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Jun Zhao,1,2,&ast; Xia Li,3,&ast; Xin Wang,4 Xuefei Wang,4 Xin Hao,2 Zhigang Li,2 Lin Zhu1 1Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610044, People’s Republic of China; 2School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 3Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, People’s Republic of China; 4Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, 100010, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhigang Li; Lin Zhu, Email lizhigang620@126.com; 13880262860@163.comBackground: To identify irritable bowel syndrome with diarrhea (IBS-D) combined with anxiety and/or depression through a psychological screening tool and to further explore the relationships between patients with comorbidities and gut microbiota.Methods: The GAD-7, SAS, PHQ-9 and SDS were administered to evaluate anxiety and depression. Faeces were subsequently collected from 44 patients with emotional disorders (IBS-EDs), 22 patients without emotional disorders (IBS-nEDs) and 18 healthy controls (HCs) via 16S rRNA sequencing, depending on the participants’ wishes. The differences in gut microbiota among different groups were analysed. Spearman analysis was conducted at the genus level and was based on psychological assessment scores. Patients with IBS-D were recruited from December 2020 to November 2022.Results: This study included 124 outpatients with IBS-D. According to the GAD-7 and SAS scores, 40.3% and 19.3% of the participants, respectively, had anxiety (P < 0.05). Similarly, a significantly greater percentage of participants had depression according to the PHQ-9 than according to the SDS (61.3% vs 33.1%) (P < 0.05). Overall, approximately 66.1% of the participants had emotional disorders (anxiety and/or depression) according to the GAD-7 and PHQ-9. Correlation analysis revealed that the abundances of Eubacterium_hallii_group, Monoglobus and Lachnoclostridium were closely related to the PHQ-9 scores and that the abundances of Subdoligranulum and Holdemanella were closely related to the GAD-7 scores.Conclusion: In comparison to the SAS and SDS, both the GAD-7 and PHQ-9 identified a greater number of individuals with emotional disorders within the IBS-D population. Furthermore, our findings demonstrated that Lachnoclostridium is not only a biomarker for IBS-ED patients but also that its abundance changes are related to PHQ-9 scores, which may provide insights for further brain gut investigations.Keywords: depression, anxiety, IBS-D, 16S rRNA

Zehua Yang,&ast; Yamei Zheng,&ast; Lei Zhang, Jie Zhao, Wenya Xu, Haihong Wu, Tian Xie, Yipeng Ding Department of Respiratory and Critical Care Medicine, Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, Haikou, Hainan, 570311, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yipeng Ding; Tian Xie, Department of Respiratory and Critical Care Medicine, Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, 19 Xiuhua Road, Xiuying District, Haikou, Hainan, 570311, People’s Republic of China, Tel +86-18976335858, Email yipengding2024@163.com; hpphxietian@163.comBackground and Purpose: Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors, and genetic factors are important determinants of COPD. This study focuses on screening the best predictive models for assessing COPD-associated SNPs and then using the best models to predict potential risk factors for COPD.Methods: Healthy subjects (n=290) and COPD patients (n=233) were included in this study, the Agena MassARRAY platform was applied to genotype the subjects for SNPs. The selected sample loci were first screened by logistic regression analysis, based on which the key SNPs were further screened by LASSO regression, RFE algorithm and Random Forest algorithm, and the ROC curves were plotted to assess the discriminative performance of the models to screen the best prediction model. Finally, the best prediction model was used for the prediction of risk factors for COPD.Results: One-way logistic regression analysis screened 44 candidate SNPs from 146 SNPs, on the basis of which 44 SNPs were screened or feature ranked using LASSO model, RFE-Caret, RFE-Lda, RFE-lr, RFE-nb, RFE-rf, RFE-treebag algorithms and random forest model, respectively, and obtained ROC curve values of 0.809, 0.769, 0.798, 0.743, 0.686, 0.766, 0.743, 0.719, respectively, so we selected the lasso model as the best model, and then constructed a column-line graph model for the 25 SNPs screened in it, and found that rs12479210 might be the potential risk factors for COPD.Conclusion: The LASSO model is the best predictive model for COPD and rs12479210 may be a potential risk locus for COPD.Keywords: COPD, LASSO, machine learning, predictive model, SNP

Junmei Fan,1,&ast; Jinghui Zhao,2,&ast; Junkun Zhang,3 Yanhua Chen,1 Xingyu Bi,1 Huiping Liu,1 Junfen Liu,1 Jinbao Wang,1 Xueqing Wu1 1Department of Reproductive Medicine Center, Children’s Hospital of Shanxi and Women Health Center of Shanxi, Taiyuan, Shanxi, 030013, People’s Republic of China; 2Department of Pediatric and Adolescent Gynecology, Shenzhen Children’s Hospital, Shenzhen, Guangdong, 518000, People’s Republic of China; 3Department of Intensive Care Unit, Shanxi Bethune Hospital, The Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xueqing Wu, Department of Reproductive Medicine Center, Children’s Hospital of Shanxi and Women Health Center of Shanxi, 13th Xinmin North Street, Xinghualing District, Taiyuan, Shanxi, 030013, People’s Republic of China, Tel +86 351 3360725, Email xueqingw_wu95@163.comBackground: This study aimed to explore the effect of vitamin D supplementation on lymphocyte subsets in infertile women.Methods: The study involved a total of 247 patients who suffered recurrent embryo implantation failure (RIF) or recurrent spontaneous abortion (RSA) between January and December 2019 in the Reproductive Medicine Center of Children’s Hospital of Shanxi and Women Health Center of Shanxi. The differences in the vitamin D and lymphocyte subsets of the two diseases, the correlation between the 25-hydroxy vitamin D and lymphocyte subsets, the changes in the lymphocyte subsets after vitamin D supplementation and the impact on pregnancy outcome were analysed.Results: The prevalence of vitamin D deficiency was 77.33% (191/247). After vitamin D supplementation, there were no significant differences in helper T cells (Th), cytotoxic T cells (Tc), Th/Tc and natural killer cells (NK) (p > 0.05), but there were significant differences in leukocyte differentiation antigens 3+ (CD3+), natural killer T cells (NKT), B lymphocytes and vitamin D (p < 0.05). Before vitamin D supplementation, the difference in the composition ratio of different vitamin D levels between the RIF and RSA groups was not statistically significant. At different vitamin D levels, there were no significant differences in CD3+, Th, Tc, Th/Tc, NK or B lymphocyte (p > 0.05), but there was a significant difference in NKT (p < 0.05).Conclusion: Vitamin D supplementation can reduce the level of NKT in infertile women, which may be of benefit to the pregnancy outcome of couples who experience RIF.Keywords: recurrent embryo implantation failure, infertility, lymphocyte subsets, recurrent spontaneous abortion, vitamin D

XingYun Liu,1,&ast; JingDuo Zhao,2,&ast; FuRong Liu,1 ZhiZhong Xie,2 XiaoYong Lei,2 Zhe Wang,3 Zerui Yang,4 YuSheng Zhou,1,3 GuoTao Tang2 1The Affiliated Nanhua Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China; 2Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, People’s Republic of China; 3The Second Affiliated Hospital, Department of Pharmacy, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China; 4NMPA Key Laboratory for Technology Research and Evaluation of Pharmacovigilance, Guangdong Pharmaceutical University, Guangzhou, 510086, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: YuSheng Zhou, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China, Email yszhou08@126.com GuoTao Tang, Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, Hengyang, Hunan, 421001, People’s Republic of China, Email tgtzq@163.comBackground: Breast cancer treatment has been a global puzzle, and targeted strategies based on the hypoxic tumor microenvironment (TME) have attracted extensive attention. As a signature transcription factor overexpressed in hypoxia tumor, hypoxia-inducible factor-1 (HIF-1) contribute to cancer progression. Compound 7-(3-(2-chloro-1H-benzo[d]1midazole-1-yl) propoxy)-2-(3,4,5-trime-thoxyphenyl)-4H-chromen-4-one, synthesized and named FB15 in our earlier research, a potential inhibitor of HIF-1α signaling pathway, has been proved a promising drug candidate for many kinds of cancer chemotherapy. However, the poor solubility and undesirable pharmacokinetics of FB15 leads to limited treatment efficacy of tumor, which ultimately restricts its potential clinical applications. Carbonic anhydrase IX (CAIX), a tumor cell transmembrane protein, was overexpressed in hypoxia tumor site. Acetazolamide (AZA), a highly selective ligand targeting CAIX, can be utilized to delivery FB15 to hypoxia tumor site.Methods: In this study, we prepared and characterized FB15 loaded nano-mixed micelles with the AZA conjugated poloxamer 188 (AZA-P188) and D-a-Tocopherol Polyethylene 1000 Glycol Succinate (TPGS), denoted as, AZA-P188/TPGS@FB15. Its delivery efficiency in vitro and in vivo was assessed by in vitro drug release, cytotoxicity assay, cellular uptake, and in vivo pharmacokinetics and fluorescence imaging. Finally, therapeutic effect of AZA-P188/TPGS@FB15 was investigated using a preclinical breast cancer subcutaneous graft model in vivo.Results: In vitro studies revealed that AZA-P188/TPGS@FB15 could efficiently target breast cancer cells mediated by CAIX receptor, trigger FB15 release in response to acidic condition, and enhance cellular uptake and cytotoxicity against breast cancer cells. The pharmacokinetic studies showed that FB15-loaded AZA-functionalized micelles exhibited significantly increased AUC0-t over free FB15. In vivo imaging demonstrated that AZA-functionalized micelles significantly increased the drug distribution in the tumor site. In vivo experiments confirmed that AZA-P188/TPGS@FB15 exhibited superior inhibition of tumor growth in nude mice with good biosafety.Conclusion: AZA-P188/TPGS@FB15 hold promise as a potentially effective therapeutic way for breast cancer. Its targeted delivery system utilizing AZA as a carrier shows potential for improving the efficacy of FB15 in cancer therapy.Keywords: carbonic anhydrase IX-targeting, FB15, hypoxia inducible factor-1, nano-mixed micelles, pH-responsive

Ling Hou,1,2,&ast; Ke Su,1,&ast; Ting He,1 Jinbo Zhao,1 Yuanhong Li1 1Cardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Enshi, Hubei Province, People’s Republic of China; 2Department of Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan, Hubei Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanhong Li, Email lyh0101@vip.163.comBackground: Percutaneous coronary intervention (PCI) is the primary treatment for acute myocardial infarction (AMI). However, in-stent restenosis (ISR) remains a significant limitation to the efficacy of PCI. The cholesterol-to-lymphocyte ratio (CLR), a novel biomarker associated with inflammation and dyslipidemia, may have predictive value for ISR. Deep learning-based models, such as the multilayer perceptron (MLP), can aid in establishing predictive models for ISR using CLR.Methods: A retrospective analysis was conducted on clinical and laboratory data from 1967 patients. The Boruta algorithm was employed to identify key features associated with ISR. An MLP model was developed and divided into training and validation sets. Model performance was evaluated using ROC curves and calibration plots.Results: Patients in the ISR group exhibited significantly higher levels of CLR and low-density lipoprotein (LDL) compared to the non-ISR group. The Boruta algorithm identified 21 important features for subsequent modeling. The MLP model achieved an AUC of 0.95 on the validation set and 0.63 on the test set, indicating good predictive performance. Calibration plots demonstrated good agreement between predicted and observed outcomes. Feature importance analysis revealed that the number of initial stent implants, hemoglobin levels, Gensini score, CLR, and white blood cell count were significant predictors of ISR. Partial dependence plots (PDP) confirmed CLR as a key predictor for ISR.Conclusion: The CLR, as a biomarker that integrates lipid metabolism and inflammation, shows significant potential in predicting coronary ISR. The MLP model, based on deep learning, demonstrated robust predictive capabilities, offering new insights and strategies for clinical decision-making.Keywords: cholesterol-to-lymphocyte ratio, deep learning, multilayer perceptron, Boruta algorithm, in-stent restenosis

Mengyao Shi,1,&ast; Xueyu Mao,2,&ast; Xuechun Wu,2 Min Chu,2 Huicong Niu,2 Lulu Sun,1 Xinyue Chang,1 Yu He,1 Yi Liu,1 Daoxia Guo,3 Yonghong Zhang,1 Zhengbao Zhu,1 Jing Zhao2,4 1Department of Epidemiology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, People’s Republic of China; 2Department of neurology, Minhang Hospital, Fudan University, Shanghai, People’s Republic of China; 3School of Nursing, Suzhou Medical College of Soochow University, Suzhou, People’s Republic of China; 4Institute of Healthy Yangtze River Delta, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Zhao, Department of Neurology, Minhang Hospital, Fudan University, Shanghai, People’s Republic of China, Email zhao_jing@fudan.edu.cn Zhengbao Zhu, Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, Jiangsu Province, 215123, People’s Republic of China, Email zbzhu@suda.edu.cnBackground: Prealbumin is a symbol of protein nutrition and is involved in anti-inflammatory and neuron regeneration, but its association with the prognosis of ischemic stroke remains unclear. We aimed to prospectively explore the associations between serum prealbumin levels and adverse clinical outcomes after ischemic stroke in a large-scale cohort study.Methods: We measured serum prealbumin levels among 6609 ischemic stroke patients admitted at Minhang hospital. The primary outcome was composite of death and major disability (modified Rankin Scale [mRS] score ≥ 3) at 3 months after stroke onset, and secondary outcomes included death and the ordered 7-level categorical score of mRS.Results: During 3 months of follow-up, a total of 2118 patients developed the primary outcome. After multivariable adjustment, high prealbumin levels were associated with a decreased risk of primary outcome (odds ratio, 0.71; 95% CI, 0.59– 0.85; Ptrend< 0.0001) when 2 extreme quartiles were compared. Each unit increase of log-transformed prealbumin was associated with a 42% (95% CI, 28-53%) decreased risk of primary outcome. There was a better shift in the distribution of mRS score at 3 months with higher quartiles of serum prealbumin in ischemic stroke patients (Ptrend< 0.0001). Multivariable-adjusted spline regression model showed a linear relationship between prealbumin and the risk of primary outcome (P for linearity = 0.0036).Conclusion: High serum prealbumin level was independently associated with decreased risks of adverse clinical outcomes among ischemic stroke patients. Our findings suggested that prealbumin may be a valuable prognostic biomarker and indicated the importance of keeping nourished in the daily life.Keywords: prealbumin, ischemic stroke, prognosis, cohort study

