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Guanxiang Huang,1– 3,&ast; Wenyu Lin,1– 3,&ast; Hangjing Gao,1– 3 Yuan Ren,1– 3 Jun Shen,4 Shuxia Xu,5 Dabin Liu,6 Yuanjun Cai,6 Chengbin Lin,6 Xite Lin,1– 3 Tingting Jiang,1– 3 Binhua Dong,1– 3 Pengming Sun1– 3 1College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China; 2Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children’s Hospital), Fuzhou, Fujian, 350001, People’s Republic of China; 3Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, Fujian, 350001, People’s Republic of China; 4Fujian Provincial Cervical Disease Diagnosis and Treatment Health Center, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China; 5Department of Pathology, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China; 6Department of Gynecology, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pengming Sun; Binhua Dong, Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China, Tel +86-591-87558732 ; +86-13599071900, Fax +86-591-87551247, Email fmsun1975@fjmu.edu.cn, sunfemy@hotmail.com; dongbinhua86@fjmu.edu.cn, dbh18-jy@126.comBackground: There are currently few prognostic models for conization in patients with high-grade squamous intraepithelial lesion (HSIL) because it is a rapid procedure that typically collects less case information. The present study aimed to establish a rapid/accurate postoperative prognostic assessment model for these patients.Methods: This study included 631 nonpregnant participants with HSIL confirmed by histopathology from January 2015 to January 2018. The recurrent/residual cervical intraepithelial neoplasia (CIN) were divided into residual CIN, simple recurrent CIN and recurrent CIN accompanied with CIN progression. The recurrence/residual-free survival (RFS) time was defined as the time span from the time of surgery (baseline) until the first lesion of CIN was detected or the 1-/3-/5-year follow-up endpoint was reached.Results: After LASSO regression selection, the higher platelet-to-lymphocyte ratio (PLR) (OR = 1.006, p = 0.002), positive margin status (OR = 2.451, p = 0.021), HPV-16 (OR = 4.414, p < 0.001), − 18 (OR = 3.040, p = 0.009), − 56 (OR = 10.715, p=0.021), and non-HR-HPV (OR = 2.487, p = 0.028) infection showed significant difference in the Logistic model. And HPV-16 infection (OR = 6.159, p = 0.001) could promote recurrent CIN accompanied with CIN progression. In multivariate Cox regression models, the higher PLR (HR = 1.005/1.005/1.005, p = 0.020/0.002/0.003) and HPV-16 infection (HR = 2.758/2.836/2.674, p < 0.001) showed statistical difference during 1-/3-/5-year follow-up. While gland invasion (p = 0.081), margin status (p = 0.075) and HPV infection genotype (p = 0.150) did not showed statistical difference in multivariate Cox regression models based on LASSO regression. And gland invasion (p = 0.251/0.686) and HPV-58 infection (p = 0.148/0.813) also showed no statistical difference in optimized Logistic regression models.Conclusion: HPV-16, − 18, − 56 and non-HR-HPV infection status can be considered as indicators for recurrent CIN during the 5-year follow-up, especially for HPV-16 infection, which also lead to a CIN recurrence accompanied with disease progression. And the preoperative PLR level, gland invasion, positive margin may be predictors for recurrent/residual CIN during 1-, 3- and 5-year follow-up.Keywords: cervical intraepithelial neoplasia, higher platelet-to-lymphocyte ratio, human papillomavirus, conization, prognosis

Shuai Guo,1,&ast; Zhaoting Gong,1,&ast; Xiaona Sun,2 Fei Gao,1 Xiang Li,1 Xiaolin Zu,1 Chao Qu,1 Hongliang Zhang,3 Hai Gao1 1Center for Coronary Artery Disease, Division of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Cardiology, Laizhou City People’s Hospital, Laizhou, People’s Republic of China; 3Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hai Gao, Center for Coronary Artery Disease, Division of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, People’s Republic of China, Email gaohai1221@mail.ccmu.edu.cn Hongliang Zhang, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100037, People’s Republic of China, Email 13810694497@163.comBackground: Ischemic cardiomyopathy (ICM) significantly contributes to global disease burden, while the role of ferroptosis in ICM remains underexplored.Methods: We identified differentially expressed ferroptosis-related genes (DEFRGs) by analyzing the GSE57338 dataset and cross-referencing with FerrDb. Consensus clustering was then used to identify ferroptosis-associated clusters within the ICM samples. A ferroptosis-specific predictive signature was developed using the least absolute shrinkage and selection operator (LASSO) method and validated with the GSE5406 dataset. Additionally, quantitative real-time PCR (qRT-PCR) experiments were performed to validate the 11 feature genes in a rat ICM model.Results: We identified 15 DEFRGs in GSE57338, which distinguished two patient clusters with distinct ferroptosis gene expression, pathway enrichment profiles, and metabolic characteristics. All DEFRGs were upregulated in cluster 2. Potential therapeutic targets were also identified for different ICM patient clusters. The 11-gene predictive signature (TXNRD1, STEAP3, STAT3, SCL2A1, PLIN2, NQO1, NNMT, IL33, ENPP2, ARRDC3, ALOX5) showed robust predictive power in both training and validation sets. High-risk patients exhibited increased infiltration of CD8+ T cells, CD4+ naïve T cells, M0/M1 macrophages, and resting mast cells, along with significant enrichment in epithelial mesenchymal transition and interferon responses. Low-risk patients had higher infiltration of regulatory T cells and monocytes. Results of qPCR analysis confirmed the bioinformatic analysis, validating the expression of the 11 feature genes in the rat ICM model.Conclusion: We identified two ferroptosis-related clusters in ICM patients and developed a predictive signature based on ferroptosis-related genes. Our findings highlight the importance of ferroptosis in ICM and offer new insights for its diagnosis and treatment.Keywords: ischemic cardiomyopathy, ferroptosis, bioinformatics analysis, predictive signature

Danwei Zhang,1 Yating Zeng,1 Bin Sun,2 Wei Li,2 Wenjuan Liu,2 Haiyan Gao,2 Yibing Zhu,2 Haibo Li,2,&ast; Qiang Chen1,&ast; 1Department of Cardiac Surgery, Fujian Children’s Hospital (Fujian Branch of Shanghai Children’s Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China; 2Division of Birth Cohort Study, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiang Chen, Department of Cardiac Surgery, Fujian Children’s Hospital (Fujian Branch of Shanghai Children’s Medical Center), College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, No. 966 Hengyu Road, Jinan District, Fuzhou, 350014, People’s Republic of China, Email chenqiang2228@163.com Haibo Li, Division of Birth Cohort Study, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, No. 18 Daoshan Road, Gulou District, Fuzhou, 350001, People’s Republic of China, Email haiboli89@163.comPurpose: Gestational diabetes mellitus (GDM) is a prevalent complication during pregnancy. This study aimed to explore the associations between inflammatory indices during pregnancy and the development of GDM.Methods: Data from the Fujian Birth Cohort Study between March 2019 and December 2022 were used. Participants who delivered a live-born singleton were included and categorized into GDM and non-GDM groups. Two inflammatory indices, the systemic immune-inflammation index (SII) and systemic inflammatory response index (SIRI), were calculated for each trimester of pregnancy via hematological parameters from complete blood count tests. The distributions of inflammatory indicators across trimesters were compared between the GDM and non-GDM groups. Additionally, multivariable logistic regression models were employed to investigate the associations between inflammatory indices and the incidence of GDM.Results: A total of 17297 participants were included, 21.2% of whom were diagnosed with GDM. In the first trimester, the median SIIs for the GDM and non-GDM groups were 817.7× 109/L and 756.9× 109/L, respectively, whereas the median SIRIs were 1.6× 109/L and 1.5× 109/L, respectively. In both groups, the SII increased to its peak in the second trimester before declining, whereas the SIRI progressively increased throughout pregnancy. The SII and SIRI were greater in the GDM group than in the non-GDM group during the first two trimesters but lower in the third trimester. Nonlinear positive associations between first-trimester SII and SIRI levels and GDM were observed, with extreme quartile odds ratios of 1.32 (95% CI: 1.19, 1.48) and 1.39 (95% CI: 1.24, 1.55), respectively.Conclusion: The SII and SIRI increased and reached their peak values in the second and third trimesters of pregnancy, respectively. Elevated levels of the SII and SIRI in early pregnancy were linked to an increased risk of GDM, suggesting their potential utility as screening tools for GDM.Keywords: gestational diabetes mellitus, GDM, systemic immune-inflammation index, SII, systemic inflammatory response index, SIRI

Yanye Tu,1 Hui Gao,1 Rongqing Zhao,1 Jiliang Yan,1 Diyu Wu2 1Clinical Laboratory of Ningbo Medical Centre Lihuili Hospital, Ningbo University, Ningbo, Zhejiang Province, People’s Republic of China; 2School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Hui Gao, Email gaoh711@126.comObjective: This study aims to investigate the association between antimicrobial resistance genes and virulence factors in ST11 and non-ST11 types of CR-KP in bloodstream infections in the intensive care unit, providing a theoretical basis for infection control and clinical diagnosis and treatment.Methods: From January 2021 to June 2023, samples of Klebsiella pneumoniae from bloodstream infections were collected at our hospital, focusing on those resistant to carbapenems. The resistance genes, housekeeping genes, and virulence genes were identified through PCR and analyzed using the GrapeTree software to perform MLST-based minimum spanning tree typing.Results: Among the 85 CR-KP cases, 61.18% were of the ST11 type, predominantly of the KL64 capsular type; non-ST11 types were mainly ST15, accounting for 25.88%, predominantly of the KL5 capsular type. The carriage rates of virulence genes such as rmpA2, entB, silS, kpn, iucA, peg-344, and terB were significantly higher in the ST11 group than in the non-ST11 group. The primary carbapenemase identified was class A enzyme blaKPC-2, with a higher carriage rate in the ST11 group. Drug susceptibility tests showed that the resistance rates for cefepime, ertapenem, nitrofurantoin, amikacin, and gentamicin were also higher in the ST11 group, consistent with the resistance genotype findings.Conclusion: The study reveals that ST11 type CR-KP in intensive care unit bloodstream infections exhibits stronger resistance and higher virulence compared to non-ST11 types, posing significant challenges to clinical treatment. Thus, strict control over the use of carbapenem antibiotics is essential to prevent the spread of resistant plasmids.Keywords: intensive care unit, bloodstream infections, ST11 CR-KP, Non-ST11 CR-KP, resistance genes, virulence genes

Shaojie Li,1,&ast; Qiangqiang Feng,1,&ast; Jiayin Wang,1 Baofang Wu,1 Weizhi Qiu,1 Yiming Zhuang,2 Yong Wang,3 Hongzhi Gao1 1Department of Neurosurgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China; 2Internal Medicine, Quanzhou Quangang District Hillside Street Community Health Service Center, Quanzhou, Fujian, 362000, People’s Republic of China; 3Child and Adolescent Psychiatry, The Third Hospital of Quanzhou, Quanzhou, Fujian, 362000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yong Wang; Hongzhi Gao, Email 120432246@qq.com; gaohongzhi@fjmu.edu.cnObjective: To develop a validated machine learning (ML) algorithm for predicting the risk of hospital-acquired pneumonia (HAP) in patients with traumatic brain injury (TBI).Materials and Methods: We employed the Least Absolute Shrinkage and Selection Operator (LASSO) to identify critical features related to pneumonia. Five ML models—Logistic Regression (LR), Extreme Gradient Boosting (XGB), Random Forest (RF), Naive Bayes Classifier (NB), and Support Vector Machine (SVC)—were developed and assessed using the training and validation datasets. The optimal model was selected based on its performance metrics and used to create a dynamic web-based nomogram.Results: In a cohort of 858 TBI patients, the HAP incidence was 41.02%. LR was determined to be the optimal model with superior performance metrics including AUC, accuracy, and F1-score. Key predictive factors included Age, Glasgow Coma Score, Rotterdam Score, D-dimer, and the Systemic Immune Response to Inflammation Index (SIRI). The nomogram developed based on these predictors demonstrated high predictive accuracy, with AUCs of 0.818 and 0.819 for the training and validation datasets, respectively. Decision curve analysis (DCA) and calibration curves validated the model’s clinical utility and accuracy.Conclusion: We successfully developed and validated a high-performance ML algorithm to assess the risk of HAP in TBI patients. The dynamic nomogram provides a practical tool for real-time risk assessment, potentially improving clinical outcomes by aiding in early intervention and personalized patient management.Keywords: traumatic brain injury, machine learning, hospital-acquired pneumonia, dynamic nomogram, imaging metrics

Zhuajin Bi,1,2 Huajie Gao,1,2 Jing Lin,1,2 Mengcui Gui,1,2 Yue Li,1,2 Zhijun Li,1,2 Bitao Bu1,2 1Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China; 2Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Zhijun Li, Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China, Email lizhijun@tjh.tjmu.edu.cn Bitao Bu, Email bubitao@tjh.tjmu.edu.cnPurpose: To investigate the predictors for poor outcomes (including disease exacerbation, hospitalization and myasthenic crisis) in patients with pre-existing myasthenia gravis (MG) following Coronavirus disease 2019 (COVID-19), and to explore the potential effects of COVID-19 on inflammatory and immune responses in MG patients.Patients and Methods: This retrospective cohort study analyzed medical records of 845 MG patients who were diagnosed with COVID-19 between January 2020 to March 2023 at a single medical center.Results: Generalized MG at onset and comorbidities (chronic kidney disease and malignancy) were independent risk factors of poor outcomes. Patients achieving minimal manifestation or better status before COVID-19 had a significantly reduced risk for poor outcomes. Furthermore, patients with older onset age or anti-acetylcholine receptor antibody had a higher risk of exacerbation and hospitalization than those without. Prednisone or immunosuppressant treatment had the potential to reduce the occurrence of poor outcomes, while the duration of prednisone or immunosuppressant usage was associated with a higher risk of poor outcomes. Of the 376 MG patients with blood results available, patients with COVID-19 tended to have higher levels of leukocyte counts, neutrophil-lymphocyte-ratio, hypersensitive C-reactive protein, and Interleukin-6, as well as lower percentages of lymphocytes and regulatory T cells compared to patients without COVID-19.Conclusion: Disease severity at onset, comorbidities, and unsatisfactory control of myasthenic symptoms predicted the occurrence of poor outcomes in MG patients following COVID-19. The risk of poor outcomes was reduced in patients controlled by short-term immunosuppressive therapy. Novel coronavirus might affect inflammatory and immune responses in MG patients, particularly in altering interleukin-6 and regulatory T cell levels.Keywords: myasthenia gravis, COVID‐19, poor outcomes, immunosuppressive treatment, immune responses

