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Huizhong Hu, Yuanjie Qiu, Nirui Shen, Huan Chen, Jia Zhang, Yan Wang, Xiangyu Shi, Manxiang Li Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Manxiang Li, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China, Tel\Fax +86-029-85324053, Email manxiangli@hotmail.comPurpose: Although low-carbohydrate and low-fat diets improve weight loss, cardiovascular disease, and diabetes, the relationship between these dietary patterns, highlighting macronutrient sources, and chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to assess the association between low-carbohydrate diets (LCDs) and low-fat diets (LFDs) and the odds of COPD and mortality among people with COPD in the National Health and Nutrition Examination Survey.Patients and Methods: Clinical data were extracted from the 2007– 2008, 2009– 2010, and 2011– 2012 National Health and Nutrition Examination Survey (NHANES) cycles that met the inclusion criteria. Multivariable logistic regression was used to evaluate the associations between LCD and LFD scores and COPD, and multivariable Cox proportional hazards regression and restricted cubic spline (RCS) regression were used to assess the relationship between all-cause mortality and LCD and LFD scores.Results: Comparing extreme tertiles, multivariable-adjusted odds ratio (OR) were 1 (reference), 1.09 (95% CI, 0.77– 1.55), 1.84 (95% CI, 1.09– 3.09) (P = 0.045 for trend) for unhealthy LFD scores. After multivariate adjustment, a per 5-point increase in unhealthy LCD score was associated with a 21% higher risk of total mortality (hazard ratio, 1.21; 95% CI, 1.03– 1.43); while a per 5-point increase in healthy LFD scores was associated with a 21% lower risk of total mortality (HR, 0.79; 95% CI, 0.67– 0.94).Conclusion: Higher unhealthy LFD score was associated with an increased odds of COPD. Unhealthy LCD scores were significantly associated with higher total mortality, whereas healthy LFD scores were associated with lower total mortality in patients with COPD.Keywords: low-carbohydrate diet, low-fat diet, chronic obstructive pulmonary disease, mortality, NHANES

Qingcheng Song,1,2,* Yiran Zhang,3,* Hongzhi Hu,4,* Xuemei Yang,5 Xin Xing,1,2 Jianhua Wu,6 Yanbin Zhu,1,2 Yingze Zhang1,2 1Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Orthopaedic Institution of Hebei Province, Shijiazhuang, Hebei, People’s Republic of China; 3School of Medicine, Nankai University, Tianjin, People’s Republic of China; 4Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 5The Fourth Hospital of Shijiazhuang, Shijiazhuang, Hebei, People’s Republic of China; 6The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingze Zhang; Yanbin Zhu, Email yzling_liu@163.com; 38600312@hebmu.edu.cnIntroduction: Ferroptosis-driven tumor ablation strategies based on nanotechnology could be achieved by elevating intracellular iron levels or inhibiting glutathione peroxidase 4 (GPX4) activity. However, the intracellular antioxidative defense mechanisms endow tumor cells with ferroptosis resistance capacity. The purpose of this study was to develop a synergistic therapeutic platform to enhance the efficacy of ferroptosis-based tumor therapy.Methods: In this study, a multifunctional nano-catalytic therapeutic platform (mFeB@PDA-FA) based on chemodynamic therapy (CDT) and photothermal therapy (PTT) was developed to effectively trigger ferroptosis in tumor. In our work, iron-based mesoporous Fe3O4 nanoparticles (mFe3O4 NPs) were employed for the encapsulation of L-buthionine sulfoximine (BSO), followed by the modification of folic acid-functionalized polydopamine (PDA) coating on the periphery. Then, the antitumor effect of mFeB@PDA-FA NPs was evaluated using Human OS cells (MNNG/HOS) and a subcutaneous xenograft model of osteosarcoma.Results: mFe3O4 harboring multivalent elements (Fe2+/3+) could catalyze hydrogen peroxide (H2O2) into highly cytotoxic ˙OH, while the tumor microenvironment (TME)-responsive released BSO molecules inhibit the biosynthesis of GSH, thus achieving the deactivation of GPX4 and the enhancement of ferroptosis. Moreover, thanks to the remarkable photothermal conversion performance of mFe3O4 and PDA shell, PTT further synergistically enhanced the efficacy of CDT and facilitated ferroptosis. Both in vivo and in vitro experiments confirmed that this synergistic therapy could achieve excellent tumor inhibition effects.Conclusion: The nanotherapeutic platform mFeB@PDA-FA could effectively disrupted the redox homeostasis in tumor cells for boosting ferroptosis through the combination of CDT, PTT and GSH elimination, which provided a new perspective for the treatment of ferroptosis sensitive tumors. Keywords: ferroptosis, chemodynamic therapy, photothermal therapy, Fenton reaction, BSO

Fengtao Zhang,1,&ast; Sheng Zhong,2,&ast; Qiming Wei,3 Haiming Zhang,4 Honglei Hu,5 Bicheng Zeng,6 Xiang Zheng7 1Vascular Interventional Surgery, Huazhong University of Science and Technology Union Shenzhen Hospital(Shenzhen Nanshan People’s Hospital), Shenzhen, Guangdong, 518000, People’s Republic of China; 2Department of Tumor and Vascellum Intervention, DongGuan Tungwah Hospital, DongGuan, Guangdong, 523000, People’s Republic of China; 3Department of Interventional Therapy, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510000, People’s Republic of China; 4Department of Radiology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, 510080, People’s Republic of China; 5Department of Radiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China; 6Hepatobiliary Surgery, The Sixth Affiliated Hospital of Jinan University, Dongguan, Guangdong, 523000, People’s Republic of China; 7Department of Interventional Therapy, Zhuhai People’s Hospital(Zhuhai Clinical Medical College of Jinan University), Zhuhai, Guangdong, 519000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiang Zheng, Department of Interventional Therapy,Zhuhai People’s Hospital(Zhuhai Clinical Medical College of Jinan University), No. 79 Kangning Road, Zhuhai, 519000, People’s Republic of China, Email zhengxiangzxzx@sina.comAim: To investigate the efficacy and safety of HAIC combined with programmed cell death protein-1 (PD1) inhibitors in MVI-positive advanced hepatocellular carcinoma(HCC).Methods: From September 2017 to May 2019, we retrospectively collected the clinical data from three medical centers in China pertaining to patients diagnosed with BCLC C stage HCC with MVI and receiving treatment with a combination of HAIC and PD-1 inhibitors treatment or HAIC alone, and we compared the efficacy of HAIC combined with PD-1 inhibitors and HAIC monotherapy. Propensity score matching(PSM) was utilized to adjust for baseline differences between groups. Survival outcomes and tumor response rate were used to assess survival benefits, while the incidence of adverse events was used to evaluate safety.Results: After screening for eligibility, 489 patients diagnosed with HCC and concomitant MVI were enrolled. Of these, 173 patients received treatment combining HAIC with PD-1 inhibitors, while 316 patients underwent HAIC monotherapy. After PSM adjustment, the combination therapy group demonstrate superior survival outcomes. Median overall survival(OS) and progression free survival(PFS) were 31.8 months and 10.8 months, respectively, significantly higher than those in the monotherapy group (OS: 10.0 months; PFS: 6.1 months; both P< 0.0001). Moreover, ORR and DCR remained significantly elevated in the combination therapy group (ORR: 44.3% vs 20.4%, P< 0.0001; DCR: 89.8% vs 82.0%, P=0.041). Safety profiles indicated no significant differences in adverse event rates between the two treatment groups, encompassing both overall and grade-specific assessments.Conclusion: Compared to HAIC alone, the combination of HAIC with PD-1 inhibitors represents a more promising and effective approach for patients with HCC complicated by macrovascular invasion.Keywords: hepatocellular carcinoma, programmed cell death protein 1, hepatic artery infusion chemotherapy, macrovascular invasion, propensity score matching

Zhen Ruan,1,&ast; Xianwen Chen,1,&ast; Menghuan Song,1 Ruxu Jia,2 Hang Luo,3 Carolina Oi Lam Ung,1,4,5 Hao Hu1,4,5 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, Macau SAR, People’s Republic of China; 2Global Business School for Health, University College London, London, UK; 3Shanghai Palan DataRx Co., Ltd, Shanghai, People’s Republic of China; 4Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Macau, Macau SAR, People’s Republic of China; 5Centre for Pharmaceutical Regulatory Sciences, University of Macau, Macau, Macau SAR, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Hu, University of Macau, Room 1050, E12 Research Building, Macau, Macau SAR, People’s Republic of China, Email haohu@um.edu.moAim: This study aimed to conduct a retrospective observational study in China to investigate the real-world utilization of glucagon-like peptide-1 receptor (GLP-1RA) in China.Methods: Type 2 diabetes mellitus (T2DM) patients were retrieved from the electronic medical records of 18 hospitals from 2016 to 2020. A descriptive analysis detailed patient characteristics and clinical outcomes. Multivariate logistic regression analysed the factors associated with daily and weekly GLP-1RA.Results: Fifteen thousand one hundred and seventy-six individuals were included. At the 6-month follow-up, the overall estimated mean change from baseline in HbA1c was − 1.26± 1.91% (p < 0.001), the “Weekly GLP-1RA” group was − 1.58± 2.03% (p < 0.001), and the “Daily GLP-1RA” group was − 1.25± 1.90% (p < 0.001). At the 12-month follow-up, the overall estimated mean change from baseline in HbA1c was − 0.95± 1.80% (p < 0.001), the “Weekly GLP-1RA” group was − 1.05± 1.93% (p < 0.001), and the “Daily GLP-1RA” group was − 0.95± 1.80% (p < 0.001). At 6 months following GLP-1RA initiation, there were statistically significant improvements in the mean TC, LDL-C, and TG at 6 months or 12 months separately following GLP-1RA initiation. Statistically significant improvements were observed in the mean HDL-C after 6 months. Compared with the baseline (11.92%), the proportion of patients who had an incidence of all hypoglycemia was lower at the 6-month follow-up (9.73%). Patients with dyslipidemia were more likely to use weekly GLP-1RA (OR =1.61, 95% CI: 1.27– 2.06, p < 0.001).Conclusion: In China, weekly GLP-1RA demonstrated better effectiveness compared to the daily GLP-1RA. The results confirmed the efficacy of GLP-1RA in clinical trials.Keywords: type 2 diabetes mellitus, glucagon-like peptide-1 receptor agonist, GLP-1RA, retrospective, China, electronic medical record, real-world

Yali Yuan,1,2,&ast; Hairong Hu,1,&ast; Zhongmei Sun,3,&ast; Wenting Wang,4 Zhibin Wang,1 Mengyu Zheng,5 Yunqi Xing,1 Wenji Zhang,1 Muyuan Wang,1 Xinyu Lu,1 Yitong Li,1 Chengtao Liang,1 Zhengdao Lin,1 Chune Xie,6 Junxiang Li,1 Tangyou Mao1 1Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Hebei North University, Zhangjiakou, Hebei, People’s Republic of China; 3Tianjin Nankai Hospital, Tianjin, People’s Republic of China; 4Beitaipingzhuang Community Health Service Center, Beijing, People’s Republic of China; 5King’s College, London, UK; 6Shenzhen Bao’an Traditional Chinese Medicine Hospital, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tangyou Mao; Junxiang Li, Email maotangyouqun@126.com; lijunxiang1226@163.comBackground: Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease that lacks effective treatments. Qingchang Wenzhong Decoction (QCWZD) is a clinically effective herbal prescription that has been proven to attenuate intestinal inflammation in IBD. However, its molecular mechanism of action has not been clearly elucidated.Purpose: We aimed to probe the mechanism of QCWZD for the treatment of IBD.Methods: The dextran sulfate sodium (DSS)-induced mouse model of IBD was used to identify the molecular targets involved in the mechanism of action of QCWZD. Metagenomics sequencing was utilized to analyze the differences in gut microbiota and the functional consequences of these changes. Network pharmacology combined with RNA sequencing (RNA-seq) were employed to predict the molecular targets and mechanism of action of QCWZD, and were validated through in vivo experiments.Results: Our results demonstrated that QCWZD treatment alleviated intestinal inflammation and accelerated intestinal mucosal healing that involved restoration of microbial homeostasis. This hypothesis was supported by the results of bacterial metagenomics sequencing that showed attenuation of gut dysbiosis by QCWZD treatment, especially the depletion of the pathogenic bacterial genus Bacteroides, while increasing the beneficial microorganism Akkermansia muciniphila that led to altered bacterial gene functions, such as metabolic regulation. Network pharmacology and RNA-seq analyses showed that Th17 cell differentiation plays an important role in QCWZD-based treatment of IBD. This was confirmed by in vivo experiments showing a marked decrease in the percentage of CD3+CD4+IL-17+ (Th17) cells. Furthermore, our results also showed that the key factors associated with Th17 cell differentiation (IL-17, NF-κB, TNF-α and IL-6) in the colon were significantly reduced in QCWZD-treated colitis mice.Conclusion: QCWZD exerted beneficial effects in the treatment of IBD by modulating microbial homeostasis while inhibiting Th17 cell differentiation and its associated pathways, providing a novel and promising therapeutic strategy for the treatment of IBD. Keywords: intestinal bowel disease, Qingchang Wenzhong Decoction, microbial homeostasis, Th17 cells, mucosal immunity