Jing Zhao,&ast; Jiuxiang He,&ast; Xiaoyan Ding, Yuxin Zhou, Minchi Liu, Xiaozhong Chen, Wenxuan Quan, Dong Hua, Jun Tong, Jintao Li College of Basic Medicine, Army Medical University, Chongqing, 400038, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jintao Li, College of Basic Medicine, Army Medical University, Gaotanyan Street, No. 30, Shapingba District, Chongqing, 400038, People’s Republic of China, Tel +1-86-23-68771389, Fax +1-86-23-68771391, Email ljtqms@tmmu.edu.cnBackground: The global prevalence of Dengue virus (DENV) infection poses a significant health risk, urging the need for effective vaccinations. Peptide vaccines, known for their capacity to induce comprehensive immunity against multiple virus serotypes, offer promise due to their stability, safety, and design flexibility. Spherical nucleic acid (SNA), particularly those with gold nanoparticle cores, present an attractive avenue for enhancing peptide vaccine efficacy due to their modularity and immunomodulatory properties.Methods: The spherical nucleic acid-TBB (SNA-TBB), a novel nanovaccine construct, was fabricated through the co-functionalization process of SNA with epitope peptide, targeting all four serotypes of the DENV. This innovative approach aims to enhance immunogenicity and provide broad-spectrum protection against DENV infections. The physicochemical properties of SNA-TBB were characterized using dynamic light scattering, zeta potential measurement, and transmission electron microscopy. In vitro assessments included endocytosis studies, cytotoxicity evaluation, bone marrow-dendritic cells (BMDCs) maturation and activation analysis, cytokine detection, RNA sequencing, and transcript level analysis in BMDCs. In vivo immunization studies in mice involved evaluating IgG antibody titers, serum protection against DENV infection and safety assessment of nanovaccines.Results: SNA-TBB demonstrated successful synthesis, enhanced endocytosis, and favorable physicochemical properties. In vitro assessments revealed no cytotoxicity and promoted BMDCs maturation. Cytokine analyses exhibited heightened IL-12p70, TNF-α, and IL-1β levels. Transcriptomic analysis highlighted genes linked to BMDCs maturation and immune responses. In vivo studies immunization with SNA-TBB resulted in elevated antigen-specific IgG antibody levels and conferred protection against DENV infection in neonatal mice. Evaluation of in vivo safety showed no signs of adverse effects in vital organs.Conclusion: The study demonstrates the successful development of SNA-TBB as a promising nanovaccine platform against DENV infection and highlights the potential of SNA-based peptide vaccines as a strategy for developing safe and effective antiviral immunotherapy.Keywords: nanovaccine, dengue virus, spherical nucleic acid, immunogenicity, peptide antigen

Li Wang, Li Liu, Jing Zhao, Xin Yu, Chunxia Su Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of ChinaCorrespondence: Chunxia Su, Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, People’s Republic of China, Email susu_mail@126.comBackground: Immunotherapy has become the standard treatment for driving gene-negative advanced non-small cell lung cancer (NSCLC). However, compared to PD-L1-positive patients, the efficacy of Anti-PD-(L)1 monotherapy is suboptimal in PD-L1-negative advanced NSCLC. In this study, we aim to analyze the optimal immunotherapy approach for PD-L1-negative NSCLC patients and develop a new nomogram to enhance the clinical predictability of immunotherapy for NSCLC patients.Methods: In this study, we retrieved clinical information and genomic data from cBioPortal for NSCLC patients undergoing immunotherapy. Cox regression analyses were utilized to screen the clinical information and genomic data that related to survival. The prognostic-relate genes function was studied by comprehensive bioinformatics analyses. The Kaplan-Meier plot method was employed for survival analysis.Results: A total of 199 PD-L1-negative NSCLC patients were included in this study. Among them, 165 patients received Anti-PD-(L)1 monotherapy, while 34 patients received Anti-PD-(L)1+Anti-CTLA-4 combination therapy. The Anti-PD-(L)1+Anti-CTLA-4 combination therapy demonstrated significantly higher PFS compared to the Anti-PD-(L)1 monotherapy. The mutation status of KRAS, ANO1, COL14A1, LTBP1. ERBB4 and PCSK5 were found to correlate with PFS. Utilizing the clinicopathological parameters and genomic data of the patients, a novel nomogram was developed to predict the prognosis of Anti-PD-(L)1+Anti-CTLA-4 combination therapy.Conclusion: Our study revealed that KRAS, ANO1, COL14A1, LTBP1. ERBB4 and PCSK5 mutation could serve as predictive biomarkers for patients with Anti-PD-(L)1+Anti-CTLA-4 combination therapy. Our systematic nomogram demonstrates significant potential in predicting the prognosis for NSCLC patients with responsive to dual PD-1/CTLA-4 blockade.Keywords: NSCLC, immunotherapy, immune checkpoint inhibitors, nomogram, cBioPortal

Yang Liu,1 Lanxi Zhang,2 Jie Zhao,1,3 Ruilong Lu,1 Xuejie Shao,1 Kexin Xu,1 Jiansheng Li,1,3,4,&ast; Yange Tian1,3,&ast; 1Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed by Henan Province and Education Ministry of People’s Republic of China, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 2School of Basic Medicine (Zhongjing School), Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 3Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 4First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiansheng Li; Yange Tian, Email li_js8@163.com; yange0910@126.comPurpose: The main objective of this study was to explore the mechanism of effective component compatibility of Bufei Yishen formula III (ECC-BYF III) in inhibiting mitochondrial oxidative stress in a rat model of chronic obstructive pulmonary disease (COPD).Methods: A549 cells exposed to cigarette smoke extract (CSE) were used to establish a model of mitochondrial oxidative damage. The cells were treated with the plasmid encoding Pkm2 and the enzymes and proteins involved in oxidative stress and mitochondrial function were measured. A rat model of COPD was established using CS and bacteria. Two different treatments were established, ECC-BYF III (5.5 mg/kg/d) and N-acetylcysteine (54 mg/kg/day). Animals were tested for pulmonary function (Vt, PEF, FVC, FEV0.1s and Cdyn) after eight weeks of therapy and were sacrificed. Pulmonary H&E staining was performed, and the total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) content were measured. The mitochondrial function was also examined. Furthermore, the Pkm2/Nrf2 signaling pathway was evaluated.Results: Overexpression of Pkm2 dramatically ameliorated the CS-induced mitochondrial oxidative damage. Further studies indicated that ECC-BYF III significantly improved mitochondrial function and inhibited oxidative stress in the lung tissues of COPD rats. Moreover, it can upregulate mitochondrial respiratory chain enzyme activity. ECC-BYF III also decreased the MDA content and increased T-SOD, GSH-Px, and T-AOC expression to facilitate oxidative homeostasis. Finally, our results indicated that the Pkm2/Nrf2 pathway is regulated by ECC-BYF III in A549 cells and lung tissue.Conclusion: These results indicate that ECC-BYF III exerts a strong effective therapeutic effect against cigarette smoke combined with bacteria-induced COPD in rats by activating the Pkm2/Nrf2 signaling pathway and restoring mitochondrial oxidative stress. Although more in vivo animal model research is needed to confirm these findings, this study contributes new data to support the conventional usage of ECC-BYF III.Keywords: chronic obstructive pulmonary disease, oxidative stress, ECC-BYF III, Pkm2, Nrf2

Ling Hou,1,&ast; Jinbo Zhao,2,&ast; Ting He,1,&ast; Yinhua Luo,3 Ke Su,2 Yuanhong Li,2 Ruiyang Zhu3 1Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan, People’s Republic of China; 2Cardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Enshi, Hubei Province, People’s Republic of China; 3Center for Gene Diagnosis and Department of Clinical Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanhong Li, Cardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Enshi, 445400, People’s Republic of China, Email lyh0101@vip.163.com Ruiyang Zhu, Center for Gene Diagnosis and Department of Clinical Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China, Email zhuruiyang@whu.edu.cnAbstract: Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous vasculitis classified as an autoimmune small-vessel vasculitis. Clinically, approximately 80% of affected organs in GPA involve the upper/lower respiratory tract and kidneys, with cardiovascular system involvement being rare. Here, we report a case of a 50-year-old female patient who presented with sudden-onset chest pain lasting for 1 hour. The patient had normal body temperature, and markers of infection such as C-reactive protein and erythrocyte sedimentation rate were within normal limits. Electrocardiography revealed ST-segment elevation in inferior, precordial, and posterior leads. Emergency coronary angiography showed no significant obstructive disease, prompting consideration of vasospastic angina given the patient’s recurrent chest pain symptoms and findings on laboratory and imaging studies. The patient underwent treatment including coronary vasospasm antagonists and immunomodulation, resulting in clinical improvement and subsequent discharge. During a 7-month follow-up period, the patient did not experience any further adverse cardiovascular events.Keywords: granulomatosis with polyangiitis, vasospastic angina, case report

Ling Hou,1,&ast; Ke Su,2,&ast; Ting He,1 Jinbo Zhao,2 Yuanhong Li2 1Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan, Hubei Province, People’s Republic of China; 2Cardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Enshi, Hubei Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanhong Li, Email lyh0101@vip.163.comObjective: This study aims to investigate their correlation and predictive utility for in-stent restenosis (ISR) in patients with acute coronary syndrome (ACS) following percutaneous coronary intervention (PCI).Methods: We collected medical records of 668 patients who underwent PCI treatment from January 2022 to December 2022. Based on follow-up results (ISR defined as luminal narrowing ≥ 50% on angiography), all participants were divided into ISR and non-ISR groups. The XGBoost machine learning (ML) model was employed to identify the optimal predictive variables from a set of 31 variables. Discriminatory ability was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC), while calibration and performance of the prediction models were assessed using the Hosmer-Lemeshow (HL) test and calibration plots. Clinical utility of each model was evaluated using decision curve analysis (DCA).Results: In the XGBoost importance ranking of predictive factors, LMR and RC ranked first and fourth, respectively. The AUC of the entire XGBoost ML model was 0.8098, whereas the model using traditional stepwise backward regression, comprising five predictive factors, had an AUC of 0.706. The XGBoost model showed superior predictive performance with a higher AUC, indicating better discrimination and predictive accuracy for ISR compared to traditional methods.Conclusion: LMR and RC are identified as cost-effective and reliable biomarkers for predicting ISR risk in ACS patients following drug-eluting stent (DES) implantation. LMR and RC represent cost-effective and reliable biomarkers for predicting ISR risk in ACS patients following drug-eluting stent implantation. Enhances the accuracy and clinical utility of ISR prediction models, offering clinicians a robust tool for risk stratification and personalized patient management.Keywords: Lymphocyte-to-monocyte ratio, residual cholesterol, XGBoost, machine learning, in-stent restenosis, drug-eluting stent

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

Wenwu Zhang,1,2,&ast; Yuhan Xiao,3,&ast; Xin Zhu,1 Yanxia Zhang,1 Qin Xiang,1 Shunhong Wu,1 Xiaoyu Song,1 Junxiu Zhao,3 Ruanfei Yuan,1 Qiguang Li,1 Bin Xiao,1 Linhai Li1 1Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, Qingyuan, Guangdong, 511518, People’s Republic of China; 2Department of Laboratory Medicine, Suzhou Municipal Hospital, Affiliated to Nanjing Medical University, Suzhou, 21500, People’s Republic of China; 3School of Public Health, Dali University, Dali, 671000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Linhai Li; Bin Xiao, Email mature303@126.com; xiaobin2518@163.comPurpose: Meiotic nuclear division 1 (MND1) is a meiosis-specific protein that promotes lung adenocarcinoma progression. However, its expression and biological function across cancers remain largely unexplored.Patients and Methods: The expression, prognostic significance, mutation status, and methylation profile of MND1 in various cancers were comprehensively analyzed using the TIMER, GTEX, Kaplan-Meier plotter, cBioPortal, and GSCA databases. Additionally, we constructed a PPI network, enrichment analysis and single-cell transcriptomic sequencing to elucidate the underlying mechanism of MND1. Furthermore, we investigated the association between MND1 expression and drug sensitivity using CellMiner. Moreover, we also explored the correlation between MND1 expression and immune infiltration. Finally, we validated the functional role of MND1 in breast cancer through IHC staining, CCK8, EdU, colony formation, and flow cytometry assays.Results: MND1 has been reported to be highly expressed in Pan-cancer, High MND1 expression was significantly associated with poor prognosis in cancers. Additionally, MND1 mutation frequency is high in most cancers, and its expression correlates with methylation. Furthermore, MND1 expression significantly correlates with immune checkpoint blockade (ICB) markers, including PD-L1, PD-1, and CTLA-4. The PPI network reveals interactions between MND1 and PSMC3IP, BRCA1, and BRCA2. Enrichment analysis and single-cell sequencing indicate that MND1 positively correlates with cell cycle. ROC curve reveals favorable diagnostic efficacy of MND1 in breast cancer. In vitro, MND1 overexpression promotes breast cancer cell proliferation and increases the expression of key cell cycle regulators (CDK4, CDK6, and cyclin D3), accelerating the G1/S phase transition and leading to abnormal breast cancer cell proliferation. The immunohistochemical analysis revealed a robust expression of MND1 in breast cancer tissues, exhibiting a significant positive correlation with PD-L1 and FOXP3.Conclusion: MND1 is an oncogene and may serve as a biomarker for cancer prognosis and immunotherapy. Targeting MND1 may be a potential tumor treatment strategy.Keywords: meiosis-specific protein, pan-cancer, prognosis biomarker, immune infiltration, cell cycle