Zhi-Yu Yin,&ast; Hao Gao,&ast; Jing Wang, Pan Wei, Jun Guo, Wei Tang Department of Anesthesiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Tang; Jun Guo, Department of Anesthesiology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, No. 185 of Pu-an Road, Shanghai, Huangpu District, 200001, People’s Republic of China, Tel +86-021-53827217, Email weiwwtang@126.com; jun_guo82@126.comObjective: This study aims to evaluate the safety and efficacy of using bilateral nasopharyngeal airways (NPA) during colonoscopic polypectomy performed under sedation anesthesia in obese patients.Methods: Ninety obese patients undergoing colonoscopic polypectomy under elective sedation anesthesia at Shanghai Shuguang Hospital were randomly allocated to two groups. Patients in group B had a nasopharyngeal airway inserted bilaterally after induction of anesthesia, whereas patients in group U had a nasopharyngeal airway inserted in only one nostril. Spontaneous breathing was maintained in both groups. The primary observation parameter was the incidence of oxygen saturation (SpO2) ≤ 92% during anesthesia, while secondary observation parameters included preoperative, intraoperative, and post-operative SpO2 levels, mean arterial pressure (MAP), heart rate (HR), dosage of propofol, duration of the operation, time to anesthesia recovery, need for emergency airway intervention, and occurrence of other adverse events.Results: Hypoxia occurred in 5 out of 45 patients (11.1%) in group B, whereas it was observed in 14 out of 45 patients (31.1%) in group U (P < 0.05). Patients in group B exhibited higher SpO2 levels during and after surgery compared to those in group U (P

Hui Gao,1 Xi Cheng,1 Xu Zuo,2 Zhaolan Huang2 1Department of General Practice, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei Province 430000, People’s Republic of China; 2Department of Respiratory and Digestive, Geriatric Hospital Affiliated with Wuhan University of Science and Technology, Wuhan, Hubei Province, 430000, People’s Republic of ChinaCorrespondence: Zhaolan Huang, Department of Respiratory and Digestive, Geriatric Hospital Affiliated with Wuhan University of Science and Technology, No. 2, Huangjiahu West Road, Hongshan District, Wuhan, Hubei Province, 430000, People’s Republic of China, Tel +86-19819051958, Email 45477428@qq.comBackground: Chronic Obstructive Pulmonary Disease (COPD) progression in the elderly is notably influenced by nutritional, immune, and inflammatory status. This study aimed to investigate the impact of adequate energy supply on these indicators in COPD patients.Methods: COPD patients meeting specific criteria were recruited and categorized into energy-adequate and energy-deficient groups based on their energy supply. Comparable demographic factors such as age, gender, smoking and drinking history, COPD duration, inhaled drug classification, and home oxygen therapy application were observed. Notable differences were found in BMI and inhaled drug use between the two groups.Results: The energy-adequate group exhibited significant improvements in various health indicators, including lymphocyte count, hemoglobin, CRP, total cholesterol, prealbumin, albumin, PNI, SII, SIRI, CAR, and CONUT scores in the secondary auxiliary examination. These positive changes suggest a notable enhancement in nutritional, immune, and inflammatory status.Conclusion: This research highlights the substantial benefits of adequate energy supply in elderly COPD patients. The observed improvements in nutritional, immune, and inflammatory markers underscore the importance of addressing energy needs to positively influence disease-related outcomes in this population. These findings have implications for developing targeted interventions to optimize the well-being of elderly individuals with COPD.Keywords: elderly, chronic obstructive pulmonary disease, energy supply, nutritional status, immune function, inflammatory response

Weihua Han,1,&ast; Peiyao Zhou,2,&ast; Chun Chen,3,&ast; Chunyang Wu,2 Li Shen,1 Cailing Wan,4 Yanghua Xiao,4 Jiao Zhang,2 Bingjie Wang,1 Junhong Shi,1 Xinru Yuan,1 Haojin Gao,1 Hongxiu Wang,1 Ying Zhou,1 Fangyou Yu1 1Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China; 4School of Public Health, Nanchang University, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Zhou; Fangyou Yu, Email 18702195157@163.com; wzjxyfy@163.comBackground: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are a great threat to public health worldwide. Ceftazidime-avibactam (CZA) is an effective β-lactam/β-lactamase inhibitors against CRKP. However, reports of resistance to CZA, mainly caused by Klebsiella pneumoniae carbapenemase (KPC) variants, have increased in recent years. In this study, we aimed to describe the resistance characteristics of KPC-12, a novel KPC variant identified from a CZA resistant K. pneumoniae.Methods: The K. pneumoniae YFKP-97 collected from a patient with respiratory tract infection was performed whole-genome sequencing (WGS) on the Illumina NovaSeq 6000 platform. Genomic characteristics were analyzed using bioinformatics methods. Antimicrobial susceptibility testing was conducted by the broth microdilution method. Induction of resistant strain was carried out in vitro as previously described. The G. mellonella killing assay was used to evaluate the pathogenicity of strains, and the conjugation experiment was performed to evaluate plasmid transfer ability.Results: Strain YFKP-97 was a multidrug-resistant clinical ST11-KL47 K. pneumoniae confers high-level resistance to CZA (16/4 μg/mL). WGS revealed that a KPC variant, KPC-12, was carried by the IncFII (pHN7A8) plasmids (pYFKP-97_a and pYFKP-97_b) and showed significantly decreased activity against carbapenems. In addition, there was a dose-dependent effect of blaKPC-12 on its activity against ceftazidime. In vitro inducible resistance assay results demonstrated that the KPC-12 variant was more likely to confer resistance to CZA than the KPC-2 and KPC-3 variants.Discussion: Our study revealed that patients who was not treated with CZA are also possible to be infected with CZA-resistant strains harbored a novel KPC variant. Given that the transformant carrying blaKPC-12 was more likely to exhibit a CZA-resistance phenotype. Therefore, it is important to accurately identify the KPC variants as early as possible.Keywords: carbapenem-resistant Enterobacterales, Klebsiella pneumoniae, ceftazidime-avibactam, KPC-12, carbapenemase

Yue Lu,1– 3,&ast; Simin Pan,4,&ast; Wenzhen Li,5 Yao Qi,6,7 Li Li,1– 3 Yu-Hong Yan,1– 3 Jianan Wei,1– 3 Dan-Ni Yao,1– 3 Jingjing Wu,1– 3 Hao Deng,1– 3 Shuyan Ye,1– 3 Haiming Chen,1– 3 Qubo Chen,1– 3 Hengjun Gao,6,7 Ling Han,1– 3 Chuanjian Lu1– 3 1State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, People’s Republic of China; 3Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5The Clinical College of Acupuncture Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 6Shanghai Molecular Medicine Engineering Technology Research Center, Shanghai, People’s Republic of China; 7Shanghai National Engineering Research Center of Biochip, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Han; Chuanjian Lu, Email linghan99@gzucm.edu.cn; lcj@gzucm.edu.cnBackground: Psoriasis is a widespread chronic, immune-mediated skin disease with frequent recurrences, and is extremely harmful to the physical and mental health of patients, causing enormous suffering and exerting considerable economic burdens on the health care system as a whole. In more than a decade of clinical use, the optimized formula of Yinxieling (PSORI-CM01) has consistently demonstrated its effectiveness for treating psoriasis. However, its underlying mechanism remains largely unexplored.Methods: The network pharmacology analysis was conducted to predict the mechanism and protective effect of PSORI-CM01 in treating psoriasis. Subsequently, we collected blood samples from 21 patients with psoriasis as part of a randomized, double-blind, and double-dummy clinical trial for microRNA expression profiling. Finally, it was experimentally confirmed that PSORI-CM01 improved psoriasis by regulating miR-20a-3p and miR-3184-3p expression.Results: As a result of the network pharmacology analysis, PSORI-CM01 improved psoriasis through the regulation of autophagy, cellular apoptosis, cellular proliferation, and anti-inflammatory processes. In the target-miRNA regulatory network, these key targets were mainly associated with the regulation of hsa-miR-20a-3p, hsa-miR-155-5p, has-miR-3184-3p, hsa-miR-328-3p and hsa-miR-124-3p. Based on the microRNA expression profiling results, the PSORI-CM01 treatment group exhibited five up-regulated genes and 16 down-regulated genes compared with the healthy control group. In particular, miR-20a-3p and miR-3184-3p were the primary differentially expressed microRNAs, and they were significantly enriched in the signaling pathways involving autophagy, apoptosis, proliferation, and anti-inflammation. Further experiments confirmed that PSORI-CM01 effectively regulates miR-20a-3p and miR-3184-3p, resulting in increased autophagy.Conclusion: We demonstrated by combining network pharmacology and clinical studies of miRNA expression profiles in PBMCs that PSORI-CM01 effectively modulated miR-20a-3p and miR-3184-3p, leading to an increase in autophagy and a decrease in keratinocyte proliferation.Keywords: PSORI-CM01, Psoriasis vulgaris, MicroRNA expression profile, network pharmacology, autophagy

Huina Gao,1,* Yijun Song,2,* Kun Liu,1,* Xinyuan Lu,3 Jiacheng Shen,2 Sulan Wei,2 Hongni Jiang,1,2 Nuo Xu2 1Department of Pulmonary Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 3School of Public Health, Key Laboratory of Public Health Safety, Ministry of Education, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Nuo Xu, Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People’s Republic of China, Email xu.nuo@zs-hospital.sh.cn; Hongni Jiang, Department of Pulmonary Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, 668 Jinhu Road, Xiamen, 361015, People’s Republic of China, Email jiang.hongni@zs-hospital.sh.cnPurpose: Cigarette smoking is the most recognized risk factor of chronic obstructive pulmonary disease (COPD) in China. However, there are no studies analyzing the impact of different smoking behaviors on pulmonary function and pulmonary hypertension (PH) among Chinese male patients with COPD.Patients and Methods: Chinese male smokers with COPD performed pulmonary function tests. Clinical characteristics, smoking behavior features, spirometry and echocardiographic results were compared between the two groups stratified by initial smoking age (18 years old) or complicated PH.Results: The early-smoking group had more respiratory symptoms, more severe smoking behavior, worse pulmonary function with lower FEV1%pre (38.5% vs 70.2%) and FEV1/FVC% (47.5% vs 63.8%), and higher systolic pulmonary artery pressure (sPAP: 38.6 vs 33.9 mmHg) than the late-smoking group. Initiating smoking before adulthood was an independently contributing factor of ventilatory dysfunction and Global Initiative for Obstructive Lung Disease (GOLD) stage escalation. It also had a significant interaction with long smoking duration (≥ 30 years), characterized by markedly decreased lung volumes (VC%pre: 64.0% vs 84.5%), impaired diffusing capacity (DLCO%pre: 58.0% vs 76.8%) and severe emphysema (RV/TLC%pre: 145.2% vs 130.2%). COPD patients complicated with PH exhibited worse ventilatory function (FEV1%pre: 43.2% vs 56.2%), impaired diffusion capacity (DLCO%pre: 56.7% vs 77.1%) and decreased lung volume (VC%pre: 67.67% vs 75.38%). Both severe smoking behaviors and impaired pulmonary function had close correlations with sPAP.Conclusion: The early-smoking group exhibited predominantly ventilation dysfunction and had complex interactions with long smoking duration to further affect lung volume and diffusion capacity. Different smoking behaviors influenced variations of pulmonary dysfunction and comorbid PH in patients with COPD.Keywords: chronic obstructive pulmonary disease, pulmonary function, smoking behavior, initial smoking age, pulmonary hypertension

Shuqi Wang,1,2 Haina Gao,3 Mengmeng Zhang,1,2 Shuchun Chen1,2 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 3Department of Internal Medicine, The Second Hospital of Shijiazhuang, Shijiazhuang, People’s Republic of ChinaCorrespondence: Shuchun Chen, Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China, Tel/Fax +86 31185988406, Email chenshuc2014@163.comPurpose: To explore the relationship between vitamin D (VitD) deficiency and the apolipoprotein B/apolipoprotein A1 (apo B/A1) in type 2 diabetes mellitus (T2DM) patients.Methods: This was a retrospective study that lasted 2 years and 6 months, collecting information and laboratory data from 784 patients with T2DM. Patients were divided into VitD deficiency group (n = 433) and non-VitD deficiency group (n = 351) based on VitD levels. Calculated apo B/A1 ratio, and patients were further divided into high-apo B/A1 group (n = 392) and low-apo B/A1 group (n = 392) based on the median of the apo B/A1. All data were analyzed using Prism 8.0.1 and R version 4.3.1 software.Results: Apo B/A1 levels of T2DM patients combined with VitD deficiency was significantly higher than that of non-VitD deficiency patients, and the VitD levels of patients with high apo B/A1 was significantly lower than that patients with low apo B/A1 (all P< 0.001). Spearman correlation analysis showed that VitD levels were negatively correlated with apo B/A1 (r=-0.238, P< 0.001). Multiple linear regression analysis revealed after adjusting other factors, VitD levels were significantly negatively associated with apo B/A1 (β=-0.123, P=0.001). Binary logistic regression analysis showed apoB/A1 was an independent risk factor for VitD deficiency in T2DM patients. Restrictive cubic spline indicated a significant linear relationship between apoB/A1 and VitD deficiency (P general trend < 0.0001, P nonlinear = 0.0896), after stratification of gender, the results showed that apo B/A1 was more susceptible to VitD deficiency in female patients. The receiver operating characteristic (ROC) curve analysis showed that the area under the curve, sensitivity and specificity of the apo B/A1 for VitD deficiency were 0.654, 66.3% and 59.8%, respectively.Conclusion: The apo B/A1 was significantly negatively associated with VitD levels and an independent risk factor for VitD deficiency in patients with T2DM.Keywords: type 2 diabetes mellitus, vitamin D deficiency, apolipoprotein B/apolipoprotein A1