Mingtao Liu,1,&ast; Zhangkai J Cheng,1,&ast; Jiaxi Chen,2,&ast; Haiyang Li,1,3 Mingshan Xue,4,5 Xing Fu,1 Yanjun Li,2 Jiaxin Wang,2 Chenwei You,2 Haisheng Hu,1 Haojie Wu,1 Huimin Huang,1 Baoqing Sun1,4 1Department of Clinical Laboratory of the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, 510120, People’s Republic of China; 2KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 511495, People’s Republic of China; 3MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, UK; 4Guangzhou Laboratory, Guangzhou, 510005, People’s Republic of China; 5Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, 510440, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Baoqing Sun; Huimin Huang, Department of Clinical Laboratory of the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, 510120, People’s Republic of China, Tel +86 13824124015 ; +86 13631496651, Email sunbaoqing@vip.163.com; huanghuimin311@126.comBackground: While serum periostin and Krebs von den Lungen-6 (KL-6) have been acknowledged as independent markers in idiopathic pulmonary fibrosis (IPF) diagnosis, the clinical combinatory potential of these biomarkers combined with high-resolution computed tomography (HRCT) has yet to be fully explored.Methods: This retrospective study involved 78 participants, comprising 51 UIP-IPF patients and 27 healthy controls. All subjects underwent clinical and laboratory examinations, particularly the detection of periostin and KL-6 using ELISA with innovative HRCT fibrosis score evaluations at admission and discharge during hospitalization in UIP-IPF patients.Results: In our cohort of patients with IPF, predominantly male, over an average follow-up period of 195.27 days. Serum levels of periostin and KL-6 were significantly elevated in IPF patients compared to healthy controls (&ast;p < 0.05). Post-treatment, KL-6 levels decreased significantly, while periostin levels increased. Notably, periostin exhibited superior prognostic accuracy over KL-6, with a higher AUC of 0.875 than 0.639 in ROC analysis. An increase in periostin levels correlated with disease progression, as evidenced by worsened HRCT fibrotic scores and decreased survival probability. These findings underscore periostin’s potential as a reliable biomarker for assessing IPF severity and therapeutic response.Conclusion: Our findings underscore the preeminence of serum periostin over KL-6 in UIP-IPF diagnosis, particularly when conjoined with HRCT fibrosis score.Keywords: periostin, Krebs von den Lungen-6, idiopathic pulmonary fibrosis, HRCT fibrosis score, diagnostic hematology

Longqing Xia,1 Mengmeng Yang,1 Nan Zang,1– 4 Jia Song,1– 4 Jun Chen,1– 4 Huiqing Hu,1 Kewei Wang,1 Yingyue Xiang,1 Jingwen Yang,1 Liming Wang,1 Ying Zou,1 Xiaoyu Lv,1 Xinguo Hou,1– 4 Li Chen1– 4 1Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China; 2Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, People’s Republic of China; 3Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, People’s Republic of China; 4Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, People’s Republic of ChinaCorrespondence: Li Chen, Department of Endocrinology, Qilu Hospital of Shandong University, Shandong, People’s Republic of China, Email chenli3@email.sdu.edu.cnBackground: The depletion of β cell mass is widely recognized as a significant contributor to the progression of type 2 diabetes mellitus (T2DM). Exosomes derived from mesenchymal stem cells (MSC-EXOs) hold promise as cell-free therapies for treating T2DM. However, the precise effects and mechanisms through which MSC-EXO affects β cell function remain incompletely understood, and the limited ability of MSC-EXO to target β cells and the short blood circulation time hampers its therapeutic effectiveness.Methods: The effects of MSC-EXO were investigated in T2DM mice induced by a high-fat diet combined with STZ. Additionally, the high glucose-stimulated INS-1 cell line was used to investigate the potential mechanism of MSC-EXO. Michael addition reaction-mediated chemical coupling was used to modify the surface of the exosome membrane with a β-cell-targeting aptamer and polyethylene glycol (PEG). The β-cell targeting and blood circulation time were evaluated, and whether this modification enhanced the islet-protective effect of MSC-EXO was further analyzed.Results: We observed that the therapeutic effects of MSC-EXO on T2DM manifested through the reduction of random blood glucose levels, enhancement of glucose and insulin tolerance, and increased insulin secretion. These effects were achieved by augmenting β cell mass via inhibiting nuclear factor erythroid 2–related factor 2 (NRF2)-mediated ferroptosis. Mechanistically, MSC-EXOs play a role in the NRF2-mediated anti-ferroptosis mechanism by transporting active proteins that are abundant in the AKT and ERK pathways. Moreover, compared to MSC-EXOs, aptamer- and PEG-modified exosomes (Apt-EXOs) were more effective in islet protection through PEG-mediated cycle prolongation and aptamer-mediated β-cell targeting.Conclusion: MSC-EXO suppresses NRF2-mediated ferroptosis by delivering bioactive proteins to regulate the AKT/ERK signaling pathway, thereby improving the function and quantity of β cells. Additionally, Apt-EXO may serve as a novel drug carrier for islet-targeted therapy.Keywords: exosome, type 2 diabetes mellitus, β-cell-targeting, polyethylene glycol modification, ferroptosis

Yaonan Hong,1,2,&ast; Qi Liu,1,2,&ast; Chuanao Xin,1,2,&ast; Huijin Hu,1,2 Zhenchao Zhuang,1– 3 Hangping Ge,1,2,4 Yingying Shen,1,2,4 Yuechao Zhao,1,2,4 Yuhong Zhou,1,2,4 Baodong Ye,1,2,4 Dijiong Wu1,2,4,5 1Department of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China; 2The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Clinical Laboratory, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4National Traditional Chinese Medicine Clinical Research Base (Hematology), Hangzhou, Zhejiang, People’s Republic of China; 5Department of Oncology and Hematology, Wenzhou Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Zhejiang Chinese Medicine University, Wenzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dijiong Wu, Department of Hematology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou, Zhejiang, 310006, People’s Republic of China, Tel +86-571-86620325, Email wudijiong@zcmu.edu.cnBackground: Limited data were available to understand the significance of ferroptosis in leukemia prognosis, regardless of the genomic background.Methods: RNA-seq data from 151 AML patients were analyzed from The Cancer Genome Atlas (TCGA) database, along with 70 healthy samples from the Genotype-Tissue Expression (GTEx) database. Ferroptosis-related genes (FRGs) features were constructed by multivariate COX regression analysis and risk scores were calculated for each sample and a novel prediction model was identified. The validation was carried out using data from 35 AML patients and 13 healthy controls in our cohort. Drug sensitivity analysis was conducted on various chemotherapeutic drugs.Results: A signature of 10 FRGs was identified, as prognostic predictors for AML, and the risk scores were calculated to constructed the prognostic features of FRGs. Significantly lower overall survival was observed in the high-risk group. The predictive ability of these features for AML prognosis was confirmed using Cox regression analysis, ROC curves, and DCA. The prediction model performed well in our clinical practices, and had its potential superiority when comparing to classical NCCN risk stratification. Multiple chemotherapy drugs, including paclitaxel, dactinomycin, cisplatin, etc. had a lower IC50 in FRGs high-risk group than low-risk group.Conclusion: The AML prognosis model based on FRGs accurately predicts AML prognosis and drug sensitivity, and the drugs identified worthy further investigation.Keywords: ferroptosis, prediction model, TCGA, acute myeloid leukemia, drug sensitivity

Jie Zhang, Xuelin Yao, Yijing Chen, Qing Feng, Yi Zhang, Tian Jiang, Songtao Tang, Nan Zhang, Fang Dai, Honglin Hu, Qiu Zhang Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Qiu Zhang; Honglin Hu, Department of Endocrinology, First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, Shushan District, 230032, People’s Republic of China, Email zhangqiu@ahmu.edu.cn; huhonglin@ahmu.edu.cnBackground: Diabetes mellitus and hypertension often coexist and share common risk factors. This study investigated the correlation between glycemic management and the prevalence of hypertension among Chinese adults diagnosed with type 2 diabetes mellitus (T2DM).Methods: This study included 1715 patients with T2DM from four cities in Anhui Province, China. Sociodemographic characteristics of the sample participants were collected via questionnaires. A univariate analysis of variance (ANOVA) was utilized for continuous variables, and chi-square testing was used for categorical variables. Binary logistic regression was utilized to examine the relationship between blood pressure and variables including fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c), body mass index (BMI), waist circumference (WC), physical activity, dyslipidemia, and family history of hypertension.Results: FPG levels did not increase the risk of hypertension, while HbA1c was significantly and negatively associated with hypertension risk. HbA1c levels ranged from 7.2 to 8.6%, with odds ratios (OR) of 0.68 and 95% confidence intervals (CI) of 0.48 to 0.97 and a significant p value of less than 0.05. For the HbA1c levels above 8.6%, the OR was 0.58 with a 95% CI of 0.39 to 0.87 and a significant p value of less than 0.01. Furthermore, advanced age, higher BMI, greater waist circumference, presence of dyslipidemia, and positive family history of hypertension were all found to be significantly and independently linked to a heightened risk of developing hypertension. These associations remain significant after further adjustment.Conclusion: There was a negative association between HbA1c and the risk of hypertension, and the association remained significant after adjustment for antihypertensive drug use.Keywords: FPG, HbA1c, T2DM, hypertension

Yibin Lin,1,2 Lehua Liu,1 Siyang Lu,1 Linqi Fan,1 Huaqi Hu,1 Xuanyin Wang,1 Jichao Zhu,3 Xinhua Qiang,4 Jie He,5 Hongchang Zhou,1,2,6 Shengwen Shao,1,6 Gaoming Zheng7 1School of Medicine, Huzhou University, Huzhou, 313000, People’s Republic of China; 2Key Laboratory for Precise Prevention and Control of Major Chronic Diseases, Huzhou University, Huzhou, 31300, People’s Republic of China; 3Clinical Laboratory, Huzhou Central Hospital, Huzhou, 313000, People’s Republic of China; 4Clinical Laboratory, First People’s Hospital Affiliated to Huzhou University, Huzhou, 313000, People’s Republic of China; 5Infectious Diseases Department, First People’s Hospital Affiliated to Huzhou University, Huzhou, 313000, People’s Republic of China; 6Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou University, Huzhou, 313000, People’s Republic of China; 7Clinical Laboratory, Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, People’s Republic of ChinaCorrespondence: Gaoming Zheng; Shengwen Shao, Email zheng151031@sina.com; shaoshw@zjhu.edu.cnBackground: Bacillus cereus is a common bacterium found in the environment. Some strains can cause food poisoning, and very few can cause clinically severe infections, leading to death. Here, we characterized the genome sequence of B. cereus LIN78 isolated from teeth with deep caries and compared it with those of 25 other related species.Methods: Third-generation sequencing technology, bacteriological analyses, biochemistry, and mass spectrometry were applied to characterize the drug-resistance genes and virulence factors of B. cereus LIN78.Results: The complete genome sequence of B. cereus Lin78 consists of 5647 genes distributed on a circular chromosome, a 393 kbp plasmid, and 928 pseudogenes (37.4% of whole-genome DNA). The LIN78 genome contains 14 sets of 16s, 23s, and 5s ribosomal RNA operons; 106 tRNA genes, one tmRNA, 12 genomic islands, six prophases, 64 repeats; 37 antibiotic-resistant genes; and 1119 putative virulence genes, including enterotoxins and cytolysins. The B. cereus LIN78 genome carries multiple copies of non-ribosomal polypeptide synthetase (NRPS) and post-translationally modified peptides (RiPPs). Phylogenetic analysis of the 26 B. cereus strains showed that B. cereus LIN78 is evolutionarily closely related to B. thuringiensis ATCC 10792 and B. cereus ATCC 14579.Conclusion: The newly isolated B. cereus carries many virulence genes, including enterotoxins and hemolysins, similar to B. anthracis, and multiple antibiotic resistance genes. These findings suggest that the strain has a potential risk of causing disease. Our studies are vital for further exploration of the evolution of B. cereus, its pathogenic mechanisms, and the control and treatment of bacterial infections.Keywords: bacillus cereus, whole-genome DNA sequencing, virulence factor, drug resistance gene, human teeth

Yu-Xiang Deng,1,&ast; Yu-Jie Zhao,2,&ast; Qiao-Hong Nong,3 Hong-Mei Qiu,1 Qiao-Li Guo,1 Hui Hu1 1Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People’s Republic of China; 2Department of Radiotherapy, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People’s Republic of China; 3Department of Oncology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Hu, Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, 1120 Lianhua Road, Shenzhen, 518000, People’s Republic of China, Tel +86-755-83923333, Email Sapphiretjmu@163.comBackground: The immune system appears to play a crucial role in how breast cancer responds to chemotherapy. In this study, we investigated a peripheral marker of immune and inflammation named the neutrophil to albumin ratio (NAR) to explore its potential relationship with pathological complete response (pCR) in locally advanced breast cancer patients who underwent neoadjuvant chemotherapy (NAC).Methods: We conducted a retrospective analysis of 212 consecutive breast cancer patients who received NAC. The NAR was calculated by examining the complete blood cell count and albumin level in peripheral blood before starting NAC. Through ROC curve analysis, we determined the optimal cutoff value for NAR as 0.0877. We used Pearson’s chi-square test or Fisher’s exact test to evaluate the relationship between NAR and pCR, as well as other clinical and pathological characteristics. Logistic regression models were employed for univariate and multivariate analyses.Results: The results of both univariate and multivariate logistic regression analyses showed that NAR was associated with tumor pathological regression. The NAR high group had a higher pCR rate compared to the NAR low group (OR 3.127 [95% CI 1.545– 6.328]; p = 0.002).Conclusion: According to this study, it was observed that patients with breast cancer who had high levels of NAR were more likely to achieve pCR when undergoing NAC.Keywords: breast cancer, neoadjuvant chemotherapy, pathological complete response, neutrophil to albumin ratio, predictive factors

Yingzi Zhang,1 Xiajuan Yao,1 Yaoquan Zhang,1 Zhuyun Chen,1 Zhongke Qin,1 Ying Cai,2 Wenkai Xia,1 Hong Hu1 1Department of Nephrology, Jiangyin People’s Hospital Affiliated to Nantong University, Jiangyin, Jiangsu, 214400, People’s Republic of China; 2Department of Hematology, Jiangyin People’s Hospital Affiliated to Nantong University, Jiangyin, Jiangsu, 214400, People’s Republic of ChinaCorrespondence: Wenkai Xia; Hong Hu, Department of Nephrology, Jiangyin People’s Hospital Affiliated to Nantong University, 3 Yingrui Road, Jiangyin, Jiangsu, 214400, People’s Republic of China, Email xiawenkai.xia@gmail.com; huhong1523@163.comBackground: The albumin-to-globulin ratio (AGR) and neutrophil-to-lymphocyte ratio (NLR) have been recently regarded as promising prognostic factors in various malignancies. The present study investigated the prognostic value of combining the AGR and NLR (ANS) for risk assessments in multiple myeloma (MM) with renal impairment (RI).Methods: From 2011 to 2018, 79 patients with MM and RI were enrolled in this study. Receiver operating curves (ROCs) were constructed to determine optimal AGR and NLR thresholds for predicting overall survival (OS) and progression-free survival (PFS) during follow up. The prognostic values of AGR, NLR, and ANS were evaluated with Cox regression and Kaplan-Meier methods. We also created a predictive nomogram for prognostic evaluations of OS and PFS, and the predictive accuracy was assessed with a concordance index (c-index).Results: The ROC curves analyses showed that the optimal cut-off levels were 2.27 for NLR and 1.57 for AGR. A high NLR and a high ANS were significantly associated with worse OS and PFS. However, a high NLR combined with a low AGR was associated with worse OS. Multivariate analyses demonstrated that both the NLR and ANS were independent predictors for both OS and PFS and that a low AGR was an independent predictor of a reduced OS. The nomogram accurately predicted OS (c-index: 0.785) and PFS (c-index: 0.786) in patients with MM and RI.Conclusion: ANS may serve as a potential prognostic biomarker in patients with MM and RI. The proposed nomograms may facilitate prognostic predictions for patients with MM and RI.Keywords: multiple myeloma, renal impairment, neutrophil–lymphocyte ratio, albumin-to-globulin ratio, prognosis

