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Licai Miao,1,* Zihao Xu,1,* Junhao Sui,1,* Xiangyu Meng,1,* Shicheng Huo,2 Shu Liu,1 Mengchen Chen,1 Zhong Zheng,1 Xiaobin Cai,3 Hao Zhang1 1Department of Orthopedics, Changhai Hospital Affiliated to the Navy Military Medical University, Shanghai, 200433, People’s Republic of China; 2Department of Orthopedic Surgery, Spine Center, Changzheng Hospital, Navy Medical University, Shanghai, 200003, People’s Republic of China; 3Department of Orthopedics Shanghai Tenth People’s Hospital Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaobin Cai, Department of Orthopedics Shanghai Tenth People’s Hospital Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China, Tel +8613122575295, Email caixbjn@163.com Hao Zhang Department of Orthopedics, Changhai Hospital Affiliated to the Navy Military Medical University, Tel +8613917856377, Email zhanghsmmu@126.comPurpose: Skin injury, often caused by physical or medical mishaps, presents a significant challenge as wound healing is critical to restore skin integrity and tissue function. However, external factors such as infection and inflammation can hinder wound healing, highlighting the importance of developing biomaterials with antibiotic and wound healing properties to treat infections and inflammation. In this study, a novel photothermal nanomaterial (MMPI) was synthesized for infected wound healing by loading indocyanine green (ICG) on magnesium-incorporated mesoporous bioactive glass (Mg-MBG) and coating its surface with polydopamine (PDA).Results: In this study, Mg-MBG and MMPI was synthesized via the sol-gel method and characterized it using various techniques such as scanning electron microscopy (SEM), the energy dispersive X-ray spectrometry (EDS) system and X-ray diffraction (XRD). The cytocompatibility of MMPI was evaluated by confocal laser scanning microscopy (CLSM), CCK8 assay, live/dead staining and F-actin staining of the cytoskeleton. The antibacterial efficiency was assessed using bacterial dead-acting staining, spread plate method (SPM) and TEM. The impact of MMPI on macrophage polarization was initially evaluated through flow cytometry, qPCR and ELISA. Additionally, an in vivo experiment was performed on a mouse model with skin excision infected. Histological analysis and RNA-seq analysis were utilized to analyze the in vivo wound healing and immunomodulation effect.Conclusion: Collectively, the new photothermal and photodynamic nanomaterial (MMPI) can achieve low-temperature antibacterial activity while accelerating wound healing, holds broad application prospects.Keywords: infection-related wounds, magnesium-doped bioactive glass, photothermal therapy, photodynamic therapy, immunomodulation

Xiaoqing Ma,* Ruoying Zhang,* Xinjun Cai, Yuying Lang, Huaichong Wang, Jinmeng Li Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinmeng Li, Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang Province, 310000, People’s Republic of China, Email jinmeng608@163.comAbstract: As a new generation of oxazolidinone antibacterial drugs, contezolid has been shown to have comparable or even stronger activity than linezolid and has a low risk of adverse reactions such as bone marrow suppression toxicity. However, there are currently very few clinical reports and pharmacokinetic data of contezolid on the anti-tuberculosis therapy. Therefore, we report a case study of the pharmacokinetic study of contezolid in elderly patients with renal insufficiency and tuberculosis. The patient’s condition improved after receiving an anti-tuberculosis regimen containing contezolid, with significant absorption of pleural effusion and lung plaques and nodules reduced. During the treatment, the patients’ platelet and white blood cell levels fluctuated within normal ranges, but hemoglobin levels significantly decreased and did not recover after discontinuation of contezolid. The trough concentration of contezolid and the concentration at 2, 4, 6, and 10 h after administration were 1.27μg/mL, 3.88μg/mL, 6.32μg/mL, 8.99μg/mL, and 3.14μg/mL, respectively. The plasma concentrations of bedaquiline and cycloserine during the treatment were also monitored. This study demonstrated the efficacy and safety of contezolid in the treatment of multidrug-resistant tuberculosis and analyzed its pharmacokinetic changes in elderly patients with renal insufficiency, providing a reference for the clinical use of contezolid.Keywords: contezolid, tuberculosis, plasma concentration, efficacy, safety