Zhaohua Xiao,1,&ast; Jiangfeng Zhao,1,&ast; Guanhong Ji,1 Xiangqing Song,1 Xia Xue,2 Wenhao Zhang,1 Guomeng Sha,1 Yongjia Zhou,1 Jie Zhou,1 Zhongxian Tian,1,3 Xiaogang Zhao,1,3 Ning Jiang1 1Department of Thoracic Surgery, the Second Hospital of Shandong University, Jinan, 250033, People’s Republic of China; 2Department of Pharmacy, the Second Hospital of Shandong University, Jinan, People’s Republic of China; 3Key Laboratory of Chest Cancer, Shandong University, the Second Hospital of Shandong University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Jiang, Department of Thoracic Surgery, the Second Hospital of Shandong University, Jinan, 250033, People’s Republic of China, Tel +86-17660081908, Email sdujiangning@163.comBackground: Exosomal microRNAs (miRNAs) in the tumor microenvironment play crucial roles in tumorigenesis and tumor progression by participating in intercellular cross-talk. However, the functions of exosomal miRNAs and the mechanisms by which they regulate esophageal squamous cell carcinoma (ESCC) progression are unclear.Methods: RNA sequencing and GEO analysis were conducted to identify candidate exosomal miRNAs involved in ESCC development. Receiver operating characteristic curve analysis was performed to assess the diagnostic value of plasma exosomal miR-493-5p. EdU, tube formation and Transwell assays were used to investigate the effects of exosomal miR-493-5p on human umbilical vein endothelial cells (HUVECs). A subcutaneous xenograft model was used to evaluate the antitumor effects of miR-493-5p and decitabine (a DNA methyltransferase inhibitor). The relationship between miR-493-5p and SP1/SP3 was revealed via a dual-luciferase reporter assay. A series of rescue assays were subsequently performed to investigate whether SP1/SP3 participate in exosomal miR-493-5p-mediated ESCC angiogenesis.Results: We found that miR-493-5p expression was notably reduced in the plasma exosomes of ESCC patients, which showed the high potential value in early ESCC diagnosis. Additionally, miR-493-5p, as a candidate tumor suppressor, inhibited the proliferation, migration and tube formation of HUVECs by suppressing the expression of VEGFA and exerted its angiostatic effect via exosomes. Moreover, we found that SP1/SP3 are direct targets of miR-493-5p and that re-expression of SP1/SP3 could reverse the inhibitory effects of miR-493-5p. Further investigation revealed that miR-493-5p expression could be regulated by DNA methyltransferase 3A (DNMT3A) and DNMT3B, and either miR-493-5p overexpression or restoration of miR-493-5p expression with decitabine increased the antitumor effects of bevacizumab.Conclusion: Exosomal miR-493-5p is a highly valuable ESCC diagnosis marker and inhibits ESCC-associated angiogenesis. miR-493-5p can be silenced via DNA methylation, and restoration of miR-493-5p expression with decitabine increases the antitumor effects of bevacizumab, suggesting its potential as a therapeutic target for ESCC treatment.Keywords: esophageal squamous cell carcinoma, exosomes, miR-493-5p, VEGFA, angiogenesis

Ling Hou,1,&ast; Jinbo Zhao,2,&ast; Ting He,2 Ke Su,2 Yuanhong Li2 1Department of Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Shiyan, Hubei Province, People’s Republic of China; 2Cardiovascular Disease Center, Central Hospital of Tujia and Miao Autonomous Prefecture, Hubei University of Medicine, Enshi, Hubei Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanhong Li, Email lyh0101@vip.163.comIntroduction: Coronary artery disease (CAD) remains a significant global health challenge, with percutaneous coronary intervention (PCI) being a primary revascularization method. In-stent restenosis (ISR) post-PCI, although reduced, continues to impact patient outcomes. Inflammation and platelet activation play key roles in ISR development, emphasizing the need for accurate risk assessment tools. The systemic inflammation aggregation index (AISI) has shown promise in predicting adverse outcomes in various conditions but has not been studied in relation to ISR.Methods: A retrospective observational study included 1712 patients post-drug-eluting stent (DES) implantation. Data collected encompassed demographics, medical history, medication use, laboratory parameters, and angiographic details. AISI, calculated from specific blood cell counts, was evaluated alongside other variables using machine learning models, including random forest, Xgboost, elastic networks, logistic regression, and multilayer perceptron. The optimal model was selected based on performance metrics and further interpreted using variable importance analysis and the SHAP method.Results: Our study revealed that ISR occurred in 25.8% of patients, with a range of demographic and clinical factors influencing the risk of its development. The random forest model emerged as the most adept in predicting ISR, and AISI featured prominently among the top variables affecting ISR prediction. Notably, higher AISI values were positively correlated with an elevated probability of ISR occurrence. Comparative evaluation and visual analysis of model performance, the random forest model demonstrates high reliability in predicting ISR, with specific metrics including an AUC of 0.9569, accuracy of 0.911, sensitivity of 0.855, PPV of 0.81, and NPV of 0.948.Conclusion: AISI demonstrated itself as a significant independent risk factor for ISR following DES implantation, with an escalation in AISI levels indicating a heightened risk of ISR occurrence.Keywords: coronary artery disease, percutaneous coronary intervention, Systemic inflammation aggregation index, machine learning models, In-stent restenosis

Kebang Hu,1 Dongqi Zhang,1 Weiran Ma,2 Yanzhi Gu,2 Jiang Zhao,3 Xupeng Mu4 1Department of Urology, Lequn Branch, The First Hospital of Jilin University, Changchun, 130031, People’s Republic of China; 2College of Pharmacy, Jilin University, Changchun, 130021, People’s Republic of China; 3Department of Urology, Xi’an First Hospital, Xi’an, 710002, People’s Republic of China; 4Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, 130033, People’s Republic of ChinaCorrespondence: Jiang Zhao, Department of Urology, Xi’an First Hospital, Xi’an, 710002, People’s Republic of China, Email 765398883@qq.com Xupeng Mu, Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, 130033, People’s Republic of China, Email muxupeng@jlu.edu.cnIntroduction: Immune regulatory small molecule JQ1 can block its downstream effector PD-L1 pathway and effectively reverse the PD-L1 upregulation induced by doxorubicin (DOX). So the synergistic administration of chemotherapeutic drug DOX and JQ1 is expected to increase the sensitivity of tumors to immune checkpoint therapy and jointly enhance the body’s own immunity, thus effectively killing tumor cells. Therefore, a drug delivery system loaded with DOX and JQ1 was devised in this study.Methods: Polydopamine nanoparticles (PDA NPs) were synthesized through spontaneous polymerization. Under appropriate pH conditions, DOX and JQ1 were loaded onto the surface of PDA NPs, and the release of DOX and JQ1 were measured using UV-Vis or high performance liquid chromatography (HPLC). The mechanism of fabricated nanocomplex in vitro was investigated by cell uptake experiment, cell viability assays, apoptosis assays, and Western blot analysis. Finally, the tumor-bearing mouse model was used to evaluate the tumor-inhibiting efficacy and the biosafety in vivo.Results: JQ1 and DOX were successfully loaded onto PDA NPs. PDA-DOX/JQ1 NPs inhibited the growth of prostate cancer cells, reduced the expression of apoptosis related proteins and induced apoptosis in vitro. The in vivo biodistribution indicated that PDA-DOX/JQ1 NPs could accumulated at the tumor sites through the EPR effect. In tumor-bearing mice, JQ1 delivered with PDA-DOX/JQ1 NPs reduced PD-L1 expression at tumor sites, generating significant tumor suppression. Furthermore, PDA-DOX/JQ1 NPs could reduce the side effects, and produce good synergistic treatment effect in vivo.Conclusion: We have successfully prepared a multifunctional platform for synergistic prostate cancer therapy. Keywords: prostate cancer, doxorubicin, JQ1, polydopamine, chemotherapy, PD-L1

Jianwen Zhao,1– 5,&ast; Xintian Cai,1– 5,&ast; Junli Hu,1– 5 Shuaiwei Song,1– 5 Qing Zhu,1– 5 Di Shen,1– 5 Wenbo Yang,1– 5 Qin Luo,1– 5 Xiaoguang Yao,1– 5 Delian Zhang,1– 5 Jing Hong,1– 5 Nanfang Li1– 5 1Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, 830001, People’s Republic of China; 2Xinjiang Hypertension Institute, Urumqi, Xinjiang, 830001, People’s Republic of China; 3NHC Key Laboratory of Hypertension Clinical Research, Urumqi, Xinjiang 830001 People’s Republic of China; 4Key Laboratory of Xinjiang Uygur Autonomous Region ”Hypertension Research Laboratory”, Urumqi, Xinjiang, 830001, People’s Republic of China; 5Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang, 830001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nanfang Li, Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumuqi, Xinjiang, 830001, People’s Republic of China, Tel +86 8564818, Email lnanfang2016@sina.comBackground: A newly introduced obesity-related index, the weight-adjusted-waist index (WWI), emerges as a promising predictor of cardiovascular disease (CVD). Given the known synergistic effects of hypertension and obstructive sleep apnea (OSA) on cardiovascular risk, we aimed to explore the relationship between the WWI and CVD risk specifically within this high-risk cohort.Methods: A total of 2265 participants with hypertension and OSA were included in the study. Multivariate Cox regression analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD events. The restricted cubic spline (RCS) was used to further evaluate the nonlinear dose-response relationship.Results: During a median follow-up period of 6.8 years, 324 participants experienced a CVD event. Multivariate Cox regression analysis revealed that compared to the reference group, the HRs for the second, third, and fourth groups were 1.12 (95% CI, 0.79– 1.59), 1.35 (95% CI, 0.96– 1.89), and 1.58 (95% CI, 1.13– 2.22), respectively. Moreover, RCS analysis illustrated a clear J-shaped relationship between the WWI and CVD risk, particularly notable when WWI exceeded 11.5 cm/, signifying a significant increase in CVD risk.Conclusion: There was a J-shaped relationship between WWI and CVD in hypertensive patients with OSA, especially when the WWI was greater than 11.5 cm/, the risk of CVD was significantly increased.Keywords: hypertensive, obstructive sleep apnea, weight-adjusted-waist index, cardiovascular disease, visceral obesity

Jing Luo,1,2 Yi Luo,2 Maoru Zhao,3 Yulong Liu,2 Jiayin Liu,2 Zhulin Du,2 Hong Gong,2 Lian Wang,2 Jinghui Zhao,2 Xiaqing Wang,2 Zhanjun Gu,3 Wenhui Zhao,1 Tianyao Liu,2 Xiaotang Fan2 1School of Life Sciences, Chongqing University, Chongqing, 401331, People’s Republic of China; 2Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing, 400038, People’s Republic of China; 3Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, Institute of High Energy Physics and National Center for Nanoscience and Technology, Chinese Academy of Sciences, Beijing, 100049, People’s Republic of ChinaCorrespondence: Xiaotang Fan; Tianyao Liu, Email fanxiaotang2005@163.com; squall277@163.comBackground: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR T+Itpr3tf/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments.Methods: Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining.Results: Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX+ and SOX2+/GFAP+ cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment.Conclusion: In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment. Keywords: fullerenols, BTBR, neurogenesis, autism spectrum disorder, hippocampus

Wensheng Lu,1 JianFeng Wang,2 YuanJing Zhang,1 Ruixue Chang,1 Jun Zhao3 1Department of Dermatology, The No. 1 Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 2Department of Dermatology, The No. 1 Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, Anhui, People’s Republic of China; 3Department of Dermatology, The Lu’an Hospital Affiliated to Anhui Medical University, Lu’an, Anhui, People’s Republic of ChinaCorrespondence: Wensheng Lu; Jun Zhao, Email 492051693@qq.com; 13085092159@163.comIntroduction: This study observed the effectiveness of ustekinumab and reactivation risk of concurrent latent tuberculosis infection (LTBI) and inactive hepatitis B virus (HBV) infection in Chinese mainland psoriasis patients on ustekinumab treatment.Methods: This retrospective, multicenter, observational study was conducted in three centers in China. Adult patients with moderate to severe plaque psoriasis were treated with ustekinumab for 28 weeks. The effectiveness endpoint included 75% and 90% improvement in Psoriasis Area Severity Index (PASI75/90) response rate, percentage of PASI improvement, change of absolute PASI score and body surface area involvement (BSA) score, absolute PASI ≤ 1/3 and Physicians’ Global Assessment (PGA)=0/1, as well as Dermatology life quality index (DLQI)=0/1 response rate at week 4, 16 and 28. Screening of tuberculosis and hepatitis were performed at baseline and week 28.Results: A total of 82 patients were enrolled between March 2021 and May 2023 and the number of patients combined with LTBI and inactive HBV infection was 20 and 21 respectively. The PASI75 and PASI90 response rate at week 28 was 95.1% and 81.7% respectively. The mean PASI score decreased from 14.93 ± 12.07 at baseline to 0.78 ± 1.86 at week 28, and the mean BSA score decreased from 21% ± 18% at baseline to 1% ± 2% at week 28 (both P< 0.001 compared with baseline). DLQI 0/1 response rate at week 28 was 73.2%. No reactivation of LTBI and inactive HBV infection and also no new-onset tuberculosis and hepatitis B occurred in patients without LTBI and inactive HBV infection at baseline.Conclusion: Ustekinumab demonstrated great effectiveness in Chinese plaque psoriasis patients and good safety in psoriasis concurrent with LTBI and inactive HBV infection under the real-world setting.Keywords: ustekinumab, plaque psoriasis, real-world effectiveness, LTBI, inactive HBV infection