Xiaoyan Wu,1,2 Yuzhe Sun,2,3 Shuyi Wei,2,3 Huoyou Hu,1 Bin Yang2 1Shenzhen Second People’s Hospital, the First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, People’s Republic of China; 2Department of Dermatology, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China; 3Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, 510091, People’s Republic of ChinaCorrespondence: Huoyou Hu, Shenzhen Second People’s Hospital, 3002 Sungang West Road, Shenzhen, Guangdong, 518035, People’s Republic of China, Tel +86-13554918106, Email huhuoyou1029@163.com Bin Yang, Jinan University, 601 West Huangpu Avenue, Guangzhou, Guangdong, 510632, People’s Republic of China, Tel +86-13922207231, Email yangbin1@smu.edu.cnBackground: Ferroptosis is a type of cell death characterized by the accumulation of iron-dependent lethal lipid peroxides, which is associated with various pathophysiological processes. Psoriasis is a chronic autoimmune skin disease accompanied by abnormal immune cell infiltration and excessive production of lipid reactive oxygen species (ROS). Currently, its pathogenesis remains elusive, especially the potential role of ferroptosis in its pathophysiological process.Methods: The microarrays GSE13355 (58 psoriatic skin specimens versus 122 healthy skin specimens) and the ferroptosis database were employed to identify the common differentially expressed genes (DEGs) associated with psoriasis and ferroptosis. The functions of common DEGs were investigated through functional enrichment analysis and protein-protein interaction analysis. The potential diagnostic markers for psoriasis among the common DEGs were identified using four machine-learning algorithms. DGIdb was utilized to explore potential therapeutic agents for psoriasis. Additionally, CIBERSORT was employed to investigate immune infiltration in psoriasis.Results: A total of 8 common DEGs associated with psoriasis and ferroptosis were identified, which are involved in intercellular signaling and affect pathways of cell response to stress and stimulation. Four machine-learning algorithms were employed to identify poly (ADP-ribose) polymerase 12 (PARP12), frizzled homolog 7 (FZD7), and arachidonate 15-lipoxygenase (ALOX15B) among the eight common DEGs as potential diagnostic markers for psoriasis. A total of 18 drugs targeting the five common DEGs were identified as potential candidates for treating psoriasis. Additionally, significant changes were observed in the immune microenvironment of patients with psoriasis.Conclusion: This study has contributed to our enhanced comprehension of ferroptosis-related genes as potential biomarkers for psoriasis diagnosis, as well as the alterations in the immune microenvironment associated with psoriasis. Our findings offer valuable insights into the diagnosis and treatment of psoriasis.Keywords: psoriasis, ferroptosis, biomarker, immune

Cheng Wang,1,&ast; Jiaoyang Pan,1,&ast; Shaoqing Chen,2 Lin Qiu,1 Huaanzi Hu,1 Li Ji,3 Jianhao Wang,1 Wenjia Liu,4 Xinye Ni2 1School of Pharmacy, Changzhou University, Changzhou, Jiangsu Province, People’s Republic of China; 2Department of Radiology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China; 3Department of Otorhinolaryngology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 4Department of Gastroenterology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenjia Liu; Xinye Ni, Email 13813016290@126.com; nxy@njmu.edu.cnBackground: The in vivo barriers and multidrug resistance (MDR) are well recognized as great challenges for the fulfillment of antitumor effects of current drugs, which calls for the development of novel therapeutic agents and innovative drug delivery strategies. Nanodrug (ND) combining multiple drugs with distinct modes of action holes the potential to circumvent these challenges, while the introduction of photothermal therapy (PTT) can give further significantly enhanced efficacy in cancer therapy. However, facile preparation of ND which contains dual drugs and photothermal capability with effective cancer treatment ability has rarely been reported.Methods: In this study, we selected curcumin (Cur) and doxorubicin (Dox) as two model drugs for the creation of a cocktail ND (Cur-Dox ND). We utilized polyvinylpyrrolidone (PVP) as a stabilizer and regulator to prepare Cur-Dox ND in a straightforward one-pot method.Results: The size of the resulting Cur-Dox ND can be easily adjusted by tuning the charged ratios. It was noted that both loaded drugs in Cur-Dox ND can realize their functions in the same target cell. Especially, the P-glycoprotein inhibition effect of Cur can synergistically cooperate with Dox, leading to enhanced inhibition of 4T1 cancer cells. Furthermore, Cur-Dox ND exhibited pH-responsive dissociation of loaded drugs and a robust photothermal translation capacity to realize multifunctional combat of cancer for photothermal enhanced anticancer performance. We further demonstrated that this effect can also be realized in 3D multicellular model, which possibly attributed to its superior drug penetration as well as photothermal-enhanced cellular uptake and drug release.Conclusion: In summary, Cur-Dox ND might be a promising ND for better cancer therapy. Keywords: one-pot synthesis, size-tunable, multifunctional, cancer

Siyi Zhang,1,2,&ast; Yue Zhou,1,&ast; Jinghui Wang,2 Qingan Fu,1 Tianzhou Shen,2 Guanrui Pan,2 Renfei Luo,1 Xinlei Yang,3 Long Jiang,1 Hui Hu4 1Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 2Department of Clinical Medicine, Queen Mary School of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 3Department of Biobank Center, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China; 4Department of Medical Big Data Center, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Long Jiang, Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China, Tel +86-13767026990, Email skyiadx@hotmail.com Hui Hu, Department of Medical Big Data Center, the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, People’s Republic of China, Tel +86-13576978125, Email huhuillz@sina.comBackground: Lipoprotein(a) [Lp(a)] is a well-established risk factor for ischaemic stroke (IS). It is unclear whether Lp(a) is associated with IS in patients with atrial fibrillation (AF). The aim of this study is to explore the association between the concentration of Lp(a) and the risk of IS in AF patients, hope to find the potential risk factor for the IS in AF patients.Methods: This study is a retrospective cohort study. The screened AF patients between January 2017 and July 2021 were matched at 1:1 by the propensity score matching (PSM) method in the Second Affiliated Hospital of Nanchang University. Associations between Lp(a) and ischaemic stroke were analysed using logistic regression models, stratified analysis and sensitivity analysis. Statistical analyses were conducted using IBM SPSS software.Results: The number of enrolled participates is 2258, which contains 1129 non-AF patients and 1129 AF patients. Among IS patients, the median Lp(a) concentration was higher than that of controls (17.03 vs. 15.36 mg/dL, P = 0.032). The Spearman rank-order correlation coefficients revealed significant positive relationships between IS and Lp(a) (P = 0.032). In addition, a significant increase in IS risk was associated with Lp(a) levels > 30.00 mg/dL in unadjusted model [OR:1.263, 95% CI(1.046– 1.523), P = 0.015], model 1 [OR:1.284, 95% CI(1.062,1.552), P = 0.010], model 2 [OR: 1.297, 95% CI(1.07,1.573). P = 0.008], and model 3 [OR: 1.290, 95% CI (1.064, 1.562). P = 0.009]. The stratified analysis indicated that this correlation was not affected by female sex [1.484 (1.117, 1.972), P = 0.006], age ≤ 60 [1.864 (1.067-3.254), P=0.029], hypertension [1.359 (1.074, 1.721), P = 0.011], or non-coronary heart disease (CHD) [1.388 (1.108, 1.738), P = 0.004].Conclusion: High levels of Lp(a) were significantly related to IS in AF patients and may be a potential risk factor in the onset of an IS in AF patients. Keywords: ischaemic stroke, Lipoprotein(a), atrial fibrillation, risk factor, retrospective cohort study

Haiyang Hu, Xiaoxiao Wang, Yangsheng Ren, Tishuo Zhang, Lin Sun Department of Gynecology, Affiliated Hospital of Jining Medical University, Jining, Shandong, 272029, People’s Republic of ChinaCorrespondence: Lin Sun Department of Gynecology, Affiliated Hospital of Jining Medical University, 89 Guhuai Road, Jining, Shandong, 272029, People’s Republic of China, Tel +86 18678760870 ; +86-05372908731, Email sunlingyn@outlook.comPurpose: To evaluate the association between Composite Dietary Antioxidant Index (CDAI) and the risk of endometriosis (EM)-related rheumatoid arthritis (RA) in women of childbearing age.Methods: Using the data from the National Health and Nutrition Examination Survey database, this cross-sectional study included women of childbearing age. The CDAI was obtained by summing the standardized Z-values of the dietary intakes. EM was diagnosed based on a questionnaire-based survey. The outcome of this study was the presence of RA, which was defined by a questionnaire. The associations of CDAI and EM with the risk of RA were determined using weighted logistic analysis. Additive interaction was evaluated using the relative excess risk due to interaction (RERI), the attributable proportion due to interaction (AP), and the synergy index (S).Results: In total, 3803 patients were included, of which 74 patients (1.99%) were with RA. A lower CDAI [odds ratio (OR): 1.85, 95% confidence interval (CI): 1.12 to 3.04, P= 0.015] and the presence of EM (OR: 3.05, 95% CI: 1.19 to 7.81, P= 0.023) was associated with the risk of RA. The result demonstrated an additive interaction of a lower CDAI and the presence of EM on the risk of RA (OR: 6.19, 95% CI: 2.33 to 16.43, P < 0.001, P of trend =0.007). Nevertheless, there was no significant additive interaction after being assessed by the RERI, AP, and S. However, a joint effect of a lower CDAI and EM on the risk of RA (OR: 3.94, 95% CI: 1.35 to 11.51, P= 0.013) was observed.Conclusion: Our study identified EM, and lower CDAI, was related to the risk of RA. Lower CDAI score was also associated with the risk of EM-related RA. This study indicates the importance of antioxidant intake in daily diet for the management of EM-related RA.Keywords: composite dietary antioxidant index, endometriosis, rheumatoid arthritis, cross-sectional study

Xiaoli Wang,1,&ast; Heng Hu,1,2,&ast; Xinhui Yu,1 Chengcheng Liang,1 Yanquan Han,1 Hongxia Chen,1 Jijun Chu1 1The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, People’s Republic of China; 2Anhui University of Chinese Medicine, Hefei, Anhui, 230038, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongxia Chen; Jijun Chu, Department of Gynaecology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, People’s Republic of China, Email 13305690727@163.com; chujijun8888@163.comEthnopharmacological Relevance: Zishen Yutai pills (ZYP), a traditional Chinese patent medicine, was listed in China in 1981. It is composed of 15 traditional Chinese medicines and has the effects of regulating menstruation, helping pregnancy, and preventing abortion. In clinical practice, it is effective in preventing habitual and threatened miscarriages, and continuing to explore its mechanism of action is very meaningful research.Aim of the Study: To explore the possible mechanism of ZYP promoting angiogenesis at the maternal-fetal interface in recurrent spontaneous abortion (RSA).Materials and Methods: In vitro experiments, placental trophoblast cells (PTCs) were isolated from the placental tissue of RSA mice and divided into six groups: Control group, Model group, ZYP group, miR-187 inhibitor NC group, miR-18 7 inhibitor group, and miR-187 inhibitor+ZYP group. Cell viability and cell cycle were measured using CCK8 and flow cytometry, respectively. The expression levels of miR-187, VEGF, VEGF-R1, and VEGF-R2 were measured using RT-qPCR, WB, and IF staining. Animal experiments first establish an RSA mice model (CBA/J × DBA/2) and then randomly divide the mice into four groups (n=10): normal pregnancy group, RSA model group, ZYP group, and progesterone capsule group. Observed the changes in embryo absorption rate, pathological morphology of decidual tissue, and ultrastructure of vascular endothelial cells in each group of mice. RT-qPCR, WB, and IF staining methods were used to determine the expression of miR-187, VEGF, VEGF-R1, and VEGF-R2.Results: In vitro, ZYP promoted the viability of PTCs and regulated their cell cycle, and ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2 levels. miR-187 inhibitor showed the same effects, and further ZYP intervention enhanced the effects. In vivo, ZYP remarkably reduced embryo resorption rates, and improved the pathological morphology of decidual tissues and ultrastructure of vascular endothelial cells. Moreover, ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2.Conclusion: In summary, ZYP can regulate the expression of VEGF via miR-187, then promote the angiogenesis at the maternal-fetal interface, and playing a therapeutic role in RSA. Keywords: recurrent spontaneous abortion, Zishen Yutai pills, miR-187, vascular endothelial growth factor, VEGF, angiogenesis

Qi Wang,1,2 Quanai Zhang,1 Fengyan Lu,1 Hantong Hu,1 Muru Zhu2 1Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Quanai Zhang, Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, NO. 219 Moganshan Road, Hangzhou, Zhengjiang, 310005, People’s Republic of China, Tel +86 0571 88075439, Email 20071029@zcmu.edu.cnBackground: The aim of this study is to explore and illustrate the focal points concerning acupuncture’s impact on microcirculation and hemorheology over the past 26 years, and to identify future directions in this field.Methods: Data in this area were gathered from the Web of Science Core Collection database. Employing CiteSpace, VOSviewer, Scimago Graphica, and Microsoft Excel software, we analyzed authors, institutions, and countries to evaluate scientific collaboration. Moreover, we carried out an analysis of keyword clustering, references, and burst detection to examine the prominent research areas and emerging trends in this domain.Results: The study analyzed 706 documents, 471 institutions, 632 journals, 40 countries, 581 keywords, and 3289 authors related to acupuncture for microcirculation and hemorheology. Data revealed a consistent increase in research output over 26 years. China, with the most publications and citations, significantly contributed to the field, often collaborating with the United States. Elisabet Stener-Victorin and the China Academy of Chinese Medical Sciences were the most productive author and institution, respectively. The journal Evidence-based Complementary and Alternative Medicine held the most influence. Common keywords included “vasoactive substances”, “neurotransmitters”, “signaling pathways”, and “oxidative stress”, among others. Research topics focused on female infertility, ischemic stroke, and pain syndromes, with treatment approaches such as electroacupuncture, manual acupuncture, auricular acupuncture, and cupping therapy.Conclusion: Women’s infertility, ischemic stroke, and pain syndromes have emerged as hotspots in research. Future directions may include comparative studies of traditional and modern acupuncture techniques to evaluate their respective therapeutic effects. There is potential for in-depth research in these areas and the discovery of new intervention strategies as well as mechanisms.Keywords: acupuncture, microcirculation, hemorheology, bibliometric analysis, visual analysis, pain

