%, p = 0.018; ISR > 70%: 41.5% vs 4.5%, p < 0.001). In addition, ISR occurred more frequently in patients with a higher SII than in patients with a lower SII (ISR > 50%: 52.6% vs 35.7%, p = 0.001; ISR > 70%: 51.9% vs 23%, p < 0.001). In multivariate logistic regression analysis, SIRI and SII were found to be independent predictive factors for ISR, both as continuous and categorical variables. In the ROC analysis, the optimal cutoff value for SIRI was set at 0.54 (sensitivity: 84.5%, specificity: 27%), and the optimal cutoff value for SII was set at 545.29 (sensitivity: 44.1%, specificity: 71.7%).Conclusion: Elevated preoperative SIRI and SII values help predict ISR and may serve as a useful screening tool to perform interventional procedures based on the patient’s risk of ISR after stent implantation.Keywords: SIRI, SII, in-stent restenosis, percutaneous coronary intervention

Wenze Han,1,2 Ran Zhang,1,2 Shuzhi Liu,1,2 Tong Zhang,1,2 Xuemin Yao,1,2 Yuxin Cao,1,2 Jiadi Li,1,2 Xiaoming Liu,1,2 Bing Li1,2 1Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, 030001, People’s Republic of China; 2Shanxi Province Key Laboratory of Oral Diseases Prevention and New Materials, Taiyuan, 030001, Shanxi, People’s Republic of ChinaCorrespondence: Xiaoming Liu; Bing Li, Shanxi Medical University School and Hospital of Stomatology, Taiyuan, Shanxi, 030001, People’s Republic of China, Email lxming0912@163.com; libing1975vip@163.comAbstract: Whiskers are nanoscale, high-strength fibrous crystals with a wide range of potential applications in dentistry owing to their unique mechanical, thermal, electrical, and biological properties. They possess high strength, a high modulus of elasticity and good biocompatibility. Hence, adding these crystals to dental composites as reinforcement can considerably improve the mechanical properties and durability of restorations. Additionally, whiskers are involved in inducing the value-added differentiation of osteoblasts, odontogenic osteocytes, and pulp stem cells, and promoting the regeneration of alveolar bone, periodontal tissue, and pulp tissue. They can also enhance the mucosal barrier function, inhibit the proliferation of tumor cells, control inflammation, and aid in cancer prevention. This review comprehensively summarizes the classification, properties, growth mechanisms and preparation methods of whiskers and focuses on their application in dentistry. Due to their unique physicochemical properties, excellent biological properties, and nanoscale characteristics, whiskers show great potential for application in bone, periodontal, and pulp tissue regeneration. Additionally, they can be used to prevent and treat oral cancer and improve medical devices, thus making them a promising new material in dentistry.Keywords: whiskers, dentistry, growth mechanism, biomaterials

Peijun Li,1,&ast; Yingqi Wang,1,&ast; Yuanyuan Cao,2 Jiacheng Shi,1 Meiling Jiang,2 Xiaoyu Han,2 Linhong Jiang,1 Yidie Bao,1 Weibing Wu,2 Xiaodan Liu1,3,4 1School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Department of Sports Rehabilitation, Shanghai University of Sport, Shanghai, 200438, People’s Republic of China; 3Institute of Rehabilitation Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 4Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai, 201203, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaodan Liu; Weibing Wu, Email hzhp403@126.com; wwb75@126.comBackground: Exercise is an indispensable component of pulmonary rehabilitation with strong anti-inflammatory effects. However, the mechanisms by which exercise prevents diaphragmatic atrophy in COPD (chronic obstructive pulmonary disease) remain unclear.Methods: Forty male C57BL/6 mice were assigned to the control (n=16) and smoke (n=24) groups. Mice in the smoke group were exposed to the cigarette smoke (CS) for six months. They were then divided into model and exercise training groups for 2 months. Histological changes were observed in lung and diaphragms. Subsequently, agonist U46639 and antagonist Y27632 of RhoA/ROCK were subjected to mechanical stretching in LPS-treated C2C12 myoblasts. The expression levels of Atrogin-1, MuRF-1, MyoD, Myf5, IL-1β, TNF-α, and RhoA/ROCK were determined by Western blotting.Results: Diaphragmatic atrophy and increased RhoA/ROCK expression were observed in COPD mice. Exercise training attenuated diaphragmatic atrophy, decreased the expression of MuRF-1, and increased MyoD expression in COPD diaphragms. Exercise also affects the upregulation of RhoA/ROCK and inflammation-related proteins. In in vitro experiments with C2C12 myoblasts, LPS remarkably increased the level of inflammation and protein degradation, whereas Y27632 or combined with mechanical stretching prevented this phenomenon considerably.Conclusion: RhoA/ROCK plays an important role in the prevention of diaphragmatic atrophy in COPD.Keywords: chronic obstructive pulmonary disease, diaphragmatic atrophy, exercise training, inflammation, RhoA/ROCK signaling

Yi Zhang,1 Dang Liu,2 Bin Qiao,3 Yuanli Luo,3 Liang Zhang,3 Yang Cao,3 Haitao Ran,3,&ast; Chao Yang4,&ast; 1Department of Ultrasound, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Radiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Chongqing Key Laboratory of Ultrasound Molecular Imaging & Department of Ultrasound, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Radiology, Jiulongpo District People’s Hospital, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haitao Ran, Chongqing Key Laboratory of Ultrasound Molecular Imaging & Department of Ultrasound, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China, Tel +86 13512373563, Email ranhaitao@cqmu.edu.cn Chao Yang, Department of Radiology, Jiulongpo District People’s Hospital, Chongqing, People’s Republic of China, Tel +86 13883095836, Email ychaof737@163.comPurpose: To address the problem of suboptimal reactive oxygen species (ROS) production in Radiation therapy (RT) which was resulted from exacerbated tumor hypoxia and the heterogeneous distribution of radiation sensitizers.Materials and Methods: In this work, a novel nanomedicine, designated as PLGA@IR780-Bi-DTPA (PIBD), was engineered by loading the radiation sensitizer Bi-DTPA and the photothermal agent IR780 onto poly(lactic-co-glycolic acid) (PLGA). This design leverages the tumor-targeting ability of IR780 to ensure selective accumulation of the nanoparticles in tumor cells, particularly within the mitochondria. The effect of the photothermal therapy-enhanced radiation therapy was also examined to assess the alleviation of hypoxia and the enhancement of radiation sensitivity.Results: The PIBD nanoparticles exhibited strong capacity in mitochondrial targeting and selective tumor accumulation. Upon activation by 808 nm laser irradiation, the nanoparticles effectively alleviated local hypoxia by photothermal effect enhanced blood supplying to improve oxygen content, thereby enhancing the ROS production for effective RT. Comparative studies revealed that PIBD-induced RT significantly outperformed conventional RT in treating hypoxic tumors.Conclusion: This design of tumor-targeting photothermal therapy-enhanced radiation therapy nanomedicine would advance the development of targeted drug delivery system for effective RT regardless of hypoxic microenvironment.Keywords: Bi-DTPA, IR780, radiotherapy, tumor microenvironment hypoxia, photothermal therapy

Shifu Sun,1,2,&ast; Yongqing Cheng,2,&ast; Lei Li,2 Honghong Zhu,3 Changxia Liu,2 Yongjun Cao1 1Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, People’s Republic of China; 2Department of Neurology, the Yancheng Clinical College of Xuzhou Medical University, the First People’s Hospital of Yancheng, Yancheng, Jiangsu Province, 224000, People’s Republic of China; 3Department of Rheumatology and Immunology, the Yancheng Clinical College of Xuzhou Medical University, the First People’s Hospital of Yancheng, Yancheng, Jiangsu Province, 224000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongjun Cao, Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215004, People’s Republic of China, Tel +86-18361077906, Email yongjuncao@126.com Yongqing Cheng, Department of Neurology, the Yancheng Clinical College of Xuzhou Medical University, the First People’s Hospital of Yancheng, Yancheng, Jiangsu Province, People’s Republic of China, Tel +86-13851190252, Email chengyq1990@163.comPurpose: The fibrinogen-to-albumin ratio (FAR) is a novel inflammation marker associated with various diseases. This study aimed to investigate the correlation between FAR and early neurological deterioration (END) after intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS).Patients and Methods: From September 1, 2021, to March 31, 2023, continuously recruited AIS patients who received IVT within 4.5 hours were included in the study. Blood samples were collected in the emergency room before IVT. The National Institutes of Health Stroke Scale (NIHSS) score was assessed upon admission and after thrombolysis within the first 24 hours. END was defined as an increase in the NIHSS score by ≥ 4 points within 24 hours after thrombolysis. Multivariate logistic regression analysis was conducted to explore the relationship between FAR and END, and a receiver operating characteristic (ROC) curve was used to evaluate the predictive ability of FAR for END.Results: 343 participants were recruited, and 59 (17.2%) experienced END. Patients with END had higher FAR levels than those without END (P< 0.001). Multivariate logistic regression analysis showed that FAR was independently associated with END, both as a continuous variable and as a tertile variable (P< 0.005). After excluding patients with hemorrhagic transformation (HT), FAR remained independently associated with END (P< 0.005). The area under the curve (AUC) of FAR for predicting END was 0.650 (95% CI=0.571– 0.729, P< 0.001), with an optimal cutoff of 72.367 mg/g, a sensitivity of 61.6%, and a specificity of 62.6%.Conclusion: FAR upon admission was independently associated with END after IVT and can be an effective predictor.Keywords: fibrinogen-to-albumin ratio, early neurological deterioration, intravenous thrombolysis, acute ischemic stroke, inflammation marker