Chang Tang,1,2,&ast; Lanting Wang,1,2,&ast; Zihua Chen,1,2,&ast; Jin Yang,1,2 Haiqing Gao,1,2 Chenggong Guan,1,2 Qiaozhi Gu,1,2 Shan He,1,2 Fanping Yang,1,2 Shengan Chen,1,2 Li Ma,1,2 Zhen Zhang,1,2 Ying Zhao,1,2 Lin Tang,1,2 Yu Xu,1,2 Yue Hu,3 Xiaoqun Luo1,2 1Department of Allergy & Immunology, Huashan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 2Department of Dermatology, Huashan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 3Department of Clinical Laboratory, Huashan Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoqun Luo, 12 Wulumuqi Zhong Road, Jing’an District, Shanghai, People’s Republic of China, Tel +86 13918825230, Email luoxiaoqun913@126.comPurpose: Several in vivo experiments have shown that molecular hydrogen is a promising therapeutic agent for interstitial lung diseases (ILD). In this study, hydrogen therapy was investigated to determine whether it is superior to N-Acetylcysteine (NAC) for the treatment of patients with early-stage ILD.Patients and Methods: A prospective, single-center, randomized, controlled clinical trial was conducted in 87 patients with early-stage ILD. Hydrogen or NAC therapy was randomly assigned (1:1 ratio) to the eligible patients. The primary endpoint was the change in the high-resolution computed tomography (HRCT) and composite physiologic index (CPI) scores from baseline to week 48. Pulmonary function was evaluated as a secondary endpoint, and adverse events were recorded for safety analysis.Results: The rate of HRCT image improvement from the baseline in the HW group (63.6%) was higher than that in the NAC group (39.5%). A significant decrease in CPI and improvement in DLCO-sb were observed in the hydrogen group compared with those in the control group. Changes in other pulmonary function parameters, including FVC, FEV1, FEV1/FVC%, and TLC, were not significantly different between the two groups. Adverse events were reported in 7 (15.9%) patients in the HW group and 10 (23.3%) patients in the NAC group, but the difference was not significant (P=0.706).Conclusion: Hydrogen therapy exhibits superior efficacy and acceptable safety compared with NAC therapy in patients with early-stage ILD.Keywords: hydrogen, N-acetylcysteine, interstitial lung disease, therapeutic effects

Hui Gao,1,&ast; Nan Jiang,2,&ast; Qiannan Niu,3 Shenglin Mei,4,5 Håvard Jostein Haugen,6 Qianli Ma6,7 1Department of Stomatology, the Eighth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of Community Dentistry, Institute of Clinical Dentistry, University of Oslo, Oslo, Norway; 3State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China; 4Xingrui Dental Clinic, Xi’an, Shaanxi Province, People’s Republic of China; 5Department of Physics & Materials Science, City University of Hong Kong, Hong Kong, People’s Republic of China; 6Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Oslo, Norway; 7Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Håvard Jostein Haugen; Qianli Ma, Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Oslo, 0317, Norway, Email h.j.haugen@odont.uio.no; qianlima@odont.uio.noIntroduction: Titanium (Ti) and its alloys are widely utilized in endosseous implants. However, their clinical efficacy is marred by complications arising from bacterial infections owing to their inadequate antibacterial properties. Consequently, enhancing the antibacterial attributes of implant surfaces stands as a pivotal objective in the realm of implantable materials research.Methods: In this study, we employed sequential anodization and plasma immersion ion implantation (PIII) technology to fabricate a silver-embedded sparsely titania nanotube array (SNT) on the near-β titanium alloy Ti-5Zr-3Sn-5Mo-15Nb (TLM) implants. The surface characteristics, antimicrobial properties, biocompatibility, and osteogenic activity of the silver-nanomodified SNT implant (SNT Ag) surface, alongside peri-implant inflammatory responses, were meticulously assessed through a combination of in vitro and in vivo analyses.Results: Compared with polished TLM and SNT, the silver-embedded SNT (SNT Ag) surface retained the basic shape of nanotubes and stably released Ag+ at the ppm level for a long time, which demonstrated an effective inhibition and bactericidal activity against Staphylococcus aureus (SA) while maintaining ideal cytocompatibility. Additionally, the subtle modifications in nanotubular topography induced by silver implantation endowed SNT Ag with enhanced osteogenic activity and mitigated inflammatory capsulation in soft tissue peri-implants in a rat model.Conclusion: Incorporating a silver-embedded SNT array onto the implant surface demonstrated robust antibacterial properties, impeccable cytocompatibility, exceptional osteogenic activity, and the potential to prevent inflammatory encapsulation around the implant site. The Silver-PIII modification strategy emerges as a highly promising approach for surface applications in endosseous implants and trans-gingival implant abutments.Keywords: implant surface modification, silver PIII, anti-bacterial activity, cytocompatibility, osteogenic differentiation, host inflammatory response

Hongyan Gao,1 Guanghui An2 1Institute of Science, Technology and Humanities, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2School of Acupuncture-Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of ChinaCorrespondence: Guanghui An, School of Acupuncture-Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China, Email 83546328@qq.com

Man Li,1,2,&ast; Xintao Li,3,&ast; Hongwei Gao,4 Peng Li,1 Li Zhang,1 Xiaoling Zhang,1 Peipei Liu,5 Xuemei Yang,2 Lili Wu,6 Jiangwei Zeng,2 Shouling Wu,7 Lixia Sun1 1Department of Emergency, The Affiliated Hospital of North China University of Science and Technology, Tangshan, People’s Republic of China; 2Graduate School, North China University of Science and Technology, Tangshan, People’s Republic of China; 3Department of Cardiology, The First Hospital of Soochow University, Jiangsu, People’s Republic of China; 4Department of Emergency, Caofeidian District hospital of Tangshan City, Tangshan, People’s Republic of China; 5School of Public Health, North China University of Science and Technology, Tangshan, People’s Republic of China; 6Department of Cardiology, Shanghai Songjiang District Central Hospital, Shanghai, People’s Republic of China; 7Department of Cardiology, Kailuan Hospital, Tangshan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lixia Sun, Department of Emergency, The Affiliated Hospital of North China University of Science and Technology, Tangshan, 063000, People’s Republic of China, Email 13323151999@189.cn Shouling Wu, Department of Cardiology, Kailuan General Hospital, Tangshan, 063000, People’s Republic of China, Email drwusl@163.comPurpose: Inflammation plays a critical role in the development of cardiac conduction block (CCB), which is associated with an increased risk of morbidity and mortality. The monocyte-lymphocyte ratio (MLR) acts as a novel inflammatory marker; however, its association with CCB has not yet been studied. This study aimed to investigate the association between MLR and CCB risk.Patients and Methods: In total, 82,472 CCB-free participants were identified from the Kailuan study. MLR was calculated using the monocyte count/lymphocyte count. The participants were stratified based on quartiles of MLR levels. Incident CCB and its subtypes were ascertained from electrocardiograms at biennial follow-up visits. The Cox proportional hazards model and restricted cubic spline analysis were used to investigate the association between MLR with CCB and its subtypes.Results: During a median follow-up of 10.4 years, 3222 incident CCB cases were observed. A U-shaped association was observed between MLR and CCB risk (Pnonlinearity < 0.05). After multivariate adjustment, individuals in the highest MLR quartile had a hazard ratio (HR) of 1.212 (95% CI: 1.097-1.340; Q4 vs Q2), while those in the lowest MLR quartile had an HR of 1.106 (95% CI: 1.000-1.224; Q1 vs Q2). Sensitivity and subgroup analyses yielded consistent results. The U-shaped association persisted for atrioventricular block (AVB) in subtype analyses.Conclusion: MLR was significantly associated with an increased risk of new-onset CCB. Assessing MLR may have clinical relevance for predicting CCB risk, providing valuable insights for preventive strategies and patient management.Pre-Registered Clinical Trial Number: The pre-registered clinical trial number is ChiCTR-TNC-11001489. Keywords: cardiac arrhythmia, cardiac conduction block, inflammation, monocyte-lymphocyte ratio, risk factors

Hantong Hu,1,2,&ast; Xiaoqi Lin,3,&ast; Lianqiang Fang,1 Yang Li,1 Hong Gao1 1Department of Acupuncture and Moxibustion, the Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China; 2Department of Neurobiology and Acupuncture Research, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou City, People’s Republic of China; 3The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Gao, Department of Acupuncture and Moxibustion, the Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 219 Moganshan Road, Hangzhou City, People’s Republic of China, Email qtgh@vip.qq.comObjective: This study aims to evaluate the efficacy and safety of acupuncture for chronic subjective tinnitus and explore the central mechanism underlying acupuncture for chronic subjective tinnitus using functional near-infrared spectroscopy (fNIRS).Methods: We will randomly assign 60 tinnitus patients to either an acupuncture group or a waiting-list control group. The acupuncture group will undergo 12 treatment sessions over 4 weeks, whereas the waiting-list control group will receive no intervention concurrently. Clinical outcome measures include the Tinnitus Handicap Inventory (THI) score, tinnitus loudness assessed by 11-point NRS, average pure-tone threshold, and Hamilton Anxiety Scale (HAM-A) score. Neuroimaging outcomes assessed by fNIRS included blood oxygen concentration and resting-state functional connectivity (RSFC). All outcome measurements will be assessed at the baseline, after 4-week treatment, and at 3-month follow-ups.Results: Our investigation will determine if significant differences exist between the two groups regarding THI, NRS, average pure-tone threshold, and HAM-A scores. Moreover, the analysis will reveal whether the acupuncture group demonstrates significant change in blood oxygen concentration and RSFC between specific brain regions compared to the waiting-list control group.Conclusion: With the novel technique of fNIRS, in addition to efficacy evaluation of acupuncture, this study’s findings are anticipated to partly elucidate the neural mechanisms underlying acupuncture treatment for subjective tinnitus and offer an objective assessment method for its therapeutic impact, thereby contributing to filling the research gap.Trial Registration: Clinicaltrials registry (identification code NCT05829278).Keywords: acupuncture, functional near-infrared spectroscopy, randomized controlled trial, subjective tinnitus, neural mechanisms

Haiting Xu,1 Lina Zheng,2 Leilei Wang,1 Huanqin Gao,1 Yanyan Wei,1 Jingxu Chen1 1Psychology and Psychiatric Department, Beijing Hui-Long-Guan Hospital, Peking University, Beijing, People’s Republic of China; 2Psychology and Psychiatric Department, Liaocheng People’s Hospital, Liaocheng, People’s Republic of ChinaCorrespondence: Jingxu Chen, Email chenjx1110@163.comBackground: Inflammation is relevant to the pathophysiology of severe neuropsychiatric disorders, schizophrenia (SCZ) and bipolar disorders (BD). Multiple pathophysiological biomarkers are valuable for the study of inflammatory processes. This study investigated albumin-related biomarkers in SCZ and BD to explore their roles in disease.Methods: A total of 5,577 SCZ, 3442 BD-manic (BD-M) and 1405 BD-depression (BD-D) in acute stage and 5000 health controls (HCs) were enrolled. The differences in these biomarker levels among different groups were compared, and the contributing factors for the occurrence of SCZ, BD, and subgroups of BD were analyzed.Results: Both SCZ and BD exhibit lower prognostic nutritional index (PNI), but higher neutrophil percentage-to-albumin ratio (NPAR) and creatinine–albumin ratio (CRA) compared with HC. Compared with BD-D, BD-M had higher NPAR and platelet-to-albumin ratio (PAR) and lower CRA. In logistic regression, lower prognostic nutritional index (PNI) and higher CRA were associated with both SCZ and BD, while higher NPAR was associated with BD. In the subgroup of BD, higher NPAR, CRA and lower PNI were associated with BD-M; lower PAR, PNI and higher CRA were associated with BD-D.Conclusion: Our study reaffirmed the role of inflammation in the pathophysiology of SCZ and BD. Diagnostic value has been demonstrated in NPAR, PAR, PNI and CRA for BD and SCZ.Keywords: schizophrenia, bipolar disorder, inflammation, albumin, neutrophil percentage-to-albumin ratio, platelet to albumin ratio, prognostic nutritional index

Xia Lei,1,&ast; Hongdan Xu,2,&ast; Yan Wang,3 Hainan Gao,4 Deping Zhao,4 Jinfeng Zhang,4 Ziyue Zhu,4 Kun Zuo,4 Ying Liu,3 Xiaoliang Li,3,5 Ning Zhang4 1Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, 214071, People’s Republic of China; 2Department of Pharmacy, Wuxi Higher Health Vocational Technology School, Wuxi, 214000, People’s Republic of China; 3Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, 571199, People’s Republic of China; 4College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China; 5Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Cardiovascular Diseases Institute of the First Affiliated Hospital, Hainan Medical University, Haikou, 571199, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Zhang, College of Pharmacy, Heilongjiang University of Chinese Medicine, No. 24, Heping Road, Xiangfang District, Harbin, Heilongjiang Province, 150040, People’s Republic of China, Email zhangning0454@163.com Xiaoliang Li, College of Pharmacy, Hainan Medical University, No. 3 Xueyuan Road, Longhua District, Haikou City, Hainan Province, 571199, People’s Republic of China, Email lixiaoliang-1984@163.comPurpose: To elucidate the potential mechanisms of QFY for the treatment of Alzheimer’s Disease (AD), and explore the effective substances of QFY.Materials and Methods: UPLC-LTQ-Orbitrap-MS was used to identify the chemical constituents of the serum samples and the cerebrospinal fluid samples of rats after QFY administration. Network pharmacology was used to predict potential targets and pathways of QFY against AD. The AD mice model was established by subcutaneous injection of D-gal for 8 consecutive weeks. New object recognition (NOR) and Morris water maze test (MWM) were used to evaluate the learning and memory abilities of mice. Moreover, the levels of TNF-α, IL-1β, and IL-18 in the brain hippocampus of mice were determined by ELISA. The expression of Bax, Bcl-2, Caspase-1, PSD95, SYP, ICAM-1 and MCP-1 proteins in the hippocampus was detected by Western blotting. Furthermore, qRT-PCR was used to detect the gene expressions of PSD95, SYP, M1 and M2 polarization markers of microglia, including iNOS, CD16, ARG-1, and IL-10 in the hippocampus.Results: A total of 51 prototype compounds were detected in rat serum and 15 prototype components were identified in rat cerebrospinal fluid. Behavioral experiments revealed that QFY significantly increased the recognition index, decreased the escape latency, increased the platform crossing times and increased the residence time in the target quadrant. QFY also could alleviate the ultrastructural pathological changes in the hippocampus of AD mice. Meanwhile, QFY treatment suppressed the expression of inflammatory factors, such as TNF-α, IL-1β, and IL-18. QFY improved the synaptic plasticity of the hippocampus in D-gal model mice by significantly increasing the expression of proteins and mRNAs of PSD95 and SYP.Conclusion: QFY could effectively improve the learning and memory impairment of D-gal-induced AD mice by inhibiting the excessive activation of microglia, enhancing the expression of M2 microglia, inhibiting the increase of inflammatory factors, cell adhesion factors and chemokines, anti-apoptosis, and improving synaptic plasticity.Graphical Abstract: Keywords: Qi-Fu-Yin, Alzheimer’s disease, D-galactose, microglia phenotype, neuroinflammation