Weihua Yu,* Jionghuang Chen,* Shengxi Jin, Xiaoxiao Fan, Xiujun Cai Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiujun Cai, Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, People’s Republic of China, Tel/Fax +86-571-86006617, Email srrsh_cxj@zju.edu.cnBackground: Obesity is reaching epidemic proportions in the developed world. The biosynthesis and degradation of human glycoproteins take place at the highest level in the liver. However, the association between glycosylation and the factors affecting obesity and metabolism-associated steatohepatitis (MASH) is still unclear.Materials and Methods: Gene expression data of liver samples from obese patients were retrieved from GSE83452 and GSE89632 databases. Difference analysis and machine learning were used to identify hub genes involved in glycosylation and associated with the response of weight loss treatment. A total of 7 glycosylation-related hub genes were identified and then subjected to correlation analysis, immune cells infiltration analysis and ROC (Receiver Operating Characteristic) analysis. We also evaluated the potential function of 7 hub genes in obesity patients. MASH mice were used to validate the glycosylation-related hub genes.Results: A total of 25 overlapped glycosylation-related genes were identified by DEGs analysis. ACER2, STX17, ARF5, GPC4, ENTPD5, NANP, and DPY19L2 were identified as hub genes. Among these hub genes, ACER2, STX17, ARF5, and ENTPD5 were also differential expressed in MASH patients. ENTPD5 showed increased transcription in obese MASH mice.Conclusion: The current study identified seven glycosylation-related genes, ACER2, STX17, ARF5, GPC4, ENTPD5, NANP, and DPY19L2, that might play key roles in the development of obesity. ENTPD5 might play a key role in the development of MASH. These findings provide fresh perspectives for expanding the investigation of obesity and MASH.Keywords: obesity, MASH, glycosylation, machine learning

Jianwen Zhao,1– 5,* Xintian Cai,1– 5,* 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*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

Junjie Cheng,1,* Yuan Yuan,1,* Jinmeng Li,1 Ruoying Zhang,1 Xudong Fan,1 Zhirou Xu,2 Huirong Lin,3 Xinjun Cai,1 Mingfeng Zheng4 1Department of Pharmacy, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, People’s Republic of China; 2Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, People’s Republic of China; 3Department of Pharmacy, Taizhou Cancer Hospital, Taizhou, People’s Republic of China; 4Department of Orthopaedics, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingfeng Zheng; Xinjun Cai, Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou, Zhejiang Province, 310003, People’s Republic of China, Email zmfyxz3@163.com; zjtcmcxj@zcmu.edu.cnPurpose: Previous studies have indicated that the development of severe adverse events is associated with linezolid peak concentration (Cmax), but the factors affecting linezolid Cmax and evidences on therapeutic drug monitoring to anticipate toxicity in drug-resistant tuberculosis (DR-TB) patients have not been clarified clearly. This study aimed to explore the factors influencing linezolid Cmax and investigate the association between linezolid concentration and hematological toxicity.Patients and Methods: This study included patients with drug-resistant tuberculosis treated with linezolid from January 2022 to September 2023. We analyzed the factors affecting linezolid Cmax using chi-squared and binary logistic regression. The diagnostic utility of linezolid Cmax in predicting hematological toxicity was evaluated using receiver operating characteristic (ROC) analysis.Results: A total of 76 patients were enrolled in the study. 