Shan-Wen Liu,1 Xiao-Ting Ma,1 Shuai Yu,2 Xiao-Fen Weng,3 Meng Li,4 Jiangtao Zhu,4 Chun-Feng Liu,1 Hua Hu1 1Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, People’s Republic of China; 2Department of Neurology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215000, People’s Republic of China; 3Department of Geriatric Medicine, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215000, People’s Republic of China; 4Department of Imaging, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, People’s Republic of ChinaCorrespondence: Hua Hu, Department of Neurology, the Second Affiliated Hospital of Soochow University, 1055 San Xiang Road, Suzhou, Jiangsu Province, 215004, People’s Republic of China, Email sz_huhua@126.comObjective: To investigate the correlation between specific fiber tracts and grip strength and cognitive function in patients with Alzheimer’s disease (AD) by fixel-based analysis (FBA).Methods: AD patients were divided into AD with low grip strength (AD-LGS, n=29) and AD without low grip strength (AD-nLGS, n=25), along with 31 normal controls (NC). General data, neuropsychological tests, grip strength and cranial magnetic resonance imaging (MRI) scans were collected. FBA evaluated white matter (WM) fiber metrics, including fiber density (FD), fiber cross-sectional (FC), and fiber density and cross-sectional area (FDC). The mean fiber indicators of the fiber tracts of interest (TOI) were extracted in cerebral region of significant statistical differences in FBA to further compare the differences between groups and analyze the correlation between fiber properties and neuropsychological test scores.Results: Compared to AD-nLGS group, AD-LGS group showed significant reductions in FDC in several cerebral regions. In AD patients, FDC values of bilateral uncinate fasciculus and left superior longitudinal fasciculus were positively correlated with Clock Drawing Test scores, while FDC of splenium of corpus callosum, bilateral anterior cingulate tracts, forceps major, and bilateral inferior longitudinal fasciculus were positively correlated with the Executive Factor Score of Memory and Executive Screening scale scores.Conclusion: Reduced grip strength in AD patients is associated with extensive impairment of WM structural integrity. Changes in FDC of specific WM fiber tracts related to executive function play a significant mediating role in the reduction of grip strength in AD patients.Keywords: Alzheimer disease, grip strength, white matter, fixel-based analysis, cognition function

Qing Zhang,1,&ast; Wenjun Hu,1,&ast; Mingxue Guo,1 Xinyu Zhang,1 Qin Zhang,1 Fengqi Peng,1 Liwen Yan,1 Zucheng Hu,1 Jakkree Tangthianchaichana,2 Yan Shen,3 Haiyan Hu,4 Shouying Du,1 Yang Lu1 1School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China; 2Chulabhorn International College of Medicine, Thammasat University, Pathum Thani, 12120, Thailand; 3School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 4School of Pharmacy, Beijing Health Vocational College, Beijing, 101100, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyan Hu, School of Pharmacy, Beijing Health Vocational College, Beijing, 101100, People’s Republic of China, Email yxyhhy@163.com Yang Lu, School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, People’s Republic of China, Email luyang@bucm.edu.cnIntroduction: Responsive drug delivery systems hold great promise for tumor treatment as they focus on therapeutic agents directly, thus minimizing systemic toxicities and drug leakage. In this study, we covalently bound a matrix metalloproteinases-2 (MMP-2) enzyme-sensitive peptide to a tissue-penetrating peptide to rationally design a MMP-2 responsive multifunctional peptide hydrogel platform (aP/IR@FMKB) for cancer photothermal-chemo-immunotherapy. The constructed aP/IR@FMKB with bufalin (BF) loaded in trimethyl chitosan nanoparticles (TB NPs), photothermal agent IR820, and immune checkpoint inhibitor aPD-L1 by self-assembly could be dissociated in the presence of MMP-2 enzyme, triggering content release.Methods: TB NPs, IR820, and aPD-L1 were encapsulated by intermolecular self-assembly and enzyme-sensitive nanogels (aP/IR@FMKB) were constructed. The in vitro cytotoxicity of the blank gels and their ability to induce immunogenic cell death (ICD) in aP/IR@FMKB were evaluated using 4T1 cells. The promotion of deep tumor penetration and enzyme responsiveness was analyzed using a 3D cell model. The retention and antitumor activity at the tumor sites were examined using the primary tumor model. To assess the antitumor effect of aP/IR@FMKB induced by the immune response and its mechanism of action, recurrent tumor and distal tumor models were constructed.Results: This hydrogel system demonstrated exceptional photothermal performance and displayed prolonged local retention. Furthermore, the induction of ICD through IR820 and TB NPs sensitized the PD-L1 blockade, resulting in a remarkable 3.5-fold and 5.2-fold increase in the frequency of intratumor-infiltrating CD8+ T-cells in the primary tumor and distal tumor, respectively. Additionally, this system demonstrated remarkable efficacy in suppressing primary, distal, and recurrent tumors, underscoring its potential as a highly potent therapeutic strategy.Conclusion: This innovative design of the responsive hydrogel can effectively modulate the tumor immune microenvironment while also demonstrating sensitivity to the PD-1/PD-L1 blockade. This significant finding highlights the promising potential of this hydrogel in the field of multimodal tumor therapy.Keywords: responsive drug delivery systems, peptide hydrogels, immunogenic cell death, PD-1/PD-L1 blockade

Yiran Zhang,1– 4,&ast; Qingcheng Song,2,3,&ast; Yueyao Zhang,2,3,&ast; Jiheng Xiao,5 Xiangtian Deng,6 Xin Xing,2,3 Hongzhi Hu,5 Yingze Zhang1– 3 1School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China; 2Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 4HeBei Ex&Invivo Biotechnology Co. Ltd, Shijiazhuang, Hebei, 050051, People’s Republic of China; 5Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 6Orthopaedics Research Institute, Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingze Zhang; Hongzhi Hu, Email yzling_liu@163.com; 13720105746@163.comBackground: Although systemic chemotherapy is a standard approach for osteosarcoma (OS) treatment, its efficacy is limited by the inherent or acquired resistance to apoptosis of tumor cells. Ferroptosis is considered as an effective strategy capable of stimulating alternative pathways of cancer cell demise. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy.Methods and Results: A novel nanovehicle composed of arginine-glycine-aspartate (RGD) modified mesoporous silica-coated iron oxide loading Fin56 was rationally prepared (FSR-Fin56). With the RGD-mediated targeting affinity, FSR-Fin56 could achieve selective accumulation and accurate delivery of cargos into cancer cells. Upon exposure to NIR light, the nanovehicle could generate localized hyperthermia and disintegrate to liberate the therapeutic payload. The released Fin56 triggered the degradation of GPX4, while Fe3+ depleted the intracellular GSH pool, producing Fe2+ as a Fenton agent. The local rise in temperature, in conjunction with Fe2+-mediated Fenton reaction, led to a rapid and significant accumulation of ROS, culminating in LPOs and ferroptotic death. The outstanding therapeutic efficacy and safety of the nanovehicle were validated both in vitro and in vivo.Conclusion: The Fin56-loaded FSR nanovehicle could effectively disturb the redox balance in cancer cells. Coupled with NIR laser irradiation, the cooperative CDT and PTT achieved a boosted ferroptosis-inducing therapy. Taken together, this study offers a compelling strategy for cancer treatment, particularly for ferroptosis-sensitive tumors like osteosarcoma. Keywords: chemodynamic therapy, photothermal therapy, Fenton reaction, Fin56, ferroptosis

Yijie Wang,1,&ast; Weixiang Weng,2,&ast; Ruiming Liang,3,&ast; Qian Zhou,3 Hangtong Hu,4 Mingde Li,4 Lida Chen,4 Shuling Chen,4 Sui Peng,1,3 Ming Kuang,2,4,5 Han Xiao,6 Wei Wang4 1Department of Gastroenterology and Hepatology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China; 2Center of Hepato-Pancreato-Biliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China; 3Clinical Trials Unit, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China; 4Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China; 5Cancer Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China; 6Department of Medical Ultrasonics, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Han Xiao, Department of Medical Ultrasonics, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China, Tel/Fax +86-20-87755766-8576, Email xiaoh69@mail.sysu.edu.cn Wei Wang, Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China, Tel/Fax +86-20-87755766-8576, Email wangw73@mail.sysu.edu.cnPurpose: The T cell-inflamed gene expression profile (GEP) quantifies 18 genes’ expression indicative of a T-cell immune tumor microenvironment, playing a crucial role in the immunotherapy of hepatocellular carcinoma (HCC). Our study aims to develop a radiomics-based machine learning model using contrast-enhanced ultrasound (CEUS) for predicting T cell-inflamed GEP in HCC.Methods: The primary cohort of HCC patients with preoperative CEUS and RNA sequencing data of tumor tissues at the single center was used to construct the model. A total of 5936 radiomics features were extracted from the regions of interest in representative images of each phase, and the least absolute shrinkage and selection operator and logistic regression were used to construct four models including three phase-specific models and an integrated model. The area under the curve (AUC) was calculated to evaluate the performance of the model. The independent cohort of HCC patients with preoperative CEUS and Immunoscore based on immunohistochemistry and digital pathology was used to validate the correlation between model prediction value and T-cell infiltration.Results: There were 268 patients enrolled in the primary cohort and 46 patients enrolled in the independent cohort. Compared with the other three models, the AP model constructed by 36 arterial phase (AP) features showed good performance with a mean AUC of 0.905 in the 5-fold cross-validation and was easier to apply in the clinical setting. The decision curve and calibration curve confirmed the clinical utility of the model. In the independent cohort, patients with high Immunoscores showed significantly higher GEP prediction values than those with low Immunoscores (t=− 2.359, p=0.029).Conclusion: The CEUS-based model is a reliable predictive tool for T cell-inflamed GEP in HCC, and might facilitate individualized immunotherapy decision-making.Keywords: Radiomics, Contrast-enhanced ultrasound, Hepatocellular carcinoma, T cell-inflamed gene expression profile

Qingyuan Huang,1– 3,&ast; Hang Cao,1– 3,&ast; Qianlan Yao,3– 5,&ast; Xiaoyan Zhou,3– 5 Hang Li,1– 3 Qianming Bai,3– 5 Hong Hu1– 3 1Departments of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China; 2Institute of Thoracic Oncology, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China; 4Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China; 5Institute of Pathology, Fudan University, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Hu; Qianming Bai, Email huhong0997@163.com; baiqianming@163.comBackground: NOTCH1 is frequently mutated in non-small cell lung cancer (NSCLC), and also is a poor therapeutic target. It is of clinical importance to investigate the effects of NOTCH1 mutations on anti-tumor immunity and response to immune checkpoint blockade (ICB).Methods: An observational study with targeted sequencing in 963 NSCLC patients at our center were performed (FUSCC cohort). Data of the Cancer Genome Atlas Pan-Lung Cancer study (TCGA cohort) were analyzed, and gene set enrichment analysis (GSEA) was performed. The Samstein et al cohort included 350 patients with advanced NSCLC undergoing genomic profiling with the MSK-IMPACT assay, and receiving at least one dose of ICB therapy.Results: NOTCH1 mutations were more common in smokers and patients with squamous-cell carcinoma (SCC) (all P value < 0.05). For patients who did not receive ICB therapy (TCGA cohort), the overall survival (OS) of NOTCH1-mutant and -WT patients were comparable (log-rank P = 0.72), while for patients who received ICB therapy in the Samstein et al cohort, NOTCH1-mutant patients had significantly superior OS than WT patients (log-rank P = 0.041). On multivariate Cox analysis, the predictive value of NOTCH1 mutations reached marginal statistical significance (HR, 0.42; 95% CI, 0.17– 1.04; P = 0.059). The median of TMB for NOTCH1-mutant tumors was significantly higher than that for NOTCH1-WT tumors, and GSEA revealed that NOTCH1 mutations manifested various defects in the repair of DNA damage. NOTCH1-mutant tumors displayed an inflamed tumor microenvironment (TME), manifesting as increased PD-L1 expression and tumor-infiltrating CD8+ T cells.Conclusion: NOTCH1 mutations define a molecular subtype of NSCLC, which are more common in smokers and patients with SCC, are characterized with higher TMB, inflamed TME, and display improved survival of ICB therapy for NSCLC patients.Keywords: NOTCH1, non-small cell lung cancer, immunotherapy, survival, tumor mutational burden, tumor microenvironment

Guiqiang Qi,1 Guangyue Shi,1 Shengchao Wang,1 Haifeng Hu,2 Zhichen Zhang,1 Qiangqiang Yin,1 Zhongtao Li,1 Liguo Hao1,3 1Department of Molecular Imaging, School of Medical Technology, Qiqihar Medical University, Qiqihar, Heilongjiang, 161006, People’s Republic of China; 2Medical Imaging Center, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, 161000, People’s Republic of China; 3Department of Molecular Imaging, The First Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang, 161041, People’s Republic of ChinaCorrespondence: Liguo Hao, Email haoliguo@qmu.edu.cnIntroduction: This study developed a pancreatic cancer targeted drug delivery system that responds to changes in acidity. The system was based on iron oxide core-shell magnetic mesoporous silica nanoparticles (M-MSNs) to treat pancreatic cancer through combined chemotherapy and starvation therapy.Methods: Glucose oxidase (Gox) was coupled to the cancer cell surface to reduce glucose availability for cancer cells, exacerbating the heterogeneity of the tumor microenvironment. Reduced pH accelerated the depolymerization of pH-sensitive polydopamine (PDA), thereby controlling the spatial distribution of Gox and release of doxorubicin (DOX) within tumor cells.Results: Characterization results showed the successful synthesis of DG@M-MSN-PDA-PEG-FA (DG@NPs) with a diameter of 66.02 ± 3.6 nm. In vitro data indicated DG@NPs were highly effective and stable with good cellular uptake shown by confocal laser scanning microscopy (CLSM). DG@NPs exhibited high cytotoxicity and induced apoptosis. Additionally, in vivo experiments confirmed DG@NPs effectively inhibited tumor growth in nude mice with good biosafety. The combination of starvation therapy and chemotherapy facilitated drug release, suggesting DG@NPs as a novel drug delivery system for pancreatic cancer treatment.Conclusion: This study successfully constructed a doxorubicin release system responsive to acidity changes for targeted delivery in pancreatic cancer, providing a new strategy for combination therapy.Keywords: mesoporous silica nanoparticle, drug delivery, multitherapy modality, magnetic resonance imaging, glucose oxidase