Yingxiu Liang,1 Xiaohong Hou,1 Haoying Chen,1 Ruqing Yang,1 Ruina Wang,1 Ruotong Mao,1 Junzhao Zhao,1 Hui Chen,2 Jing Cheng1 1Reproductive Center, Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325088, People’s Republic of China; 2School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, New South Wales, 2007, AustraliaCorrespondence: Jing Cheng, Reproductive Center, Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, No. 306 Hualongqiao Road, Lucheng District, Wenzhou, Zhejiang Province, 325088, People’s Republic of China, Tel +86 13780193700, Fax +86 57788002304, Email jingchengdoc_gyn@hotmail.com Hui Chen, Faculty of Science, University of Technology Sydney, No. 15 of Broadway, Ultimo, New South Wales, 2007, Australia, Tel/Fax +61 295141328, Email chenhuimind@sina.comObjective: Additive human menopausal gonadotropin (HMG)/recombinant luteinizing hormone (r-LH) to follicle-stimulating hormone (FSH) can improve pregnancy outcomes in patients with poor ovarian response during assisted reproductive procedures. However, their effects on patients with normal ovarian response during such procedures are unclear, which formed the aim of this study.Methods: This retrospective study enrolled 456 infertile women who underwent in vitro fertilization or intracytoplasmic sperm injection treatment. Group 1 received FSH; Group 2 received FSH+HMG/r-LH; Group 3 received FSH+HMG+r-LH.Results: The age and Body Mass Index were significantly greater in Group III. The endometrial thickness was greater in Groups II and III, suggesting better endometrial receptivity. Better pregnancy and birth outcomes were seen in Group 3. In sub-cohorts of women older than 32 years old or with overweight/obesity, pregnancy and birth outcomes were also much better in Group 3, albeit without statistical significance.Conclusion: The addition of both HMG and r-LH to FSH may improve the chance of infertile women with normal ovarian responses to have more success in having live birth babies, specifically in those over 32 years of age or with overweight/obese patients who typically face challenges in conceiving and sustaining a pregnancy.Keywords: in vitro fertilization, intracytoplasmic sperm injection, live birth rate, cumulative live birth rate

Zhengjie Chen,1,2,&ast; Jinjie Zeng,3,&ast; Xiang Pei,1,2 Jingjing Zhao,1,2 Fang Zhao,1,2 Guoxin Zhang,1,2 Kexin Liang,1,2 Jiarong Li,2 Xiaoyun Zhao1,2,4,5 1Clinical School of Thoracic, Tianjin Medical University, Tianjin, People’s Republic of China; 2Department of Respiratory & Critical Care Medicine, Tianjin Chest Hospital, Tianjin, People’s Republic of China; 3Department of Respiratory, The Third Central Hospital of Tianjin, Tianjin, People’s Republic of China; 4Department of Respiratory & Critical Care Medicine, Chest Hospital of Tianjin University, Tianjin, People’s Republic of China; 5DeepinBreath Union Laboratory, Tianjin Chest Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoyun Zhao, Department of Respiratory & Critical Care Medicine, Tianjin Chest Hospital, No. 261 Taierzhuang South Road, Jinnan District, Tianjin, People’s Republic of China, Email zxydoctor@163.comPurpose: Clinical studies have demonstrated the intricate association between the onset and progression of obstructive sleep apnea (OSA) and the activation of the inflammatory cascade reaction. This study delves into investigating the causal links between 91 circulating inflammatory proteins (CIPs) and OSA through the application of Mendelian randomization (MR) techniques.Methods: Utilizing genetic data on OSA sourced from the Finnish Biobank (FinnGen) Genome-wide Association Studies (GWAS) of the European population, alongside summary-level GWAS data of CIPs from 14,824 European participants, we conducted a bidirectional MR study.Results: This study suggests that several factors may be associated with the risk of OSA. IL-17C (odds ratio (OR) = 1.090, p = 0.0311), CCL25 (OR = 1.079, p = 0.0493), FGF-5 (OR = 1.090, p = 0.0003), CD5 (OR = 1.055, p = 0.0477), and TNFSF14 (OR = 1.092, p = 0.0008) may positively correlate with OSA risk. Conversely, IL-20RA (OR = 0.877, p = 0.0107), CCL19 (OR = 0.933, p = 0.0237), MIP-1 alpha (OR = 0.906, p = 0.0042), Flt3L (OR = 0.941, p = 0.0019), CST5 (OR = 0.957, p = 0.0320), OPG (OR = 0.850, p = 0.0001), and TRAIL (OR = 0.956, p = 0.0063) may reduce the risk of OSA. Additionally, elevated levels of IL-10RA (OR = 1.153, p = 0.0478) were observed as a consequence of OSA. Conversely, OSA may potentially lead to decreased levels of CCL28 (OR = 0.875, p = 0.0317), DNER (OR = 0.874, p = 0.0324), FGF-21 (OR = 0.846, p = 0.0344), and CSF-1 (OR = 0.842, p = 0.0396).Conclusion: Through this bidirectional MR study, we have identified 12 upstream regulatory proteins and 5 downstream effect proteins that are linked to OSA. These findings hold promise in providing potential therapeutic targets for the inflammatory mechanisms underlying OSA.Keywords: Mendelian randomization, bidirectional, obstructive sleep apnea, circulating inflammatory proteins

Jingliang Wu,1,&ast; Qiao Lu,1,2,&ast; Jialin Zhao,3,&ast; Wendi Wu,3 Zhihua Wang,1 Guohua Yu,4 Guixiang Tian,2 Zhiqin Gao,2 Qing Wang5 1School of Medicine, Weifang University of Science and Technology, Weifang, 262700, People’s Republic of China; 2School of Life Science and Technology, Shandong Second Medical University, Weifang, 261053, People’s Republic of China; 3School of Clinical Medicine, Shandong Second Medical University, Weifang, 261053, People’s Republic of China; 4Department of Oncology, Weifang People’s Hospital, Weifang, 261000, People’s Republic of China; 5Department of Stomatology, Weifang People’s Hospital, Weifang, 261000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qing Wang, Department of Stomatology, Weifang People’s Hospital, Weifang, 261000, People’s Republic of China, Tel +86 158 6362 6389, Email wfwq8899@163.comPurpose: Breast cancer is a prevalent malignancy among women worldwide, and malignancy is closely linked to the tumor microenvironment (TME). Here, we prepared mixed nano-sized formulations composed of pH-sensitive liposomes (Ber/Ru486@CLPs) and small-sized nano-micelles (Dox@CLGs). These liposomes and nano-micelles were modified by chondroitin sulfate (CS) to selectively target breast cancer cells.Methods: Ber/Ru486@CLPs and Dox@CLGs were prepared by thin-film dispersion and ethanol injection, respectively. To mimic actual TME, the in vitro “condition medium of fibroblasts + MCF-7” cell model and in vivo “ 4T1/NIH-3T3” co-implantation mice model were established to evaluate the anti-tumor effect of drugs.Results: The physicochemical properties showed that Dox@CLGs and Ber/Ru486@CLPs were 28 nm and 100 nm in particle size, respectively. In vitro experiments showed that the mixed formulations significantly improved drug uptake and inhibited cell proliferation and migration. The in vivo anti-tumor studies further confirmed the enhanced anti-tumor capabilities of Dox@CLGs + Ber/Ru486@CLPs, including smaller tumor volumes, weak collagen deposition, and low expression levels of α-SMA and CD31 proteins, leading to a superior anti-tumor effect.Conclusion: In brief, this combination therapy based on Dox@CLGs and Ber/Ru486@CLPs could effectively inhibit tumor development, which provides a promising approach for the treatment of breast cancer.Keywords: drug delivery, cancer-associated fibroblasts, glucocorticoids, combination therapy

Jingnan Zhao,1 Chengyu Qian,2 Youqiao Jiang,1,3 Wangrui He,1 Wenhua Wu1 1Tuberculosis Control Department, Jiangxi Provincial Center for Disease Control and Prevention, Nanchang, 330029, People’s Republic of China; 2Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, People’s Republic of China; 3Young Scientific Research and Innovation Team, Jiangxi Provincial Center for Disease Control and Prevention, Nanchang, Jiangxi, 330029, People’s Republic of ChinaCorrespondence: Wangrui He, Tuberculosis Control Department, Jiangxi Provincial Center for Disease Control and Prevention, No. 555, Beijing East Road, Nanchang, Jiangxi, 330029, People’s Republic of China, Email jxcdccbs@126.comPurpose: In this study, we aimed to determine the transmission pattern of multidrug-resistant tuberculosis (MDR-TB) isolates circulating in Jiangxi Province with whole-genome sequencing (WGS). In addition, we also sought to describe mutational resistome of MDR-TB isolates.Patients and Methods: A total of 115 MDR-TB isolates determined by the phenotypic proportion method of drug susceptibility testing between January 2018 and December 2022 from provincial drug surveillance (DRS) in Jiangxi were included in our analysis. The demographic data and treatment history were extracted from the National TB Registry System. WGS was used to analyze the genotypic characteristics of drug resistance and transmissions.Results: About 62.6% of MDR-TB strains were isolated from cases that received previous anti-tuberculosis treatment. According to the WGS results, 96.5% were genotypic MDR-TB, and more than half of MDR-TB isolates tested were also resistant to streptomycin (59.1%), ethambutol (56.5%), and fluroquinolones (53.0%), while resistance to cycloserine and linezolid was lowest, only in two (1.7%) and one (0.9%) isolate, respectively. Ser450Leu in rpoB (57.9%), Ser315Thr in katG (74.1%), Met306Val in embB (40.0%), Lys43Arg in rpsL (75.0%), Ala90Val in gyrA (32.8%) were predominant mutant types among the rifampin-, isoniazid-, ethambutol-, streptomycin-, fluoroquinolones-resistant isolates, respectively. Lineage 2 (East Asian genotype) occurred at the highest frequency with 97 cases (84.3%), followed by lineage 4 (Euro-American genotype) with 18 cases (15.7%). Additionally, 5 clusters consisting of 10 isolates were identified in the present study, demonstrating a clustering rate of 8.7%.Conclusion: MDR/Rifampicin-Resistant (RR)-TB epidemic in this region is driven by lineage 2 clade that also show higher resistance to other anti-tuberculosis drugs. Lower cluster rates compared with a relatively higher proportion of new MDR-TB cases indicate that a considerable number of MDR-TB cases remain undiagnosed.Keywords: Mycobacterium tuberculosis, drug resistant, whole-genome sequencing, genetic diversity, transmission dynamics

Fuyu Zhao,1– 3,&ast; Jianan Zhao,1– 3,&ast; Kai Wei,1– 3 Ping Jiang,1– 3 Yiming Shi,1– 3 Cen Chang,1– 3 Yixin Zheng,1– 3 Yu Shan,1– 3 Yunshen Li,1– 3 Bingheng He,4 Mi Zhou,1,3 Jia Liu,1,3 Li Li,1,3 Shicheng Guo,1 Dongyi He1– 3 1Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4Department of Rehabilitation, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongyi He, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Email dongyihe@medmail.com.cnAbstract: Psoriasis is a chronic inflammatory skin disease characterized by the excessive proliferation of keratinocytes and heightened immune activation. Targeting pathogenic genes through small interfering RNA (siRNA) therapy represents a promising strategy for the treatment of psoriasis. This mini-review provides a comprehensive summary of siRNA research targeting the pathogenesis of psoriasis, covering aspects such as keratinocyte function, inflammatory cell roles, preclinical animal studies, and siRNA delivery mechanisms. It details recent advancements in RNA interference that modulate key factors including keratinocyte proliferation (Fibroblast Growth Factor Receptor 2, FGFR2), apoptosis (Interferon Alpha Inducible Protein 6, G1P3), differentiation (Grainyhead Like Transcription Factor 2, GRHL2), and angiogenesis (Vascular Endothelial Growth Factor, VEGF); immune cell infiltration and inflammation (Tumor Necrosis Factor-Alpha, TNF-α; Interleukin-17, IL-17); and signaling pathways (JAK-STAT, Nuclear Factor Kappa B, NF-κB) that govern immunopathology. Despite significant advances in siRNA-targeted treatments for psoriasis, several challenges persist. Continued scientific developments promise the creation of more effective and safer siRNA medications, potentially enhancing the quality of life for psoriasis patients and revolutionizing treatments for other diseases. This article focuses on the most recent research advancements in targeting the pathogenesis of psoriasis with siRNA and explores its future therapeutic prospects.Keywords: psoriasis, siRNA, keratinocytes, targeted delivery

Xiaoyi Tang,1,2,&ast; Yijia Liu,1,2,&ast; Mengxin Zhao,3,&ast; Lei He,3 Jiahao Guo,3 Tian Wang,3 Wei Li,3 Jiaqi Zhao1 1Department of Ultrasound, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, People’s Republic of China; 2Department of Ultrasound, the Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, 200003, People’s Republic of China; 3Department of Nanomedicine, Naval Medical University, Shanghai & School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200433, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Li; Jiaqi Zhao, Email liwei@smmu.edu.cn; ultrasoundczzjq@163.comPurpose: This study aims to broaden the application of nano-contrast agents (NCAs) within the realm of the musculoskeletal system. It aims to introduce novel methods, strategies, and insights for the clinical management of ischemic muscle disorders, encompassing diagnosis, monitoring, evaluation, and therapeutic intervention.Methods: We developed a composite encapsulation technique employing O-carboxymethyl chitosan (OCMC) and liposome to encapsulate NCA-containing gold nanorods (GNRs) and perfluoropentane (PFP). This nanoscale contrast agent was thoroughly characterized for its basic physicochemical properties and performance. Its capabilities for in vivo and in vitro ultrasound imaging and photothermal imaging were authenticated, alongside a comprehensive biocompatibility assessment to ascertain its effects on microcirculatory perfusion in skeletal muscle using a murine model of hindlimb ischemia, and its potential to augment blood flow and facilitate recovery.Results: The engineered GNR@OCMC-liposome/PFP nanostructure exhibited an average size of 203.18± 1.49 nm, characterized by size uniformity, regular morphology, and a good biocompatibility profile. In vitro assessments revealed NCA’s potent photothermal response and its transformation into microbubbles (MBs) under near-infrared (NIR) irradiation, thereby enhancing ultrasonographic visibility. Animal studies demonstrated the nanostructure’s efficacy in photothermal imaging at ischemic loci in mouse hindlimbs, where NIR irradiation induced rapid temperature increases and significantly increased blood circulation.Conclusion: The dual-modal ultrasound/photothermal NCA, encapsulating GNR and PFP within a composite shell-core architecture, was synthesized successfully. It demonstrated exceptional stability, biocompatibility, and phase transition efficiency. Importantly, it facilitates the encapsulation of PFP, enabling both enhanced ultrasound imaging and photothermal imaging following NIR light exposure. This advancement provides a critical step towards the integrated diagnosis and treatment of ischemic muscle diseases, signifying a pivotal development in nanomedicine for musculoskeletal therapeutics.Keywords: ultrasonography, nanoscale contrast agent, nanotechnology, musculoskeletal ultrasound, photothermal imaging, microcirculatory perfusion