63.20% met the standard rates for linezolid Cmax. Age (P=0.036), weight (P=0.0016), and creatinine clearance (P=0.0223) significantly correlated with the Cmax. Hematological toxicity was observed in 46.05% (35/76) of patients, characterized by thrombocytopenia (31.58%, 24/76), anemia (6.58%, 5/76), and leukopenia (21.05%, 16/76). ROC curve analysis confirmed the predictive value of linezolid Cmax for thrombocytopenia with an area under curve of 0.728.Conclusion: Suboptimal linezolid Cmax was prevalent among patients with DR-TB, with age, weight, and renal function emerging as influential factors. Elevated linezolid Cmax increases the risk of thrombocytopenia. Meticulous monitoring of linezolid Cmax is imperative during anti-DR-TB therapy to tailor treatment and mitigate hematological toxicity.Keywords: linezolid, therapeutic drug monitoring, influencing factors, hematological toxicity

Shuaiwei Song,1– 5,* Xintian Cai,1– 5,* Junli Hu,1– 5 Qing Zhu,1– 5 Di Shen,1– 5 Huimin Ma,1– 5 Yingying Zhang,1– 5 Rui Ma,1– 5 Wenbo Yang,1– 5 Jing Hong,1– 5 Delian Zhang,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*These authors contributed equally to this workCorrespondence: Nanfang Li, Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Urumqi, Xinjiang, 830001, People’s Republic of China, Tel +86 8,564,818, Email lnanfang2016@sina.comObjective: While the role of aldosterone in bone metabolism is well established, the specific effects of the widely used aldosterone antagonist, spironolactone, on bone health are not fully understood. This study aimed to investigate the effects of spironolactone on osteoporosis and future fracture risk in middle-aged and elderly hypertensive patients, revealing its potential benefits for bone health.Methods: Propensity score matching was employed in this study to create matched groups of spironolactone users and non-users at a 1:4 ratio. We investigated the association between spironolactone use and the risk of osteoporosis using multivariate logistic regression analysis. Furthermore, we conducted multivariate linear regression analysis to explore the relationship between cumulative dosage and the FRAX score. Subgroup analysis was also performed to assess the effects under different stratification conditions.Results: In both pre-match and post-match analyses, multivariable logistic regression revealed a significant reduction in the risk of osteoporosis in the spironolactone usage group (pre-match: odds ratios [OR] 0.406, 95% confidence interval [CI], 0.280– 0.588; post-match: OR 0.385, 95% CI, 0.259– 0.571). Furthermore, post-match multivariable linear regression demonstrated a clear negative correlation between cumulative spironolactone dosage and the FRAX score. Subgroup analyses consistently supported these findings.Conclusion: This study offers evidence supporting the significant positive impact of the antihypertensive drug spironolactone on bone health, resulting in a substantial reduction in the risk of osteoporosis and future fractures in hypertensive patients. Future research should consider conducting large-scale, multicenter, randomized controlled trials to further investigate the long-term effects of spironolactone on bone health in hypertensive patients.Keywords: hypertensive, spironolactone, aldosterone, osteoporosis, FRAX score

Yuling Liang,1,* Yuqing Xie,1,* Xiaoli Liu,1 Lihua Yu,1 Huiwen Yan,1 Zimeng Shang,1 Yuan Wu,1 Xue Cai,2 Wanxin Shi,2 Juan Du,3 Zhiyun Yang1 1Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 2Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 3Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China*These authors contributed equally to this workCorrespondence: Juan Du, Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China, Email duj656@163.com Zhiyun Yang, Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China, Tel +86-10-84322148, Email yangzhiyun2016@163.comPurpose: Traditional Chinese medicine (TCM) therapy is an