Bingmei Hou,1,2 Xing Wei,2,3 Mianyu Yang,4,5 Yonghong Cao,1,2 Wu Dai1,2 1Department of Endocrinology, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China; 2The Fifth Clinical School of Medicine, Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China; 3Department of Cardiology, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, the Second People’s Hospital of Hefei, Bengbu Medical University, Hefei, Anhui, 230011, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, The Second People’s Hospital of Hefei, Hefei, Anhui, 230011, People’s Republic of ChinaCorrespondence: Wu Dai; Yonghong Cao, Department of Endocrinology, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China, Email HouBmei@outlook.com; fish1982cao@126.comBackground: Growing evidence indicates that there is a close relationship between type 2 diabetes mellitus (T2DM) and sarcopenia, and T2DM patients are often accompanied by obesity. However, research exploring the connection between body fat percentage (BFP) and sarcopenia is currently limited.Methods: This was a cross-sectional study that included 676 patients with T2DM over 50 years old. The appendicular skeletal muscle mass index (ASMI), handgrip strength, and 5-time chair stand test (5-TCST) were measured, and sarcopenia was diagnosed according to the Asian Working Group on Sarcopenia (AWGS). Spearman’s coefficient was used to evaluate the correlation of BFP and body mass index (BMI) with the diagnostic elements of sarcopenia, and BFP and other relevant covariates were included in the binary logistic regression model. The subgroup performed an interaction test for statistically significant population baseline information.Results: The prevalence of sarcopenia was 18.0% in males and 11.6% in females. Spearman correlation analysis showed that BFP was positively correlated with ASMI in women (R=0.107, P=0.029), but not in men. BFP was negatively correlated with grip strength (male: R= − 0.187, P=0.003; female: R=− 0.108, P=0.029). There was a positive correlation between BFP and 5-TCST (male: R=0.199, P=0.001; female: R=0.144, P=0.003). After adjusting for confounding factors, BFP was an independent risk factor for sarcopenia (men, OR: 1.33, 95% CI: 1.15– 1.54; women, OR: 1.26, 95% CI: 1.13– 1.41). This correlation was generally consistent, as demonstrated in further subgroup analyses.Conclusion: High BFP was significantly associated with sarcopenia risk, and this association was independent of gender, age, and BMI.Keywords: body fat percentage, diabetes, sarcopenia, body mass index, obesity

Wanlan Fu,1 Yunxiang Cao,2 Jian Liu,2 Chuanbing Huang,2 Kaiyan Shu,1 Nanfei Zhu1 1First Clinical Medical College, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, People’s Republic of China; 2Department of Rheumatology, First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, People’s Republic of ChinaCorrespondence: Yunxiang Cao, Department of Rheumatology, First Affiliated Hospital of Anhui University of Chinese Medicine, 117 Meishan Road, Shushan District, Hefei, Anhui, 230031, People’s Republic of China, Tel +86-13514984395 ; +0551-62838591, Email cyx800805@163.comPurpose: This study probed the mechanism of action of Xinfeng Capsule (XFC) in myocardial injury in rats with adjuvant arthritis (AA) via the growth arrest-specific transcript 5 (GAS5)/microRNA-21 (miR-21)/Toll-like receptor 4 (TLR4) axis.Methods: Rats were injected with Freund’s complete adjuvant to establish a rat model of AA. Then, some modeled rats were given normal saline or drugs only, and some modeled rats were injected with adeno-associated viruses or necrosulfonamide (NSA; a pyroptosis inhibitor) before drug administration. Toe swelling and arthritis index (AI) were calculated. Pathological and morphological changes in synovial and myocardial tissues were analyzed with hematoxylin-eosin staining, and pyroptotic vesicles and the ultrastructural changes of myocardial tissues were observed with transmission electron microscopy. The serum levels of interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α were detected, and lactate dehydrogenase (LDH) release was measured in myocardial tissues, accompanied by the examination of GAS5, miR-21, TLR4, nuclear factor-kB (NF-κB) p65, nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Caspase-1, and Gasdermin D (GSDMD) expression in myocardial tissues.Results: After AA modeling, rats presented with significantly increased toe swelling and AI scores, synovial and myocardial tissue damage, elevated pyroptotic vesicles, and markedly enhanced serum levels of IL-1β, IL-18, IL-6, and TNF-α, accompanied by significantly diminished GAS5 expression, substantially augmented miR-21, TLR4, NF-κB p65, NLRP3, Caspase-1, and GSDMD expression, greatly increased LDH release in myocardial tissues. XFC treatment significantly declined toe swelling, AI scores, synovial and myocardial tissue damage, and the serum levels of IL-1β, IL-18, IL-6, and TNF-α in AA rats. Additionally, XFC treatment markedly elevated GAS5 expression and substantially lowered LDH release and miR-21, TLR4, NF-κB p65, NLRP3, Caspase-1, and GSDMD expression in myocardial tissues of AA rats. Moreover, the above effects of XFC in AA rats were further promoted by GAS5 overexpression or NSA treatment.Conclusion: XFC alleviated myocardial injury in AA rats by regulating the GAS5/miR-21/TLR4 axis and inhibiting pyroptosis and pro-inflammatory cytokine secretion.Keywords: adjuvant arthritis, myocardial injury, GAS5/miR-21/TLR4 axis, pyroptosis, Xinfeng Capsule

Cen Cheng, Jingjing Wang, Yuanyuan Cao, Erwei Gu, Xuesheng Liu Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Xuesheng Liu, Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China, Email liuxuesheng@ahmu.edu.cnIntroduction: Rectus sheath block is an emerging technique that provide effective perioperative analgesia and is related to lower perioperative opioid consumption and decrease opioid-related adverse effects. The present research is designed to explore the effect of rectus sheath block on recovery quality in patients following transabdominal midline gynecological surgery.Methods: Ninety female patients following elective transabdominal midline gynecological surgery were enrolled. Patients were randomized to group R (n = 45) which receive preoperative ultrasound-guided RSB with 0.4% ropivacaine or group C which is control group (n = 45). The primary outcome was the quality of recovery on the first postoperative day. The quality of recovery was assessed by the 40-item Quality of Recovery questionnaire (QoR-40). Secondary outcomes included the intraoperative opioid consumption, time to first flatus and time to first discharging from bed, postoperative nausea and vomiting, and patient satisfaction.Results: The patients in two groups had comparable baseline characteristics. Postoperative global QoR-40 scores were significantly better in group R than in group C (165.0[159.5-170.0] vs 155.0[150.0-157.0], respectively; median difference 12[95% confidence interval: 8-15, P< 0.001]). Preoperative RSB reduced intraoperative opioid consumption, reduced the time to first flatus, time to first discharging from bed and the post anaesthesia care unit discharge time. Furthermore, group R showed greater patient satisfaction.Conclusion: A single preoperative administration of RSB with ropivacaine improved the quality of recovery in patients following transabdominal midline gynecological surgery.Plain Language Summary: Although laparoscopic surgery accounts for a higher proportion of gynecological procedures, open gynecological surgery remains irreplaceable for some patients. Recovery from open gynecological surgery is a combination of physical injuries and psychological challenges. Consequently, accelerating functional recovery, alleviating discomfort and improving the quality of recovery in such patients is a clinical issue that we need to focus on. The QoR 40 scale is a patient-reported assessment tool which evaluates the quality of recovery in five dimensions.Ultrasound-guided rectus sheath block is a safe and effective abdominal wall nerve block for anesthesia and analgesia of umbilical and median abdominal longitudinal incisions. This study investigated the impact of rectus sheath block on the quality of postoperative recovery after open gynecological surgery using the QoR40 scale. Participants were randomized to two groups: rectus sheath block treatments and a control group receiving standard care only.Rectus sheath block improves the quality of recovery in patients undergoing open gynecological surgery one day after surgery without adverse effects, which has successfully made rapid rehabilitation from bench to bedside.Keywords: rectus sheath block, quality of recovery, transabdominal midline gynecological surgery, QoR 40

Xulin Liu,1,&ast; Zhancheng Qiu,2,&ast; Elijah Ndhlovu,1,&ast; Yunyan Wan,3 Huapeng Sun,4 Shuai Wang,5 Yugang Cao,6 Peng Zhu1 1Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, Taihe Hospital, Shiyan City, Hubei Province, People’s Republic of China; 4Department of General Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, People’s Republic of China; 5Department of Hepatobiliary Surgery, Jingzhou Central Hospital, Jingzhou, People’s Republic of China; 6Department of Hepatobiliary and Pancreatic Surgery, Huangshi Central Hospital of Edong Healthcare Group, Huangshi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peng Zhu, Department of Hepatic Surgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China, Tel +86 13907170712, Email zhupeng@tjh.tjmu.edu.cnPurpose: Early recurrence (ER) is associated with poor prognosis in hepatocellular carcinoma (HCC). In this study, we developed and externally validated a nomogram based on the hemoglobin, albumin, lymphocytes, and platelets (HALP) score to predict ER for patients with BCLC stage 0/A HCC who underwent radical liver resection.Patients and Methods: A total of 808 BCLC stage 0/A HCC patients from six hospitals were included in this study, and they were assigned to a training cohort (n = 500) and an external validation cohort (n = 308). We used univariate and multivariate Cox regression analysis to identify the independent risk factors for disease-free survival (DFS). We also established and externally validated a nomogram based on these risk predictors. The nomogram was evaluated using the area under the receiver operating characteristic curve (AUC), the concordance index (C-index), the calibration curve, decision curve analysis (DCA), and Kaplan‒Meier analysis.Results: Multivariate COX regression showed that HBV DNA ≥ 10,000 IU/mL (P < 0.001), HALP score ≤ 38.20 (P < 0.001), tumor size (P = 0.003), clinically significant portal hypertension (P = 0.001), Edmondson-Steiner grade (III–IV) (P = 0.007), satellite nodules (P < 0.001), and MVI (P = 0.001) were independent risk factors for post-operative tumor recurrence. The AUC of our nomogram for predicting the 2-year and 5-year DFS was 0.756 and 0.750, respectively, in the training cohort and 0.764 and 0.705, respectively, in the external validation cohort. We divided the patients into low-, intermediate- and high-risk groups according to the risk score calculated by the nomogram. There were statistically significant differences in the DFS and overall survival (OS) among the three groups of patients (P < 0.001).Conclusion: We developed and externally validated a new nomogram, which is accurate and can predict ER in BCLC stage 0/A HCC patients after curative liver resection.Keywords: early recurrence, hepatocellular carcinoma, HALP score, nomogram, Barcelona Clinic of Liver Cancer staging system, disease-free survival