Bei Chen,1,2,&ast; Mingzhi Yan,1,2,&ast; Huijing Gao,1,2 Qin Ma,3 Lihua Li,4 Guodong Lü,1,2 Yuehong Gong,1,2 Limei Wen,1,2 Shaoquan Xu,5 Jianhua Wang,1,2 Jun Zhao1,2 1First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 3HuaShiDan Pharmaceutical Company Limited, Urumqi, Xinjiang, People’s Republic of China; 4Xinjiang Urumqi Maternal and Child Health Hospital, Urumqi, Xinjiang, People’s Republic of China; 5College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Zhao; Jianhua Wang, First Affiliated Hospital of Xinjiang Medical University, State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, Urumqi, Xinjiang, 830011, People’s Republic of China, Email zhaojun700326@163.com; jhw716@sohu.comIntroduction: Cystic echinococcosis (CE) is a chronic zoonotic parasitic disease caused by the larvae of the Echinococcus granulosus sensu lato (s.l.) cluster. The current existing drugs have limited therapeutic efficacy against cystic echinococcosis, and thus, there is an urgent need to develop new drugs.Methods: In this study, 7 harmine (HM) derivatives were screened and the effects of HM derivatives on E. granulosus sensu stricto (s.s.) were evaluated by in vitro and mouse experiments. The safety of the HM derivatives was assessed by cytotoxicity assays, acute toxicity study in animals and subacute toxicity study.Results: These results show that the HM derivatives H-2-168 and DH-004 exhibited more significant antiparasitic effects at an initial concentration of 40 μM. The results of further studies showed that H-2-168 and DH-004 had dose-dependent effects against protoscoleces and had satisfactory therapeutic outcomes in vivo. Electron microscopy observations demonstrated that H-2-168 and DH-004 caused severe disruption of the parasite ultrastructure. Notably, the results of the acute toxicity and subchronic toxicity studies showed that H-2-168 and DH-004 had significantly improved safety. In addition, we found that H-2-168 and DH-004 induced DNA damage in E. granulosus s.s., which may be the mechanism by which these drugs produce their therapeutic effects.Discussion: Overall, the data from this work demonstrate that H-2-168 and DH-004 are highly effective candidate compounds with low toxicity for the treatment of CE and will provide a new therapeutic strategy for CE pharmacological treatment.Graphical Abstract: Keywords: harmine derivatives, β-carboline, Echinococcus granulosus sensu stricto, cystic echinococcosis, DNA damage

Guoqi Dong, Hui Li, Hui Gao, Yingqi Chen, Huayuan Yang School of Acupuncture-Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of ChinaCorrespondence: Huayuan Yang, School of Acupuncture-Moxibustion and Tuina, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China, Email yhy4@shutcm.edu.cnBackground: Researchers have made significant progress in microglia associated with pain in recent years. However, more relevant bibliometric analyses are still needed on trends and directions in this field. The aim of this study is to provide a comprehensive perspective and to predict future directions of pain-related microglia research via bibliometric tools.Methods: English articles and reviews related with pain and microglia were extracted from the Web of Science core collection (WosCC) database between 2002 to 2022. Bibliometric tools such as VOSviewer, CiteSpace, and Bibliometrix R package were used to analyze publication characteristics, countries, authors, institutions, journals, research hotspots, and trend topics.Results: A total of 2761 articles were included in this analysis. Research on microglia associated with pain has increased significantly over the last two decades. China (n = 1020, 36.94%) and the United States (n = 751, 27.20%) contributed the most in terms of publications and citations, respectively. Kyushu University published the most articles in this field compared to other institutions, and Professor Inoue Kazuhide (n = 54) at this university made outstanding contributions in this field. Molecular Pain (n = 113) was the journal with the most publication, while Journal of Neuroscience had the highest number of citations. According to the authors keywords analysis, the research in this area can be summarized into 7 clusters such as “microglia activation pathways”, “pain treatment research”, “mental symptoms of chronic pain”, and so on.Conclusion: This study provides a comprehensive analysis of pain-related microglia research in the past two decades. We identified the countries, institutions, scholars, and journals with the highest number of publications and the most influence in the field, and the research trends identified in this paper may provide new insights for future research.Keywords: microglia, pain, bibliometrics, VOSviewer, CiteSpace

Jiecheng Lin,1,2,&ast; Na Huang,2,&ast; Mingjuan Li,2 Mengyuan Zheng,2 Zhuoxiang Wang,2 Xiaojuan Zhang,2 Huan Gao,2 Yunzhe Lao,2 Jie Zhang,2 Baoyue Ding2 1School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 214122, People’s Republic of China; 2Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, 314001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Baoyue Ding; Jie Zhang, Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, No. 118 Jiahang Road, Jiaxing, Zhejiang Province, 314001, People’s Republic of China, Tel/Fax +86-0573-83643808, Email lena_310@163.com; zhangjiepharm@zjxu.edu.cnPurpose: Malignant melanoma (MM), the most lethal skin cancer, is highly invasive and metastatic. These qualities are related to not only genetic mutations in MM itself but also the interaction of MM cells with the immune system and microenvironment. This study aimed to construct a combined immunotherapy and gene therapy drug delivery system for the effective treatment of MM.Methods: Mature dendritic cell (mDC) exosomes (mDexos) with immune induction functions were used as carriers. BRAF siRNA (siBRAF) with the ability to silence mutated BRAF in MM was encapsulated in mDexos by electroporation to construct a biomimetic nanosystem for the codelivery of immunotherapy and gene therapy drugs (siBRAF-mDexos) to the MM microenvironment. Then, we investigated the nanosystem’s serum stability and biocompatibility, uptake efficiency in mouse melanoma cells (B16-F10 cells), cytotoxicity against B16-F10 cells and inhibitory effect on BRAF expression. Furthermore, we evaluated its antimelanoma activity and safety in vivo.Results: SiBRAF-mDexos were nanosized. Compared to siBRAF, siBRAF-mDexos displayed significantly increased serum stability, biocompatibility, uptake efficiency in B16-F10 cells, and cytotoxicity to B16-F10 melanoma cells; they also had a significantly greater inhibitory effect on BRAF expression and induced T-lymphocyte proliferation. Moreover, compared with siBRAF, siBRAF-mDexos showed significantly enhanced anti-MM activity and a high level of safety in vivo.Conclusion: The study suggests that the siBRAF-mDexo biomimetic drug codelivery system can be used to effectively treat MM, which provides a new strategy for combined gene therapy and immunotherapy for MM.Keywords: malignant melanoma, dendritic cell exosomes, BRAF siRNA, immunotherapy, gene therapy

Yanyan Ma,1,&ast; Ying Cao,2,&ast; Hong Gao,3 Rui Tong,1 Jing Yi,3 Zhongwei Zhang,1 Rui Chen,1 Zhijun Pan1 1School of Anesthesia, Guizhou Medical University, Guiyang, People’s Republic of China; 2Department of Anesthesiology, The Second People’s Hospital of Guiyang, Guiyang, People’s Republic of China; 3Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Gao, Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, No. 9 Beijing Road, Guiyang, People’s Republic of China, Email 2169617@qq.com; anesth@qq.comPurpose: This study investigated the effect of exosomes derived from sevoflurane-treated cardiac fibroblasts (Sev-CFs-Exo) on reperfusion arrhythmias (RA), ventricular conduction, and myocardial ischemia-reperfusion injury (MIRI).Methods: Primary cardiac fibroblasts (CFs) were isolated from the hearts of neonatal rats and identified by morphology and immunofluorescence. Exosomes were isolated from CFs at passages 2– 3 after they had been treated with 2.5% sevoflurane for an hour and cultivated for 24– 48 hours. The control group was CFs that did not receive any treatment. The hypothermic global ischemia-reperfusion injury model was established using the Langendorff perfusion technique following injection with exosomes through the caudal vein. Multi-electrode array (MEA) mapping was used to investigate the changes in RA and ventricular conduction in isolated hearts. Western blots and immunofluorescence were used to examine the relative expression and location of connexin 43 (Cx43). In addition, the MIRI was evaluated with triphenyl tetrazolium chloride and Hematoxylin-Eosin staining.Results: The primary CFs had a variety of morphologies, no spontaneous pulsation, and were vimentin-positive, which confirmed their successful isolation. Sev-CFs-Exo increased the heart rate (HR) at reperfusion for 15 minutes (T2) and 30 minutes (T3) and lowered the score and duration of RA and the time for restoration of heartbeat in reperfusion. Meanwhile, Sev-CFs-Exo increased conduction velocity (CV), decreased absolute inhomogeneity (P5-95) and inhomogeneity index (P5-95/P50) at T2 and T3, as well as promoted the recovery of HR, CV, P5-95 and P5-95/P50 after hypothermic global ischemia-reperfusion injury. Furthermore, Sev-CFs-Exo raised expression and reduced lateralization of Cx43, and improved myocardial infarct sizes and cellular necrosis. However, while cardiac fibroblast-derived exosomes (CFs-Exo) showed similar cardioprotective effects, the outcomes were not as significant.Conclusion: Sevoflurane reduces the risk of RA and improves ventricular conduction and MIRI by CFs-Exo, and this may be driven by the expression and location of Cx43.Keywords: anesthetic, extracellular vesicles, arrhythmia, electrophysiology, electrical mapping, connexin 43, Cx43

Yaping Zhang,1,&ast; Lixing Wang,1,&ast; Furong Yan,1 Meili Yang,2 Hongzhi Gao,1 Yiming Zeng3 1Clinical Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, People’s Republic of China; 2Department of Neurology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Respirology Medicine Centre of Fujian Province, Quanzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yaping Zhang, Clinical Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, No. 34 Zhongshan North Road, Licheng District, Quanzhou, Fujian, People’s Republic of China, Email icesuri@126.comPurpose: Persistent inflammation and epithelial-mesenchymal transition are essential pathophysiological processes in chronic obstructive pulmonary disease (COPD) and involve airway remodeling. m6A methylation modification was discovered to play an important role in various diseases. Nevertheless, the regulatory role of m6A methylation has not yet been investigated in cigarette smoking-induced COPD. The study aims to explore the regulatory role of m6A methylation in cigarette smoking-induced COPD.Patients and Methods: In this study, two Gene Expression Omnibus (GEO) datasets were first utilized to analyze the expression profiles of m6A RNA methylation regulators in COPD. We then established a cell model of COPD by exposing human bronchial epithelial cells (HBECs) to cigarette smoke extract (CSE) in vitro and detected the expression of m6A writer Mettl3 and EMT phenotype markers. RNA interference, cycloleucine, RT-qPCR, western blot, MeRIP-sequencing, and cell migration assay were performed to investigate the potential effect of Mettl3 on the EMT process in CSE-induced HBECs.Results: Our results showed that Mettl3 expression was significantly elevated in cigarette smoking-induced COPD patients and in a cellular model of COPD. Furthermore, Mettl3 silence and cycloleucine treatment inhibited the EMT process of HBECs caused by CSE. Mechanically, Mettl3 silence weakens the m6A methylation of SOCS3 mRNA to enhance the protein expression of SOCS3, inhibiting CSE-induced SOCS3/STAT3/SNAI1 signaling and EMT processes in HBECs.Conclusion: Our study inferred that Mettl3-mediated m6A RNA methylation modification modulates CSE-induced EMT by targeting SOCS3 mRNA and ultimately serves as a crucial regulator in the emergence of COPD. This conclusion reinforces the regulatory role of m6A methylation in COPD.Keywords: inflammation, COPD, MeRIP–sequencing, cycloleucine