Yanchao Liu,1 Jianhui Li,2 Hainan Wen,1 Cuixin Qiang,3 Shoujun Xie,1 Jianhong Zhao3,4 1Department of Clinical Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China; 2Department of Preventive Medicine, Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China; 3Hebei Provincial Center for Clinical Laboratories, Shijiazhuang, Hebei, 050000, People’s Republic of China; 4Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of ChinaCorrespondence: Jianhong Zhao, Email zhaojh_2002@hebmu.edu.cnObjective: To compare the epidemiological characteristics and drug resistance of Burkholderia cepacia isolated from blood cultures, and to provide data support and a scientific basis for the clinical treatment and detection of hospital infections.Methods: The Hebei Province Antimicrobial Surveillance Network received 349 B. cepacia strains isolated from blood cultures reported by 83 hospitals, from 2016 to 2021. These strains were identified by MALDI-TOF MS and, the antibiotic sensitivity tests were carried out using the VITEK 2 COMPACT system. The 2023 Institute of Clinical and Laboratory Standardization drug-susceptibility breakpoints were used for drug susceptibility testing and the data were analyzed using WHONET5.6 software.Results: A total of 349 B. cepacia strains were isolated from 2016 to 2021, including 68 strains from secondary hospitals and 281 strains from tertiary hospitals. The ratios of male: female patients with B. cepacia bloodstream infections in all hospitals, secondary hospitals, and tertiary hospitals were 1.49:1 (209/140), 2.09:1 (46/22), and 1.38:1 (163/118), respectively. Most B. cepacia strains were isolated in intensive care units (ICUs), followed by internal medicine departments, accounting for 49.57% (173/349) and 22.92% (80/349), respectively. Regarding the age distribution, most patients were elderly (> 65 years, 57.59%, 201/349), with numbers of patients gradually declining with decreasing of age. The resistance rates for levofloxacin, ceftazidime, and sulfamethoxazole decreased over the 6-year period (P< 0.05), while there were no significant changes in the resistance rates for meropenem, chloramphenicol, and minocycline (P> 0.05). There was no significant difference in drug-resistance rates between secondary and tertiary hospitals (P> 0.05).Conclusion: Attention should be paid to bloodstream infections caused by B. cepacia, especially elderly patients and patients admitted to the ICU. The difficult treatment characteristics of B. cepacia bloodstream infections mean that laboratories and clinicians should pay careful attention to drug resistance to provide a basis for their prevention and empirical treatment.Keywords: B. cepacia, antimicrobial resistance, secondary hospital, tertiary hospital, multicenter investigation

Jiaxin Zhao,1 Cheng Wang,1 Liang Zhao,1 Huiying Zhou,1 Rui Wu,1 Tao Zhang,1 Jiawei Ding,1 Junjie Zhou,2 Huilin Zheng,3 Lei Zhang,3 Tianci Kong,3 Jie Zhou,4 Zhenhua Hu1,4 1Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang Province, People’s Republic of China; 2Department of Radiology, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang Province, People’s Republic of China; 3Zhejiang Provincial Collaborative Innovation Center of Agricultural Biological Resource Biochemical Manufacturing, School of Biological and Chemical Engineering, Zhejiang University of Science and Technology, Hangzhou, Zhejiang Province, People’s Republic of China; 4Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Zhenhua Hu, Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, Zhejiang Province, People’s Republic of China, Tel/Fax +86-570-89935878, Email huzhenh@zju.edu.cn Jie Zhou, Department of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China, Tel +86-13429661721, Email jzhou329@zju.edu.cnPurpose: Nonsense-mediated RNA decay (NMD), a surveillance pathway for selective degradation of aberrant mRNAs, is associated with cancer progression. Its potential as a predictor for aggressive hepatocellular carcinoma (HCC) is unclear. Here, we present an innovative NMD risk model for predicting HCC prognosis.Methods: The Cancer Genome Atlas (TCGA) data of 374 liver HCC (LIHC) and 50 normal liver samples were extracted. A risk model based on NMD-related genes was developed through least absolute shrinkage and selection operator Cox (LASSO-Cox) regression of the LIHC-TCGA data. Prognostic validation was done using GSE54236, GSE116174, and GSE76427 data. Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of the model. We also constructed nomograms for survival prediction. Tumor immune infiltration was evaluated using the CIBERSORT algorithm, and the tumor cell phenotype was assessed. Finally, mouse experiments verified UPF3B knockdown effects on HCC tumor characteristics.Results: We developed a risk model based on four NMD-related genes (PABPC1, RPL8, SMG5, and UPF3B) and validated it using GSE54236, GSE116174, and GSE76427 data. The model effectively distinguished high- and low-risk groups corresponding to unfavorable and favorable HCC outcomes. Its prognostic prediction accuracy was confirmed through time-dependent ROC analysis, and clinical-use nomograms with calibration curves were developed. Single-cell RNA sequencing results indicated significantly higher expression of SMG5 and UPF3B in tumor cells. Knockdown of SMG5 and UPF3B inhibited HCC cell proliferation, invasion, and migration, while affecting cell-cycle progression and apoptosis. In vivo, UPF3B knockdown delayed tumor growth and increased immune cell infiltration.Conclusion: Our NMD-related gene-based risk model can help identify therapeutic targets and biomarkers for HCC. Additionally, it assists clinicians in predicting the prognosis of HCC patients.Keywords: nonsense-mediated RNA decay, hepatocellular carcinoma, biomarker, LASSO, survival, tumor immunity

Xiaochun Zhou,1– 3,&ast; Kaiying He,1,3,&ast; Jing Zhao,1,3 Guohua Wei,3 Qicai You,1,3 Hongxuan Du,1,3 Wenjiao Gu,1,2 Haiyu Niu,1,4 Qiaoying Jin,1,5 Jianqin Wang,3 Futian Tang1,2 1The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 2Department of Cardiovascular Disease, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 3Department of Nephrology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 4Department of Tumor, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 5Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Futian Tang, Department of Cardiovascular Disease, The Second Hospital & Clinical Medical School, Lanzhou University, No. 82, Cuiyingmen, Lanzhou, Gansu, People’s Republic of China, Tel +8613321330515, Email Tangfutian2023@126.comPurpose: To investigate the therapeutic effect and underlying mechanism of a traditional Chinese medicine (TCM) mixture consisting of Astragalus, rhubarb, and saffron in a mouse model of diabetic kidney disease (DKD).Methods: Forty-eight db/db mice received no TCM (DKD model), low-dose TCM, medium-dose TCM, or high-dose TCM, and an additional 12 db/m mice received no TCM (normal control). Intragastric TCM or saline (controls) was administered daily for 24 weeks. Blood glucose, body weight, serum creatinine (SCr), blood urea nitrogen (BUN), blood lipids, and urinary microalbumin were measured every four weeks, and the urinary albumin excretion rate (UAER) was calculated. After 24 weeks, kidney tissues were collected for transcriptome sequencing, and the main functions of these genes were determined via functional enrichment analysis.Results: Compared with the DKD model group, the medium-dose and high-dose TCM groups had significantly decreased levels of SCr, BUN, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and UAER (all p< 0.05). We identified 42 genes that potentially functioned in this therapeutic response, and the greatest effect on gene expression was in the high-dose TCM group. We also performed functional enrichment analysis to explore the potential mechanisms of action of these different genes.Conclusion: A high-dose of the Astragalus-rhubarb-saffron TCM provided the best prevention of DKD. Analysis of the kidney transcriptome suggested that this TCM mixture may prevent DKD by altering immune responses and oxygen delivery by hemoglobin.Keywords: diabetic kidney disease (DKD), mixture of astragalus, rhubarb, saffron, transcriptome sequencing, db/db mice

Rui Zhang,1,&ast; Zhengwei Gui,2,&ast; Jianguo Zhao,1 Lu Zhao2 1Department of Thyroid and Breast Surgery, Wuhan No. 1 Hospital, Wuhan, 430030, People’s Republic of China; 2Department of Thyroid and Breast Surgery, Tongji Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lu Zhao, Department of Thyroid and Breast Surgery, Tongji Hospital affiliated with Tongji Medical College of Huazhong University of Science and Technology, No. 1095 of Jiefang Avenue, Wuhan, 430030, People’s Republic of China, Email luzhao268@outlook.comPurpose: B-cell lymphoma 9 (BCL9), a key transcription co-activator of the Wnt pathway, contributed to tumor progression and metastasis in various tumors, whereas, the role of BCL9 in papillary thyroid cancer (PTC) has not been investigated.Methods: We acquired PTC gene expression data from The Cancer Genome Atlas (TCGA) database. Fifty-nine PTC tissues were applied to validate the clinical significance of BCL9. Cell experiments were applied to investigate the role of BCL9. Bioinformatics analysis was employed to investigate the biological functions of BCL9.Results: We found that BCL9 was higher expressed (P < 0.05) and an independent risk factor for lymph node metastasis (OR = 3.770, P = 0.025), as well as associated with poorer progression-free survival (PFS) (P = 0.049) in PTC. BCL9 knockdown inhibited proliferation and invasion of PTC cells. BCL9 was positively associated with the key genes of Wnt/β-catenin and MAPK pathway by co-expression analysis. GO, KEGG and GSEA analysis showed BCL9 might participated in PPAR, cAMP, and focal adhesion pathway. CIBERSORT analysis found BCL9 was negatively associated with CD8+ T cells and NK cell infiltration and positively with PD-L1 expression.Conclusion: Therefore, BCL9 was associated with lymph node metastasis and shorter PFS of PTC, due to promotion of PTC cell proliferation and invasion, activation of Wnt/β-catenin and MAPK pathway, inhibition of CD8+ T and NK cell infiltration, and promotion of PD-L1 expression.Keywords: BCL9, papillary thyroid cancer, lymph node metastasis, tumor immune microenvironment, tumor-infiltrating immune cells

Abdelhalim A Awidi,1 Jiawei Zhao,2 Ximin Li,1 Fatemeh Rajaii,1 Meleha Ahmad,3 Adrianna Jensen,4 Fasika A Woreta1 1Wilmer Eye Institute, Johns Hopkins Medicine, Baltimore, MD, USA; 2Plastic Surgery Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Ophthalmic Plastic and Reconstructive Surgery Department, University of California, San Francisco, CA, USA; 4Ophthalmic Plastic and Reconstructive Surgery Department, Pacific Center for Oculofacial and Aesthetic Plastic Surgery, San Francisco, CA, USACorrespondence: Fasika A Woreta, Ophthalmology Department, Wilmer Eye Institute, Baltimore, MD, USA, Tel +1 410 955 5650, Email fworeta1@jhmi.eduPurpose: To investigate the etiology and demographic associations of patients presenting with eyelid lacerations to a US level 1 trauma center emergency department (ED).Patient and Methods: A retrospective chart review of all patients with eyelid lacerations presenting to the ED at a single level 1 trauma center was performed. Eyelid lacerations were categorized as simple eyelid lacerations, eyelid lacerations with eyelid margin involvement, and eyelid lacerations with nasolacrimal system involvement. Data on demographics and clinical characteristics were analyzed.Results: A total of 303 eyelid laceration cases were identified, 56% were simple eyelid lacerations, followed by 24% with nasolacrimal involvement and 20% involving the eyelid margin. Sixty percent of animal bites/scratches resulted in a nasolacrimal system involving laceration, most commonly affecting children. Falls were the most common etiology in children and patients over the age of 60. Black patients, patients presenting with concomitant ophthalmic injuries, and those with Medicaid insurance were more likely to have an assault etiology (p < 0.05 for all).Conclusion: Falls were the most common etiology for eyelid lacerations in children and the elderly, while assault was the most common in adults. Identifying the most common etiology by demographic factors can help raise awareness regarding targeted prevention strategies for high-risk populations.Keywords: eyelid lacerations, ocular trauma, eye injury, emergency department