Xiaoqing Peng,1– 4,&ast; Yuanyuan Yang,3,4,&ast; Ruirui Hou,1 Longbiao Zhang,1 Can Shen,3 Xiaoyan Yang,3 Zhigang Luo,5 Zongzhi Yin,3,4 Yunxia Cao3,4 1School of Pharmacy, Anhui Medical University, Hefei, People’s Republic of China; 2Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, Anhui, People’s Republic of China; 3Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 4The Key National Health Commission Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei, People’s Republic of China; 5Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunxia Cao; Zongzhi Yin, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Sushan District, Hefei, Anhui, People’s Republic of China, Email caoyunxia5972@ahmu.edu.cn; yinzongzhi@ahmu.edu.cnAbstract: Mitochondrial carrier homolog 2 (MTCH2) is a member of the solute carrier 25 family, located on the outer mitochondrial membrane. MTCH2 was first identified in 2000. The development in MTCH2 research is rapidly increasing. The most well-known role of MTCH2 is linking to the pro-apoptosis BID to facilitate mitochondrial apoptosis. Genetic variants in MTCH2 have been investigated for their association with metabolic and neurodegenerative diseases, however, no intervention or therapeutic suggestions were provided. Recent studies revealed the physiological and pathological function of MTCH2 in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction via regulating mitochondrial apoptosis, metabolic shift between glycolysis and oxidative phosphorylation, mitochondrial fusion/fission, epithelial-mesenchymal transition, etc. This review endeavors to assess a total of 131 published articles to summarise the structure and physiological/pathological role of MTCH2, which has not previously been conducted. This review concludes that MTCH2 plays a crucial role in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction, and the predominant molecular mechanism is regulation of mitochondrial function. This review gives a comprehensive state of current knowledgement on MTCH2, which will promote the therapeutic research of MTCH2. Keywords: Mimp, MTCH2, mitochondrial carrier homolog 2, BID, apoptosis

Jiejie Guo,1– 3 Yanzi Cao,1 Ting Zhang,2 Chunshuang Xu,1 Zhitao Liu,1,4 Wanyi Li,1 Qinwen Wang1 1Zhejiang Key Laboratory of Pathophysiology, NBU Health Science Center, Ningbo University, Ningbo, People’s Republic of China; 2Department of Clinical Laboratory, The First People’s Hospital of Wenling, Taizhou, People’s Republic of China; 3Department of Neurology, The First People’s Hospital of Wenling, Taizhou, People’s Republic of China; 4Fujian Normal University, Fuzhou, People’s Republic of ChinaCorrespondence: Qinwen Wang, Zhejiang Key Laboratory of Pathophysiology, NBU Health Science Center Ningbo University, Ningbo, People’s Republic of China, Email wangqinwen@nbu.edu.cnBackground: There is growing interest in the role of physical activity in patients with of Alzheimer’s disease (AD), particularly regarding its impact of cognitive function, gut microbiota, metabolites, and neurotrophic factors.Objective: To investigate the impact of multisensory fusion training (MSFT) combined with 7, 8-dihydroxyflavone (DHF) on the behavioral characteristics, protein expression, microbiome, and serum metabolome using the AD model in mice induced with amyloid-β (Aβ).Methods: We assessed cognitive ability, anxiety-like and depression-like behaviors in Aβ mice using behavioral measures. Western blotting was employed to detect the expression of relevant proteins. The 16S rRNA gene sequencing and metabolomics were used to analyze changes in the intestinal microbial composition and serum metabolic profile, respectively, of Aβ mice.Results: The behavioral outcomes indicated that a 4-week intervention combining DHF and MSFT yielded remarkable improvements in cognitive function and reduced anxiety and depression-like behaviors in Aβ mice. In the hippocampus of Aβ mice, the combined intervention increased the levels of BDNF, VGF, PSD-95, Nrf2, p-GSK3β and p-CREB proteins. Analyses of sequence and metabolomic data revealed that Bacteroides and Ruminococcaceae were remarkably more abundant following the combined intervention, influencing the expression of specific metabolites directly linked to the maintenance of neuronal and neurobehavioral functions. These metabolites play a crucial role in vital processes, such as amino acid metabolism, lipid metabolism, and neurotransmitter metabolism in mice.Conclusion: Our study highlighted that MSFT combined with DHF improves cognitive impairment, anxiety, and depression-like behavior in Aβ mice through multiple mechanisms, and further validated the correlation between the gut microbiome and serum metabolome. These findings open up a promising avenue for future investigations into potential treatment strategies for AD.Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, cognitive impairment, acousto-optic stimulation, treadmill exercise

Yu Li,1 Guangren Yue,1 Shuying Yu,1 Zheng Liu,1 Yilin Cao,1– 3 Ximei Wang1 1Department of Plastic and Reconstructive Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3National Tissue Engineering Center of China, Shanghai, People’s Republic of ChinaCorrespondence: Ximei Wang, Department of Plastic and Reconstructive Surgery, The First Affiliated Hospital of Zhengzhou University, 1st Jianshe Eastern Road, Zhengzhou, 450052, People’s Republic of China, Tel +86 371-66278102, Email tracywang@zzu.edu.cnIntroduction: Autologous stem cell transplantation has emerged as a promising strategy for bone repair. However, the osteogenic potential of mesenchymal stem cells derived from diabetic patients is compromised, possibly due to hyperglycemia-induced senescence. The objective of this study was to assess the preconditioning effects of extracellular vesicles derived from H2O2-stimulated adipose-derived stem cells (ADSCs) and non-modified ADSCs on the osteogenic potential of diabetic bone marrow mesenchymal stem cells (BMSCs).Methods: Sprague-Dawley (SD) rats were experimentally induced into a diabetic state through a high-fat diet followed by an injection of streptozotocin, and diabetic BMSCs were collected from the bone marrow of these rats. Extracellular vesicles (EVs) were isolated from the conditioned media of ADSCs, with or without hydrogen peroxide (H2O2) preconditioning, using density gradient centrifugation. The effects of H2O2 preconditioning on the morphology, marker expression, and particle size of the EVs were analyzed. Furthermore, the impact of EV-pretreatment on the viability, survivability, migration ability, osteogenesis, cellular senescence, and oxidative stress of diabetic BMSCs was examined. Moreover, the expression of the Nrf2/HO-1 pathway was also assessed to explore the underlying mechanism. Additionally, we transplanted EV-pretreated BMSCs into calvarial defects in diabetic rats to assess their in vivo bone formation and anti-senescence capabilities.Results: Our study demonstrated that pretreatment with EVs from ADSCs significantly improved the viability, senescence, and osteogenic differentiation potential of diabetic BMSCs. Moreover, in-vitro experiments revealed that diabetic BMSCs treated with H2O2-activated EVs exhibited increased viability, reduced senescence, and enhanced osteogenic differentiation compared to those treated with non-modified EVs. Furthermore, when transplanted into rat bone defects, diabetic BMSCs treated with H2O2-activated EVs showed improved bone regeneration potential and enhanced anti-senescence function t compared to those treated with non-modified EVs. Both H2O2-activated EVs and non-modified EVs upregulated the expression of the Nrf2/HO-1 pathway in diabetic BMSCs, however, the promoting effect of H2O2-activated EVs was more pronounced than that of non-modified EVs.Conclusion: Extracellular vesicles derived from H2O2-preconditioned ADSCs mitigated senescence in diabetic BMSCs and enhanced their bone regenerative functions via the activation of the Nrf2/HO-1 pathway.Keywords: extracellular vesicles, ADSCs, BMSCs, diabetes mellitus, bone regeneration

Chenxi Ouyang,1,2 Changjiang Meng,3 Fei Li,3 Shanshan Nie,3 Liying Gong,4 Yu Cao,5 Hong Yuan,3,5 Zeying Feng6 1School of Pharmacology, University of South China, Hengyang, Hunan, People’s Republic of China; 2The Affiliated Nanhua Hospital, Department of Pharmacy, Hengyang Medical School University of South China, Hengyang, Hunan, People’s Republic of China; 3Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 5Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 6Clinical Trial Institution Office, Liuzhou Hospital of Guangzhou Women and Children’s Medical Center, Liuzhou, Guangxi, People’s Republic of ChinaCorrespondence: Zeying Feng, Clinical Trial Institution Office, Liuzhou Hospital of Guangzhou Women and Children’s Medical Center, No. 50 Boyuan Avenue, Liuzhou, Guangxi, 545000, People’s Republic of China, Email fengzeying@foxmail.comPurpose: Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators.Patients and Methods: Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis.Results: Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42– 5.28, false discovery rate adjusted-P =3.55&ast;10− 209). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI.Conclusion: The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.Keywords: P2Y12 receptor inhibitors, morphine, kidney injury, Mendelian randomization

Yuansheng Cao,1 Lijuan Fu,1 Xianjie Zhang,1 Leqiang Xia,1 Rui Zhou2 1Department of Anesthesiology, Deyang People’s Hospital, Deyang, People’s Republic of China; 2Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain-Like Intelligence, Clinical Research Center for Anesthesiology and Perioperative Medicine, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of ChinaCorrespondence: Rui Zhou, Shanghai Fourth People’s Hospital, No. 1279, Sanmen Road, Hongkou District, Shanghai, 200434, People’s Republic of China, Email ruizhoukepler@126.comPurpose: To determine whether perioperative esketamine use decreases the risk of postpartum depression (PPD).Methods: Online search of PubMed, Web of Science, and Embase was conducted to identify relevant studies. Key words for search included, but were not limited to, postpartum depression, esketamine, and clinical trials. The mean and standard deviation of the Edinburgh Postnatal Depression Scale (EPDS) scores were extracted from the studies as primary parameters.Results: The literature search identified 226 articles, of which 5 met the criteria and were enrolled in the study. In total, 886 patients in the studies were taken into analysis. The EPDS scores in the esketamine group were lower than those of the control group at the early stage of puerperium (WMD=− 2.05, 95% CI: − 3.77, − 0.34, p=0.019), whereas there was no significant difference at the middle and later stages (WMD=− 1.41, 95% CI: − 2.86, 0.04, p=0.056). The sensitivity analyses indicated that the result for the early stage was stable, whereas it was unreliable for the middle and later stages. The results of the Egger’s test indicated no publication bias.Conclusion: Perioperative use of esketamine contributes to a lower risk of PPD at the early stage of puerperium but not at the middle and later stages. To further verify this conclusion, more high-quality studies are required.Keywords: esketamine, postpartum depression, pregnant women, mental health