Shenglan Ma,1– 3,&ast; Peijun Ju,4,&ast; Qingrong Xia,1– 3 Zhongde Pan,5 Jianliang Gao,1– 3 Loufeng Zhang,1– 3 Hua Gao,1– 3 Junwei Yan,1– 3 Jie Zhang,1– 3 Keming Wang,1– 3 Chao Li,1– 3 Wen Xie,1– 3,&ast; Cuizhen Zhu1– 3,&ast; 1Affiliated Psychological Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 2Clinical Center for Psychiatry and Mental Health, Hefei Fourth People’s Hospital, Hefei, 230022, People’s Republic of China; 3Anhui Mental Health Center, Hefei, People’s Republic of China; 4Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Traditional Chinese Medicine for Mental Health, Shanghai, People’s Republic of China; 5Shanghai Key Laboratory of Forensic Medicine, Academy of Forensic Science, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen Xie; Cuizhen Zhu, Affiliated Psychological Hospital of Anhui Medical University, No. 316 Huangshan Road, Shushan District, Hefei, Anhui, People’s Republic of China, Tel +86 13339102285 ; +86 13705535258, Fax +86 055163616000, Email xiewen0808@sina.com; zhucuizhen88@126.comPurpose: The study aims to clarify the negative psychological state and resilience impairments of schizophrenia (SCZ) with metabolic syndrome (MetS) while evaluating their potential as risk factors.Patients and Methods: We recruited 143 individuals and divided them into three groups. Participants were evaluated using the Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale (HAMD)-24, Hamilton Anxiety Rating Scale (HAMA)-14, Automatic Thoughts Questionnaire (ATQ), Stigma of Mental Illness scale and Connor–Davidson Resilience Scale (CD-RISC). Serum biochemical parameters were measured by automatic biochemistry analyzer.Results: The score of ATQ was highest in the MetS group (F = 14.5, p < 0.001), and the total score of CD-RISC, subscale tenacity score and subscale strength score of CD-RISC were lowest in the MetS group (F = 8.54, p < 0.001; F = 5.79, p = 0.004; F = 10.9, p < 0.001). A stepwise regression analysis demonstrated that a negative correlation was observed among the ATQ with employment status, high-density lipoprotein (HDL-C), and CD-RISC (β=− 0.190, t=− 2.297, p = 0.023; β=− 0.278, t=− 3.437, p = 0.001; β=− 0.238, t=− 2.904, p = 0.004). A positive correlation was observed among the ATQ with waist, TG, WBC, and stigma (β=0.271, t = 3.340, p = 0.001; β=0.283, t = 3.509, p = 0.001; β=0.231, t = 2.815, p = 0.006; β=0.251, t=− 2.504, p = 0.014). The area under the receiver-operating characteristic curve analysis showed that among all independent predictors of ATQ, the TG, waist, HDL-C, CD-RISC, and stigma presented excellent specificity at 0.918, 0.852, 0.759, 0.633, and 0.605, respectively.Conclusion: Results suggested that the non-MetS and MetS groups had grievous sense of stigma, particularly, high degree of ATQ and resilience impairment was shown by the MetS group. The TG, waist, HDL-C of metabolic parameters, CD-RISC, and stigma presented excellent specificity to predict ATQ, and the waist showed excellent specificity to predict low resilience level.Keywords: years of education, negative symptoms, waist circumstance

Jiayi Li,1,2 Jiao Zhang,2 Xu Wang,2 Xumin Zheng,2 Hongmei Gao,2 Shimin Jiang,2 Wenge Li1,2 1Department of Nephrology, Peking University China-Japan Friendship School of Clinical Medicine, Beijing, People’s Republic of China; 2Department of Nephrology, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaCorrespondence: Wenge Li, Department of Nephrology, China-Japan Friendship Hospital, No. 2, Yinghua Dong Street, Chaoyang District, Beijing, 100029, People’s Republic of China, Email wenge_lee2002@126.comIntroduction: Complement activation is highly involved in membranous nephropathy. Identifying the mechanism of the complement activation pathway carries crucial therapeutic implications yet remains controversial. This study explored lectin complement pathway activation in PLA2R-associated membranous nephropathy (MN).Methods: One hundred and seventy-six patients with biopsy-proven PLA2R-associated MN were enrolled in the retrospective study and divided into the remission group (24-hour urine protein < 0.75g and serum albumin > 35 g/L) and the nephrotic syndrome group. The clinical manifestation and C3, C4d, C1q, MBL, and B factor in renal biopsy tissues and C3, C4, and immunoglobulins in serum were evaluated.Results: Deposition of glomerular C3, C4d, and mannose-binding lectin (MBL) was significantly higher in the activated state than in the remission state in PLA2R-associated MN. MBL deposition was the risk factor for no remission. During follow-up, the persistent non-remission patients have significantly lower serum C3 levels.Conclusion: Activation of the lectin complement pathway in PLA2R-associated MN may contribute to proteinuria progression and disease activity.Keywords: membranous nephropathy, anti-PLA2R antibody, complement, lectin pathway

Guanxiang Huang,1– 3,&ast; Hangjing Gao,1– 3,&ast; Yanlin Chen,1,2 Wenyu Lin,1– 3 Jun Shen,4 Shuxia Xu,5 Dabin Liu,6 Zhihui Wu,7 Xite Lin,1– 3 Tingting Jiang,1– 3 Binhua Dong,1– 3 Pengming Sun1– 3 1Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China; 2Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children’s Hospital), Fuzhou, Fujian, 350001, People’s Republic of China; 3Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, Fujian, 350001, People’s Republic of China; 4Fujian Provincial Cervical Disease Diagnosis and Treatment Health Center, Fujian Maternity and Child Health Hospital, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China; 5Department of Pathology, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China; 6Department of Gynecology, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China; 7Department of Clinical Laboratory, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pengming Sun; Binhua Dong, Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China, Tel +86-591-87558732 ; +86-13599071900, Fax +86-591-87551247, Email fmsun1975@fjmu.edu.cn; sunfemy@hotmail.com; dongbinhua86@fjmu.edu.cn; dbh18-jy@126.comPurpose: The platelet-to-lymphocyte ratio (PLR) is considered correlated with cancer prognosis including cervical cancer, in addition to high-risk papillomavirus (HR-HPV) infection, of which the predictive value in prognosis of high-grade squamous intraepithelial lesions (HSILs) remains unknown. Here, the prognostic predictive value of PLR in HSIL after loop electrosurgical excision procedure (LEEP) was evaluated.Patients and Methods: This study included 335 nonpregnant participants with histopathologically confirmed HSIL and 3- and 5-year follow-ups from the Fujian Cervical Lesions Screening Cohorts (FCLSCs) between September 2016 and September 2018. PLR and other variables were evaluated to identify the factors related to the recurrence/residual cervical intraepithelial neoplasia (CIN)-free survival (RFS), namely, the time from LEEP at baseline to first detection of recurrence/residual CIN or end of follow-up, by logistic and Cox regression.Results: In the Kaplan‒Meier analysis, HR-HPV infection (p=0.049/0.012), higher PLR (p=0.031/0.038), and gland invasion (p=0.047) had a higher risk for recurrence/residual CIN at the 3-/5-year follow-up. The univariate logistic and Cox regression analyses showed significant differences and a higher cumulative risk in patients with HR-HPV infection (OR=3.917, p=0.026; HR=3.996, p=0.020) and higher PLR (OR=2.295, p=0.041; HR=2.161, p=0.030) at the 5-year follow-up. The findings by multivariate Cox regression analysis were similar, indicating a poor prognosis for patients with HR-HPV infection (HR=3.901, p=0.023) and higher PLR (HR=2.082, p=0.038) at the 5-year follow-up. The calibration plot showed a better model fit for RFS at the 3-year follow-up.Conclusion: Preoperative PLR level and HR-HPV infection could be available markers for predicting recurrence/residual disease of HSIL after LEEP. Clinically, combining PLR with HR-HPV tests may provide novel evaluation method and reference for management in post-treatment patients with cervical precancerous lesions.Keywords: systemic inflammatory response, cervical intraepithelial neoplasia, human papillomavirus, HPV, conization, prognosis

Haoran Gao,1,&ast; Chao Chen,2,&ast; Xiujie Zhao,1 Lei Zhao,1 Xiaoming Zheng,1 Haibin Sun,1 Hua Bao,1 Baojun Wang2 1Department of Neurology, Hulunbuir People’s Hospital, Hulunbuir, 021000, People’s Republic of China; 2Department of Neurology, Center Hospital of Baotou, Baotou, 014040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hua Bao, Department of Neurology, Hulunbuir People’s Hospital, No. 20 Shengli Street, Hailar District, Hulunbuir, 021000, People’s Republic of China, Tel +86-0470-3997068, Email baohuabh81@126.com Baojun Wang, Department of Neurology, Center Hospital of Baotou, No. 61 of Huancheng Road, Donghe District, Baotou, 014040, People’s Republic of China, Tel/Fax +86-0472-6955346, Email wangbaojunwbj96@126.comObjective: To study the correlation between the adenosine triphosphate (ATP) content in the hippocampus of rats and delayed encephalopathy after acute carbon monoxide (CO) poisoning.Methods: A total of 40 male Wistar rats weighing 180– 230g, in accordance with the random number table, were selected and divided into the delayed encephalopathy after acute carbon monoxide poisoning (DEACMP: Rats with cognitive impairment after carbon monoxide poisoning) group (n = 32) and the control group (n = 8). A DEACMP rat model was generated by inhalation of CO. The Morris water maze evaluated the ability to learn and memorize in rats. The changes in neurons in the hippocampus of the rats were observed by hematoxylin-eosin (HE) staining. Lastly, the ATP content in the hippocampus of the rats was measured by high-performance liquid chromatography (HPLC).Results: The ATP content of the experimental group was significantly higher than that of the control group in the hippocampus of the rat model, so the difference was statistically significant (P < 0.05); the intra-group comparison was made for the ATP content in the experimental group, and the difference was statistically significant as group 21d > group 14d > group 7d (P < 0.05); and no significant difference was found between group 21d and group 28d (P > 0.05).Conclusion: The changes in the ATP content in the hippocampus of the rats are correlated with the occurrence of delayed encephalopathy after acute carbon monoxide poisoning; it may take part in the pathogenesis of DEACMP. This offers some elicitation to the prevention and treatment of the disease.Keywords: carbon monoxide poisoning, delayed encephalopathy, ATP, HPLC

Qiqi Wu,1,&ast; Jiawei Wang,2,&ast; Xiaoqi Lin,2,&ast; Dexiong Han,3 Hantong Hu,3 Hong Gao3 1Department of Acupuncture, Moxibustion and Massage, Wenzhou Central Hospital, Wenzhou City, People’s Republic of China; 2The Third School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China; 3Department of Acupuncture and Moxibustion, the Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hantong Hu; Hong Gao, Department of Acupuncture and Moxibustion, the Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 219 Moganshan Road, Xihu District, Hangzhou City, People’s Republic of China, Email 413351308@qq.com; qtgh@vip.qq.comBackground: Menstrual migraine (MM), as a common type of headache related to women’s menstrual cycle, currently available treatments do not produce sufficient effectiveness, making it remains difficult to manage. Although acupuncture may be an effective treatment for MM, there is a lack of convincing evidence to recommend acupuncture to patients with MM until more solid evidence is produced. Therefore, the purpose of our systematic review (SR) and meta-analysis protocol is to synthesize up-to-date evidence regarding the clinical efficacy and safety of acupuncture on MM.Methods: To find qualifying RCTs, nine databases will be searched. RevMan 5.3 will be used to combine the retrieved data for meta-analyses. The Cochrane risk of bias instrument will be used to assess the methodological quality of each included trial. The strength and certainty of the evidence will be evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Additionally, we will undertake sensitivity analyses, publication bias, and subgroup analyses if available.Discussion: Our SR and meta-analysis protocol will contribute to determining acupuncture’s therapeutic effect and safety in the preventive treatment of MM. Based on the up-to-date evidence produced by the subsequent SR and meta-analysis, informed treatment decisions will be made by patients, physicians and policy makers.Keywords: menstrual migraine, acupuncture, systematic review, meta-analysis

Jing Li,&ast; Hong Gao,&ast; Yue Xiong,&ast; Ling Wang, Haojie Zhang, Fumei He, Jingxin Zhao, Shuna Liu, Liqian Gao, Ying Guo, Wenbin Deng School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Guo; Wenbin Deng, Email guoying1226@hotmail.com; dengwb5@mail.sysu.edu.cnBackground: Wound healing of skin is a complicated process. Cutaneous innervation and neurotrophic factors could participate in multiple stages of wound healing. Neurotrophic factors are mainly produced and released by neurons and neural stem cells (NSCs) which could be obtained in large quantities from human-induced pluripotent stem cells (iPSCs) in vitro. However, the potential wound healing effects of NSC secretions, such as exosomes, are unexplored yet.Methods: NSCs-derived exosomes (NSC-exo) and iPSCs-derived exosomes (iPSC-exo) were isolated from the cell culture supernatants by centrifugation, and then quantified and characterized. The effects of these exosomes on the migration of human dermal fibroblasts (HDF) cells and the tube formation of human umbilical vein endothelial cells (HUVECs) were investigated in vitro. And the in vivo wound healing effect of these exosomes were tested on the mouse skin trauma model. Therefore, a dipeptide/hyaluronic acid (Nap-FF/HA) composite hydrogel was used to encapsulate the exosomes as a sustained release carrier. Histological observations were performed to evaluate the wound healing effect of exosomes. Furthermore, the non-labeling proteomic analysis was performed to explore the possible mechanisms of NSC-exo on wound healing.Results: We obtained extracellular vesicles in a bowl-like structure with membranes which meet the general standards of exosomes. NSC-exo showed promotion effect on the migration of HDF cells and the tube formation of HUVECs in vitro. In a mouse skin injury model, NSC-exo enhanced the wound healing and the Nap-FF/HA hydrogel that contained exosomes did so with less drug frequency by sustaining release of exosomes. Further proteomic analysis demonstrated that the carried neurotrophic factors and immunity-related proteins in NSC-exo may play a functional role in wound healing.Conclusion: NSC-exo may enhance wound healing via neurotrophic factors and immunomodulation.Graphical Abstract: Keywords: wound healing, neural stem cells, exosomes, proteomic analysis