Meilan Xian,1,2,&ast; Jiaoyuan Xu,1,3,&ast; Yamei Zheng,4 Lei Zhang,4 Jie Zhao,4 Jie Chen,1 Siguang Li,1 Lingsang Lin,1 Yi Zhong,4 Zehua Yang,4 Tian Xie,4 Linhui Huang,4 Yipeng Ding1,4 1Department of General Practice, Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, Haikou, Hainan, 570311, People’s Republic of China; 2Department of General Diseases, Hainan Chengmei Hospital, Haikou, Hainan, 570300, People’s Republic of China; 3Department of General Clinic, Longbo Health Hospital, Lingao County, Hainan, 571800, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yipeng Ding; Linhui Huang, Department of General Practice, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, No. 19, Xiuhua Road, Xiuying District, Haikou, Hainan, 570311, People’s Republic of China, Email ypding@yeah.net; rochelle-11@163.comBackground: Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder in pulmonology. Chuanbeimu (CBM) is a traditional Chinese medicinal herb for treating COPD and has been widely utilized in clinical practice. However, the mechanism of CBM in the treatment of COPD remains incompletely understood. This study aims to investigate the underlying therapeutic mechanism of CBM for COPD using network pharmacology and experimental approaches.Methods: Active ingredients and their targets were obtained from the Traditional Chinese Medicine Systems Pharmacology database. COPD-associated targets were retrieved from the GeneCards database. The common targets for CBM and COPD were identified through Venn diagram analysis. Protein-protein interaction (PPI) networks and disease-herb-ingredient-target networks were constructed. Subsequently, the results of the network pharmacology were validated by molecular docking and in vitro experiments.Results: Seven active ingredients and 32 potential targets for CBM were identified as closely associated with COPD. The results of the disease-herb-ingredient-target network and PPI network showed that peimisine emerged as the core ingredient, and SRC, ADRB2, MMP2, and NOS3 were the potential targets for CBM in treating COPD. Molecular docking analysis confirmed that peimisine exhibited high binding affinity with SRC, ADRB2, MMP2, and NOS3. In vitro experiments demonstrated that peimisine significantly upregulated the expression of ADRB2 and NOS3 and downregulated the expression of SRC and MMP2.Conclusion: These findings indicate that CBM may modulate the expression of SRC, ADRB2, MMP2, and NOS3, thereby exerting a protective effect against COPD.Keywords: chuanbeimu, molecular docking, network pharmacology, experiment verification, chronic obstructive pulmonary disease

Manqiao Wang,&ast; Rong Luan,&ast; Boshi Liu, Yi Gong, Jinzhi Zhao, Xiteng Chen, Qianhui Yang, Jingjie Liu, Juping Liu, Yan Shao, Xiaorong Li Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Shao; Xiaorong Li, Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, People’s Republic of China, Tel +86 17622651170; +86 18622818042, Email sytmueh@163.com; xiaorli@163.comPurpose: To investigate the 3-months outcomes of patients who underwent intraoperative intravitreal injection of Ozurdex for proliferative diabetic retinopathy (PDR).Methods: This is a prospective randomized controlled clinical trial (ChiCTR2100043399). Seventy-one patients with PDR who had indications for surgery without intravitreal injection history within 3 months preoperatively were enrolled. Patients were randomly divided into three groups based on the medicine injected intraoperatively: Ozurdex, Conbercept, and Control group. The primary outcome is the best-corrected visual acuity (BCVA) within 3 months postoperatively. The secondary outcomes include the intraocular pressure (IOP), mean sensitivity, central retinal thickness and vessels perfusion.Results: The BCVA and the mean sensitivity improved in the three groups (F = 130.8, P < 0.0001; F = 34.18, P < 0.0001), but there was no statistical difference among the three groups (F = 0.858, P = 0.552; F = 0.964, P = 0.452). The IOP was no significant differences among the three groups within 3 months postoperatively (F = 0.881, P = 0.533). Compared with the other two groups, central retinal thickness (CRT) and outer retinal layer (ORL) thickness decreased significantly in patients of the Ozurdex group (F = 3.037, P = 0.008; F = 2.626, P = 0.018), especially in the diabetic macular edema (DME) patients (F = 2.761, P = 0.0164; F = 2.572, P = 0.0240). In macular region, superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) perfusion were not shown statistical difference at 3 months postoperatively in the all three groups compared with 1 day postoperatively (P > 0.05).Conclusion: Compared with the other two groups, anatomical outcomes was improved significantly in Ozurdex group for DR patients. Ozurdex may help to improve the visual acuity and visual sensitivity, and there is no significant difference in the change of IOP and microvascular improvement.Clinical Trial Registration: This trial is registered with the Chinese Clinical Trial Registry (http://www.chictr.org.cn, registration number ChiCTR2100043399).Keywords: proliferative diabetic retinopathy, ozurdex, pars plana vitrectomy, optical coherence tomography angiography, microperimetry

Yuting Feng, Xue Bao, Jinxuan Zhao, Lina Kang, Xuan Sun, Biao Xu Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, People’s Republic of ChinaCorrespondence: Xuan Sun; Biao Xu, Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, No. 321 Zhongshan Road, Nanjing, 210008, People’s Republic of China, Email sunxuan891119@163.com; xubiao62@nju.edu.cnIntroduction: Acute inflammatory storm is a major cause of myocardial ischemia/reperfusion (I/R) injury, with no effective treatment currently available. The excessive aggregation of neutrophils is correlated with an unfavorable prognosis in acute myocardial infarction (AMI) patients. Exosomes derived from mesenchymal stromal cells (MSC-Exo) have certain immunomodulatory potential and might be a therapeutic application. Therefore, we investigated the protective role of MSC-Exo in modulating neutrophil infiltration and formation of neutrophil extracellular traps (NETs) following myocardial I/R injury.Methods: Exosomes were isolated from the supernatant of MSCs using a gradient centrifugation method. We used flow cytometry, histochemistry, and immunofluorescence to detect the changes of neutrophils post-intravenous MSC-Exo injection. Additionally, cardiac magnetic resonance (CMR) and thioflavin S experiments were applied to detect microvascular obstruction (MVO). The NLR family pyrin domain containing 3 (NLRP3) inflammasome was examined for mechanism exploration. Primary neutrophils were extracted for in vitro experiment. Antibody of Ly6G was given to depleting the neutrophils in mice for verification the effect of MSC-Exo. Finally, we analyzed the MiRNA sequence of MSC-Exo and verified it in vitro.Results: MSC-Exo administration reduced neutrophil infiltration and NETs formation after myocardial I/R. MSC-Exo treatment also could attenuate the activation of NLRP3 inflammasome both in vivo and in vitro. At the same time, the infarction size and MVO following I/R injury were reduced by MSC-Exo. Moreover, systemic depletion of neutrophils partly negated the therapeutic effects of MSC-Exo. Up-regulation of miR-199 in neutrophils has been shown to decrease the expression of NETs formation after stimulation.Discussion: Our results demonstrated that MSC-Exo mitigated myocardial I/R injury in mice by modulating neutrophil infiltration and NETs formation. This study provides novel insights into the potential therapeutic application of MSC-Exo for myocardial ischemia/reperfusion injury. Keywords: myocardial ischemia/reperfusion injury, mesenchymal stromal cells, exosomes, neutrophil extracellular traps, mir-199

Jian Zhao,1 Surong Liang,2 Boyang Zhou,1 Min Li,3 Linfeng Li1 1Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Clinical Epidemiology and Evidence Based Medicine Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Linfeng Li, Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Beijing, 100050, People’s Republic of China, Tel +86-10-63139108, Email zoonli@sina.comObjective: To assess the correlations between Immunoglobulin E (IgE) levels, pruritus, and lesion severity in patients with eczema, atopic dermatitis, or urticaria.Methods: A retrospective study was conducted and data of 814 patients who visited the dermatology or allergy clinics of multiple hospitals, from December 2019 to December 2021, were collected. Patients were divided into children group (< 18 years, 325 cases), adult group (18– 60 years, 435 cases), and older population group (> 60 years, 54 cases) based on the age. Baseline information, pruritus severity, severity of skin lesions, total IgE level, and specific IgE level were recorded to analyze the complex relationship between them.Results: The prevalence of allergic conjunctivitis and allergic rhinitis in the children group was significantly higher than that in the adult and older population group (P < 0.01 or P < 0.05). The positive rate of specific IgE in children group was significantly higher than that in the adult and older population group (P < 0.01). The IgE levels in children with moderate pruritus were significantly lower than those of severe pruritus (63.39vs 114.42 IU/mL, P < 0.05). The IgE levels in children with mild and moderate skin lesions were significantly lower than those in children with severe skin lesions (58.95 vs 72.88 vs 169.15 IU/mL, P < 0.001 or P < 0.01, respectively).Conclusion: Relationships among age, severity of skin pruritus and lesions, and allergen-specific IgE response are complex and subtle, displaying dynamic patterns.Keywords: multi-center analysis, immunoglobulin E, pruritus severity, lesion severity

Yun Sun,1,&ast; Tongtong Yin,2,&ast; Mengli Li,2,3 Fangfang Wang,2 Jiaying Qi,2 Hui Zhang,2,4 Li Wang,2 Jiehua Zhao,5 Yu Zhang5 1Department of Oncology, Suzhou BenQ Medical Center, Suzhou, Jiangsu, People’s Republic of China; 2School of Nursing, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 3School of Nursing, Hong Kong Polytechnic University, Hongkong, People’s Republic of China; 4School of Nursing, Vocational Health College, Suzhou, Jiangsu, People’s Republic of China; 5Department of Nursing, Suzhou BenQ Medical Center, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Zhang; Jiehua Zhao, Email zhangyu-sz1985@outlook.com; hannah.zhao@benqmedicalcenter.comPurpose: This study aimed to establish equations for estimating muscle mass through anthropometric parameters or together with physical function parameters in the community-dwelling older adults, providing a simple way of muscle mass assessment.Methods: In this cross-sectional descriptive study, a total of 1537 older adults were recruited from the community and accepted the measurements of height, weight, upper arm and calf circumferences, grip strength, and walking speed. Body composition including appendicular skeletal muscle mass (ASM) was measured using bioelectrical impedance analysis (BIA). Participants were randomly divided into the development or validation group. Stepwise multiple linear regression was applied to develop equations in the development group. Thereafter, Pearson correlation coefficients, Bland-Altman plots, paired t-test, intraclass correlation coefficient (ICC) and paired-samples t-tests were used to assess the validity of the equations.Results: All parameters were significantly correlated with ASM (r = 0.195~0.795, P < 0.001) except for the age in the validation group (P = 0.746). The most optimal anthropometric equation was: [adjusted R2 = 0.911, standard error of the estimate (SEE) = 1.311, P < 0.001]. Comparatively speaking, this equation showed high correlation coefficient (r = 0.951, P < 0.001) and ICC (ICC = 0.950, P < 0.001). No significant differences were found between BIA-measured ASM and the estimated ASM. The Bland-Altman plot showed that the mean difference between the estimated ASM and BIA-measured ASM was 0 kg and the limits of agreement of ASM was − 2.70~2.60 kg. Furthermore, inclusion of physical function did not significantly improve the adjusted R2 and SEE.Conclusion: The anthropometric equation offers a practical alternative simple and dependable method for estimating ASM in community-dwelling older adults.Keywords: appendicular muscle mass, anthropometry, physical function, estimation equation, older adults

Jiemei Ye,1,2,&ast; Xiaoying Huang,3,4,&ast; Weiling Qin,1,2,&ast; Pan Liang,3,4 Jun Zhao,4 Yinxin Ye,1,2 Huojin Ji,1,2 Xinyun Peng,1,2 Yushan Liang,3,4 Yonglin Cai1,5 1Guangxi Health Commission Key Laboratory of Molecular Epidemiology of Nasopharyngeal Carcinoma, Wuzhou Red Cross Hospital, Wuzhou, Guangxi, People’s Republic of China; 2Department of Clinical Laboratory, Wuzhou Red Cross Hospital, Wuzhou, Guangxi, People’s Republic of China; 3Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 4Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 5Department of Preventive Medicine, Wuzhou Cancer Center, Wuzhou, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yonglin Cai, Guangxi Health Commission Key Laboratory of Molecular Epidemiology of Nasopharyngeal Carcinoma, Wuzhou Red Cross Hospital, Wuzhou, Guangxi, 543002, People’s Republic of China, Email cylzen@163.com Yushan Liang, Department of Otolaryngology-Head and Neck Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China, Email yushanliang33@outlook.comPurpose: Paired Box 5 (PAX5) is a transcription factor that is widely associated with carcinogenesis. PAX5 can maintain Epstein-Barr virus (EBV) latency in B cells, while a close association exists between EBV infection and nasopharyngeal carcinoma (NPC). However, there are very few reports on the correlation between PAX5 and NPC development. The aim of this study was to investigate the role of PAX5 in NPC.Patients and Methods: The clinical value and prognostic significance of PAX5 in NPC and the association with PAX5 expression and immune cell infiltration were analyzed by multiple GEO datasets. In vivo and in vitro experiments including real-time PCR, Western blot, CCK-8 assay, and methylation sequencing were used to validate the results of bioinformatics analysis.Results: The expression of PAX5 was significantly reduced in NPC tissues, with the low expression being correlated with advanced clinical stage, low tumor mutation burden and immune activation, high relative expression of EBV, poor survival for NPC patients. PAX5 exhibited excellent diagnostic performance and had potential as a predictive factor for response to the immune checkpoint inhibitors therapy. Enrichment analysis suggested that the low expression of PAX5 was associated with the dysregulation of Hippo and Wnt signaling pathways. The promoter of PAX5 gene was hypermethylated in NPC tissues. Furthermore, the in vitro and in vivo experiments revealed that NPC tissue and cell lines had low mRNA expression levels of PAX5, the PAX5 promoter was hypermethylated in NPC cell lines, and PAX5 overexpression inhibited NPC cell proliferation and tumor growth in nude mice.Conclusion: PAX5 may be a tumor suppressor and serve as a novel potential diagnostic and prognostic marker for NPC.Keywords: nasopharyngeal carcinoma, transcription factor, PAX5, prognosis, immunity, Epstein-Barr virus