Yinan Cao,1– 3,&ast; Fan Li,1– 3,&ast; Zhenxuan Sun,1– 3 Jin Liu,1– 3 Jie Liu,1– 3 Qi Yang,1– 3 Peng Ge,1– 3 Yalan Luo,1– 3 Hailong Chen1– 3 1Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 2Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China; 3Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yalan Luo; Hailong Chen, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Zhongshan Road 222, Dalian, 116011, Liaoning, People’s Republic of China, Tel +86-411-83635963, Fax +86-411-83622844, Email luoyalanxueshu@163.com; chenhailong@dmu.edu.cnPurpose: Explore the therapeutic effects and regulatory mechanism of Qingyi Decoction (QYD) on severe acute pancreatitis (SAP) associated acute lung injury (ALI).Methods: We identified the constituents absorbed into the blood of QYD based on a network pharmacological strategy. The differentially expressed genes from the GEO database were screened to identify the critical targets of QYD treatment of SAP-ALI. The SAP-ALI rat model was constructed.Some methods were used to evaluate the efficacy and mechanism of QYD in treating SAP-ALI. LPS-stimulated pulmonary microvascular endothelial cell injury simulated the SAP-induced pulmonary endothelial injury model. We further observed the therapeutic effect of QYD and CDK5 plasmid transfection on endothelial cell injury.Results: 18 constituents were absorbed into the blood, and 764 targets were identified from QYD, 25 of which were considered core targets for treating SAP-ALI. CDK5 was identified as the most critical gene. The results of differential expression analysis showed that the mRNA expression level of CDK5 in the blood of SAP patients was significantly up-regulated compared with that of healthy people. Animal experiments have demonstrated that QYD can alleviate pancreatic and lung injury inflammatory response and reduce the upregulation of CDK5 in lung tissue. QYD or CDK5 inhibitors could decrease the expression of NFAT5 and GEF-H1, and increase the expression of ACE-tub in SAP rat lung tissue. Cell experiments proved that QYD could inhibit the expression of TNF-α and IL-6 induced by LPS. Immunofluorescence results suggested that QYD could alleviate the cytoskeleton damage of endothelial cells, and the mechanism might be related to the inhibition of CDK5-mediated activation of NFAT5, GEF-H1, and ACE-tub.Conclusion: CDK5 has been identified as a critical target for pulmonary endothelial injury of SAP-ALI. QYD may partially alleviate microtubule disassembly by targeting the CDK5/NFAT5/GEF-H1 signaling pathway, thus relieving SAP-induced pulmonary microvascular endothelial cell injury. Keywords: Qingyi decoction, severe acute pancreatitis, acute lung injury, CDK5, microtubule

Yan Feng,&ast; Jia-Feng Sun,&ast; Hai-Chao Wei,&ast; Ying Cao, Lei Yao, Bo-Xiang Du The Affiliated Hospital 2 of Nantong University, Nantong City, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo-Xiang Du; Lei Yao, Email boxiang_du@163.com; yaoleijiangsu1987@163.comPurpose: This study aims to investigate how the type of anesthesia used during major orthopedic surgery may impact adverse short-term postoperative outcomes depending on frailty.Methods: To conduct this investigation, we recruited individuals aged 65 years and older who underwent major orthopedic surgery between March 2022 and April 2023 at a single institution. We utilized the FRAIL scale to evaluate frailty. The primary focus was on occurrences of death or the inability to walk 60 days after the surgery. Secondary measures included death within 60 days; inability to walk without human assistance at 60 days; death or the inability to walk without human assistance at 30 days after surgery, the first time out of bed after surgery, postoperative blood transfusion, length of hospital stay, hospital costs, and the occurrence of surgical complications such as dislocation, periprosthetic fracture, infection, reoperation, wound complications/hematoma.Results: In a study of 387 old adult patients who had undergone major orthopedic surgery, 41.3% were found to be in a frail state. Among these patients, 262 had general anesthesia and 125 had neuraxial anesthesia. Multifactorial logistic regression analyses showed that anesthesia type was not linked to complications. Instead, frailty (OR 4.04, 95% CI 1.04 to 8.57, P< 0.001), age (OR 1.05, 95% CI 1.00– 1.10, P= 0.017), and aCCI scores, age-adjusted Charlson Comorbidity Index, (OR 1.36, 95% CI 1.12 to 1.66, P= 0.002) were identified as independent risk factors for death or new walking disorders in these patients 60 days after surgery. After adjusting for frailty, anesthesia methods was not associated with the development of death or new walking disorders in these patients (P > 0.05).Conclusion: In different frail populations, neuraxial anesthesia is likely to be comparable to general anesthesia in terms of the incidence of short-term postoperative adverse outcomes.Keywords: anesthesia, frailty, major orthopedic surgery, death, impaired walking ability

Ying Chen,1,2,&ast; Wen-Xia Li,1,2,&ast; Jia-Hua Wu,1,2 Geng-Hang Chen,2 Chun-Min Yang,1,2 Hai Lu,1,2 Xi Wang,3 Shu-Sen Wang,4 Heng Huang,5 Li Cai,6 Li Zhao,7 Rou-Jun Peng,8 Ying Lin,9 Jun Tang,3 Jian Zeng,10 Le-Hong Zhang,11 Yong-Li Ke,12 Xian-Ming Wang,13 Xin-Mei Liu,14 An-Qin Zhang,15 Fei Xu,4 Xi-Wen Bi,4 Jia-Jia Huang,4 Ji-Bin Li,16 Dan-Mei Pang,17 Cong Xue,4 Yan-Xia Shi,4 Zhen-Yu He,18 Huan-Xin Lin,18 Xin An,4 Wen Xia,4 Ye Cao,16 Ying Guo,16 Ruo-Xi Hong,4 Kui-Kui Jiang,4 Yong-Yi Zhong,4 Ge Zhang,19 Piyawan Tienchaiananda,20 Masahiro Oikawa,21 Zhong-Yu Yuan,4 Qian-Jun Chen22,23 1Department of Breast Surgery, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Breast Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 4Department of Medical Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 5Department of Breast Oncology, Lianjiang People’s Hospital, Lianjiang, People’s Republic of China; 6Department of Medical Oncology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, People’s Republic of China; 7Department of Breast Oncology, Guangzhou First People Hospital, Guangzhou, People’s Republic of China; 8Department of Integrated Therapy in Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 9Department of Breast Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 10Department of Breast Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 11Department of Breast Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 12Department of Breast Oncology, General Hospital of PLA Guangzhou Military Area, Guangzhou, People’s Republic of China; 13Department of Breast Oncology, Shenzhen Second People’s Hospital, Shenzhen, People’s Republic of China; 14Department of Breast Oncology, Haikou People’s Hospital, Haikou, People’s Republic of China; 15Department of Breast Oncology, Maternal and Child Health Care Hospital of Guangdong Province, Guangzhou, People’s Republic of China; 16Department of Good Clinical Practice, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 17Department of Medical Oncology, Foshan First People’s Hospital, Foshan, People’s Republic of China; 18Department of Radiotherapy, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 19Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong; 20Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Rangsit University, Rajavithi Hospital, Bangkok, Thailand; 21The Department of Breast Surgery, New-wa-kai Oikawa Hospital, Fukuoka, Japan; 22State Key Laboratory of Traditional Chinese Medicine Syndrome/Departments of Gynecologic Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 23State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qian-Jun Chen, 55N, Neihuanxi Road, Guangzhou, Guangdong, 510006, People’s Republic of China, Tel +86 1868883505, Email cqj55@163.com Zhong-Yu Yuan, 651 Dongfeng Road, Guangzhou, Guangdong, 510060, People’s Republic of China, Tel +86 13798027658, Email yuanzhy@sysucc.org.cnPurpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not.Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into “consistent” (standard acceptable dose) and “inconsistent” (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes.Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the “inconsistent” dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the “inconsistent” dose of anthracycline and taxane did not affect DFS compared with the “consistent” dose. Moreover, in the capecitabine group, the “inconsistent” anthracycline dose did not affect DFS compared with the “consistent” dose. However, patients with “consistent” taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06).Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.Keywords: adjuvant chemotherapy, capecitabine, SYSUCC-001, triple-negative breast cancer, TNBC

Fan Li,1– 3,&ast; Zhengjian Wang,4,&ast; Yinan Cao,1– 3 Boliang Pei,1– 3 Xinyu Luo,1– 3 Jin Liu,1– 3 Peng Ge,1– 3 Yalan Luo,1– 3 Shurong Ma,1,3 Hailong Chen1– 3 1Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 2Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 3Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 4Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shurong Ma; Hailong Chen, Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Zhongshan Road 222, Dalian, Liaoning, 116011, People’s Republic of China, Tel +86-411-83635963, Fax +86-411-83622844, Email shurongma94@163.com; chenhailong@dmu.edu.cnAbstract: The pathogenesis of severe acute pancreatitis-associated acute lung injury (SAP-ALI), which is the leading cause of mortality among hospitalized patients in the intensive care unit, remains incompletely elucidated. The intestinal mucosal immune barrier is a crucial component of the intestinal epithelial barrier, and its aberrant activation contributes to the induction of sustained pro-inflammatory immune responses, paradoxical intercellular communication, and bacterial translocation. In this review, we firstly provide a comprehensive overview of the composition of the intestinal mucosal immune barrier and its pivotal roles in the pathogenesis of SAP-ALI. Secondly, the mechanisms of its crosstalk with gut microbiota, which is called gut-lung axis, and its effect on SAP-ALI were summarized. Finally, a number of drugs that could enhance the intestinal mucosal immune barrier and exhibit potential anti-SAP-ALI activities were presented, including probiotics, glutamine, enteral nutrition, and traditional Chinese medicine (TCM). The aim is to offer a theoretical framework based on the perspective of the intestinal mucosal immune barrier to protect against SAP-ALI.Keywords: severe acute pancreatitis-associated acute lung injury, intestinal mucosal immune barrier, gut microbiota, gut-lung axis, migration of immune cells