important means to treat hepatocellular carcinoma (HCC), Astragalus (Latin name: Hedysarum Multijugum Maxim; Chinese name: Huangqi, HQ) and Atractylodes (Latin name: Atractylodes Macrocephala Koidz; Chinese name: Baizhu, BZ) (HQBZ), a classic herb pair, is often used in combination to HCC. However, the main components and potential mechanisms of HQBZ therapy in HCC remain unclear. This study aimed to identify the potential active ingredients and molecular mechanisms of action of HQBZ in HCC treatment.Methods: The HQBZ-Compound-Target-HCC network and HQBZ-HCC transcriptional regulatory network were constructed to screen the core active compound components and targets of HQBZ therapy for HCC. Molecular docking techniques are used to verify the stability of binding core active compound components to targets. GO and KEGG enrichment analysis were used to explore the signaling pathway of HQBZ in HCC treatment, the mechanism of HQBZ treatment of HCC was verified based on in vivo H22 tumor bearing mice and in vitro cell experiments.Results: Network pharmacology and molecular docking studies showed that HQBZ treatment of HCC was related to the targeted regulation of IL-6 and STAT3 by the active compound biatractylolide, KEGG pathway enrichment analysis suggest that HQBZ may play a role in the treatment of HCC through IL-6/STAT3 signaling pathway. In vitro experiment results proved that HQBZ could regulate IL-6/STAT3 signaling pathway transduction on CD8+T cells, inhibit CD8+T cell exhaustion and restore the function of exhausted CD8+T cells. In vivo experiment results proved that HQBZ can regulate IL-6/STAT3 signaling pathway transduction in H22 liver cancer model mouse tumor tissue, increased the proportion of tumor infiltrating CD8+T cells.Conclusion: This study found that HQBZ may play a therapeutic role in HCC by targeting IL-6 and STAT3 through biatractylolide, its mechanism of action is related to regulating IL-6/STAT3 signaling pathway, reversing T cell failure and increasing tumor infiltration CD8+T cells.Keywords: Astragalus–Atractylodes herb pair, hepatocellular carcinoma, IL-6/STAT3 signaling pathway, molecular docking, network pharmacology

Jingping Sun,1,2,* Jun Zhang,3,* Bailong Xin,1 Zekang Ye,1,2 Yaozhuo Cai,2 Ke Lu,2 Yuzhen Wang,2 Xueyao Lei,2 Chanjuan Zheng,2 Xueli Cai3 1Department of Neurology, the Municipal Central Hospital of Lishui, Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, Zhejiang, People’s Republic of China; 2Lishui Clinical Research Center for Neurological Diseases, Lishui, Zhejiang, People’s Republic of China; 3Zhejiang University, School of Medicine, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xueli Cai, Department of Neurology, the Municipal Central Hospital of Lishui, Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, Zhejiang, People’s Republic of China, Email xueli_cai_official@126.comPurpose: Lipid-lowering therapy is integral in acute ischemic stroke (AIS), yet the connection between lipid parameters and parenchymal hemorrhage (PH) after endovascular treatment (EVT) for AIS is not well-defined. This research aims to assess the association between various lipid parameters and the PH risk following EVT.Patients and Methods: We examined a database of patients who underwent EVT for AIS between September 2021 and May 2023 retrospectively. Traditional and non-traditional lipid parameters were documented. PH was identified on dual energy computed tomography images within 48 h. We employed logistic regression analysis and restricted cubic splines to examine the association between various lipid parameters and the risk of PH. The predictive capacity of the lipid parameters for PH was evaluated by comparing the area under the curve.Results: The study included 384 patients, 65 of whom (17.7%) developed PH. After adjusting for potential confounders, only triglyceride was associated with PH among the traditional lipid parameters, while all non-traditional lipid parameters were related to PH. Based on ROC curve, the ratio of remnant cholesterol to high-density lipoprotein cholesterol (RC/HDL-C) exhibited the highest predictive capability for PH. Furthermore, our analysis revealed a significant nonlinear correlation between triglyceride, non-high-density lipoprotein cholesterol, RC, RC/HDL-C and PH risk.Conclusion: In assessing the risk of PH after EVT, non-traditional lipid parameters are often superior to traditional lipid parameters. It is recommended that routine evaluation of non-traditional lipid parameters could also be conducted in clinical practice as well.Keywords: endovascular treatment, hemorrhagic transformation, serum lipids