Jing Zhao,&ast; Li Yu,&ast; Kangyun Sun, Yun Wang, Fangfei Xie Physical Examination Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fangfei Xie; Yun Wang, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People’s Republic of China, Tel +86 – 13913186601 ; +86 – 18913151605, Email fangfeixie@hotmail.com; 714388761@qq.comBackground: Studies on the associations between Systemic Immune-Inflammation (SII) and hepatic steatosis in China are still lacking. It is necessary to clarify the relationship between SII and hepatic steatosis in the Chinese population.Methods: This study was conducted from January 2022 to December 2022. A total of 37,095 participants were enrolled, among them, with 20,709 (55.83%) being males, and 16,386 (44.17%) being females. Physical and biochemical indicators were measured during a morning health examination after the examinees had fasted overnight. Diagnoses of hepatic steatosis were determined using an ultrasound test in accordance with the Chinese Guideline. Analysis of variance and chi-square tests were used to analyze the association between SII and hepatic steatosis. Stratification analyses were conducted based on age, gender, and obese status. Restricted cubic spline regression was also performed to explore the shapes of associations between SII and hepatic steatosis.Results: The average age of the 37,095 participants was 44.78 years old, with those with hepatic steatosis (11,599 (31.27%)) averaging 47.06 years old and those (25,496 (68.73%)) in the control group averaging 43.73 years old. SII was positively associated with hepatic steatosis. This association remained significant after conducting stratification analysis by age and gender. The inflection points in the inverted U-shaped curve for the relationship between SII and hepatic steatosis were 399.78 for gender (1000 cells /μL)(nonlinear P< 0.01, OR=1.31 (male), 1.00 (female)) and 385.79 for age (1000 cells /μL)(nonlinear P< 0.01, OR=1.35 (18~44 years old), 1.87 (45~59 years old), 1.93 (60~ years old)).Conclusion: SII is an independent risk factor for hepatic steatosis, and this effect appears to be stronger in subjects with BMI < 28 kg/m2. The nonlinear relationship between SII and hepatic steatosis, characterized by an inverted U-shaped distribution, may serve as a reference for diagnosing and evaluating hepatic steatosis.Keywords: hepatic steatosis, systemic immune-inflammation index, inflammation, association

Jing Zhao,1 Yan Li,1 Miao Guo,1 Guijuan Zhang,2 Ping Chen1 1Department of Gynaecology and Obstetrics, the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of China; 2Department of Gynaecology and Obstetrics, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Ping Chen, Department of Gynaecology and Obstetrics, the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of China, Tel +8613783589566, Fax +86037166262974, Email pingping6768@126.comBackground: COVID-19 is a highly contagious respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which became a global public health crisis. In the past 3 years, the COVID-19 pandemic has resulted in a dramatic increase in the occurrence of psychological symptoms such as depression, anxiety, and stress in global populations. Therefore, it is important to help pregnant women cope with major public emergencies and improve their physical and mental health.Objective: To investigate the status and influencing factors of anxiety, insomnia, and psychological stress disorder in pregnant women with COVID-19 to provide a theoretical basis for psychological intervention in pregnant women in the case of public health emergency events.Patients and methods: A cross-sectional survey was conducted with 435 pregnant women from multiple tertiary hospitals in Zhengzhou from November 6 to December 6, 2022. The questionnaire contents included the general information of pregnant women, insomnia scale, generalized anxiety scale, and the revised version of the Accident Impact Scale.Results: There are 251 pregnant women with anxiety (57.7%, 95% CI: (53.0%-62.4%).There are 166 pregnant women with insomnia.(38.2%, 95% CI: 33.6%-42.7%), There are 314 pregnant women with stress disorder.(72.2%, 95% CI: 68.0%– 76.4%). During the epidemic prevention and control period, whether pregnant women had a history of adverse pregnancy had a statistically significant difference in anxiety, insomnia and stress disorders.Conclusion and Recommendation: During the COVID-19 pandemic, pregnant women appeared to generally have anxiety, insomnia, and stress disorders. Poor pregnancy history is a protective factor for pregnant women with anxiety, insomnia, and post-traumatic stress disorder. In the case of similar public health emergencies, attention bias modification (ABM) may be a potential intervention measure to provide potentially new ideas for alleviating the psychological disorders of pregnant women during this special period.Keywords: novel coronavirus infection, pregnancy, anxiety, insomnia, psychological stress disorder

The main task in the production of steel in the basic oxygen furnace (BOF) is dephosphorization Therefore, the prediction and control of the end-point phosphorus content of molten steel is of great significance. Four machine learning regression models (Lasso, Random Forest, Xgboost, and Neural Network) were established to predict the end-point phosphorus content of molten steel in the BOF based on raw and auxiliary material data, process parameters, and production quality data. The prediction effect of the four models was further compared, and their prediction results were interpreted based on the interpretability of the models and the permutation importance method. The results showed that compared with linear regression and neural network regression model, two types of ensemble tree model have higher prediction accuracy, better stability with small data sets, and lower data preprocessing requirements. The factors influencing the end-point phosphorus (P) content in BOF were ranked in order of importance as: Tapping temperature > Turning down times > Steel scrap quantity> Operation habits of different working groups > Amount of oxygen injection> Sulfur and phosphorus content of molten iron > Addition amount of lime, limestone, and lightly burnt dolomite in the slag > Slag-splashing amount.

Jingqian Zhao,1,2,&ast; Chenyu Zhao,1,3,&ast; Tianrong Xun,1 Xiaokang Wang,1 Sui Wei,1,3 Chunxiao Ye,1 Mimi Zhang,1 Dan Guo,4 Xixiao Yang1 1Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, People’s Republic of China; 2School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 3School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People’s Republic of China; 4Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dan Guo; Xixiao Yang, Email nfyyyxb@smu.edu.cn; yaxx@smu.edu.cnPurpose: This study aims to investigate the effects of Huang Gan formula (HGF), a Chinese herbal prescription used for chronic kidney disease (CKD), on the regulation of the gut microbiota and colonic microenvironment of CKD.Methods: CKD rats were induced by 150 mg/kg adenine gavage for 4 weeks, then orally treated with or without 3.6 g/kg or 7.2 g/kg of HGF for 8 weeks. The renal function and structure were analyzed by biochemical detection, hematoxylin and eosin, Masson’s trichrome, Sirius red and immunochemical staining. Average fecal weight and number in the colon were recorded to assess colonic motility. Further, the changes in the gut microbiota and colonic microenvironment were evaluated by 16S rRNA sequencing, RT-PCR or immunofluorescence. The levels of inflammatory cytokines, uremic toxins, and NF-κB signaling pathway were detected by RT-PCR, ELISA, chloramine-T method or Western blotting. Redundancy analysis biplot and Spearman’s rank correlation coefficient were used for correlation analysis.Results: HGF significantly improved renal function and pathological injuries of CKD. HGF could improve gut microbial dysbiosis, protect colonic barrier and promote motility of colonic lumens. Further, HGF inhibited systemic inflammation through a reduction of TNF-α, IL-6, IL-1β, TGF-β 1, and a suppression of NF-κB signaling pathway. The serum levels of the selected uremic toxins were also reduced by HGF treatment. Spearman correlation analysis suggested that high-dose HGF inhibited the overgrowth of bacteria that were positively correlated with inflammatory factors (eg, TNF-α) and uremic toxins (eg, indoxyl sulfate), whereas it promoted the proliferation of bacteria belonging to beneficial microbial groups and was positively correlated with the level of IL-10.Conclusion: Our results suggest that HGF can improve adenine-induced CKD via suppressing systemic inflammation and uremia, which may associate with the regulations of the gut microbiota and colonic microenvironment.Keywords: chronic kidney disease, systemic inflammation, colonic microenvironment, gut-kidney axis

Xiaoling Feng,1 Xun Mao,1 Jianlin Zhao2,3 1Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, People’s Republic of China; 2The Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Jianlin Zhao; Xun Mao, Email zjlchongqing@gmail.com; maoxun@hospital.cqmu.edu.cnObjective: To explore the prenatal diagnosis, clinical characteristics, and perinatal outcomes of placenta accreta spectrum in different placental locations.Methods: This was a retrospective cohort study. Pregnant women who delivered at two tertiary referral hospitals from January 2013 to December 2022 and were ultimately pathologically diagnosed with placenta accreta spectrum were included. They were divided into three groups based on different placental locations (anterior, posterior, and lateral wall/fundus). The differences in prenatal diagnosis, clinical characteristics, and perinatal outcomes among the three groups were compared.Results: There were 115,470 deliveries in a ten-year period at the two hospitals, and 118 case patients were confirmed to have a pathologically diagnosed placenta accreta spectrum. The posterior placenta group had a lower rate of placenta previa (76.9% vs 94.9% vs 100%, p< 0.05) and a higher gestational age at delivery (36.4± 2.45 vs 34.91± 1.76 vs 34.31± 3.41, p< 0.05) compared to the other two groups. The anterior placenta group had a significantly higher rate of invasive (increta/percreta) form placenta accreta spectrum (81.4% vs 36.5% vs 28.6%, p< 0.05) and planned cesarean section (96.6% vs 80.8% vs 71.4%, p< 0.05) compared to the other two groups. In terms of prenatal diagnosis, the anterior placenta group had a significantly higher rate of placenta accreta spectrum prenatal suspicion rate compared to the other two groups (86.4% vs 36.5% vs 57.1%, p< 0.05). The posterior placenta group had a lower rate of preoperative abdominal aortic balloon placement compared to the other two groups (5.8% vs 28.8% vs 28.6%, p< 0.05). There were no statistically significant differences among the three groups in primary perinatal outcomes, though the anterior placenta group had a longer postoperative hospital stay.Conclusion: The prenatal diagnosis rate and proportion of invasive form of placenta accreta spectrum occurring in non-anterior placenta are relatively lower than anterior placenta. There were no significant differences in major perinatal outcomes among the three groups.Keywords: placenta accreta spectrum, placenta location, clinical characteristics, perinatal outcomes

Ying Qin,1 Jingwen Zhao,1 Yong Yang,1 Yanjing Liu,1 Hui Xiang,2 Jingfeng Tong,3 Chengchen Huang3 1Department of Psychiatry, the Second People’s Hospital of Guizhou Province, Guiyang, 550004, People’s Republic of China; 2Department of Psychology, Guizhou Provincial People’s Hospital, Guiyang, 550002, People’s Republic of China; 3Shanghai Conlight Medical Laboratory, Co, Ltd, Shanghai, 200032, People’s Republic of ChinaCorrespondence: Chengchen Huang, Shanghai Conlight Medical Laboratory Co, Ltd, Shanghai, People’s Republic of China, Email huangcc@kangliyixue.comPurpose: We investigate the association of HTR1A rs10042486 and rs6295 with efficacy and plasma concentrations of atypical antipsychotics in the treatment of male patients with schizophrenia.Patients and Methods: A total of 140 male patients diagnosed with schizophrenia who were treated with any single atypical antipsychotic between May 2020 and May 2022 were retrospectively included. Clinical symptoms were assessed using Positive and Negative Syndrome Scale (PANSS). All SNPs were typed using Agena Bioscience MassARRAY DNA mass spectrometry. Plasma concentrations of antipsychotics at week 3, 6 and 12 after treatment commence were analyzed using mass spectrometry.Results: For efficacy of atypical antipsychotics, we observed no significant difference between HTR1A rs10042486, rs6295 and positive symptom improvement, where the patients with heterozygous mutant at the rs10042486 and rs6295 locus were superior to those with wild-type or homozygous mutant genotypes on negative symptom improvement, especially at 12 weeks of follow-up when the difference between genotypes at the rs6295 locus have statistical significance (P = 0.037). For plasma concentration, we found that quetiapine plasma concentrations were significantly lower in patients with mutation-heterozygous types than in wild-type and homozygous mutation genotypes at week 6. In contrast, higher plasma concentrations were found for mutant heterozygous than wild genotypes in the risperidone monotherapy analysis, and the difference among genotypes at the rs6295 locus was statistically significant at 6 weeks of follow-up.Conclusion: The assessment of the correlation of genetic polymorphisms of HTR1A rs6295 and rs10042486 in male patients with schizophrenia with the monitoring of therapeutic drug concentrations and therapeutic efficacy provides a constructive foundation for the clinical individualization of antipsychotics, such as quetiapine and risperidone, which is important in selecting the dose of the medication and improving the improvement of negative symptoms.Keywords: schizophrenia, HTR1A, polymorphism, plasma concentration, atypical antipsychotics, asian male patients

Mei Wu,1,2,&ast; Jingui Zhao,1,2,&ast; Zhongqiang Liu,1,2 Haiyang Zhang1,2 1Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyang Zhang, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China, Tel + 86 15756273633, Fax + 86 15756273633, Email icudoc@163.comBackground: Clinically, Carbapenem-resistant Pseudomonas aeruginosa (CRPA) meningitis is extremely difficult to cure and has a high mortality rate. Intrathecal injection of polymyxins B is suggested to be an effective anti-infective means to treat intracranial infection with CRPA. However, due to the potential drug toxicity of polymyxin B in children, this regimen has rarely been reported in pediatrics.Case Description: A 5-year-old male patient diagnosed with Epstein-Barr virus-induced hemophagocytic syndrome (HPS) exhibited persistent fever for over a month despite antibacterial and chemotherapy regimens. During hospitalization, the patient presented with unconsciousness, nystagmus, and myasthenia. Cerebrospinal fluid (CSF) analysis indicated elevated leukocyte counts and protein levels. Sputum and blood cultures, as well as metagenomic next-generation sequencing (mNGS) of CSF, identified CRPA. Intravenous and intrathecal polymyxin B administration resulted in temperature normalization and amelioration of consciousness disturbances and nystagmus. Subsequent CSF analysis yielded normal results, while polymyxin B treatment exhibited no nephrotoxicity or neurotoxicity.Conclusion: Intrathecal injection of polymyxin B in children with meningitis caused by CRPA is an effective treatment without remarkable adverse events.Keywords: polymyxin B, intrathecal injection, carbapenem resistant, Pseudomonas aeruginosa, meningitis