Tham T Le,1 Benjamin Emmanuel,1 Rohit Katial,2 Trung N Tran,1 Justin Joseph Kwiatek,1 David S Cohen,1 Shoshana R Daniel,3 Yunhui Cao,1 Vivian H Shih,1 Maria Gil Melcón,4 Gilles Devouassoux,5 Girolamo Pelaia6 On behalf of the RANS Study Investigators1BioPharmaceuticals Medical, AstraZeneca, Gaithersburg, MD, USA; 2Center for Clinical Immunology, National Jewish Health & University of Colorado School of Medicine, Denver, CO, USA; 3Market Access Consulting, Fortrea Inc., Durham, NC, USA; 4Otorhinolaryngology and Head and Neck Surgery Department, University Hospital of Salamanca, Salamanca, Spain; 5Department of Pulmonology, Hospices Civils de Lyon (HCL), Hôpital de la Croix-Rousse, Lyon, and F-CRIN INSERM Network CRISALIS, Toulouse, France; 6Department of Health Sciences, University “Magna Graecia” of Catanzaro, Catanzaro, ItalyCorrespondence: Girolamo Pelaia, University “Magna Graecia” of Catanzaro, Viale Europa, 88100 Catanzaro, Italy, Tel +39 961 3647171, Fax +39 961 3647193, Email pelaia@unicz.itPurpose: Real-world evidence of benralizumab effectiveness on nasal polyps (NP) and asthma outcomes in patients with severe eosinophilic asthma (SEA) and comorbid chronic rhinosinusitis with NP are limited. The objective of this study was to assess NP and asthma outcomes in benralizumab-treated patients with SEA and comorbid NP in a real-world setting.Patients and Methods: RANS was a retrospective, multi-country observational study (ClinicalTrials.gov: NCT05180357) using medical chart reviews of adults with SEA and comorbid NP. Total NP Score (NPS), SinoNasal Outcome Test-22 (SNOT-22) total score, annualized exacerbation rate (AER), and 6-item Asthma Control Questionnaire (ACQ-6) and Asthma Control Test (ACT) scores during the 12 months pre-index (baseline) and post-index (follow-up) were measured. Clinically meaningful improvement from baseline following treatment, in terms of total NPS (≥ 1-point reduction), SNOT-22 total (≥ 8.9-point reduction), ACQ-6 (≥ 0.5-point reduction) or ACT (≥ 3-point increase) scores, were reported.Results: A total of 233 patients were included. Baseline mean (standard deviation [SD]) NPS and SNOT-22 total scores were 3.8 (2.4) and 47.5 (22.6), respectively. The mean change (95% confidence interval [CI]) from baseline was – 1.2 (– 1.7, – 0.6) for NPS, and – 19.8 (– 23.6, – 15.9) for SNOT-22. The AER (95% CI) was 1.2 (0.96, 1.41) at baseline and 0.2 (0.13, 0.28) at follow-up. Mean (SD) ACQ-6 and ACT scores were 1.6 (1.3) and 15.0 (5.2) at baseline and 0.8 (1.0) and 22.0 (3.9) at follow-up, respectively. The proportion of patients who achieved clinically meaningful improvements in NPS, SNOT-22 total, ACQ-6, and ACT scores was 49.1%, 67.6%, 56.6%, and 81.1%, respectively.Conclusion: In this real-world study, improvements in NP and asthma outcomes in patients with SEA and comorbid NP were observed during the 12 months following benralizumab initiation.Keywords: exacerbations, comorbidity, biologics, patient-reported outcomes, SinoNasal Outcome Test-22, Nasal Polyps Score

Tingting Wang,1– 3,&ast; Xia Wu,4,&ast; Xiaoli Zhao,2,3,&ast; Jiaqi Li,5,&ast; Jian Yu,4 Maozheng Sheng,4 Mingyuan Gao,4 Yutang Cao,5 Jiawen Wang,6 Xiaozhen Guo,5 Kai Zeng1 1Department of Anesthesiology, Anesthesiology Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 2Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Department of Anesthesiology, Changning Maternity and Infant Health Hospital, Shanghai, People’s Republic of China; 4Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People’s Republic of China; 5State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People’s Republic of China; 6College of Life Sciences, Wuhan University, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kai Zeng; Xiaozhen Guo, Email fymzk6822@163.com; guoxz@simm.ac.cnPurpose: Postoperative cognitive dysfunction (POCD) is a central nervous system complication that occurs after anesthesia, particularly among the elderly. However, the neurological pathogenesis of postoperative cognitive dysfunction remains unclear. The aim of this study was to evaluate the effects of sevoflurane exposure on serum metabolites and hippocampal gene expression in elderly patients and aging mice by metabolomics and transcriptomic analysis and to explore the pathogenesis of sevoflurane induced POCD.Patients and Methods: Human serum samples from five patients over 60 years old were collected before sevoflurane anesthesia and 1 hour after anesthesia. Besides, mice aged at 12 months (n=6 per group) were anesthetized with sevoflurane for 2 hours or with sham procedure. Subsequently, serum and hippocampal tissues were harvested for analysis. Further investigation into the relationship between isatin and neuroinflammation was conducted using BV2 microglial cells.Results: Sevoflurane anesthesia led to the activation of inflammatory pathways, an increased presence of hippocampal astrocytes and microglia, and elevated expression of neuroinflammatory cytokines. Comparative analysis identified 12 differential metabolites that exhibited changes in both human and mouse serum post-sevoflurane anesthesia. Notably, isatin levels were significantly decreased after anesthesia. Notably, isatin levels significantly decreased after anesthesia, a factor known to stimulate proliferation and proinflammatory gene expression in microglia—the pivotal cell type in inflammatory responses.Conclusion: Sevoflurane-induced alterations in serum metabolites in both elderly patients and aging mice, subsequently contributing to increased inflammation in the hippocampus.Keywords: sevoflurane, hippocampus, neuroinflammation, RNA-seq, metabolomics, isatin

Yumeng Cao,1,&ast; Huaqin Pan,2,&ast; Yanwei Yang,3 Jingrun Zhou,1 Guqin Zhang1 1Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China; 2Transplantation Intensive Care Unit, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan, Hubei, 430071, People’s Republic of China; 3Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guqin Zhang, Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China, Email zgqxiaoxiao@126.comPurpose: Ferroptosis plays essential roles in the development of COPD. We aim to identify the potential ferroptosis-related genes of COPD through bioinformatics analysis.Methods: The RNA expression profile dataset GSE148004 was obtained from the GEO database. The ferroptosis-related genes were obtained from the FerrDb database. The potential differentially expressed ferroptosis-related genes of COPD were screened by R software. Then, protein–protein interactions (PPI), correlation analysis, gene-ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were applied for the differentially expressed ferroptosis-related genes. Finally, hub gene-microRNA(miRNA), hug gene-transcription factor interaction networks were constructed by miRTarBase v8.0 and JASPAR respectively, and hub gene drugs were predicted by the Enrichr database.Results: A total of 41 differentially expressed ferroptosis-related genes (22 up-regulated genes and 19 down-regulated genes) were identified between 7 COPD patients and 9 healthy controls. The PPI results demonstrated that these ferroptosis-related genes interacted with each other. The GO and KEGG enrichment analyses of differentially expressed ferroptosis-related genes indicated several enriched terms related to ferroptosis, central carbon metabolism in cancer, and the HIF-1 signaling pathway. The crucial miRNAs and drugs associated with the top genes were identified.Conclusion: We identified 41 potential ferroptosis-related genes in COPD through bioinformatics analysis. HIF1A, PPARG, and KRAS may affect the development of COPD by regulating ferroptosis. These results may expand our understanding of COPD and might be useful in the treatment of COPD.Keywords: ferroptosis, COPD, bioinformatics analysis, gene expression omnibus dataset

Feifei Sun,1,&ast; Chenjing Wang,1,&ast; Yi Xu,1 Pingping Lin,1 Yaozhong Cao,2 Jiahui Zhang,3 Xin Li,1 Xin Jiang,1 Yao Fu,1 Yu Cao1 1Clinical Trials Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 2Clinical Medical Center, Xiuzheng Pharmaceutical Group, Hangzhou, Zhejiang, People’s Republic of China; 3Xiuzheng Bio-Medicine Research Institute, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Cao, Clinical Trials Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China, Tel +86 532 82911767, Email caoyu@qdu.edu.cnIntroduction: Hyperuricemia is a disease with abnormal purine metabolism, which leads to the increase of urate concentration. It is an independent risk factor for the occurrence and development of metabolic syndrome, type 2 diabetes, hypertension, cardiovascular disease, chronic kidney disease, and gout. The enzyme urate oxidase can metabolize urate to allantoin, resulting in decreased urate concentrations. Pegylated the urate oxidase can extend half-life and decrease immunogenicity of the protein. This trial aims to evaluate the safety, tolerability, pharmacokinetics(PK), pharmacodynamics(PD) and immunogenicity of a new intravenous PEGylated urate oxidase produced by Xiuzheng Bio-Medicine Research Institute Co., Ltd.Methods and Analysis: A randomized, double-blind, placebo-controlled, phase I, dose escalation study will be conducted in China. In total, 56 subjects will be enrolled in the study, with 24 healthy subjects in the low dose-escalation stage and 32 patients with hyperuricemia in the high dose-escalation stage. There is a bridging between the two stages. Subjects are randomized to PEGylated urate oxidase or the placebo in a 3:1 ratio in each group and followed up for 71 days observation. The primary outcomes include PK, PD, tolerability; the secondary outcomes include safety and immunogenicity.Ethics and Dissemination: The trial is performed abiding by the Declaration of Helsinki, Good clinical practice (GCP) and the guidelines of China National Medical Products Administration (NMPA). Relevant documents, including protocol, informed consent and drug inspection report, are all approved independently by the Medical Ethics Committee of the Affiliated Hospital of Qingdao University. The first subject was enrolled on January 17, 2022.Trial Registration: Clinicaltrials, NCT05226013 (Registered April 2, 2022, Retrospectively registered). ChinaDrugTrials, CTR20211801(Registered July 27, 2021).Keywords: PEGylated urate oxidase, healthy volunteers, patients with hyperuricemia, study protocol