Haibo Li,1,&ast; Chong Miao,2,&ast; Wenjuan Liu,1,3 Haiyan Gao,1,4 Wei Li,1,4 Zhengqin Wu,1,4 Hua Cao,1,5 Yibing Zhu1 1Division of Birth Cohort Study, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Information, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China; 3Division of Birth Cohort Study, Fujian Children’s Hospital, Fuzhou, People’s Republic of China; 4Division of Birth Cohort Study, Fujian Obstetrics and Gynecology Hospital, Fuzhou, People’s Republic of China; 5Fujian Key Laboratory of Women and Children’s Critical Disease Research, Fuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yibing Zhu, Division of Birth Cohort Study, Fujian Maternity and Child Health Hospital, Fuzhou, 350001, People’s Republic of China, Tel +86-0591-87560934, Fax +86-0591-87505886, Email zybfmc@163.com Hua Cao, Department of Cardiac Surgery, Fujian Maternity and Child Health Hospital, Fuzhou, 350001, People’s Republic of China, Tel +86-0591-87562990, Fax +86-0591-87505886, Email caohua69@fjmu.edu.cnPurpose: To evaluate the relationships of the triglyceride-glucose (TyG) index with pregnancy-related complications (PRCs) and to clarify the predictability of the TyG index for PRCs.Patients and Methods: Totally of 11,387 women with a singleton pregnancy were prospectively followed until after delivery. Maternal fasting lipids and glucose concentration were measured in the first trimester (11 weeks gestation on average). The TyG index was calculated as ln [triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2]. We used generalized linear models to calculate the relative risks and 95% confidence intervals. Receiver-operating characteristic curve analysis was employed to assess the ability of the TyG index to predict the risks of PRCs.Results: Smooth spline reveals that the probability of gestational diabetes mellitus (GDM) is intensified with the increasing TyG index. Multivariate logistic regression adjusted for risk factors demonstrates a 1-unit and a 1-SD increment in the TyG index raises the risk of GDM by 3.63 and 1.57 times, respectively. Identically, the risk of GDM maximizes in the TyG quintile 5 (OR: 3.14; 95% CI: 2.55~3.85) relative to the lowest TyG index group. However, no association between TyG index and the risk of other PRCs was observed after full adjustment. The area under receiver operating characteristic curves is 0.647 (95% CI: 0.632– 0.66) for GDM, and the optimal predictive cut-off is 8.55, with a specificity of 0.679 and sensitivity of 0.535.Conclusion: The first-trimester TyG index is significantly associated with the risk of incident GDM, while the relationships between the TyG index and other PRCs need further exploration.Keywords: first-trimester, triglyceride-glucose index, pregnancy-related complications, gestational diabetes mellitus, singleton pregnancy

Yimin Han1 &ast;, Boya Wang2 &ast;, Han Gao,3 Chengwei He,3 Rongxuan Hua,4 Chen Liang,4 Sitian Zhang,4 Ying Wang,5 Shuzi Xin,3 Jingdong Xu3 1Department of Oral Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People’s Republic of China; 2Undergraduate Student of 2018 Eight Program of Clinical Medicine, Peking University People’s Hospital, Beijing, 100083, People’s Republic of China; 3Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People’s Republic of China; 4Department of Clinical Medicine, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People’s Republic of China; 5Department of Dermatology, Beijing Tong Ren Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jingdong Xu, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, No. 10, Xitoutiao, Youanmenwai, Fengtai District, Beijing, 100069, People’s Republic of China, Tel/Fax +86 10-8391-1469, Email xujingdong@163.comAbstract: The gut microbiota is the most abundant and diverse microbiota in the human body and the vagus nerve is the most widely distributed and complex nerve in the body, both of them are essential in maintaining homeostasis. The most important phenomenon is how they coordinate to regulate functions, which has attracted the great attention of scientists. The academic literature on the correlation with a host of intestinal diseases and even systemic diseases has revealed the bidirectional communication between the gut microbiota and the brain, which can be carried out via multiple patterns. In the review, firstly, we have a general overview of the gut microbiota and the gut microbiota-brain axis. Secondly, according to the distribution characteristics of the vagus nerve, we analyzed and summarized its function in the intestinal tract. At the same time, we have summarized the underlying mechanism of some behavior changes such as depressive and anxiety-like behaviors and related neurodegenerative diseases caused by the vagus nerve and intestinal microecological environment disorders, and then we also analyzed inconsistency of the experimental evidence in order to propose novel strategies for the clinical practice.Keywords: gut microbiota-brain axis, gut microbiota, brain, vagus nerve, behavior, neurodegenerative diseases

Yujie Li,1,2 Linjia Peng,1,2 Ke Zhang,1,2 Yong Wu,3 Huifeng Gao,1,2 Hao Chen1,2 1Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Oncology, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, People’s Republic of ChinaCorrespondence: Hao Chen, Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai, People’s Republic of China, Tel +86-18017312356, Email chengkll@sina.comObjective: Ablation serves as a common local treatment for liver metastases from pancreatic cancer (PCLM), but the correlation between the prognosis of PCLM and inflammatory cytokines has been rarely reported. This study aimed to establish a cytokine-based prognostic model for patients with PCLM who are receiving ablation.Patients and Methods: Serum samples from peripheral blood were collected from patients with PCLM before their first ablation. Cytokines were measured using Luminex chips and ELISA. Cox regression and least absolute shrinkage and selection operator regression were used to select prognostic factors for overall survival (OS). Area under the receiver operating characteristic curve (AUC) was applied to compare the ability to predict survival.Results: The relationship between cytokines and clinical factors was evaluated and their prognostic value was compared. Six optimal predictors were selected, including IL-2, IL-7, HGF, IFN-γ, CA19-9 and CEA. The risk model based on these predictors was built and named circulating tumor-associated inflammatory index (CTII). The CTII (AUCs > 0.90) showed superior performance to systemic immune-inflammation index (SII, AUCs < 0.65) in OS.Conclusion: A circulating cytokine-based risk model for patients with PCLM before first ablation has been proposed and validated, which has demonstrated superior performance in predicting survival and has the potential to inform clinical treatment strategies.Keywords: inflammation, cytokines, advanced pancreatic cancer, ablation, prognosis

Lijuan Fan,1,&ast; Yiqi Gao,2,&ast; Jie Zhou,3 Hantong Hu,3 Hong Gao3 1The Third Clinical College, Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China; 2Department of Traditional Therapy Centre, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China; 3Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hantong Hu; Hong Gao, Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 219 Moganshan Road, Xihu District, Hangzhou City, People’s Republic of China, Email 413351308@qq.com; qtgh@vip.qq.comBackground: Tinnitus accounts for a significant proportion of the factors that cause insomnia, and insomnia, in turn, aggravates tinnitus. Given that tinnitus and insomnia have a bidirectional relationship, tinnitus-associated insomnia is prevalent. Nonetheless, current treatments including medication and psychological therapies for tinnitus-associated insomnia do not yield satisfactory efficacy, thereby making it challenging to manage. Although acupuncture is a potentially effective treatment option, the current evidence on the efficacy and safety of acupuncture for tinnitus-associated insomnia remains inconclusive. Therefore, this systematic review and analysis protocol aims to investigate whether acupuncture is beneficial for tinnitus-associated insomnia with an acceptable safety profile.Methods: Nine mainstream English-language and Chinese-language databases will be searched to include qualified RCTs and meta-analyses will be conducted by combining extracted data using RevMan 5.3. The risk of bias 2.0 tool recommended by Cochrane will be adopted to evaluate the methodological quality of the included RCTs. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach will be utilized to appraise the strength and certainty of evidence. Where available, we will also perform sensitivity analyses, publication bias and subgroup analysis.Discussion: Expected results from our systematic review and meta-analysis will verify the efficacy and safety of acupuncture in tinnitus-associated insomnia. The evidence generated by this review will help patients and clinicians make informed treatment decisions.Keywords: systematic review, meta-analysis, acupuncture, tinnitus, insomnia

Hongye Gao,&ast; Yanfeng Xu,&ast; Yanfei Liu, Lan Mi, Xiaopei Wang, Weiping Liu, Jun Zhu, Yuqin Song Department of Lymphoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiping Liu; Jun Zhu, Department of Lymphoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China, Tel +86 10 88196109, Fax +86 10 88196115, Email dreaming2217@126.com; zhu-jun2017@outlook.comBackground: There is no consensus regarding the risk stratification scores for elderly patients with diffuse large B-cell lymphoma (DLBCL). We aimed to compare the prognostic predictive ability of the current clinical scoring indices in DLBCL elderly patients treated with the R-CODP regimen (rituximab, cyclophosphamide, pegylated liposomal doxorubicin, vincristine, and prednisone).Methods: We retrospectively collected the data of elderly DLBCL patients who received the R-CODP regimen as the first-line treatment. The efficacy of the regimen was evaluated. The Akaike information criteria (AIC), concordance index (C-index), and integrated discrimination improvement (IDI) were used to assess the fitness and prognostic performance of the current clinical prognostic indices.Results: In the total of 158 patients enrolled, the median follow-up time was 6.7 years (95% CI: 6.3– 7.9), and the 5-year OS was 52.8% (95% CI: 45.5%– 61.2%). The International Prognostic Index (IPI), National Comprehensive Cancer Network-IPI (NCCN-IPI), and Elderly International Prognostic Index (E-IPI) were all significantly associated with OS (P < 0.001 for all). However, no significance was observed in 5-year OS in the low- vs low-intermediate-risk groups for IPI (P = 0.377), NCCN-IPI (P = 0.238), and E-IPI (P = 0.080). Compared with the IPI and NCCN-IPI, the E-IPI had the lowest AIC value of 747.5 and the highest C-index of 0.692. For predicting 5-year mortality, the E-IPI showed better performance (AUC: 0.715 for E-IPI vs 0.676 for IPI, P = 0.036), with the IDI of 6.29% (95% CI: 3.71%-8.88%, P < 0.001) and 4.80% (95% CI: 1.32%-8.28%, P = 0.007) compared to the IPI and NCCN-IPI, respectively.Conclusion: The E-IPI might be a better prognostic prediction model in Chinese DLBCL generics treated with R-CODP for predicting 5-year mortality. However, the IPI, NCCN-IPI, and E-IPI did not seem to be able to distinguish patients with a favorable prognosis well.Keywords: lymphoma, large B cell, diffuse, liposomal doxorubicin, survival analysis, prognosis

Jie Zhou,1,&ast; Lijuan Fan,2,&ast; Hantong Hu,1 Ke Shen,2 Liya Wu,2 Xiaoqi Lin,2 Hong Gao1 1Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2The Third Clinical College of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Gao, Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 219 Moganshan Road, Hangzhou, People’s Republic of China, Email qtgh@vip.qq.cnBackground: Post-stroke anxiety (PSA) remains a challenging medical problem. Integrated rehabilitation involves a combination of traditional Chinese medicine (TCM) and Western conventional rehabilitation techniques. Theoretically, integrated rehabilitation is likely to have significant advantages in treating PSA. Nevertheless, the therapeutic effect of integrated rehabilitation needs to be verified based on large-scale trials with sound methodology. Thus, the aim of this trial is to assess the efficacy and safety of integrated rehabilitation on PSA.Methods: The study is a prospective, multicenter, randomized, controlled trial involving 188 PSA patients from four clinical centers in China. Eligible participants will be randomly divided into the integrated rehabilitation group or the standard care group. Participants in the integrated rehabilitation group will receive a combination of TCM and Western conventional rehabilitation methods, including acupuncture, repeated transcranial magnetic stimulation, traditional Chinese herbal medicine, and standard care. The primary outcome will be the Hamilton Anxiety Rating Scale (HAM-A). The secondary outcomes will include the Self-Rating Anxiety Scale (SAS), the Activities of Daily Living (ADL) scale, the Montreal Cognitive Assessment (MoCA) scale, the simplified Fugl–Meyer Assessment of motor function (FMA) scale, and the Pittsburgh Sleep Quality Index (PSQI). Outcome measurements will be performed at baseline, at the end of the 4-week treatment and the 8-week follow-up.Conclusion: Results of this trial will ascertain the efficacy and safety of integrated rehabilitation on PSA, thereby providing evidence regarding integrated rehabilitation strategies for treating PSA. It will also promote up-to-date evidence for patients, clinicians, and policy-makers.Trial Registration: ClinicalTrials.gov NCT05147077.Keywords: post-stroke anxiety, traditional Chinese medicine, Western medicine, repeated transcranial magnetic stimulation, rehabilitation, randomized controlled trial

Hao Gao,1 Hao Yin,1 Li Peng,1 Han Wang2 1School of Journalism and Communication, Nanjing Normal University, Nanjing, 210097, People’s Republic of China; 2School of Journalism and Communication, Jinan University, Guangzhou, Guangdong, 510632, People’s Republic of ChinaCorrespondence: Han Wang, School of Journalism and Communication, Jinan University, No. 601, West Huangpu Avenue, Guangzhou, Guangdong, 510632, People’s Republic of China, Email jacobwang0606@163.comBackground: With the widespread promotion of the COVID-19 vaccination in China, videos about the vaccination have become increasingly available on social video platforms. With the User Generated Content model, different creators’ interpretations of COVID-19 vaccines may influence the attitudes towards the vaccines and vaccination.Objective: To explore the overview of COVID-19 vaccine-related videos on Bilibili, discussing the communication effects of COVID-19 topic videos and its influencing factors.Methods: A content analysis was applied to the 202 video samples obtained through data mining regarding the creator’s information, video presentation, and COVID-19 vaccine-related content.Results: Individuals and medical professionals preferred VLOG videos, media chose to upload informational videos, and enterprises preferred to post showcase videos. Individuals were more likely to discuss the adverse reactions in their videos, while medical professionals were more likely to discuss the vaccination process for the COVID-19 vaccine. Videos with core issues positively influenced the video’s dissemination breadth. The attitudes toward the COVID-19 vaccine in the videos positively influence the recognition of the videos. The richness of knowledge points related to the COVID-19 vaccine negatively affected the recognition and participation.Conclusion: Social video platforms could play an active role in the vaccination promotion for the youth. Health promotion-related departments and individuals could strengthen agenda setting, grasp the characteristics of young groups, and express positive attitudes toward health issues to achieve better health (vaccine) promotion.Keywords: COVID-19 vaccine, social media, Bilibili, health promotion, vaccination