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

Yue Wang,1,2 Jun Li,3 Jianming Wu,3 Shihong Gu,3 Huishu Hu,3 Rongjuan Cai,2 Man Wang,4 Yue Zou3 1Institute of Shanghai Oriental Beauty Valley, Shanghai Institute of Technology, Shanghai, People’s Republic of China; 2School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai, People’s Republic of China; 3R&D Center, JALA (Group) Co., Ltd, Shanghai, People’s Republic of China; 4Department of Nutrition, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus, Shanghai, People’s Republic of ChinaCorrespondence: Yue Zou, R&D Center, JALA (Group) Co., Ltd, Building 2, No. 333, Guiping Road, Xuhui District, Shanghai, 200233, People’s Republic of China, Email zouyue3@jala.com.cnIntroduction: Sensitive scalp is one of the most frequent complaints related to sensitive skin syndrome, characterized by unpleasant sensory reactions in the absence of visible signs of inflammation. In this study, the effects of topical application of postbiotic Himalaya-derived Saccharomyces and Lactobacillus ferment complex (SLFC) on the bacterial and fungal scalp microbiome at the taxonomic level and alleviation of sensitive skin syndrome were investigated.Methods: Firstly, healthy female participants (aged 30– 45) were classified into a healthy scalp group and a sensitive scalp group based on the questionnaire. Thereafter, topical application of SLFC on sensitive scalp as well as scalp microbiome was evaluated, with the difference in the distribution of microbial taxa between healthy and sensitive scalp communities was assessed using 16S rRNA and ITS1 sequencing analysis. In addition, the effect of SLFC on scalp microbiome at the species level for Cutibacterium acnes, Staphylococcus epidermidis, and Malassezia restricta was evaluated by the qPCR assessment.Results: After treatment with SLFC for 28 days, the abundance of Staphylococcus, Lawsonella, and Fusarium in the sensitive scalp group was highly significantly increased (p < 0.001), while the abundance of Cutibacterium and Malassezia was highly significantly decreased (p < 0.001). Furthermore, the self-assessment questionnaire indicated a syndrome alleviation effect of 100% after 28 days with a twice-daily application of the SLFC.Discussion: The obtained results would help to better understand the microbial community of the sensitive scalp and provide useful information on utilization of SLFC for maintaining a healthy scalp and modulating the scalp microbiome.Keywords: sensitive scalp, scalp microbiome, postbiotics, microbial diversity, questionnaire analysis

Honghao Hu,1,2 Yuechao Du,1,2 Zhongming Wang1,2 1School of Management, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China; 2Global Entrepreneurship Research Center, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Yuechao Du, Email ycdu@zju.edu.cnIntroduction: In the aftermath of the COVID-19 pandemic, innovation has become a crucial factor for the success of entrepreneurial ventures in China. However, the mechanisms underlying the promotion of innovation by entrepreneurs are not yet fully understood. Drawing on self-determination theory, this study develops a comprehensive “motivation-behaviors-performance” model to examine the relationship between entrepreneurs’ felt responsibility for constructive change and ventures’ innovation performance.Methods: Two waves of questionnaire surveys with a sample of 376 entrepreneurs in East China were conducted. Hierarchical regression analysis was performed to test the hypotheses.Results: The empirical findings demonstrate that entrepreneurs’ felt responsibility for constructive change is a key driver of innovation performance in ventures. Furthermore, external learning, encompassing technological and market learning, serves as a mediator for the positive link between entrepreneurs’ felt responsibility and innovation performance. The study also reveals that entrepreneurs’ perception of shared vision moderates the relationships between entrepreneurs’ felt responsibility and both technological and market learning, such that the relationships are stronger when the perception of shared vision is higher.Discussion: These results yield important contributions to the entrepreneurial psychology research and self-determination theory. The study also has managerial implications for entrepreneurs aiming to enhance ventures’ innovation performance.Keywords: entrepreneur, felt responsibility for constructive change, innovation performance, technological learning, market learning, shared vision

Xinnan Xu,1 Yu Zheng,1,2 Minjian Jiang,1,2 Hantong Hu,1,2 Xiaofen He,1,2 Jianqiao Fang,1,2 Yongliang Jiang1,2 1The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province, 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, Zhejiang Province, People’s Republic of ChinaCorrespondence: Jianqiao Fang; Yongliang Jiang, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang Province, People’s Republic of China, Email fangjianqiao7532@163.com; jyl2182@126.comObjective: Currently, acupuncture for shoulder pain has been widely used in clinical and scientific research worldwide, but the bibliometric literature on acupuncture for shoulder pain is still scarce. This study reviews the application of acupuncture in the treatment of shoulder pain over the past 15 years, to analyze the current state of research, research hotspots, and trends. The article can also provide a reference for future research.Methods: This paper searches the core collection of the Web of Science database for publications related to acupuncture therapy for shoulder pain between 2008 and 2022. And the data were visualized and analyzed using VOSviewer and CiteSpace for annual publications, countries, institutions, journals and co-cited journals, authors and co-cited authors, keywords, and emergent keywords.Results: A total of 135 papers were included, with an overall increasing trend in the number of annual publications. The country with the highest centrality in publishing articles is the United States (0.28). In terms of research institutions, Kyung Hee University has the highest number of publications (18). In terms of authors, Lewith George, Lind Klaus, MacPherson Hugh, Sherman Karen J, and Vickers Andrew J are the five most published authors. Vickers, Andrew J. is the most co-cited author (50 times). In terms of journals, PAIN has the highest number of publications (82) and co-cited frequency (232), while the highest impact factor was BMJ-BRIT MED J (96.216). “Acupuncture” was the most frequently mentioned keyword (65 times), with the keyword “protocol” appearing the most recently. Emerging keywords that are still in vogue are “stroke”, “systematic review” and “stimulation”.Conclusion: This study provides statistics on current research on the treatment of shoulder pain with acupuncture, which may be able to inform future research directions for all researchers and physicians, as well as facilitate closer communication and collaboration.Keywords: shoulder pain, acupuncture, bibliometric analysis, VOSviewer, CiteSpace

Xiaodie Mu, Aihua Wu, Huiyue Hu, Hua Zhou,&ast; Min Yang&ast; Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hua Zhou; Min Yang, Department of Nephrology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, People’s Republic of China, Tel +86 0519 68872082, Email zhouhua2323@suda.edu.cn; yangmin1516@suda.edu.cnBackground: Diabetic kidney disease (DKD), a common microvascular complication of diabetes mellitus (DM), is always asymptomatic until it develops to the advanced stage. Thus, we aim to develop a nomogram prediction model for progression to DKD in newly diagnosed type 2 diabetes mellitus (T2DM).Methods: This was a single-center analysis of prospective data collected from 521 newly diagnosed patients with T2DM. All related clinical records were incorporated, including the triglyceride-glucose index (TyG index). The least absolute shrinkage and selection operator (LASSO) was used to build a prediction model. In addition, discrimination, calibration, and clinical practicality of the nomogram were evaluated.Results: In this study, 156 participants were incorporated as the validation set, while the remaining 365 were incorporated into the training set. The predictive factors included in the individualized nomogram prediction model included 5 variables. The area under the curve (AUC) for the prediction model was 0.826 (95% CI 0.775 to 0.876), indicating excellent discrimination performance. The model performed exceptionally well in terms of predictive accuracy and clinical applicability, according to calibration curves and decision curve analysis.Conclusion: The predictive nomogram for the risk of DKD in newly diagnosed T2DM patients had outstanding discrimination and calibration, which could help in clinical practice.Keywords: diabetic kidney disease, type 2 diabetes mellitus, nomogram, prediction model, risk assessment

Hazrat Bilal,1 Dongxing Zhang,2,3 Muhammad Shafiq,4 Muhammad Nadeem Khan,5 Canhua Chen,6 Sabir Khan,1 Qian Wang,1,7 Lin Cai,1 Muhammad Awais,8 Haibin Hu,9 Yuebin Zeng1,10 1Department of Dermatology, Second Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of China; 2Department of Dermatology, Meizhou Dongshan Hospital, Meizhou, Guangdong Province, 514023, People’s Republic of China; 3Department of Dermatology, Meizhou People’s Hospital, Meizhou, Guangdong Province, 514023, People’s Republic of China; 4Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, People’s Republic of China; 5Faculty of Biological Sciences, Department of Microbiology, Quaid-I-Azam University, Islamabad, 45320, Pakistan; 6Clinical Laboratory, Meizhou People’s Hospital, Meizhou, Guangdong Province, 514023, People’s Republic of China; 7Department of Medical-Surgical and Experimental Sciences University of Sassari Neurology Unit, Azienda Ospedaliera Universitaria (AOU), Sassari, Italy; 8Department of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China; 9The First Clinical Medical college, Guangdong Medical University, Zhanjiang, 523808, People’s Republic of China; 10Department of Dermatology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610021, People’s Republic of ChinaCorrespondence: Yuebin Zeng, Tel +8618607549813, Email zeng_yb@163.comObjective: Cryptococcosis is a fatal infection that can affect both immunocompetent and immunocompromised patients, and it is little understood in China’s various regions. This research aimed to look at the epidemiology, risk factors, and antifungal susceptibility pattern of Cryptococcus neoformans in eastern Guangdong, China.Methods: A six-year (2016– 2022) retrospective study was conducted at Meizhou People’s Hospital, China. Demographical, clinical, and laboratory data of cryptococcal patients were collected from hospital records and statistically analyzed using the chi-square and ANOVA tests.Results: Overall, 170 cryptococcal infections were recorded, of which meningitis accounted for 78 (45.88%), cryptococcemia for 50 (29.41%), and pneumonia for 42 (24.7%). The number of cases increased 8-fold during the study duration. The median age of patients was 58 years (Inter quartile range: 47– 66), and the high proportion of cases was from the male population (n = 121, 71.17%). The underlying diseases were identified only in 60 (35.29%) patients, of which 26 (15.29%) were severely immunocompromised, and 26 (15.29%) others were mildly immunocompromised. A statistically significant difference was reported for chronic renal failure, and anemia (p < 0.05) persisted in cases of three infection types. A high number of non-wild type (NWT) isolates were found against amphotericin B (n=13/145, 8.96%), followed by itraconazole (n=7/136, 5.15%) and voriconazole (n=4/158, 2.53%). Only six isolates (3.79%) were multidrug-resistant, four of which were from cryptococcemia patients. Compared to meningitis and pneumonia, cryptococcemia revealed a higher percentage of NWT isolates (p < 0.05).Conclusion: In high-risk populations, cryptococcal infections require ongoing monitoring and management.Keywords: cryptococcosis, Cryptococcus neoformans, epidemiology, risk factors, antifungal susceptibility

Zhigang Liu,1,&ast; Jiahui Liang,1,&ast; Hangzhan Hu,1,&ast; Mengli Wu,1,&ast; Jingjing Ma,1 Ziwei Ma,1 Jianing Ji,1 Hengyi Chen,2 Xiaoquan Li,1 Zhizeng Wang,1,2 Yang Luo2,3 1Joint National Laboratory for Antibody Drug Engineering, Clinical Laboratory of the First Affiliated Hospital, School of Medicine, Henan University, Kaifeng, 475004, People’s Republic of China; 2Center of Smart Laboratory and Molecular Medicine, Jiangjin Hospital, School of Medicine, Chongqing University, Chongqing, 400044, People’s Republic of China; 3College of Life Science and Laboratory Medicine, Kunming Medical University, Kunming, 650500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhizeng Wang, Joint National Laboratory for Antibody Drug Engineering, Clinical Laboratory of the First Affiliated Hospital, School of Medicine, Henan University, Kaifeng, 475004, People’s Republic of China, Tel +86 15093628687, Email wzhzeng@126.com Yang Luo, Center of Smart Laboratory and Molecular Medicine, Jiangjin Hospital, School of Medicine, Chongqing University, Chongqing, 400044, People’s Republic of China, Tel +86 13594088001, Email luoy@cqu.edu.cnIntroduction: Neutralizing antibodies (NAbs) are essential for preventing reinfection with SARS-CoV-2 and the recurrence of COVID-19; nonetheless, the formation of NAbs following vaccination and infection remains enigmatic due to the lack of a practical and effective NAb assay in routine laboratory settings. In this study, we developed a convenient lateral flow assay for the rapid and precise measurement of serum NAb levels within 20 minutes.Methods: Receptor-binding domain-fragment crystallizable (RBD-Fc) and angiotensin-converting enzyme 2-histidine tag (ACE2-His) were expressed by the eukaryotic expression systems of Spodoptera frugiperda clone 9 and human embryonic kidney 293T, respectively. Then, colloidal gold was synthesized and conjugated with ACE2. After optimizing various operating parameters, an NAb lateral flow assay was constructed. Subsequently, its detection limit, specificity, and stability were systematically evaluated, and clinical samples were analyzed to validate its clinical feasibility.Results: RBD-Fc and ACE2-His were obtained with 94.01% and 90.05% purity, respectively. The synthesized colloidal gold had a uniform distribution with an average diameter of 24.15 ± 2.56 nm. With a detection limit of 2 μg/mL, the proposed assay demonstrated a sensitivity of 97.80% and a specificity of 100% in 684 uninfected clinical samples. By evaluating 356 specimens from infected individuals, we observed that the overall concordance rate between the proposed assay and conventional enzyme-linked immunosorbent assay was 95.22%, and we noticed that 16.57% (59/356) of individuals still did not produce NAbs after infection (both by ELISA and the proposed assay). All the above tests by this assay can obtain results within 20 minutes by the naked eye without any additional instruments or equipment.Conclusion: The proposed assay can expediently and reliably detect anti-SARS-CoV-2 NAbs after infection, and the results provide valuable data to facilitate effective prevention and control of SARS-CoV-2.Clinical trial registration: Serum and blood samples were used under approval from the Biomedical Research Ethics Subcommittee of Henan University, and the clinical trial registration number was HUSOM-2022-052. We confirm that this study complies with the Declaration of Helsinki.Keywords: clinical detection, colloidal gold, neutralizing antibody, point-of-care test, SARS-CoV-2