Cui Jin, Yongmei Cao, Yingchuan Li Department of Critical Care Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of ChinaCorrespondence: Yingchuan Li, Department of Critical Care Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China, Email yingchuan_li@tongji.edu.cnIntroduction: The incidence and mortality rates of sepsis-induced acute kidney injury (SAKI) remain high, posing a substantial healthcare burden. Studies have implicated a connection between the development of SAKI and inflammation response, apoptosis, and autophagy. Moreover, evidence suggests that manipulating autophagy could potentially influence the prognosis of this condition. Notably, exosomes derived from bone mesenchymal stem cells (BMSCs-Exo) have exhibited promise in mitigating cellular damage by modulating pathways associated with inflammation, apoptosis, and autophagy. Thus, this study aims to investigate the influence of BMSCs-Exo on SAKI and the potential mechanisms that drive this impact.Methods: The SAKI model was induced in HK-2 cells using lipopolysaccharide (LPS), while rats underwent cecal ligation and puncture (CLP) to simulate the condition. Cell viability was assessed using the CCK-8 kit, and kidney damage was evaluated through HE staining, blood urea nitrogen (BUN), and serum creatinine (SCr) measurements. Inflammatory-related RNAs and proteins were quantified via qPCR and ELISA, respectively. Apoptosis was determined through apoptosis-related protein levels, flow cytometry, and TUNEL staining. Western blot analysis was utilized to measure associated protein expressions.Results: In vivo, BMSCs-Exo ameliorated kidney injury in CLP-induced SAKI rats, reducing inflammatory cytokine production and apoptosis levels. Fluorescence microscope observed the absorption of BMSCs-Exo by renal cells following injection via tail vein. In the SAKI rat kidney tissue, there was an upregulation of LC3-II/LC3-I, p62, and phosphorylated AMP-activated protein kinase (p-AMPK) expressions, indicating blocked autophagic flux, while phosphorylated mammalian target of rapamycin (p-mTOR) expression was downregulated. However, BMSCs-Exo enhanced LC3-II/LC3-I and p-AMPK expression, concurrently reducing p62 and p-mTOR levels. In vitro, BMSCs-Exo enhanced cell viability in LPS-treated HK-2 cells, and exerted anti-inflammation and anti-apoptosis effects which were consistent with the results in vivo. Similarly, rapamycin (Rapa) exhibited a protective effect comparable to BMSCs-Exo, albeit partially abrogated by 3-methyladenine (3-MA).Conclusion: BMSCs-Exo mitigate inflammation and apoptosis through autophagy in SAKI, offering a promising avenue for SAKI treatment. Keywords: exosomes, bone mesenchymal stem cells, acute kidney injury, sepsis, autophagy

Yue Cao, Yue-Yue Feng, Wei Du, Jing Li, Ya-Lan Fei, Hao Yang, Meng Wang, Shi-Jie Li, Xian-Jin Li, Bing Han Division of Cardiology, Xuzhou Central Hospital, Xuzhou, People’s Republic of ChinaCorrespondence: Bing Han, Division of Cardiology, Xuzhou Central Hospital, 199 South Jiefang Road, Xuzhou, 221009, People’s Republic of China, Tel +86-516-83985069, Fax +86-516-83956012, Email hbing777@hotmail.comPurpose: To investigate the reasons for elderly atrial fibrillation (AF) patients not continuing their oral anticoagulation (OAC) treatment and the factors that influence this behavior.Methods: Elderly AF patients (aged≥ 75 years) hospitalized from December 2019 to May 2022 were consecutively enrolled. Clinical, demographic, and concomitant medication data were collected. The endpoint was defined as OAC discontinuation for more than 30 days or a switch to an alternative therapy. Predictors of OAC non-persistence were investigated using a multivariable Cox regression model.Results: This study included 560 participants (51.1% men, mean age 80.9± 0.2 years). During a median follow-up of 20 months, medication persistence was observed in 322 patients (57.5%). Non-persistence was found to be significantly higher with warfarin than with NOAC (48.8% vs 33.6%, p = 0.006). In the multivariate analysis, OAC non-persistence was independently predicted by a history of permanent pacemaker implantation, the use of antiplatelet drugs, employee Medicare, living with children, college degree or above, and persistent AF (HR = 1.580, 1.586, 0.604, 0.668, 0.028, 0.769, p < 0.05, respectively). Treatment discontinuation within 3 months of discharge was observed in a large number of patients (81.8%). Medication discontinuation due to bleeding was more frequently observed in patients who continued for longer than 3 months (p < 0.001), while discontinuation due to patient preference was more frequent in those with shorter durations (≤ 3 months) (p = 0.049). Patient preference was the second leading cause of non-persistence in patients, regardless of whether they were taking warfarin or NOAC.Conclusion: OAC non-persistence remains high among elderly AF patients during long-term follow-up, with a significant proportion discontinuing shortly after discharge. This pattern of non-persistence is heavily influenced by demographic factors and patient preference. Further interventions should be developed based on the reasons and risk factors to improve persistence and initiated early in the treatment process.Keywords: atrial fibrillation, the elderly, oral anticoagulants, non-persistence

Min Yi,1 Yuebin Cao,2 Jiangjun Wang,3 Chenyi Shi,1 Yalin Cheng,1 Yanlin Cao1 1Institute of Medical Information and Library, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100020, People’s Republic of China; 2Health Commission of Hunan Province, Changsha, 410008, People’s Republic of China; 3China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of ChinaCorrespondence: Yanlin Cao, Institute of Medical Information and Library, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 3 Yabao Street, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86-010-52328845, Email cao.yanlin@imicams.ac.cnBackground: Medical disputes are a recurrent and pressing issue in hospitals, posing significant challenges to the functioning of medical institutions. We aimed to investigate whether receiving rule of law publicity on short video platforms is relevant to preventing medical disputes among healthcare professionals.Methods: We collected the data from 37,978 medical professionals from 130 tertiary public hospitals. Participants were classified into two groups according to the presence of receiving rule of law publicity on short video platforms. A subgroup analysis was performed before and after propensity score analysis, and multiple logistic regression was used to identify risk factors for medical disputes.Results: Among all participants, 46.1% (17,506/37,978) experienced medical disputes. Before propensity score analysis, the prevalence of medical disputes among participants who received rule of law publicity on short video platforms was similar to that among participants who did not (P = 0.639). However, after propensity score analysis, participants who received the rule of law publicity on short video platforms did not show a benefit effect. These participants had a significantly higher rate of suffering from medical disputes than participants who did not receive publicity on this platform (P=0.020). Multiple logistic regression analysis confirmed that receiving the rule of law publicity through short video platforms (P=0.010) or MicroBlog (P = 0.016), and previously facing legal issues outside of medical work (P < 0.001) were risk factors for medical disputes; participating in legal training organized by hospitals (P=0.004) and the hospital rule of law being very good (P=0.045) were protective factors.Conclusion: Medical disputes are a common occurrence within the healthcare profession. However, using short video platforms to promote the rule of law is not an effective method to prevent disputes. Instead, healthcare professionals can benefit from participating in legal training and having a well-established rule of law within the hospital construct.Keywords: healthcare professionals, medical disputes, rule of law publicity, short video platforms, construction of hospital rule of law

Yu Cao,1 Ying Han,2 Jiangping Wu,1 Jianping Sun,3 Yanchao Dai,3 Guifang Qiao,3 Kang Li,3 Ang Li,3 Yonghong Zhang,4 Yingmin Ma,5,&ast; Qingkun Song1,3,&ast; 1Department of Clinical Epidemiology, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Center of Liver Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Center of Biobank, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Hepatic Intervention, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Department of Respiratory and Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingmin Ma, Department of Respiratory and Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Youanmen Wai 8, Fengtai District, Beijing, 100069, People’s Republic of China, Tel/Fax +86-10-83997022, Email ma.yingmin@163.com Qingkun Song, Department of Clinical Epidemiology, Beijing Youan Hospital, Capital Medical University, Youanmen Wai 8, Fengtai District, Beijing, 100069, People’s Republic of China, Tel/Fax +86-10-83997022, Email songqingkun@ccmu.edu.cnBackground: For the distinct immune/inflammatory responses from Omicron variant infection, this study aimed to investigate the diagnostic efficacy of systemic inflammatory indicators and the clinical efficacy of corticosteroids on the in-hospital mortality among COVID-19 patients.Methods: Under a retrospective cohort study, 1081 COVID-19 patients were recruited from Beijing Youan Hospital, Capital Medical University between November 16, 2022 and January 30, 2023. We chose neutrophil-to-lymphocyte ratio (NLR), CRP-to-lymphocyte ratio (CLR), and CRP-to-albumin ratio (CAR) as the systemic inflammatory indicators. Receiver operating curve (ROC) and multivariate logistic regression analysis were used to determine the diagnostic efficacy of systemic inflammatory indicators and the association between systemic inflammatory indicators and in-hospital mortality.Results: Among 684 patients included in analysis, 96 died during hospitalization. NLR, CLR and CAR performed well (with an area under the curve (AUC) greater than 0.75) in discriminating in-hospital mortality among COVID-19 patients. The severe status of systemic inflammation, with optimal cut-off value derived from ROC analysis, significantly associated higher risk of in-hospital mortality (OR = 3.81 for NLR ≥ 6.131; OR = 3.76 for CLR ≥ 45.455; OR = 5.10 for CAR ≥ 1.436). Corticosteroids use within 72 hours of admission increased the in-hospital mortality 2.88-fold for COVID-19 patients. In the subgroup of patients with severe systemic inflammation, corticosteroids increased the risk of in-hospital mortality (OR = 2.11 for NLR, p = 0.055; OR = 2.94 for CLR, p = 0.005; OR = 2.31 for CAR, p = 0.036).Conclusion: Systemic inflammatory indicators had good diagnostic performance for in-hospital mortality. Patients with severe systemic inflammatory status should not receive corticosteroid treatment and further studies are warranted for confirmation.Keywords: COVID-19, systemic inflammatory indicators, in-hospital mortality, anti-inflammatory treatment