Hao-Ran Zheng,1,2,&ast; Ai-Min Jiang,1,&ast; Huan Gao,1 Na Liu,1 Xiao-Qiang Zheng,1 Xiao Fu,1 Rui Zhang,1 Zhi-Ping Ruan,1 Tao Tian,1 Xuan Liang,1 Yu Yao1 1Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Department of Medical Oncology, Xi’an No.3 Hospital, Xi’an, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuan Liang; Yu Yao, Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an, Shaanxi, 710061, People’s Republic of China, Tel +86-29-85324600, Fax +86-29-85324086, Email liangxuan029@163.com; 13572101611@163.comPurpose: Anlotinib, an antiangiogenic multi-target tyrosine kinase inhibitor (TKI), has shown favorable anticancer efficacy and acceptable safety in treating extensive-stage small cell lung cancer (ES-SCLC) in some clinical studies. This research aimed to explore the real-world efficacy and safety of anlotinib in ES-SCLC.Methods: Pathologically confirmed ES-SCLC patients receiving anlotinib were enrolled for this retrospective study. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions.Results: In total, 202 patients were included in this study. The median PFS of all patients was 4.8 months [95% confidence interval (CI): 3.9– 5.7], and the median OS was 7.6 months (95% CI 6.5– 8.7). Respectively, the overall ORR and DCR were 30.2% and 87.1%. The univariate and multivariate Cox regression analyses revealed that patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 1, plus chemotherapy or immunotherapy, plus radiotherapy, and post-medication hypertension might have longer PFS and OS. The PFS and OS were significantly prolonged in combination group than that in monotherapy group [PFS 6.0 vs 3.6 months, hazards ratio (HR)=0.49, 95% CI 0.34– 0.70, P < 0.001; OS 9.2 vs 4.8 months, HR = 0.48, 95% CI 0.32– 0.72, P < 0.001]. The main treatment-related adverse reactions were generally tolerated. The incidence of adverse reactions in combination group was higher than that in monotherapy group (75.0% vs 52.6%, P = 0.001). The most common adverse reaction was hypertension, followed by hand-foot syndrome and fatigue, regardless of monotherapy or combination group.Conclusion: Anlotinib is effective and well tolerated in patients with ES-SCLC in the real-world. The clinical efficacy of anlotinib combined with chemotherapy or immunotherapy is better than that of monotherapy. Further investigations are needed for prospective studies with larger sample size.Keywords: anlotinib, small cell lung cancer, real-world, efficacy, safety

Xiao-Fan Xu,1– 3 Jian-Wei Fan,2 Jia-Qi Xin,4 Nan Wu,4 He Gao,2 Li-Fang Duan,2 Wen-Bin Zou,3 Hong Zhang,2,5 Zhao-Shen Li3 1School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, People’s Republic of China; 2Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China; 3Department of Gastroenterology, Changhai Hospital, Shanghai, People’s Republic of China; 4Department of Gastroenterology, Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich (TUM), Munich, Germany; 5Shaanxi International Cooperation Base, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of ChinaCorrespondence: Zhao-Shen Li; Hong Zhang, Email zhaoshenli@smmu.edu.cn; zhangh1227@sntcm.edu.cnAim: Chronic pancreatitis (CP) is a complex and intractable disease mainly manifested as chronic inflammation and fibrosis. Aspirin(acetylsalicylic acid, ASA) has been reported to be used in the treatment of acute pancreatitis (AP), but its effectiveness on CP is unclear. This study aimed to investigate the therapeutic effects of ASA in CP mice.Methods: A murine model of CP was induced by intraperitoneal injection with 20% L-arginine. After one week of L-arginine administration, mice in the ASA treatment group were administered aspirin (100mg/kg/d) by intragastric gavage. At two, four, and six weeks after the first injection of L-arginine, mice were euthanized and the pancreas was collected for histological and molecular analysis. A second model of CP (caeruelin-induced) was used as a validation experiment to test the effect of ASA.Results: L-arginine-induced CP resulted in over-expression of the inflammatory enzyme cyclooxygenase (COX)-2. COX-2 expression decreased after ASA treatment. Pancreatic-injury inflammatory response (measured by changes in amylase, CK-19, F4/80, CD3, MCP-1, IL-6) and fibrosis degree (measured by expression of COL1A1, MMP-1 and TIMP-1) was reduce in ASA -treated mice model. The therapeutic effect of ASA was also observed in caeruelin-induced CP.Conclusion: ASA has an ameliorating effect in murine models of CP through inhibition of pancreatic inflammation and fibrosis, which may be a promising option for clinical treatment.Keywords: chronic pancreatitis, fibrosis, inflammation, aspirin, COX-2

Chunkang Liu,1,&ast; Kunzhe Wu,2,&ast; Huan Gao,3 Jianyang Li,3 Xiaohua Xu3 1Department of Gastrointestinal Surgery, China-Japan Union Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, People’s Republic of China; 3Department of Nephrology, China-Japan Union Hospital of Jilin University, Changchun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaohua Xu, Email xu_xh@jlu.edu.cnAbstract: Diabetic nephropathy (DN), a severe microvascular complication of diabetes mellitus (DM), is the most common form of chronic kidney disease (CKD) and a leading cause of renal failure in end-stage renal disease. No currently available treatment can achieve complete cure. Traditional treatments have many limitations, such as painful subcutaneous insulin injections, nephrotoxicity and hepatotoxicity with oral medication, and poor patient compliance with continual medication intake. Given the known drawbacks, recent research has suggested that nanoparticle-based drug delivery platforms as therapeutics may provide a promising strategy for treating debilitating diseases such as DN in the future. This administration method provides multiple advantages, such as delivering the loaded drug to the precise target of action and enabling early prevention of CKD progression. This article discusses the development of the main currently used nanoplatforms, such as liposomes, polymeric NPs, and inorganic NPs, as well as the prospects and drawbacks of nanoplatform application in the treatment of CKD.Keywords: diabetic nephropathy, DN, nanoplatform, route of administration

Hantong Hu,1,2,&ast; Zengtu Li,3,&ast; Yingying Cheng,1,2,&ast; Hong Gao1,2 1Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China; 2Department of Neurobiology and Acupuncture Research, the Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou City, People’s Republic of China; 3Department of Massage, the Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Gao, Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 219 Moganshan Road, Xihu District, Hangzhou City, People’s Republic of China, Email qtgh@vip.qq.comBackground: There is a bidirectional relationship between depression and insomnia. Depression-related insomnia is common and remains a challenging medical condition. Although acupuncture might be a potential treatment option and increasing randomized controlled trials (RCTs) have emerged, currently available evidence regarding the effect and safety of acupuncture on depression-related insomnia remains inconclusive. Thus, this protocol aims to systematically synthesize the evidence about the efficacy and safety of acupuncture for depression-related insomnia.Methods and Analysis: Eligible RCTs will be searched in nine representative databases and pooled in meta-analyses using RevMan 5.3. The methodological quality of included studies will be rated by Cochrane’s risk of bias 2.0 tool. The quality of evidence will be appraised using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Subgroup analysis, sensitivity analyses, and publication bias will also be conducted.Discussion: This protocol outlines the planned scope and methodology for an upcoming systematic review meta-analysis, which will critically synthesize the evidence about the efficacy and safety of acupuncture on depression-related insomnia. Findings will shed light on fulfilling evidence gaps and influence evidence-based treatment decisions for clinicians in the treatment of depression-related insomnia.Keywords: acupuncture, depression-related insomnia, systematic review, meta-analysis

Meng-ge Yang, Li Xu, Suqiong Ji, Huajie Gao, Qing Zhang, Bitao Bu Department of Neurology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Bitao Bu, Department of Neurology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Jiefang Street 1095#, Wuhan, 430000, People’s Republic of China, Email bubitao@tjh.tjmu.edu.cnPurpose: To investigate the response of tacrolimus to chronic inflammatory demyelinating polyneuropathy (CIDP) with autoantibodies against paranodal proteins, including neurofascin-155 (NF155), contactin-1 (CNTN1) and contactin-associated protein 1 (Caspr1).Methods: We retrospectively reviewed all CIDP patients who carried anti-NF155, CNTN1 and Caspr1 antibodies and were treated with tacrolimus at Tongji hospital from Jan 2018 to Apr 2021.Results: There were 58 patients with CIDP and only 9 patients had autoantibodies against paranodal proteins (17.2%). Five of the 9 patients received tacrolimus treatment with an initial dose of 2– 3 mg once daily. One patient with anti-CNTN1 antibody started tacrolimus and corticosteroid treatment, at the first episode and eventually achieved full clinical remission without relapse. Four patients with anti-NF155 or -Caspr1 antibodies experienced relapse during corticosteroids tapering. Then, they were given oral tacrolimus and presented with clinical improvement. During follow-up, only one patient developed worsening weakness due to unreasonable tacrolimus discontinuation. Moreover, 3 patients were successfully withdrawn from corticosteroids and 2 patients took corticosteroids at low maintenance dose (10mg/d) after tacrolimus treatment. No severe adverse events were observed in all the patients.Conclusion: Patients with autoantibodies against paranodal proteins had a better long-term outcome after adding tacrolimus. Combination therapy with corticosteroids and tacrolimus may be an effective therapeutic regimen.Keywords: chronic inflammatory demyelinating polyneuropathy, paranodal proteins, tacrolimus, outcome

Xueying Zhang,1– 3,* Chen He,1– 3,* Peijun Ju,4,* Qingrong Xia,1– 3 Jianliang Gao,1– 3 Loufeng Zhang,1– 3 Xuequan Chen,1– 3 Hui Yuan,1– 3 Hua Gao,1– 3 Yang Zhang,1– 3 Junwei Yan,1– 3 Wen Xie,1– 3,* Cuizhen Zhu1– 3,* 1Affiliated Psychological Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Clinical Center for Psychiatry and Mental Health, Hefei Fourth People’s Hospital, Hefei, People’s Republic of China; 3Anhui Mental Health Center, Hefei, People’s Republic of China; 4Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Psychotic Disorders, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen Xie; Cuizhen Zhu, Affiliated Psychological Hospital of Anhui Medical University, No. 316 Huangshan Road, Shushan District, Hefei, Anhui, People’s Republic of China, Tel +86 13339102285 ; +86 13705535258, Fax +86 055163616000, Email xiewen0808@sina.com; zhucuizhen88@126.comPurpose: The study aimed to clarify the cognitive impairments of schizophrenia with metabolic syndrome while evaluating their potential as risk factors.Patients and Methods: We recruited 153 participants and divided them into three groups according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria and the guideline standards for the prevention and treatment of dyslipidemia in Chinese adults in 2007 for metabolic syndrome, as follows: healthy control group (n = 47); nonmetabolic syndrome group (n = 58); and metabolic syndrome group (n = 48). Psychotic symptoms were evaluated using the Positive and Negative Syndrome Scale. Cognitive function and automatic thinking were estimated using the Montreal Cognitive Assessment Scale, Verbal Fluency Test, and Automatic Thoughts Questionnaire. Serum biochemical parameters were measured by automatic biochemistry analyzer.Results: One-way ANOVA analysis revealed that differential cognition impairments in schizophrenia patients compared to controls. Furthermore, results of multiple comparisons showed that more serious barriers in orientation, language fluency, and negative automatic thinking existed in the metabolic syndrome group than in the healthy and non-metabolic syndrome groups. Spearman correlation and stepwise linear regression analyses showed that psychopathological symptoms, high waist circumference, and high triglyceride were the predictive factors for negative automatic thoughts, orientation, and language fluency. Those results collectively revealed that high waist circumference, high triglyceride and negative automatic thinking had validity and effectiveness in predicting the cognitive function impairments of the metabolic syndrome group.Conclusion: The present findings strongly supported the notion that aberrant parameters of high waist circumference, high triglyceride and high negative automatic thoughts had validity and effectiveness predictive role for cognitive impairments in the schizophrenics with metabolic syndrome. The schizophrenia patients with metabolic syndrome should receive regular monitoring and adequate treatment for metabolic and psychological risk factors.Keywords: second-generation antipsychotics, negative symptoms, diet, Montreal Cognitive Assessment Scale, Verbal Fluency Test

Yanan Xu,1,&ast; Ying Jing,2,&ast; Lingfei Hu,2 Qiaoxiang Cheng,1 Huixia Gao,3 Zhi Zhang,3 Huiying Yang,2 Yuee Zhao,2 Dongsheng Zhou,2 Zhe Yin,2 Erhei Dai1,3 1Department of Clinical Laboratory Medicine, Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China; 2State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of China; 3Department of Laboratory Medicine, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei, 050021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Erhei Dai; Zhe Yin, Tel +86-311-85814612 ; +86-10-66948557, Email daieh2008@126.com; jerry9yin@163.comPurpose: To establish a typing scheme for IncFIB replicon and to dissect genomic features of IncFIB-4.1/4.2 single-replicon plasmids.Methods: A total of 146 representative fully sequenced IncFIB-replicon-containing plasmids were selected to construct a phylogenetic tree of repBIncFIB sequences. A collection of nine IncFIB-4.1/4.2 single-replicon plasmids from China were fully sequenced here and compared with the first sequenced IncFIB-4.1/4.2 single-replicon plasmids from GenBank to dissect their genomic diversity.Results: In this study, a repB sequence-based scheme was proposed for grouping IncFIB replicon into seven primary types and further into 70 subtypes. A collection of nine IncFIB-4.1/4.2 single-replicon plasmids were fully sequenced here and compared with the first sequenced IncFIB-4.1/4.2 single-replicon plasmids from GenBank. These 11 plasmids had small backbones and shared only three key backbone markers repB together with its iterons, parABC, and stbD. Each plasmid contained one large accessory region (LAR) inserted into the backbone, and these 11 LARs had significantly distinct profiles of mobile genetic elements (MGEs) and resistance/metabolism gene loci. Antibiotic resistance regions (ARRs; the antibiotic resistance gene-containing genetic elements) were found in seven of these 11 LARs. Besides resistance genes, ARRs carried unit or composite transposons, integrons, and putative resistance units. IncFIB-4.1/4.2 single-replicon plasmids were important vectors of drug resistance genes. This was the first report of three novel MGEs: In1776, Tn 6755, and Tn 6857.Conclusion: Data presented here provided a deeper insight into diversity and evolution of IncFIB replicon and IncFIB-4.1/4.2 single-replicon plasmids.Keywords: IncFIB, IncFIB-4 single-replicon plasmids, large accessory regions, antibiotic resistance regions, In1776, Tn 6755, Tn 6857