Yutong Zheng,1 Xiaoyi Cai,1 Gui Chen,1 Dexuan Xiang,1 Wei Shi,1 Jianliang Shen,2 Bailin Xiang1 1College of Chemistry and Materials Engineering, Huaihua University, Huaihua, 418000, People’s Republic of China; 2State Key Laboratory of Ophthalmology, Wenzhou Medical University, University of Chinese Academy of Sciences, Wenzhou, 325000, People’s Republic of ChinaCorrespondence: Bailin Xiang, College of Chemistry and Materials Engineering, Huaihua University, Huaihua, 418000, People’s Republic of China, Email xsz96@163.com Jianliang Shen, State Key Laboratory of Ophthalmology, Wenzhou Medical University, University of Chinese Academy of Sciences, Wenzhou, 325000, People’s Republic of China, Email shenjl@wiucas.ac.cnPurpose: Recently, Single-atom-loaded carbon-based material is a new environmentally friendly and stable photothermal antibacterial nanomaterial. It is still a great challenge to achieve single-atom loading on carbon materials.Materials and Methods: Herein, We doped single-atom Ag into ZIF-8-derived porous carbon to obtain Ag-doped ZIF-8-derived porous carbon(AgSA-ZDPC). The as-prepared samples were characterized by XRD, XPS, FESEM, EDX, TEM, and HAADF-STEM which confirmed that the single-atom Ag successfully doped into the porous carbon. Further, the photothermal properties and antimicrobial activity of AgSA-ZDPC have been tested.Results: The results showed that the temperature increased by 30 °C after near-infrared light irradiation(1 W/cm2) for 5 min which was better than ZIF-8-derived porous carbon(ZDPC). It also exhibits excellent photothermal stability after the laser was switched on and off 5 times. When the AgSA-ZDPC concentration was greater than 50 μg/mL and the near-infrared irradiation was performed for 5 min, the growth inhibition of S. aureus and E. coli was almost 100%.Conclusion: This work provides a simple method for the preparation of single-atom Ag-doped microporous carbon which has potential antibacterial application.Keywords: Single-atom, Ag, ZIF-8, photothermal, antibacterial

Maria González-Cao,1 Xueting Cai,2 Jilian Wilhelmina Paulina Bracht,3 Xuan Han,2 Yang Yang,2 Carlos Pedraz-Valdunciel,4 Teresa Morán,5 Javier García-Corbacho,6 Andrés Aguilar,1 Reyes Bernabé,7 Pedro De Marchi,8,9 Luciane Sussuchi da Silva,8 Leticia Ferro Leal,8 Rui Manuel Reis,8,10,11 Jordi Codony-Servat,4 Eloisa Jantus-Lewintre,12– 14 Miguel Angel Molina-Vila,4 Peng Cao,2,15 Rafael Rosell1,16 1Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital, Barcelona, Spain; 2Integrated Traditional Chinese and Western Medicine Department of Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 3Amsterdam University Medical Center (UMC), Amsterdam, The Netherlands; 4Laboratory of Oncology, Pangaea Oncology, Quirón Dexeus University Hospital, Barcelona, Spain; 5Medical Oncology Department, Catalan Institute of Oncology (ICO), Germans Trias i Pujol Hospital, Badalona, Spain; 6Medical Oncology Department (Hospital Clinic)/Translational Genomics and Targeted Therapies in Solid Tumors (IDIBAPs), Barcelona, Spain; 7Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain; 8Molecular Oncology Research Center; Barretos Cancer Hospital, Barretos, Brazil; 9Oncoclinicas, Rio de Janeiro, Brazil; 10Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; 11ICVS/3b’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal; 12Valencian Community Foundation Principe Felipe Research Center, Laboratory of Molecular Oncology, Valencia, Spain; 13Centro