Xian Wang,1 Xiaming Liu,1 Jun Zhao,1 Manyu Chen,1 Lidong Wang2 1Graduate School of Chengde Medical College, Chengde, Hebei, People’s Republic of China; 2Department of Endocrinology and Immunology, Chengde Central Hospital Affiliated to Chengde Medical College, Chengde, Hebei, People’s Republic of ChinaCorrespondence: Lidong Wang, Department of Endocrinology and Immunology, Chengde Central Hospital Affiliated to Chengde Medical College, Chengde, Hebei, People’s Republic of China, Tel +86 13703142117, Email whlfdjs@126.comIntroduction: To investigate the predictors of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients and establish a nomogram model for predicting the risk of DKD.Methods: The clinical data of T2DM patients, admitted to the Endocrinology Department of Chengde Central Hospital from October 2019 to September 2020 and divided into a case group or a control group based on whether they had DKD, were collected. The predictive factors of DKD were screened by univariate and multivariate analysis, and a nomogram prediction model was constructed for the risk of DKD in T2DM. Bootstrapping was used for model validation, receiver operating characteristic (ROC) curve and GiViTI calibration curve were used for evaluating the discrimination and calibration of prediction model, and decision analysis curve (DCA) was used for evaluating the practicality of model.Results: Predictors for DKD are diabetic retinopathy (DR), hypertension, history of gout, smoking history, using insulin, elevation of body mass index (BMI), triglyceride (TG), cystatin C (Cys-C), and reduction of 25 (OH) D. The nomogram prediction model based on the above nine predictors had good representativeness (Bootstrap method: precision: 0.866, Kappa: 0.334), differentiation [the area under curve (AUC) value: 0.868], and accuracy (GiViTI-corrected curved bands, P = 0.836); the DAC curve analysis showed that the prediction model, whose threshold probability was in the range of 0.10 to 0.70, had clinical practical value.Conclusion: The risk of DKD in T2DM could be predicted accurately by DR, hypertension, history of gout, smoking history, using insulin, elevation of BMI, TG, Cys-C, and reduction of 25 (OH) D.Keywords: type 2 diabetes mellitus, diabetic kidney disease, predictive model, 25-hydroxyvitamin D, diabetic retinopathy

Jia Zhao,1,&ast; Wenbin Ding,1,&ast; Benfang Fan,2 Chunxia Chen,1 Lihua Wang2 1Department of Interventional Radiology, Nantong First People’s Hospital, Nantong, 226001, People’s Republic of China; 2Nursing Department, Nantong First People’s Hospital, Nantong, 226001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lihua Wang, Nursing Department, Nantong First People’s Hospital, No. 666 of Shengli Road, Chongchuan District, Nantong, 226001, People’s Republic of China, Tel +86 513 81111039, Email wanglihuawlh6@126.comObjective: We develop the Readiness for Hospital Discharge Scale (RHDS) for patients with bile duct carcinoma catheterized after percutaneous transhepatic cholangial drainage (PTCD) and test the reliability and validity of the scale, so as to provide a quantitative tool for evaluating the discharge readiness of patients catheterized after PTCD.Methods: The initial scale was developed following literature review, qualitative interviews, expert consultation, and other methods based on Meleis’ Theory of Transition. We selected a total of 286 patients with bile duct carcinoma catheterized after PTCD from four tertiary A-grade hospitals in Nantong City. We conducted a cross-sectional survey using the initial scale to test the validity and reliability of the scale.Results: RHDS for patients catheterized post-PTCD consisted of five dimensions, with a cumulative variance contribution rate of 74.6%. The Cronbach’s α coefficient of the scale was 0.856, and that of each dimension was between 0.740 and 0.891; the scale-content validity index (S-CVI) was 0.875.Conclusion: RHDS for patients with bile duct carcinoma catheterized after PTCD developed in this study, has good reliability and validity, and can be a useful tool for evaluating the discharge readiness of patients with bile duct carcinoma catheterized after PTCD.Keywords: bile duct carcinoma, discharge readiness, percutaneous transhepatic cholangial drainage, scale

Wenpeng Yu,1– 4,&ast; Jingli Ding,5,&ast; Jianfeng Chen,1– 3,&ast; Ying Jiang,4 Jinping Zhao,1– 3 Jichun Liu,4,6 Jianliang Zhou,1– 3 Jinping Liu1– 3 1Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China; 2Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, 430071, People’s Republic of China; 3Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, 430071, People’s Republic of China; 4Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 5Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China; 6Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianliang Zhou; Jinping Liu, Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, People’s Republic of China, Tel +86 13767117511 ; +86 27-67812888, Email zjl20210802@whu.edu.cn; liujinping@znhospital.cnIntroduction: Excessive generation of reactive oxygen species (ROS) following myocardial ischemia-reperfusion (I/R) can result in additional death of myocardial cells. The rapid clearance of ROS after reperfusion injury and intervention during subsequent cardiac repair stages are crucial for the ultimate recovery of cardiac function.Methods: Magnesium-doped mesoporous bioactive glasses were prepared and loaded with the antioxidant drug gallic acid into MgNPs by sol-gel method. The antioxidant effects of MgNPs/GA were tested for their pro-angiogenic and anti-inflammatory effects based on the release characteristics of GA and Mg2+ from MgNPs/GA. Later, we confirmed in our in vivo tests through immunofluorescence staining of tissue sections at various time points that MgNPs/GA exhibited initial antioxidant effects and had both pro-angiogenic and anti-inflammatory effects during the cardiac repair phase. Finally, we evaluated the cardiac function in mice treated with MgNPs/GA.Results: We provide evidence that GA released by MgNPs/GA can effectively eliminate ROS in the early stage, decreasing myocardial cell apoptosis. During the subsequent cardiac repair phase, the gradual release of Mg2+ from MgNPs/GA stimulated angiogenesis and promoted M2 macrophage polarization, thereby reducing the release of inflammatory factors.Conclusion: MgNPs/GA acting on multiple cell types is an integrated solution for comprehensive attenuation of myocardial ischaemia-reperfusion injury and cardiac function protection.Keywords: myocardial ischemia/reperfusion injury, mesoporous bioactive glass, gallic acid, magnesium ion, macrophage polarization

Long Zhang,1,2,&ast; Hongyan Zhang,3,4,&ast; Xue Zhou,1 Jing Zhao,5 Xingchen Wang6 1First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 2Department of Traditional Chinese Medicine, Zibo TCM-Integrated Hospital, Zibo, Shandong, People’s Republic of China; 3Department of Traditional Chinese Medicine, Shanghai Sixth People’s Hospital, Shanghai, People’s Republic of China; 4Shaanxi Key Laboratory of Research on TCM Physical Constitution and Diseases Prevention and Treatment, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China; 5Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 6Division of Neurology, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xingchen Wang, Division of Neurology, the Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, No. 1 Jingba Road, Jinan, Shandong, 250001, People’s Republic of China, Tel +86 0531 58261203, Email sdlcwxc@163.comBackground: Both migraine and stroke heavily burden individuals, health systems, and society. The migraine-stroke association is of concern and has been studied widely. Our objective is to explore and overview the current research status and emerging trends.Materials and Methods: Studies on migraine-stroke association from January 2013 to May 2023 were retrieved and screened from the Web of Science Core Collection (WOSCC) database. Records fulfilling the selection criteria were downloaded and imported into CiteSpace for data mining and visualization.Results: A total of 862 papers on migraine-stroke association were included. Annual publications grew slowly. The United States and European countries dominated research in this area. Harvard University published the largest number of articles, while the University of London was most active with other institutions. Ayata Cenk contributed the most articles, while KURTH T and NEUROLOGY were co-cited most. Research hotspots included migraine with aura, ischemic stroke, patent foramen ovale, cortical spreading depolarization, meta-analysis, cross-sectional study, and risk factors. Pathophysiology and small vessel disease represented research frontiers and emerging trends.Conclusion: Our study scientifically outlines the migraine-stroke association over the past decade, presenting useful information.Keywords: migraine with aura, ischemic stroke, patent foramen ovale, cortical spreading depolarization, pathophysiology, CiteSpace

Wenna Zhang,1– 3 Xin Cai,1– 3 Jiayao Sun,2– 4 Weiwei Wang,2– 4 Jingfang Zhao,2– 4 Qing Zhang,1– 3 Guoliang Jiang,1– 3,5 Zheng Wang1– 3,5 1Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, People’s Republic of China; 3Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, People’s Republic of China; 4Department of Medical Physics, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China; 5Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Guoliang Jiang; Zheng Wang, Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, No. 4365 Kangxin Road, Pudong, Shanghai, 201315, People’s Republic of China, Email guoliang.jiang@sphic.org.cn; zheng.wang@sphic.org.cnPurpose: Carbon ion radiotherapy (CIRT) has emerged as a promising treatment modality for hepatocellular carcinoma (HCC). However, evidence of using the pencil beam scanning (PBS) technique to treat moving liver tumors remains lacking. The present study investigated the efficacy and toxicity of PBS CIRT in patients with HCC.Methods: Between January 2016 and October 2021, 90 consecutive HCC patients treated with definitive CIRT in our center were retrospectively analyzed. Fifty-eight patients received relative biological effectiveness-weighted doses of 50– 70 Gy in 10 fractions, and 32 received 60– 67.5 Gy in 15 fractions, which were determined by the tumor location and normal tissue constraints. Active motion-management techniques and necessary strategies were adopted to mitigate interplay effects efficiently. Oncologic outcomes and toxicities were evaluated.Results: The median follow-up time was 28.6 months (range 5.7– 74.6 months). The objective response rate was 75.0% for all 90 patients with 100 treated lesions. The overall survival rates at 1-, 2- and 3-years were 97.8%, 83.3% and 75.4%, respectively. The local control rates at 1-, 2- and 3-years were 96.4%, 96.4% and 93.1%, respectively. Radiation-induced liver disease was not documented, and 4 patients (4.4%) had their Child–Pugh score elevated by 1 point after CIRT. No grade 3 or higher acute non-hematological toxicities were observed. Six patients (6.7%) experienced grade 3 or higher late toxicities.Conclusion: The active scanning technique was clinically feasible to treat HCC by applying necessary mitigation measures for interplay effects. The desirable oncologic outcomes as well as favorable toxicity profiles presented in this study will be a valuable reference for other carbon-ion centers using the PBS technique and local effect model-based system, and add to a growing body of evidence about the role of CIRT in the management of HCC.Keywords: hepatocellular carcinoma, carbon ion radiotherapy, pencil beam scanning, local effect model

Yan Chen,1,&ast; Han Du,1,&ast; Xin Wang,1,&ast; Baixing Li,1 Xuzhuo Chen,2 Xiao Yang,1 Changqing Zhao,1 Jie Zhao1 1Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China; 2Department of Oral Surgery, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changqing Zhao; Xiao Yang, Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China, Email zhaocq9hospital@163.com; walkingweapon@outlook.comIntroduction: The crosstalk between intervertebral disc degeneration (IVDD) and type 2 diabetes mellitus (T2DM) has been investigated. However, the common mechanism underlying this phenomenon has not been clearly elucidated. This study aimed to explore the shared gene signatures of IVDD and T2DM.Methods: The expression profiles of IVDD (GSE27494) and T2DM (GSE20966) were acquired from the Gene Expression Omnibus database. Five hub genes including ANGPTL4, CCL2, CCN3, THBS2, and INHBA were preliminarily screened. GO (Gene Ontology) enrichment analysis, functional correlation analysis, immune filtration, Transcription factors (TFs)-mRNA-miRNA coregulatory network, and potential drugs prediction were performed following the identification of hub genes. RNA sequencing, in vivo and in vitro experiments on rats were further performed to validate the expression and function of the target gene.Results: Five hub genes (ANGPTL4, CCL2, CCN3, THBS2, and INHBA) were identified. GO analysis demonstrated the regulation of the immune system, extracellular matrix (ECM), and SMAD protein signal transduction. There was a strong correlation between hub genes and different functions, including lipid metabolism, mitochondrial function, and ECM degradation. The immune filtration pattern grouped by disease and the expression of hub genes showed significant changes in the immune cell composition. TFs-mRNA-miRNA co-expression networks were constructed. In addition, pepstatin showed great drug-targeting relevance based on potential drugs prediction of hub genes. ANGPTL4, a gene that mediates the inhibition of lipoprotein lipase activity, was eventually determined after hub gene screening, validation by different datasets, RNA sequencing, and experiments.Discussion: This study screened five hub genes and ANGPTL4 was eventually determined as a potential target for the regulation of the crosstalk in patients with IVDD and T2DM.Keywords: ANGPTL4, biomarker, functional analysis, intervertebral disc degeneration, type 2 diabetes mellitus

Guimei Fan,1 Mo Yi,2 Xiangmin Qiu,1 Jinfang Zhao1 1Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 2School of Nursing, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Jinfang Zhao, Shandong Provincial Hospital Affiliated to Shandong First Medical University, &num;324 Jingwuweiqi Road, Huaiyin District, Jinan City, Shandong Province, 250021, People’s Republic of China, Email zjfcqt@qq.comPurpose: This study aims to explore the complicated decision-making dilemma and challenges confronted by parents of children suffering from severe asthma within the Pediatric Intensive Care Unit (PICU) when participating in the development of their children’s discharge care plans.Patients and Methods: Employing a phenomenological methodology, a purposive sampling was performed to engage with 17 parents who participated in in-depth and semi-structured interviews between October 2022 and February 2023. The transcripts of these interviews were transcribed into textual data, which was then subjected to Colaizzi’s seven-step analysis for meticulous coding and comprehensive thematic elucidation.Results: The comprehensive analysis of the factors involved in the intricate decision-making dilemmas faced by parents of children with severe asthma during the process of crafting discharge care plans in the PICU revealed five themes and eight sub-themes: 1) Complexity of asthma-related information; 2) Insufficient provision of comprehensive decision-making support; 3) Encountering negative emotions and wavering confidence; 4) Navigating realistic constraints impacting both parents and HCPs; 5) Balancing the advantages and disadvantages of various plans.Conclusion: Parents of children with severe asthma in the PICU encounter intricate and multifaceted decision-making dilemmas while engaging in the formulation of discharge care plans. These complexities significantly dampen their decision-making enthusiasm and introduce potential risks to the children’s prognosis and recovery. In the future, it is imperative to leverage the guidance provided by healthcare professionals (HCPs) in the decision-making process, develop tailored decision support tools specifically designed for the formulation of discharge care plans for children with severe asthma in the PICU.Keywords: severe asthma, parents, discharge care plan, decision-making dilemma, phenomenological study