Liping Yang,1,&ast; Xingling Li,1,&ast; Lianqiang Fang,1 Lei Wu,1,2 Hantong Hu,1,2 YingYing Cheng1 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&ast;These authors contributed equally to this workCorrespondence: YingYing Cheng; Hantong Hu, 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 cyysince@163.com; 413351308@qq.comBackground: Acupuncture is considered as a potential treatment option for primary tinnitus, as there is a lack of conventional therapies with well-established efficacy. However, there are limited studies that compare the effectiveness of different acupuncture therapies. Thus, this systematic review and network meta-analysis protocol aims to compare the efficacy of various acupuncture-related therapies for primary tinnitus, and determine the optimal treatment.Methods: A comprehensive search of 10 representative databases will be conducted to identify eligible randomized controlled trials (RCTs) regarding multiple acupuncture-related therapies for primary tinnitus. Two independent researchers will extract data individually, and the methodological quality of each RCT will be assessed using Cochrane’s risk of bias 2.0 tool. Standard pairwise meta-analysis and Bayesian network meta-analysis will be conducted, and WinBUGS V.1.4.3 and R 3.6.2 software will be adopted to synthesize network data and generate relevant graphs. Subgroup analyses, sensitivity analyses, and assessment of publication bias will be conducted as appropriate.Discussion: This study’s results are anticipated to identify the optimal acupuncture technique for treating primary tinnitus, thereby providing evidence-based clinical decisions for patients and clinicians to select the most effective acupuncture treatment.Prospero Registration Number: CRD42023399621.Keywords: acupuncture, moxibustion, tinnitus, meta-analysis, protocol

Paihe Deng, Huimin Hu Clinical Laboratory Medicine Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210011, People’s Republic of ChinaCorrespondence: Huimin Hu, Clinical Laboratory Medicine Center, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiangjiayuan Road, Nanjing, Jiangsu, 210011, People’s Republic of China, Tel +86 1385 1616 797, Email hhm13851616797@163.comObjective: Endothelial cell pyroptosis induced by hypoxia/reoxygenation (H/R) plays a key role in the pathogenesis of myocardial infarction (MI). However, the underlying mechanism is not clearly elucidated.Methods: Human umbilical vein endothelial cells (HUVECs) exposed to H/R acted as in vitro model to investigate the mechanism of H/R-induced endothelial cell pyroptosis. CCK-8 assays were performed to investigate the viability of HUVECs. Calcein-AM/PI staining was carried out to quantify the death of HUVECs. The expression level of miR-22 was measured by RT-qPCR. The protein expression levels of zeste 2 polycomb repressive complex 2 subunit (EZH2), NLRP3, cleaved caspase-1 (c-caspase-1), GSDMD-N and heat shock protein 90 (HSP90) were measured by Western blot. Levels of IL-1β and IL-18 in culture medium were detected by ELISA. The intracellular localization of EZH2 was detected by immunofluorescence staining. Chromatin immunoprecipitation (ChIP) assay was used to detect the enrichment of EZH2 and H3K27me3 in the miR-22 promoter region. The binding between miR-22 and NLRP3 in HUVECs was confirmed by the dual luciferase assay. Reciprocal coimmunoprecipitation was conducted to detect the direct interaction between HSP90 and EZH2.Results: H/R increased EZH2 expression, and the EZH2 siRNA could inhibit H/R-induced pyroptosis in HUVECs. H/R reduced miR-22 expression, which was reversed by EZH2 siRNA. Silencing of miR-22 by its inhibitor reversed EZH2 siRNA-induced pyroptosis inhibition in H/R-exposed HUVECs. Upregulation of miR-22 by its mimic suppressed EZH2 overexpression-enhanced pyroptosis in H/R-exposed HUVECs. ChIP assay confirmed that EZH2 bound to the miR-22 promoter region and repressed miR-22 expression through H3K27me3. Furthermore, luciferase reporter assay indicated that NLRP3 was a direct target of miR- 22 in HUVECs. Finally, HSP90 siRNA inhibited H/R-induced EZH2 expression, miR-22 downregulation, and pyroptosis in HUVECs.Conclusion: H/R induces pyroptosis via the HSP90/EZH2/miR-22/NLRP3 signaling axis in endothelial cells.Keywords: HSP90, EZH2, miR-22, pyroptosis, endothelial cells

Xin Zhao,1,2,&ast; Yue Ge,1,3,&ast; Yuan Zhang,1 WenJie Zhang,1 HongBin Hu,1 LuLan Li,1 Tong Sha,1 ZhenHua Zeng,1 Feng Wu,1 ZhongQing Chen1 1Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2The First Clinical Medical School, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of School of Nursing, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: ZhongQing Chen; Feng Wu, Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China, Tel +86 13503049103 ; +86 15915751705, Email zhongqingchen2008@163.com; wishuhappy@126.comBackground: Next-generation sequencing of the metagenome (mNGS) is increasingly used in pathogen diagnosis for infectious diseases due to its short detection time. The time for Oxford Nanopore Technologies (ONT) sequencing-based etiology detection is further shortened compared with that of mNGS, but only a few studies have verified the time advantage and accuracy of ONT sequencing for etiology diagnosis. In 2022, a study confirmed that there was no significant difference in sensitivity and specificity between ONT and mNGS in suspected community-acquired pneumonia patients, which there was no clinical study verified in patients with SHAP.Methods: From October 24 to November 20, 2022, 10 patients with severe hospital-acquired pneumonia (SHAP) in the Nanfang Hospital intensive care unit (ICU) were prospectively enrolled. Bronchoalveolar lavage fluid (BALF) was collected for ONT sequencing, mNGS, and traditional culture. The differences in pathogen detection time and diagnostic agreement among ONT sequencing, mNGS, traditional culture method, and clinical composite diagnosis were compared.Results: Compared with mNGS and the traditional culture method, ONT sequencing had a significant advantage in pathogen detection time (9.6± 0.7 h versus 24.7± 2.7 h versus 132± 58 h, P < 0.05). The agreement rate between ONT sequencing and the clinical composite diagnosis was 73.3% (kappa value=0.737, P < 0.05).Conclusion: ONT sequencing has a potential advantage for rapidly identifying pathogens.Keywords: Oxford Nanopore Technologies, Nanopore sequencing, metagenomic next-generation sequencing, severe hospital-acquired pneumonia, pathogen

Yanxu Li,1 Hao Zou,2,&ast; Zekun Zheng,2 Zhuoheng Liu,2,&ast; Huiyuan Hu,2,&ast; Wei Wu,3 Tao Wang4 1Medical College of Yangzhou University, Yangzhou University, Yangzhou City, Jiangsu Province, People’s Republic of China; 2Dalian Medical University, Affiliated Hospital of Yangzhou University, Yangzhou City, Jiangsu Province, People’s Republic of China; 3Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou City, Jiangsu Province, People’s Republic of China; 4College of Veterinary Medicine, Yangzhou University, Yangzhou City, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Wu; Tao Wang, Tel/Fax +86-0514-87991201 ; +86-187 5255 5147, Email 306834397@qq.com; wtao6550@yzu.edu.cnAbstract: Primary hepatocellular carcinoma (HCC, hepatocellular carcinoma) is the third leading cause of tumor death in the world and the second leading cause in China. The high recurrence rate at 5 years after surgery also seriously affects the long-term survival of HCC patients. For reasons such as poor liver function, large tumors, or vascular invasion, only relatively limited palliative treatment is available. Therefore, effective diagnostic and therapeutic strategies are needed to improve the complex microenvironment and block the mechanism of tumor development in order to treat the tumor and prevent recurrence. A variety of bioactive nanoparticles have been shown to have therapeutic effects on hepatocellular carcinoma and have the advantages of improving drug solubility, reducing drug side effects, preventing degradation in the blood, increasing drug exposure time, and reducing drug resistance. The development of bioactive nanoparticles is expected to complete the current clinical therapeutic approach. In this review, we discuss the therapeutic advances of different nanoparticles for hepatocellular carcinoma and discuss their potential for postoperative applications with respect to possible mechanisms of hepatocellular carcinoma recurrence. We further discuss the limitations regarding the application of NPs and the safety of NPs.Keywords: HCC, NPs, treatment

Chao Cao,1– 4 Obulkasim Memet,1– 3 Fuli Liu,1,2 Hanbing Hu,1– 3 Lin Zhang,1,2 Heng Jin,4 Yiqun Cao,4 Jian Zhou,3,5,6 Jie Shen1– 3 1Center of Emergency and Critical Medicine, Jinshan Hospital of Fudan University, Shanghai, People’s Republic of China; 2Research Center for Chemical Injury, Emergency and Critical Medicine of Fudan University, Shanghai, People’s Republic of China; 3Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 4Emergency Department, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 5Department of Pulmonary and Critical Care Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital of Fudan University, Shanghai, People’s Republic of China; 6Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Jie Shen, Center of Emergency and Critical Medicine, Jinshan Hospital of Fudan University, Shanghai, 201508, People’s Republic of China, Tel +86 2134189990, Email jshen_@fudan.edu.cnPurpose: Chemically induced acute lung injury (CALI) has become a serious health concern in our industrialized world, and abnormal functional alterations of immune cells crucially contribute to severe clinical symptoms. However, the cell heterogeneity and functional phenotypes of respiratory immune characteristics related to CALI remain unclear.Methods: We performed scRNA sequencing on bronchoalveolar lavage fluid (BALF) samples obtained from phosgene-induced CALI rat models and healthy controls. Transcriptional data and TotalSeq technology were used to confirm cell surface markers identifying immune cells in BALF. The landscape of immune cells could elucidate the metabolic remodeling mechanism involved in the progression of acute respiratory distress syndrome and cytokine storms. We used pseudotime inference to build macrophage trajectories and the corresponding model gene expression changes, and identified and characterized alveolar cells and immune subsets that may contribute to CALI pathophysiology based on gene expression profiles at single-cell resolution.Results: The immune environment of cells, including dendritic cells and specific macrophage subclusters, exhibited increased function during the early stage of pulmonary tissue damage. Nine different subpopulations were identified that perform multiple functional roles, including immune responses, pulmonary tissue repair, cellular metabolic cycle, and cholesterol metabolism. Additionally, we found that individual macrophage subpopulations dominate the cell-cell communication landscape. Moreover, pseudo-time trajectory analysis suggested that proliferating macrophage clusters exerted multiple functional roles.Conclusion: Our findings demonstrate that the bronchoalveolar immune microenvironment is a fundamental aspect of the immune response dynamics involved in the pathogenesis and recovery of CALI.Graphical Abstract: Keywords: single cell RNAseq, phosgene-inhalation, chemically induced acute lung injury, immune microenvironment, heterogeneity, phenotypes

Mingqi Tu,1,&ast; Sangsang Xiong,1,&ast; Shengxia Lv,2,&ast; Xiaoting Wu,1 Hantong Hu,3 Renjie Hu,4 Jianqiao Fang,1 Xiaomei Shao1 1Key Laboratory for Research ofAcupuncture Treatment and Transformation of Emotional Diseases, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2The School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 4The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaomei Shao, Key Laboratory for Research of Acupuncture Treatment and Transformation of Emotional Diseases, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Clinical Medical College, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang Province, People’s Republic of China, Tel +86 189 5713 0287, Email 13185097375@163.comIntroduction: Acupuncture has a long history of treating major depressive disorder (MDD), yet the acupoint selection of acupuncture for MDD varies greatly. This study aimed to explore the characteristics and principles of acupuncture for MDD by analyzing clinical trials of acupuncture for MDD using data mining techniques.Methods: In this study, clinical trials of acupuncture for MDD were retrieved and relevant data were extracted, and then the data were analyzed by data mining techniques. In addition, association rule mining, network analysis and hierarchical cluster analysis were used to determine the correlation between different acupoints.Results: The results revealed that GV20, LR3, PC6, SP6 and GV29 were used most frequently; acupoints in the Yang meridian were used more often than those in the Yin meridian, with the most applied acupoints in the Governor Vessel; the percentage of specific acupoints applied was 69.39%, with the most applied being five-shu points; the frequency of acupoints used was highest in the lower limbs, while the head, face, and neck had the most acupoints used; GV29 combined with GV20 were the most used acupoint groups; the core acupoints used for MDD were GV20, PC6 and SP36; there were 5 acupoint groups according to the cluster analysis. The most used acupuncture method was manual acupuncture; the frequency of treatment was mostly 7 times per week and the duration of treatment was mostly 42 days.Discussion: We discussed the current character of acupuncture treatment on MDD, including the frequency used of acupoints, the property of used acupoints, the acupoint combination, the acupuncture method, and the frequency and duration of treatment. These findings may provide new ideas for the clinical treatment of MDD. However, further clinical/experimental studies are needed to demonstrate the significance of this concept and approach.Keywords: acupuncture treatment, data mining technology, association rule mining, network analysis, cluster analysis

Hantong Hu,1,2,&ast; Yingying Cheng,1,&ast; Lei Wu,1 Dexiong Han,1,2 Ruijie Ma1,2 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, Hangzhou City, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruijie Ma; Dexiong Han, Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou City, People’s Republic of China, Email maria7878@sina.com; han_0213@163.comIntroduction: Herpes zoster (HZ) can adversely influence patients’ quality of life and sometimes it can develop postherpetic neuralgia (PHN). To date, it remains challenging to be managed by currently available therapies. Intradermal acupuncture (IDA) has the potential to be an adjunctive therapy for acute HZ and infrared thermography (IRT) may be useful for predicting PHN; however, current evidence remains inconclusive. Therefore, the purposes of this trial are to 1) evaluate the efficacy and safety of IDA as an adjunctive therapy for acute HZ; 2) to explore the feasibility of IRT for early prediction of PHN and as an objective tool to aid in subjective pain assessment in acute HZ.Methods: This study is designed as a randomized, parallel-group, sham-controlled, and patient-assessor-blinded trial, including 1-month treatment and 3-month follow-ups. Seventy-two qualified participants will be randomly split into the IDA or sham IDA group in a ratio of 1:1. Apart from standard pharmacological treatments in both groups, the two groups will receive 10 sessions of IDA or sham IDA, respectively. Primary outcome measures are the visual analog scale (VAS), indicators of herpes lesions’ recovery, the temperature of the pain area, and the incidence rate of PHN. The secondary outcome is the 36-item Short Form Health Survey (SF-36). Indicators of herpes lesions’ recovery will be assessed at each visit and follow-ups. The remaining outcomes will be assessed at baseline, 1 month after intervention, and 3-month follow-up. Safety evaluation will be determined by adverse events during the trial.Conclusion: Expected results will determine whether IDA can enhance therapeutic effectiveness of pharmacotherapy for acute HZ with acceptable safety profile. In addition, it will verify the accuracy of IRT for early prediction of PHN and as an objective tool of subjective pain for acute HZ.Trial Registration: Clinicaltrials.gov (identification number: NCT05348382; Registered 27 April 2022, https://clinicaltrials.gov/ct2/show/NCT05348382).Keywords: acupuncture, herpes zoster, postherpetic neuralgia, infrared thermography, clinical trial