Xinyu Li,1,2,&ast; Yedi Cao,1,&ast; Nan Gu,1 Zhenfang Yuan1 1Department of Endocrinology, Peking University First Hospital, Beijing, People’s Republic of China; 2Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nan Gu, Email nan.gu@pkufh.cnAbstract: Renal cysts and diabetes syndrome (RCAD) is a rare disease caused by abnormalities in the HNF1B gene, which often leads to dysfunction in the renal, genital tracts, and pancreas. In this report, we present a rare case of a 27-year-old female with muscle mass loss who experienced a delayed diagnosis of RCAD. The patient had been misdiagnosed as “type 1 diabetes” for a long period. Her main clinical manifestations included muscle loss, renal magnesium loss, and an incomplete longitudinal uterus. Ultimately, the diagnosis of RCAD syndrome was confirmed through genetic testing. Reduction of muscle mass, although rarely reported, can progress to sarcopenia. Therefore, early intervention should be strongly emphasized. Furthermore, in future research, it is crucial to explore the mechanisms and relationships underlying these patients and their unusual manifestations.Keywords: muscle loss, special type diabetes, maturity-onset diabetes of the young type 5, 17q12 deletion syndrome, renal cysts and diabetes syndrome, case report

Qi Yang,1– 4 Yalan Luo,1– 3 Peng Ge,1– 3 Bowen Lan,1– 3 Jin Liu,1– 3 Haiyun Wen,1– 3 Yinan Cao,1– 3 Zhenxuan Sun,1– 3 Guixin Zhang,1– 3 Huiming Yuan,5 Lihua Zhang,5 Hailong Chen1– 3 1Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 2Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 3Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 4Department of Traditional Chinese Medicine, the Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, People’s Republic of China; 5CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, 116023, People’s Republic of ChinaCorrespondence: Hailong Chen, Email chenhailong@dmu.edu.cnBackground: Numerous preclinical investigations have exhibited the beneficial impact of emodin (EMO) on the management of severe acute pancreatitis (SAP)-associated acute lung injury (ALI). However, the potential of EMO to mitigate organ damage through the modulation of exosome (Exo)-specific miRNA expression profiles remains unclear.Methods: The SAP rat model was established by retrograde injection of 5% sodium taurocholate into the pancreatic bile duct. Rats received intragastric administration of EMO at 2 h and 12 h post-modeling. Plasma and bronchoalveolar lavage fluid (BALF)-derived exosomes were isolated and purified from SAP rats treated with EMO. The therapeutic effects of these Exos in SAP rats were assessed using hematoxylin-eosin staining and measurement of inflammatory factor levels. MicroRNA (miRNA) sequencing was conducted on plasma and BALF-derived Exos, and rescue experiments were performed to investigate the function of NOVEL miR-29a-3p in the treatment of SAP using EMO.Results: EMO exhibits ameliorative effects on pancreatic and lung injury and inflammation in rats with SAP. Plasma/BALF-derived Exos from EMO-treated SAP rats also have therapeutic effects on SAP rats. The miRNA expression profile of plasma and BALF-derived Exos in SAP rats underwent significant changes upon exposure to EMO. In particular, 34 differentially expressed miRNAs (DEmiRNAs) were identified when comparing BALF-SAP+EMO-Exo and BALF-SAP-Exo. 39 DEmiRNAs were identified when comparing plasma-SAP+EMO-Exo to plasma-SAP-Exo. We found that SAP rats treated with Exos derived from BALF exhibited a more potent therapeutic response than those treated with Exos derived from plasma. EMO may rely on NOVEL-rno-miR-29a-3p expression to prevent pulmonary injury in SAP rats.Conclusion: The mechanism of action of EMO is observed to have a significant impact on the miRNA expression profile of Exos derived from plasma and BALF in SAP rats. NOVEL-rno-miR-29a-3p, which is specific to Exos, and is derived from BALF, may play a crucial role in the therapeutic efficacy of EMO. Plain Language Summary: Exosomes extracted from plasma/BALF of EMO-treated SAP rats show a substantial therapeutic impact on SAP-Associated ALI, with BALF-derived exosomes having a higher therapeutic effect than plasma-derived exosomes.EMO dramatically altered the miRNA expression patterns of plasma and BALF-derived exosomes in SAP rats.The lung protective effect of EMO in SAP rats is somewhat reliant on Novel-rno-miR-29a-3p expression.Keywords: severe acute pancreatitis, acute lung injury, emodin, exosome, microRNA

Pan Pan, Tao Cheng, Tianyong Han, Yu Cao Department of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Yu Cao, Email yuyuer@126.comBackground: Post-intubation hypotension (PIH) frequently occurs in the management of critically ill patients and is associated with prognosis. The study aimed to construct a prediction model for PIH events by analyzing risk factors in patients with severe pneumonia in the emergency department.Methods: We retrospectively enrolled 572 patients with severe pneumonia diagnosed in the emergency department of West China Hospital of Sichuan University. Five hundred patients with severe pneumonia who underwent endotracheal intubation were included in the study. All patients were randomized according to 7:3 and divided into a training cohort (n=351) and a validation cohort (n=149). Risk factors for PIH were analyzed using Least Absolute Shrinkage and Selection Operator (LASSO) and multivariable logistic regression. Calibration curves, receiver operating characteristic (ROC) curve, and decision curve analysis were applied to assess the predictive model’s fitness, discrimination, and clinical utility.Results: A total of 500 patients with severe pneumonia who underwent endotracheal intubation were enrolled in this study, and PIH occurred in 234 (46.8%) of these patients. Age, heart rate, systolic blood pressure, chronic obstructive pulmonary disease, acute physiology and chronic health evaluation II score, and induction agent use were identified as significant risk factors for the occurrence of PIH. Additionally, the body mass index was the opposite of the above. The area under the ROC curve (AUC) for the model was 0.856 (95% CI, 0.818– 0.894) in the training cohort and 0.849 (95% CI, 0.788– 0.910) in the validation cohort. The nomogram model was validated and demonstrated good calibration and high net clinical benefit. Finally, to facilitate application by clinicians, an online server has been set up which can be accessed free of charge via the website https://chinahospitals.shinyapps.io/DynNomapp/.Conclusion: The nomogram is used for individualized prediction of patients with severe pneumonia prior to intubation and is simple to perform with high clinical value.Keywords: post-intubation hypotension, severe pneumonia, prognosis, induction agent, nomogram

Can Hu,1,2,&ast; Yan Qiu,1,2,&ast; Jiajun Guo,1,2 Yuchao Cao,1,2 Dairong Li,3 Yonghong Du1,2 1State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dairong Li, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-23-89012745, Fax +86-23-68485021, Email lidairong@hospital.cqmu.edu.cn Yonghong Du, State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel/Fax +86-23-68485021, Email duyonghong@cqmu.edu.cnPurpose: Tuberculosis (TB) is a chronic disease caused by Mycobacterium tuberculosis (MTB) that remains a major global health challenge. One of the main obstacles to effective treatment is the heterogeneous microenvironment of TB granulomas. This study aimed to investigate the potential of a hypoxic remission-based strategy to enhance the outcome of tuberculosis treatment when implemented in combination with ultrasound.Methods: A PLGA nanoparticle (LEV@CAT-NPs) loaded with levofloxacin (LEV) and catalase (CAT) was fabricated by a double emulsification method, and its physical characteristics, oxygen production capacity, drug release capacity, and biosafety were thoroughly investigated. The synergistic therapeutic effects of ultrasound (US)-mediated LEV@CAT-NPs were evaluated using an experimental mouse model of subcutaneous tuberculosis granuloma induced by Bacille Calmette-Guérin (BCG) as a substitute for MTB.Results: LEV@CAT-NPs exhibited excellent oxygen production capacity, biosafety, and biocompatibility. Histological analysis revealed that ultrasound-mediated LEV@CAT-NPs could effectively remove bacteria from tuberculous granulomas, significantly alleviate the hypoxia state, reduce the necrotic area and inflammatory cells within the granuloma, and increase the penetration of dyes in granuloma tissues. The combined treatment also reduced the serum levels of inflammatory cytokines (eg, TNF-α, IL-6, and IL-8), and significantly downregulated the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF). These results suggested that the synergistic treatment of ultrasound-mediated LEV@CAT-NPs effectively eradicated the bacterial infection and reversed the hypoxic microenvironment of tuberculous granulomas, further promoting tissue repair.Conclusion: This study provides a non-invasive and new avenue for treating refractory tuberculosis infections. The potential role of regulating hypoxia within infected lesions as a therapeutic target for infection deserves further exploration in future studies.Keywords: tuberculosis granulomatous, hypoxia, catalase, sonodynamic therapy, Bacille Calmette-Guérin