Hui Gao,1,2 Jin Xu,2 Qiang Ma,2 Feng Tang,1 Qin Ga,1 Yuhong Li,3 Wei Guan,3 Ri-Li Ge,1 Ying-Zhong Yang1,2 1Research Center for High Altitude Medical Sciences, School of Medicine, Qinghai University, Qinghai, People’s Republic of China; 2Basic Medical Sciences, School of Medicine, Qinghai University, Qinghai, People’s Republic of China; 3Department of Respiration, Affiliated Hospital, Qinghai University, Qinghai, People’s Republic of ChinaCorrespondence: Ying-Zhong Yang Tel/Fax +86 971 6143168Email yingzhong-yang@hotmail.comPurpose: Steroid hormone metabolism plays an essential role in high-altitude pulmonary edema (HAPE) progression. This study aimed to investigate the association between polymorphism in seven steroid hormone metabolism genes (STAR, HSD3B1, HSD3B2, CYP17A1, CYP21A2, CYP11B1, and CYP11B2) and HAPE susceptibility among Han Chinese.Patients and Methods: A total of 41 tagSNPs in the seven genes were genotyped using Sequenom MassARRAY SNP assays from 169 HAPE patients (HAPE-p) and 309 matched Han Chinese individuals resistant to HAPE (HAPE-r). The genotypic and allele frequencies, odds ratios (ORs), and 95% confidence intervals (95% CIs) were calculated.Results: Four SNPs, including the allele C of rs6203 (p = 0.034, OR [95% CI] = 1.344 [1.022− 1.767]) in HSD3B1, allele G of rs3740397 (p = 0.044, OR [95% CI] = 1.314 [1.007− 1.714]) and allele C of rs10786712 (p = 0.039, OR [95% CI] = 0.751 [0.572− 0.986]) in CYP17A1, and allele T of rs6402 (p = 0.006, OR [95% CI] = 0.504 [0.306− 0.830]) in CYP11B1, were significantly associated with HAPE. The distribution of the genotypes of these SNPs also significantly differed between the HAPE-p and HAPE-r groups. Moreover, six haplotypes (the linkage disequilibrium block including rs10883783, rs4919686, rs3740397, rs3824755, and rs10786712) of CYP17A1 were also significantly associated with HAPE.Conclusion: The four SNPs located in HSD3B1 (rs6203), CYP17A1 (rs3740397 and rs10786712), and CYP11B1 (rs6402) and the six haplotypes of CYP17A1 are likely to have an effect on HAPE.Keywords: steroid hormone metabolism gene, SNP, high-altitude pulmonary edema, susceptibility

Hui Gao,1,2,&ast; Zhaoxia Wang,1,2,&ast; Mixiao Tan,1 Weiwei Liu,1 Liang Zhang,1 Ju Huang,1 Yang Cao,1 Pan Li,1 Zhigang Wang,1 Jiexin Wen,2 Tingting Shang,1 Haitao Ran1 1Chongqing Key Laboratory of Ultrasound Molecular Imaging & Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Ultrasound, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haitao RanChongqing Key Laboratory of Ultrasound Molecular Imaging & Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chongqing Medical University, No. 76 Linjiang Road, Yuzhong District, Chongqing, 400010, People’s Republic of ChinaTel +86-13-512373563Email ranhaitao@cqmu.edu.cnBackground: Therapeutic ultrasound (US) has been extensively explored for its inherent high tissue-penetrating capability and on-demand irradiation without radioactive damage. Although high-intensity focused ultrasound (HIFU) is evolved as such an outstanding US-based approach, its insufficient therapeutic effect and the high-intensity induced potential damage to surrounding normal tissues hindered its development towards practical application. As opposed to high intensity ultrasound, sonodynamic therapy (SDT) is a low intensity US-based method which exhibits certain therapeutic effects against cancer via sonosensitizers-generated reactive oxygen species (ROS) overproduction.Methods: Hematoporphyrin monomethyl ether (HMME) loaded CaCO3 nanoparticles (designated as Ca@H) were synthesized by a gas diffusion method. The pH-responsive performance, in vitro SDT, ex vivo HIFU therapy (HIFUT), photoacoustic (PA) imaging and in vivo HIFUT combined with SDT were investigated thoroughly.Results: Ca@H NPs gradually decomposed in acid tumor microenvironment, produced CO2 and released HMME. Both CO2 and HMME enhanced photoacoustic (PA) imaging. The generated CO2 bubbles also enhanced HIFUT by inducing an enlarged ablation area. The tumor ablation efficiency (61.04%) was significantly improved with a combination of HIFU therapy and SDT.Conclusion: pH-responsive Ca@H NPs have been successfully constructed for PA imaging-guided/monitored HIFUT combined with SDT. With the assistance of pH-responsive Ca@H NPs, the combination of these two US-based therapies is expected to play a role in the treatment of non-invasive tumor in the future.Keywords: ultrasound, high-intensity focused ultrasound therapy, sonodynamic therapy, CaCO3 nanoparticles, nanomedicine

Peng Yin,* Yi Ding,* Lijin Zhou, Chunyang Xu, Haifeng Gao, Daming Pang, Yong Hai, Jincai Yang Department of Orthopaedics, Beijing Chao-Yang Hospital, China Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jincai Yang; Yong Hai Tel +86 1001085231327; +86 1001085231326Fax +86 10 85231229; +86 10 85231360Email jcyang2018@126.com; yonghaispine@126.comPurpose: Lumbar spinal stenosis (LSS) with instability is most common lumbar degenerative diseases for people with low back pain. The objective of this study was to compared the clinical effects for the treatment of lumbar spinal stenosis (LSS) with degenerative instability between the innovative percutaneous endoscopic transforaminal lumbar interbody fusion (PE-TLIF) technique and posterior lumbar interbody fusion (PLIF) technique.Patients and Methods: Between April 2019 and April 2020, 114 patients with single-segment LSS were prospectively included in our study (ChiCTR1900022492). Visual Analogue Scale (VAS) on lumbar and leg pain (VAS-LBP, VAS-LP), Oswestry Disability Index (ODI), serum creatine kinase (CK), the maximal cross-sectional area of multifidus muscle (Max-CSA) and the peak intensity of sulphur hexafluoride microbubble contrast agent (PI) around the surgical incision by contrast-enhanced ultrasonography were evaluated preoperatively, post-operatively and at regular follow-up.Results: All patients were followed up. The VAS-LBP, VAS-LP, ODI after operation were improved significantly compared to these data before operation in all the patients (P< 0.05). The VAS-LBP at 1 weeks, 3 months after operation in PE-TLIF group were significantly lower than these in PLIF group (P< 0.05). The injury degree of multifidus muscle evaluated by MAX-CSA and PI was significantly less in PE-TLIF group after operation (P< 0.05). There was no significant difference on the complication rate between these two groups (P> 0.05).Conclusion: Our results presented PE-TLIF technique could obtain comparable effective outcomes as conventional PLIF for the treatment of LSS with degenerative instability. The patients with PE-TLIF had less muscle injury, less pain and quicker postoperative rehabilitation.Keywords: pain, minimally invasive surgery, percutaneous, spinal endoscope, transforaminal lumbar interbody fusion, lumbar spinal stenosis

Hui Gao,1 Yuan Wang,1 Aidong Shen,1 Hui Chen,1 Hongwei Li1– 3 1Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China; 2Department of Internal Medical, Medical Health Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China; 3Beijing Key Laboratory of Metabolic Disorder Related Cardiovascular Disease, Beijing, 100069, People’s Republic of ChinaCorrespondence: Hongwei LiDepartment of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, No. 95 Yongan Road, Xicheng District, Beijing, 100050, People’s Republic of ChinaTel +86 10 6313 9780Fax +86 10 6313 8019Email lhw19656@sina.comAim: The prevalence of acute myocardial infarction (AMI) is increasing in young adults, especially in men. This study aims to compare the characteristics and explore the association between age and clinical outcomes in male adults who first experienced AMI.Methods: A total of 2737 male patients with AMI were divided into three groups by age: < 50, 50– 65, and ≥ 65 years. Clinical characteristics and long-term results (all-cause and cardiac deaths, nonfatal MI, revascularization, nonfatal stroke, cardiac rehospitalization) were identified across different age subgroups. The association between age and the outcomes was assessed by Cox proportional hazard models.Results: This population was followed up for a median of 36.7 months. Patients < 50 years had a lower prevalence of diabetes (19.4%) and previous stroke (1.8%), while they were more often to be smokers (77.1%), obese (26%), dyslipidemia (74.7%), and with the single-vessel disease (16.2%). The risk of cardiovascular and all-cause death in patients ≥ 65 years was higher than patients < 50 years, which was noticed through competing risk regression analysis after adjusting for confounding factors (adjusted HR 3.24; 95% CI 2.26– 4.22, p=0.020 for cardiovascular death, adjusted HR 4.17; 95% CI 1.91– 9.10, p< 0.001 for all-cause death).Conclusion: In conclusion, although men who suffered from first AMI under the age of 50 had lower mortality, they had a higher burden of modifiable traditional risk factors. The management of modifiable lifestyles should be addressed to all young AMI patients.Keywords: acute myocardial infarction, young men, the long-term prognosis

Shijie Tang,1– 4,&ast; Penghong Chen,1– 4,&ast; Haoruo Zhang,1– 4 Haiyan Weng,1– 4 Zhuoqun Fang,1– 4 Caixiang Chen,1– 4 Guohao Peng,1– 4 Hangqi Gao,1– 4 Kailun Hu,1– 4 Jinghua Chen,5 Liangwan Chen,3,6 Xiaosong Chen1– 3 1Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China; 2Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, People’s Republic of China; 3Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, 350001, People’s Republic of China; 4Oncology Institution, Fujian Medical University, Fuzhou, 350004, People’s Republic of China; 5Department of Pharmaceutical Analysis, the School of Pharmacy, Fujian Medical University, Fuzhou, 350100, People’s Republic of China; 6Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaosong Chen; Liangwan Chen Email chenxiaosong74@163.com; chenliangwan@fjmu.edu.cnIntroduction: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and their small extracellular vesicles (hUC-MSC-sEVs) have shown attractive prospects applying in regenerative medicine. This study aimed to compare the therapeutic effects of two agents on osteoarthritis (OA) and investigate underlying mechanism using proteomics.Methods: In vitro, the proliferation and migration abilities of chondrocytes treated with hUC-MSCs or hUC-MSC-sEVs were detected by Cell Counting Kit-8 assay and scratch wound assay. In vivo, hUC-MSCs (a single dose of 5 × 105) or hUC-MSC-sEVs (30 μg/time) were injected into the knee joints of anterior cruciate ligament transection-induced OA model. Hematoxylin and eosin, Safranin O/Fast Green staining were used to observe cartilage degeneration. The levels of cartilage matrix metabolic molecules (Collagen II, MMP13 and ADAMTS5) and macrophage polarization markers (CD14, IL-1β, IL-10 and CD206) were assessed by immunohistochemistry. Finally, proteomics analysis was performed to characterize the proteinaceous contents of two agents.Results: In vitro data showed that hUC-MSC-sEVs were taken up by chondrocytes. A total of 15 μg/mL of sEVs show the greatest proliferative and migratory capacities among all groups. In the animal study, hUC-MSCs and hUC-MSC-sEVs alleviated cartilage damage. This effect was mediated via maintaining cartilage homeostasis, as was confirmed by upregulation of the COL II and downregulation of the MMP13 and ADAMTS5. Moreover, the M1 macrophage markers (CD14) were significantly reduced, while the M2 macrophage markers (CD206 and IL-10) were increased in the hUC-MSCs and hUC-MSC-sEVs relative to the untreated group. Mechanistically, we found that many proteins connected to cartilage repair were more abundant in sEVs. Notably, compared to hUC-MSCs, the upregulated proteins in sEVs were mostly involved in the regulation of immune effector process, extracellular matrix organization, PI3K-AKT signaling pathways, and Rap1 signaling pathway.Conclusion: Our study indicated that hUC-MSC-sEVs protect cartilage from damage and many cartilage repair-related proteins are probably involved in the restoration process. These data suggest the promising potential of hUC-MSC-sEVs as a therapeutic agent for OA.Keywords: human umbilical cord-derived mesenchymal stem cells, small extracellular vesicles, osteoarthritis, proteomics, cell-free therapy

Honglei Li,1,2 Dongle Liu,1,2 Han Gao,3 Jiajun Sun,1,2 Huiran Bai,1,2 Xiaoming Wu1,2 1Qingdao Eye Hospital of Shandong First Medical University, Qingdao, People’s Republic of China; 2State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, People’s Republic of China; 3Department of Ophthalmology, Qingdao Central Hospital, The Second Affiliated Hospital of Medical College of Qingdao University, Qingdao, People’s Republic of ChinaCorrespondence: Xiaoming WuQingdao Eye Hospital of Shandong First Medical University, 5 Yanerdao Road, Qingdao, 26600, People’s Republic of ChinaEmail wuxiaominglmm@126.comPurpose: This study compared the clinical outcomes after cataract surgery with implantation of refractive rotationally asymmetric bifocal intraocular lens (IOL) (LS-313 MF30) and apodized diffractive bifocal IOL (ReSTOR SN6AD1).Methods: This was a prospective, non-randomized, controlled study, where patients diagnosed with age-related cataracts were selected for phacoemulsification combined with bilateral IOL implantation. Based on the type of IOL voluntarily implanted, the patients were divided into two groups, ie, refractive and diffractive groups. In total, 30 cases (60 eyes) were in a refractive group, while 30 cases (60 eyes) were in diffractive group. Three months after surgery, we examined the uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA), uncorrected near visual acuity (UNVA), defocus curve, objective visual quality, and subjective questionnaire.Results: Three months after surgery, the UIVA of the refractive group (0.18 ± 0.08) logMAR was better than that of the diffractive group (0.29 ± 0.16) logMAR (P < 0.05). No significant difference in UDVA and UNVA was noted between the two groups. For a 4mm pupil diameter, the intraocular and total eye aberration, higher-order aberration (HOA), coma, spherical aberration, and trefoil in the refractive group were significantly higher than those in diffractive group (P < 0.05). The intraocular modulation transfer function (MTF), intraocular strehl ratio (SR), total eye MTF, and total eye SR in the refractive group were lower than those in diffractive group (P < 0.05). No significant difference in glare incidence, spectacle independence rate, and patient satisfaction was observed between the two groups (P > 0.05). The halos incidence in the refractive group was lower than the diffractive group (P < 0.05).Conclusion: Both bifocal IOLs obtained satisfactory UDVA and UNVA, with higher patient satisfaction. Unlike the apodized diffractive bifocal IOL, the refractive rotationally asymmetric bifocal IOL yielded slightly better UIVA, lower halos incidence, whereas the apodized diffractive bifocal IOL showed a better objective visual quality.Keywords: refractive rotationally asymmetric, apodized diffractive, intraocular lens, visual quality