Yongjun Tan,1 Li Zhou,1 Jiagui Huang,1 Xia Chen,1 Youlin Wu,1 Xiaosong Song,1 Jiani Wang,1 Hua Hu,2 Qin Yang1 1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Qin Yang, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-23-89012008, Fax +86-23-68811487, Email xyqh200@126.com Hua Hu, Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-23-89012008, Fax +86-23-68811487, Email huhuateam@126.comPurpose: To evaluate the prevalence of abnormal vitamin B12, folate, total homocysteine (tHcy), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) levels, to analyze the relationship between these parameters and the severity of anxiety or depressive symptoms, and to explore the possible factors associated with abnormal levels of these parameters in adolescents with anxiety or depressive symptoms.Methods: Adolescent (aged 12– 18 years) outpatients with anxiety or depressive symptoms were recruited. The patient health questionnaire-9 and generalized anxiety disorder scale-7 were used to measure the severity of depression and anxiety. Serum vitamin B12, folate, tHcy, IL-6, TNF-α, and CRP levels were determined.Results: 128 subjects were recruited. The prevalence of vitamin B12 and folate deficiency, tHcy, TNF-α, IL-6, and CRP elevation was 8.6%, 10.2%, 25.8%, 14.8%, 21.9%, and 10.2%, respectively, in adolescents with anxiety or depressive symptoms. Lower vitamin B12 levels were correlated with a higher risk of severe anxiety and depressive symptoms. The severity of some symptoms of anxiety or depression were weakly correlated with vitamin B12, folate, tHcy, IL-6, and CRP levels. Vitamin B12, folate, and tHcy levels were not associated with inflammatory mediators. Vitamin B12 deficiency was associated with older age and higher tHcy levels. Folate deficiency was associated with elevated tHcy. Elevated tHcy was associated with lower vitamin B12 and folate levels. IL-6 elevation was associated with elevated CRP and TNF-α. CRP elevation was associated with older age, higher BMI, and current drinking.Conclusion: Lower vitamin B12 levels were correlated with a higher risk of severe anxiety or depressive symptoms. Weak correlations were observed between the severity of some symptoms of anxiety or depression and vitamin B12, folate, tHcy, IL-6, and CRP levels. Vitamin B12, folate, and tHcy levels were related to each other. IL-6 elevation was associated with elevated CRP and TNF-α. CRP elevation was associated with older age, higher BMI, and current drinking.Keywords: vitamin B12, adolescents, inflammatory mediators, depression, anxiety

Xudong Dong,1,2,&ast; Ailing Ding,2,&ast; Hong Hu,1 Fanping Xu,1 Lingyan Liu,1 Min Wu1,3 1The Obstetrical Department of the First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, People’s Republic of China; 2Faculty of Life Science and Technology, Kunming University of Science & Technology, Kunming, 650500, People’s Republic of China; 3Yunnan Provincial Key Laboratory of Carbon Sequestration and Pollution Control in Soils, Faculty of Environmental Science & Engineering, Kunming University of Science & Technology, Kunming, 650500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Wu, Email minwupp@163.comPurpose: As two of the most severe and common medical disorders during pregnancy, gestational diabetes mellitus (GDM) and hypertensive disorder complicating pregnancy (HDCP) cause adverse effects on placental barrier function and thus may lead to a high risk of intrauterine exposure to toxic metals from mother to fetus. This study investigates the impact of the placental barrier on the transfer of cadmium (Cd) from mother to fetus and the relationship between pregnancy complications.Methods: A total of 107 pairs of samples were collected in Kunming, China; 29 were from healthy pregnant women, and 78 were from patients with pregnancy complications. Cd was measured in each mother’s placenta and maternal and umbilical cord blood. The expressions of MT and Cd-MT complex in blood and placental tissue samples were determined by enzyme-linked immunosorbent assay (ELISA).Results: The cesarean section rate in the whole pathological group (60.7%) was higher than that in the normal group (20.7%), and the ratio of the effective barrier (ratio of maternal blood to umbilical cord blood> 1) in the pathological group (74%) was lower than that in the normal group (79%). In addition, the proportion of practical placental barriers in women aged 20– 25 years was 83.3%, 76.3% in women aged 26– 30 years, 74.3% in women aged 31– 35 years, 70% in women aged 36– 40 years, and 71% in women aged 40– 45 years. The Cd content in the placenta of the three pathological groups was significantly higher than that in maternal and umbilical cord blood (P< 0.05), and the distribution of Cd was the same as that in the normal group. However, there was no significant difference between maternal and umbilical cord blood Cd concentrations in the pathological group. The Cd concentration in the normal group’s maternal blood was significantly higher than that in cord blood (P< 0.05). In addition, the expression levels of both metallothionein (MT) and Cd-MT complex in placenta is much higher than in maternal and umbilical blood, and which in normal group are significantly higher than those in pathological group.Conclusion: Both mothers and fetuses are at increased health risk for pregnancy disorders when maternal age, BMI, or body weight increases. Increased maternal age increases the likelihood of Cd transfer from the mother to the fetus. Pregnancy complications may induce lower expression of MT, thus reducing the Cd-MT complex in the placenta, weakening the placental barrier, and increasing the risk of Cd transfer and exposure to the fetus.Keywords: gestational diabetes mellitus, gestational hypertension, maternal blood, placenta barrier, pregnancy complication

Dezhi Yang,1,&ast; Jing Lan,2,&ast; Ji Cen,3,&ast; Yong Han,4– 6 Haofei Hu6– 8 1Department of Cardiology Second Ward, Hechi People’s Hospital, Hechi, People’s Republic of China; 2Department of Gastroenterology, Hechi People’s Hospital, Hechi, People’s Republic of China; 3Department of Nephrology, Hechi People’s Hospital, Hechi, People’s Republic of China; 4Department of Emergency, Shenzhen Second People’s Hospital, Shenzhen, People’s Republic of China; 5Department of Emergency, The First Affiliated Hospital of Shenzhen University, Shenzhen, People’s Republic of China; 6Shenzhen University Health Science Center, Shenzhen University, Shenzhen, People’s Republic of China; 7Department of Nephrology, Shenzhen Second People’s Hospital, Shenzhen, People’s Republic of China; 8Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yong Han, Department of Emergency, Shenzhen Second People’s Hospital, No. 3002 Sungang Road, Futian District, Shenzhen, Guangdong Province, People’s Republic of China, Tel +86-755-83366388, Email hanyong511023@163.com Haofei Hu, Department of Nephrology, Shenzhen Second People’s Hospital, No. 3002 Sungang Road, Futian District, Shenzhen, Guangdong Province, People’s Republic of China, Tel +86-755-83366388, Email huhaofei0319@126.comBackground: Quantification of the relationship between hypertension and non-alcoholic fatty liver disease (NAFLD) risk is limited and controversial. This study aimed to investigate the relationship between hypertension and NAFLD in non-obese Chinese and to use different methods to demonstrate that hypertension is an independent risk factor for NAFLD.Methods: On 16,153 nonobese individuals, a retrospective cohort study was conducted in China to examine the impact of hypertension on incident NAFLD. We compared five methods: multivariable Cox proportional-hazards regression, propensity score-matched (PSM) analysis, propensity score adjustment method (considering the propensity score as a covariate in a multivariable Cox proportional-hazard regression), and two propensity score-based weighted methods-The first one estimated the hypertension effect in the overall study population-inverse probability of treatment weights (IPTW), the other in the hypertensive population-standardized mortality ratio (SMR) weights. We also used a genetic matching (GenMatch) algorithm to match the participants for sensitive analysis.Results: Between 2010 and 2014, 16,153 participants met our inclusion criteria, including 2427 (15.03%) with hypertension. A total of 2321 (14.37%) participants developed NAFLD during the median follow-up of 2.98 years. The crude hazard ratio (HR) between hypertension and incident NAFLD was 2.05 (95% confidence interval (CI): 1.87, 2.25). The adjusted HR depended on the different methods, ranging from 1.09 (95% CI: 0.77, 1.23) for the PSM method to 2.24 (95% CI: 2.05, 2.44) for the SMR weighted analysis. Hypertensive participants with high propensity scores had a higher risk of developing NAFLD in the future. Excluding participants with propensity scores < 8% yielded comparable hazard ratios with a narrower range, from 1.04 to 1.80. After adjusting for the confounding variables, the relationship also existed in the GenMatch cohort as a sensitivity analysis (HR=1.06, 95% CI 1.01– 1.13).Conclusion: Hypertension is a significant cause of NAFLD in Chinese adults in non-obese Chinese adults, with the hazard ratio ranging from 1.09 to 2.24.Keywords: hypertension, non-alcoholic fatty liver disease, propensity-score matching, standardized-mortality-ratio weights, inverse probability of treatment weights

Yuying Lu,1– 5 Qianlin Li,1– 5 Huahao Fan,6 Conghui Liao,1– 5 Jingsong Zhang,1– 5 Huan Hu,1– 5 Huaimin Yi,1– 5 Yuanli Peng,1– 5 Jiahai Lu,1– 5 Zeliang Chen1– 3,7 1One Health Center of Excellence for Research and Training, School of Public Health, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2National Medical Products Administration Key Laboratory for Quality Monitoring and Evaluation of Vaccines and Biological Products, Guangzhou, People’s Republic of China; 3Key Laboratory of Tropical Diseases Control, Sun Yat-Sen University, Ministry of Education, Guangzhou, People’s Republic of China; 4Research Institute of Sun Yat-Sen University in Shenzhen, Shenzhen, People’s Republic of China; 5Hainan Key Novel Thinktank “Hainan Medical University ‘One Health’ Research Center”, Haikou, People’s Republic of China; 6College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, People’s Republic of China; 7Key Laboratory of Zoonose Prevention and Control at Universities of Inner Mongolia Autonomous Region, Medical College, Inner Mongolia Minzu University, Tongliao, People’s Republic of ChinaCorrespondence: Jiahai Lu; Zeliang Chen, One Health Center of Excellence for Research and Training, School of Public Health, Sun Yat-Sen University, Guangzhou, People’s Republic of China, Email lujiahai@mail.sysu.edu.cn; chenzliang5@mail.sysu.edu.cnBackground: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants have risen to dominance, which contains far more mutations in the spike protein in comparison to previously reported variants, compromising the efficacy of most existing vaccines or therapeutic monoclonal antibodies. Nanobody screened from high-throughput naïve libraries is a potential candidate for developing preventive and therapeutic antibodies.Methods: Four nanobodies specific to the SARS-CoV-2 wild-type receptor-binding domain (RBD) were screened from a naïve phage display library. Their affinity and neutralizing activity were evaluated by surface plasmon resonance assays, surrogate virus neutralization tests, and pseudovirus neutralization assays. Preliminary identification of the binding epitopes of nanobodies by peptide-based ELISA and competition assay. Then four multivalent nanobodies were engineered by attaching the monovalent nanobodies to an antibody-binding nanoplatform constructed based on the lumazine synthase protein cage nanoparticles isolated from the Aquifex aeolicus (AaLS). Finally, the differences in potency between the monovalent and multivalent nanobodies were compared using the same methods.Results: Three of the four specific nanobodies could maintain substantial inhibitory activity against the Omicron (B.1.1.529), of them, B-B2 had the best neutralizing activity against the Omicron (B.1.1.529) pseudovirus (IC50 = 1.658 μg/mL). The antiviral ability of multivalent nanobody LS-B-B2 was improved in the Omicron (B.1.1.529) pseudovirus assays (IC50 = 0.653 μg/mL). The results of peptide-based ELISA indicated that LS-B-B2 might react with the linear epitopes in the SARS-CoV-2 RBD conserved regions, which would clarify the mechanisms for the maintenance of potent neutralization of Omicron (B.1.1.529) preliminary.Conclusion: Our study indicated that the AaLS could be used as an antibody-binding nanoplatform to present nanobodies on its surface and improve the potency of nanobodies. The multivalent nanobody LS-B-B2 may serve as a potential agent for the neutralization of SARS-CoV-2 variants.Keywords: COVID-19, bio-nanotechnology, self-assembly, nanobody multimers, thermal stability

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

Kui Wu,&ast; Hui-Hui Ke,&ast; Wei Gong, Hua Hu, Li Chen Department of Obstetrics and Gynecology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Chen; Hua Hu, Department of Obstetrics and Gynecology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai, 201399, People’s Republic of China, Tel +86 21 5802 2995, Email chenli8369@163.com; Huhua20212022@163.comAim: To assess the impact of maternal pre-pregnancy body mass index (BMI) on gestational diabetes mellitus (GDM) based on different pre-pregnancy hemoglobin levels.Methods: This retrospective cohort study included 1289 pregnant women between June 2020 and January 2022. Clinical data were collected by reviewing their medical and antepartum screening records between 24 and 28 gestational weeks, including pre-pregnancy BMI and pre-pregnancy hemoglobin (Hb) levels. The diagnosis of GDM mainly depended on oral glucose tolerance test (OGTT) during 24– 28 weeks. Restricted cubic spline (RCS) was used to investigate the association between the pre-pregnancy Hb level and the risk of GDM. Univariate and multivariate logistic regression analyses were applied to evaluate the relative risk of GDM.Results: Of the 1289 included pregnant women, 187 (14.5%) women were diagnosed with GDM in this study. The pre-pregnancy Hb level was significantly associated with GDM risk, and the pre-pregnancy Hb level of 123 g/L was identified as the threshold to stratify and assess the association between the GDM risk and the pre-pregnancy BMI. For women with a pre-pregnancy Hb level ≥ 123 g/L, the pre-pregnancy BMI showed a significant association with GDM risk, and the estimated incidence rate of GDM was 7.7%, 14.8%, 36.3% and 44% for underweight, normal-weight, overweight and obese pregnant women, respectively. After adjusting for potential influencing factors of GDM, the respective relative risk was 1.0 (reference), 2.04 (95% CI 0.84, 4.99), 7.06 (2.66, 18.61), and 10.77 (2.85, 40.63) (P for trend < 0.001).Conclusion: In pregnant women with a pre-pregnancy Hb level ≥ 123 g/L, pre-pregnancy BMI showed a more significant association with GDM risk as compared with those with a pre-pregnancy Hb level < 123 g/L.Keywords: pregnancy, body mass index, hemoglobin, gestational diabetes mellitus, overweight, obese