Shusheng Lin,1,2,&ast; Yi Cao,3,&ast; Ke Zhu,1,2,4,&ast; Caini Yang,1,2 Xiangping Zhu,2 Honghua Zhang,1,2 Rui Zhang1,2 1Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Emergency Department, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4Guangdong TCRCure Biopharma Technology Co., Ltd, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rui Zhang; Honghua Zhang, Email zhangr95@mail.sysu.edu.cn; zhanghh68@mail.sysu.edu.cnBackground: The complex tumor microenvironment of hepatocellular carcinoma (HCC) has led to a low response to immune checkpoints inhibitors (ICIs) and a poor prognosis. PD-L1, as one of the indications for ICIs, is rich in glycosylation modifications, which result in untimely ICIs. Our study constructed a prognostic model based on N-linked glycosylation related genes for predicting the prognosis and the response to ICIs.Methods: The list of N-linked glycosylation related genes is from the AmiGO2 database. The patients in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts were enrolled. The Cox regression was performed to develop a prognostic model and patients were divided into a low- and high-risk subgroups. The role of signature in HCC was well investigated by prognostic analysis, gene set enrichment analysis, and immune infiltration analysis. 21 recurrent HCC patients who received postoperative adjuvant ICIs were recruited to evaluate the relationship between immunotherapy response and the signature. In vitro studies were conducted to investigate the oncogenic effects of DDOST, STT3A and TMEM165 in HCC.Results: 59 N-linked glycosylation related differentially expressed genes were screened from HCC and normal tissues in the TCGA cohort. The prognostic model was developed with DDOST, STT3A and TMEM165. The risk score could be an independent prognostic factor. Patients in the high-risk subgroup showed a worse prognosis than patients in the low-risk one. ssGSEA showed that patients in the low-risk subgroup tended to be in the immune-activated state, with higher levels of B cell and macrophage cell infiltrations and lower levels of regulatory T cell (Treg) infiltrations in both TCGC and GEO cohorts. Immunohistochemistry studies showed that DDOST, STT3A and TMEM165 are highly expressed in tumor tissues and patients with a high-risk score correlated with poor progression free survival and worse immunotherapeutic response. Furthermore, the proliferation of HCC cells was reduced after the knockdown of DDOST, as well as upon the knockdown of STT3A and TMEM165.Conclusion: In this study, we establish that the risk model based on N-linked glycosylation related genes could efficiently predict the prognosis and tumor microenvironment immune state of HCC patients, and the risk score could serve as a novel indicator of immunotherapy.Keywords: N-linked glycosylation, prognostic signature, HCC, immune infiltration, immunotherapy

Xuejun Tan,1 Yukun Xu,1 Sirui Zhou,1 Mingyue Pan,1 Yue Cao,1 Xiuping Cai,2 Qing Zhao,1,2,&ast; Kewei Zhao1,2,&ast; 1The Third Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Guangzhou Key Laboratory of Chinese Medicine Research on Prevention and Treatment of Osteoporosis, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kewei Zhao; Qing Zhao, Department of Laboratory Medicine, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, 261 Longxi Avenue, Liwan District, Guangzhou, Guangdong, People’s Republic of China, Tel +86-13711355225 ; +86-18825144487, Email zkw2011@gzucm.edu.cn; zhaoqing900116@126.comAbstract: All humans are universally affected by inflammatory diseases, and there is an urgent need to identify new anti-inflammatory drugs with good therapeutic benefits and minimal side effects to the organism. Recently, it has been found that plant-derived vesicle-like nanoparticles (PDVLNs) have good biocompatibility, with their active ingredients exhibiting good therapeutic effects on inflammation. They can also be used as drug carriers for targeted delivery of anti-inflammatory drugs. Therefore, PDVLNs represent a popular research area for novel anti-inflammatory drugs. This paper details the origin, biological functions, isolation and purification, and identification of PDVLNs, as well as the therapeutic effects of their intrinsic bioactive components on inflammatory diseases. It also introduces their targets as drug carriers to facilitate the development and application of PDVLNs anti-inflammatory drugs.Keywords: plant, vesicle-like nanoparticles, inflammation, inflammatory diseases

Wei Lu,1 Yan Cao,2 Fanhua Zeng,1,3 Chun Chen,1,4 Zhenyu Yang,1 Zuoliang Qi,1 Xiaonan Yang1 1The Department of Hemangioma and Vascular Malformation, Plastic Surgery Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China; 2The Department of Pathology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China; 3The Department of Burn and Plastic Surgery, Hengyang No.1 People’s Hospital, Hunan, People’s Republic of China; 4E.N.T. Department, Shenzhen Longgang District Third People’s Hospital, Guangdong, People’s Republic of ChinaCorrespondence: Xiaonan Yang, The Department of Hemangioma and Vascular Malformation, Plastic Surgery Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, 100144, Tel +86 18810601889, Fax +86 01088964614, Email yxnan@aliyun.comAbstract: Benign lymphangioendothelioma (BL) is a rare, poorly identified, slow-growing benign vascular lesion characterized by asymptomatic, solitary, well-demarcated macules, or by mildly infiltrated plaque. We report a case of an atypical BL that arose as a tender, protuberant, flesh-colored mass with cyanotic vesicles, and then progressed to a persistent exudative wound after two incomplete excisions. The patient was also diagnosed with thoracic duct narrowing. Although the stenosis was removed by surgery, the right lower extremity ulceration and exudation did not improve. Thus, we performed a thorough excision and split-thickness skin graft transplant following vacuum sealing drainage, and eventually the patient had a favorable functional and cosmetic outcome. A biopsy revealed irregular, dilated vascular spaces lined with a single layer of flat endothelial cells extending from the superficial dermis to the subcutis that did not reach the striated muscles. Additionally, by reviewing the literature on BL, in this paper we summarize the diverse pathogenic, morphological, and immunohistochemical presentations for this rare disease, as well as the histopathological differential diagnosis of lymphangiomatosis, Kaposi’s sarcoma, and angiosarcoma.Keywords: acquired progressive lymphangioma, angiosarcoma, benign lymphangioendothelioma, Kaposi’s sarcoma, lymphangioma, lymphangiomatosis

Dingqi Lu,1,&ast; Xinchao Zhu,2,&ast; Tao Hong,2 Xinyi Yao,2 Zhiming Xie,3 Liying Chen,2 Yihan Wang,2 Kaiyuan Zhang,2 Yating Ren,2 Yi Cao,4 Xinchang Wang3 1First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China; 2Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China; 3The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China; 4The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinchang Wang, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, People’s Republic of China, Tel +86 13065714635, Email ossani@126.comPurpose: Systemic lupus erythematosus is a heterogeneous autoimmune disease in which skin involvement is a common manifestation. It is currently thought that the photosensitivity of SLE skin involvement is associated with anti-SSA antibodies. This study aimed to expand the current state of knowledge surrounding the molecular pathophysiology of SLE skin photosensitivity through Serum metabolomics analysis.Patients and Methods: The serum metabolites of 23 cases of skin-involved SLE (SI) group, 14 cases of no SI (NSI) group, and 30 cases of healthy controls (HC) were analyzed by using UPLC-MS/MS technology, and subgroup analysis was performed according to the expression of anti-SSA antibodies in SI. MetaboAnalyst 5.0 was used for enrichment analysis and ROC curve construction, identifying serum metabolic markers of skin-involved SLE associated with anti-SSA antibodies.Results: We identified several metabolites and metabolic pathways associated with SLE photosensitivity. Two metabolites, SM (d18:1/24:0) and gamma-CEHC can distinguish between anti-SSA antibody-positive and negative SI, with AUC of 0.829 and 0.806. These two photosensitization-related substances may be potential markers of skin involvement in SLE associated with anti-SSA antibody.Conclusion: This study provides new insights into the pathogenesis of SI patients, and provides a new molecular biological basis for the association between anti-SSA antibodies and skin photoallergic manifestations of SLE.Keywords: systemic lupus erythematosus, metabolomics, biomarkers, anti-SSA antibodies, photosensitivity

Yuliang Shi,1,2 Yuxian Yang,1,2 Miaoling Feng,1,2 Weihan Ling,1,2 Tongguo Wei,1,2 Yumin Cao,1,2 Rui Zhong,1,2 Heming Wu2 1Department of Neurology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 2Center for Precision Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Heming Wu, Center for Precision Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, No. 63 Huangtang Road, Meijiang District, Meizhou, People’s Republic of China, Email wuheming1986@126.comBackground: Cytochrome P450 2C19 (CYP2C19) genotypes and metabolic phenotypes (extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM)) are related to the metabolism of therapeutic drugs for cardiovascular and cerebrovascular diseases. This study aimed to investigate the differences of CYP2C19 gene polymorphism distribution between coronary artery disease (CAD) patients and cerebral infarction (CI) patients.Methods: We identified 413 CI patients, 509 CAD patients, and 241 CI+CAD patients from 2016 to 2020 and studied genotypes of CYP2C19 rs4986893 (636G>A) and rs4244285 (681G>A) polymorphisms using PCR-gene chip detection method. Differences in CYP2C19 genotypes and metabolic phenotypes between the groups were compared. To analyze the efficacy of CYP2C19 metabolic phenotypes in discriminating between cerebral infarction and coronary artery disease, multiple logistic regression analysis was conducted after adjusting for gender, age, smoking history, drinking history, hypertension, and diabetes.Results: There were significant differences in the distribution of CYP2C19 genotypes and metabolic phenotypes between CI and CAD patients. The results of multivariate logistic regression (adjusted for sex, age, smoking, drinking, hypertension, and diabetes) indicated that CYP2C19 IM phenotype (IM vs EM: OR 1.443, 95% CI: 1.086– 1.918, P=0.011) and CYP2C19 IM+PM phenotype (IM or PM vs EM: OR 1.440, 95% CI: 1.100– 1.885, P=0.008) may be indicators of CI from CAD.Conclusion: CYP2C19 EM metabolic phenotype was dominant in CAD patients, and CYP2C19 IM metabolic phenotype was dominant in CI patients. After adjusting for other confounding factors, patients with the CYP2C19 IM metabolic phenotype were more likely to develop CI than CAD.Keywords: CYP2C19, genotype, metabolic phenotype, cerebral infarction, coronary artery disease