Huan Hu,&ast; Guangyu Mao,&ast; Jianghong Zheng, Feng Guo Department of Plastic Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianghong Zheng; Feng Guo, Department of Plastic Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Xuhui District, Shanghai, 200233, People’s Republic of China, Email JianghongZheng2016@126.com; gfasph@163.comBackground: Keloids are fibroproliferative disorders, which seriously affect the quality of life of patients with keloids. Additionally, circRNAs are enriched within exosomes derived from human blood samples, whereas their relationship with keloids remains largely unknown. It has been reported that hsa_circ_0020792 was abnormally upregulated in keloid tissues. However, the role of keloid patient plasma-derived exosomal hsa_circ_0020792 in the formation and development of keloids is not well understood.Methods: Exosomes were isolated from the peripheral blood plasma of the patients with keloids (keloid patient-Exo) and healthy controls (Healthy control-Exo). The hsa_circ_0020792 and miR-193a-5p levels in keloid patient-Exo and healthy control-Exo, as well as in keloid fibroblasts and normal skin fibroblasts (NFs) were evaluated by RT-qPCR.Results: The level of hsa_circ_0020792 was remarkably increased in keloid patient-Exo and keloid fibroblasts compared with that in Healthy control-Exo and NFs, respectively. In addition, keloid patient-Exo obviously enhanced the viability, migration, and extracellular matrix (ECM) synthesis, but reduced the apoptosis of NFs. Moreover, keloid patient-Exo notably promoted the fibrogenesis of NFs, as characterized by enhanced TGF-β signaling, increased expressions of phosphorylated Smad2/3. However, downregulation of hsa_circ_0020792 markedly reversed the promoting effects of keloid patient-Exo on cell growth, migration, and myofibroblast activation and fibrogenesis. Furthermore, downregulation of hsa_circ_0020792 significantly reduced the viability, migration, and fibrogenesis in NFs, whereas these phenomena were reversed by miR-193a-5p inhibitor.Conclusion: Collectively, keloid patient plasma-derived exosomal hsa_circ_0020792 could promote the proliferation, migration, and fibrogenesis of NFs via modulating miR-193a-5p and activating TGF-β 1/Smad2/3 signaling.Keywords: keloid, fibroblasts, exosomes, hsa_circ_0020792, miR-193a-5p

Hongxing Hu,1 Hang Zhang,2 Ziheng Bu,3 Zhongtang Liu,3 Fang Lv,4,5 Mingmang Pan,5 Xuan Huang,3 Liming Cheng1 1Department of Orthopedics Tongji Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Orthopedics Changhai Hospital Affiliated to the Second Military Medical University, Shanghai, People’s Republic of China; 4Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Science and School of Life Science, East China Normal University, Shanghai, People’s Republic of China; 5Department of orthopedics, Shanghai Fengxian District Central Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Xuan Huang, Department of Orthopedics Changhai Hospital Affiliated to the Second Military Medical University, 168 Changhai Road, Shanghai, People’s Republic of China, Tel +86 18930172772, Email 11791709@qq.com Liming Cheng, Department of Orthopedics Tongji Hospital Affiliated to Tongji University, Tongji University School of Medicine, 389 Xincun Road, Shanghai, People’s Republic of China, Tel +86-21-56051080, Email limingcheng@tongji.edu.cnBackground: The treatment of critical-size bone defect is a great difficulty in orthopedics. Osteogenesis and angiogenesis are critical issue during the process of bone repair and remodeling. Mesenchymal stem cells (MSCs)-derived exosomes have the same therapeutic effect to MSCs-based therapies. The effect of human umbilical cord MSCs-derived sEVs (hUC-MSCs-sEVs) on vascularized bone regeneration and the potential mechanism remains to be investigated. Herein, we aimed to explore the therapeutic effect and the mechanism of hUC-MSCs-sEVs on critical-size bone defect.Methods: To investigate the potential osteogenesis and angiogenesis effects of sEVs in vitro, we extracted sEVs from hUC-MSCs, and then sEVs were co-incubated with BMSCs and HUVECs. We next investigated the effect and potential mechanism of sEVs on the effects of osteogenesis and angiogenesis. We fabricated 3D-printed bioglass scaffold with Gelma/nanoclay hydrogel coatings to load sEVs (BG-gel-sEVs) to ensure in vivo sustained efficacy of sEVs. Finally, the skull defect model was used to evaluate the capacity of vascularized bone regeneration of the composited scaffolds.Results: hUC-MSCs-sEVs facilitated calcium deposition and the endothelial network formation, inducing osteogenic differentiation and angiogenesis by delivering miR-23a-3p to activate PTEN/AKT signaling pathway. Additionally, the BG-gel-sEVs composited scaffold achieved vascularized bone regeneration in vivo.Conclusion: This finding illuminated that hUC-MSCs-sEVs promoted osteogenesis and angiogenesis by delivering miR-23a-3p to activate PTEN/AKT signaling pathway, achieving vascularized bone regeneration.Keywords: small extracellular vesicles, bone regeneration, angiogenesis, miR-23a-3p, bioglass scaffolds

Yiran Zhang,1– 4,&ast; Hongzhi Hu,5,&ast; Xiangtian Deng,6,&ast; Qingcheng Song,2 Xin Xing,2,3 Weijian Liu,5 Yingze Zhang1– 3 1School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China; 2Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3NHC Key Laboratory of Intelligent Orthopaedic Equipment, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 4HeBei Ex&Invivo Biotechnology Co. Ltd, Shijiazhuang, Hebei, 050051, People’s Republic of China; 5Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 6Orthopaedics Research Institute, Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingze Zhang; Weijian Liu, Email yzling_liu@163.com; xh_liuweijian@hust.edu.cnBackground: Although chemodynamic therapy (CDT) has attracted enormous attention in anti-tumor studies for converting endogenous hydrogen peroxide (H2O2) into toxic hydroxyl radicals (•OH) by Fenton-type reaction, the treating effects of using CDT alone is still unsatisfying. Recently, glucose oxidase (GOx) was reported to be co-delivered with Fenton agent for synergistic starvation therapy (ST) and CDT. However, the overexpressed glutathione (GSH) and hypoxia in tumor microenvironment (TME) restrict the therapeutic efficacy of ST/CDT.Methods and Results: In this work, a novel nanoplatform composed of GOx plus Fenton agent (Cu2+) encapsulated core and metformin (MET)-loaded manganese dioxide nanosheets (MNSs) shell was prepared and further functionalized by arginine-glycine-aspartate (RGD). With the RGD-mediated affinity with cancer cells, the nanocomposite (GOx-CuCaP@MNSs-MET@PEG-RGD, GCMMR) could accomplish targeting delivery and TME-activated release of cargos. The intracellular GSH was depleted by MnO2/Cu2+ and abundant H2O2 was generated along with the GOx-induced glucose deprivation, which process was further enhanced by MET-mediated hypoxia relief via inhibiting mitochondria-associated respiration. Subsequently generated •OH from Cu+-mediated Fenton-like reaction exerts severe intracellular oxidative stress and cause apoptosis. Moreover, significant inhibition of tumor growth was detected in a subcutaneous xenograft model of osteosarcoma (OS) after GCMMR treatment.Conclusion: The excellent therapeutic efficacy and biosafety of the nanoplatform were confirmed both in vitro and in vivo. Collectively, this study provides an appealing strategy with catalytic cascade enhancement on targeted ST/CDT for cancer treatment, especially for hypoxic solid tumors.Graphical Abstract: Keywords: chemodynamic therapy, starvation therapy, glucose oxidase, Fenton reaction, biomineralization, metformin

Bingxin Song,1 Shishi Zhou,2 Chenghui Li,2 Hongjuan Zheng,2 Xia Zhang,2 Xiayun Jin,2 Jianfei Fu,2 Huixian Hu1 1Department of Medical Hematology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, People’s Republic of China; 2Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, People’s Republic of ChinaCorrespondence: Jianfei Fu, Department of Medical Oncology, Zhejiang University Jinhua Hospital, 351 Mingyue Road, Jinhua, 321000, Zhejiang Province, People’s Republic of China, Fax +86-579-82552856, Email 11218276@zju.edu.cn Huixian Hu, Department of Medical Hematology, Zhejiang University Jinhua Hospital, 351 Mingyue Road, Jinhua, Zhejiang Province, 321000, People’s Republic of China, Fax +86-579-82136611, Email huhuixian@zju.edu.cnObjective: Chemotherapy-induced thrombocytopenia (CIT) can lead to chemotherapy dose delay or reduction, and even serious bleeding. This study aimed to develop a CIT-predicting model based on the laboratory indices of cancer patients undergoing chemotherapy.Material and Methods: From Jun 1, 2017 to Dec 30, 2021, a total of 2043 patients who had received 7676 cycles of chemotherapy were retrospectively enrolled. A logistic regression analysis was performed to identify predictive factors, on the basis of which a nomogram model for predicting CIT was established. A bootstrapping technique was applied for internal validation. A generalized additive mixed model (GAMM) was constructed to analyze the trends in the changes of aspartate aminotransferase (AST), ratio of AST to alanine transaminase (ALT) (AST/ALT ratio), and platelet (PLT) count in patients with solid tumors. P values ≤ 0.05 were considered statistically significant.Results: The patient-based incidence of CIT was 20.51% and the cycle-based incidence was 10.01%. The multivariate analysis showed that AST level, AST/ALT ratio, and total bilirubin (Tbil), white blood cell (WBC), platelet (PLT), hemoglobin (Hb) levels were significantly associated with the risk of CIT. The GAMM analysis showed that PLT level was inversely associated with AST/ALT ratio and AST level, more significantly with AST/ALT ratio. And both exhibited statistically predictive abilities for CIT. The model achieved an area under the receiver operating characteristic curve (AUC) of 0.793, a sensitivity of 0.543 and a specificity of 0.930.Conclusion: The AST/ALT ratio was inversely associated with the CIT risk in cancer patients. The GAMM model based on laboratory indices presented a high accuracy in predicting the risk of CIT, and a potential to be translated into clinical management.Keywords: chemotherapy-induced thrombocytopenia, solid tumors, AST/ALT-ratio, prediction model

Guohua Lin,1,&ast; Jiaqi Zheng,1,&ast; Pou Kuan Tang,1 Yu Zheng,1 Hao Hu,1,2 Carolina Oi Lam Ung1,2 1Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, People’s Republic of China; 2Department of Public Health and Medicinal Administration, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Carolina Oi Lam Ung, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR, People’s Republic of China, Email carolinaung@um.edu.moPurpose: This review aimed to summarize empirical evidence about pharmacist-led interventions for chronic obstructive pulmonary disease (COPD) patients in hospital settings and to identify the components of a logic model (including input, interventions, output, outcome and contextual factors) to inform the development of hospital pharmacist’s role in COPD management.Methods: A systematic review of literature retrieved from four English databases (PubMed, Web of Science, Scopus, ScienceDirect) and one Chinese database (CNKI) were conducted to identify eligible studies published from inception to March 2022. Studies concerning pharmacist and COPD were identified to screen for randomized controlled studies that focused on pharmacist interventions for COPD at the hospital setting.Results: Twenty-nine studies were included in this review. The components of interventions identified were categorized according to the six service domains in the International Pharmaceutical Federation’s Basel Statements, and mainly concerned prescribing, preparation, administration and monitoring but not procurement and training. Extended interventions were also identified including life guidance, psychological counseling, and respiratory function exercise. The most common outputs reported were improvement in medication adherence, rational drug use, level of knowledge, and inhalation technique. The clinical outcomes (symptomatic control, lung function, rates of hospital readmission, length of hospital stay, and adverse drug adverse reactions), humanistic outcomes (quality of life and patient satisfaction), and economic outcomes (drug costs, hospitalization costs, antibiotic costs, and direct costs) were reported only in some studies. The contextual factors mainly included geographical factors, education level of patients, socio-economic factors, and no-smoking policy.Conclusion: The evidence for hospital pharmacists’ interventions in improving COPD patients’ outcome is growing. However, considering the challenges of COPD management, hospital pharmacists should further leverage the advantages of cross-sector and multi-disciplinary collaboration in order to provide more comprehensive support to better address the needs of their patients.Keywords: chronic obstructive pulmonary disease, hospital pharmacist, systematic review, intervention, output, outcome, logic model

Renbiao Chen, Yonglei Zhao, Pierre Umba Mabombo, Hongjie Hu, Xiaoxuan Zhou Department of Radiology, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Hongjie Hu, Tel +86 57186006752, Fax +86 57186044817, Email hongjiehu@zju.edu.cnAbstract: Radiofrequency ablation (RFA) has become one of the commonly used treatment methods for hepatocellular carcinoma (HCC). It is widely available in the clinic and presents the advantages of short recovery time and a less invasive approach. Only a few complications, such as hemorrhage, ascites, and duct injury, have been reported after RFA for HCC. Herein, we report for the first time the case of a patient diagnosed with recurrent HCC in whom thrombotic thrombocytopenic purpura (TTP) was diagnosed as a complication of the RFA procedure. A 64-year-old male patient with a 2-year history of resected-stage V HCC, in whom later recurrence occurred, underwent RFA for HCC. This patient had a rapid drop in platelets and some petechiae on the wrists after RFA. Combining the clinical and laboratory tests, the diagnosis of TTP was reached. We immediately used plasmapheresis combined with drug therapy, which successfully treated the clinical condition of TTP, with no evidence of recurrence or other complications 1 year after initial treatment. TTP is a rare complication of RFA procedures. Prompt diagnosis and aggressive treatment measures are critical. Through this case report, we hope to raise awareness of the complications of RFA.Keywords: hepatocellular carcinoma, radiofrequency ablation, thrombotic thrombocytopenic purpura, complication, plasma exchange