de Investigación Biomédica en Red (CIBERONC), Madrid, Spain; 14Universitat Politècnica de Valencia, Biotechnology Department, Valencia, Spain; 15College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 16Laboratory of Molecular Biology, Germans Trias i Pujol Health Sciences Institute and Hospital (IGTP), Badalona, SpainCorrespondence: Rafael Rosell, Laboratory of Molecular Biology, Germans Trias i Pujol Health Sciences Institute and Hospital (IGTP), Camí de les Escoless/n, Badalona, Barcelona, 08916, Spain, Tel +34 930330520, Email rrosell@iconcologia.net Peng Cao, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China, Tel +86 85608666, Email cao_peng@njucm.edu.cnPurpose: High-mobility group box 1 protein (HMGB1) is subject to exportin 1 (XPO1)-dependent nuclear export, and it is involved in functions implicated in resistance to immunotherapy. We investigated whether HMGB1 mRNA expression was associated with response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC).Patients and Methods: RNA was isolated from pretreatment biopsies of patients with advanced NSCLC treated with ICI. Gene expression analysis of several genes, including HMGB1, was conducted using the NanoString Counter analysis system (PanCancer Immune Profiling Panel). Western blotting analysis and cell viability assays in EGFR and KRAS mutant cell lines were carried out. Evaluation of the antitumoral effect of ICI in combination with XPO1 blocker (selinexor) and trametinib was determined in a murine Lewis lung carcinoma model.Results: HMGB1 mRNA levels in NSCLC patients treated with ICI correlated with progression-free survival (PFS) (median PFS 9.0 versus 18.0 months, P=0.008, hazard ratio=0.30 in high versus low HMGB1). After TNF-α stimulation, HMGB1 accumulates in the cytoplasm of PC9 cells, but this accumulation can be prevented by using selinexor or antiretroviral drugs. Erlotinib or osimertinib with selinexor in EGFR-mutant cells and trametinib plus selinexor in KRAS mutant abolish tumor cell proliferation. Selinexor with a PD-1 inhibitor with or without trametinib abrogates the tumor growth in the murine Lewis lung cancer model.Conclusion: An in-depth exploration of the functions of HMGB1 mRNA and protein is expected to uncover new potential targets and provide a basis for treating metastatic NSCLC in combination with ICI.Keywords: HMGB1, immunotherapy, non-small cell lung cancer, Lewis lung cancer murine model, K-Ras mutations

Huaichong Wang,1 Yuying Lang,1 Xinjun Cai,1 Liujie Gao,2 Shengya Yang,3 Jie Jin1 1Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Oncology, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang Province, People’s Republic of China; 3Tuberculosis Diagnosis and Treatment Center, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Jie Jin, Department of Pharmacy, Hangzhou Red Cross Hospital, East Huancheng Road No. 208, Hangzhou, Zhejiang Province, People’s Republic of China, Email jinjie0916@163.comBackground: Lymphoma is complicated by intricate infections, notably Pneumocystis jirovecii pneumonia (PJP), marked by rapid progression, respiratory failure, and high mortality. Rapid diagnosis of PJP and effective administration of the first-line treatment trimethoprim-sulfamethoxazole (TMP-SMX) are important. For patients intolerant to TMP-SMX, selecting appropriate alternatives is challenging, necessitating careful decisions to optimize diagnosis and treatment. We present a lymphoma case complicated by PJP, illustrating medication adjustment until a positive response was observed.Case Description: A 41-year-old male patient with lymphoma presented with a week-long history of fever, fatigue, cough, sputum, chest tightness, and exertional dyspnea, unresponsive to treatment. Routine laboratory examinations revealed no pathogenic bacteria. PJ and Mycobacterium tuberculosis (MTB) were detected in bronchoalveolar lavage fluid (BALF) using metagenomic next-generation sequencing (mNGS). On Day 1 of admission, meropenem, TMP-SMX, and rifampicin+isoniazid+levofloxacin were administered. However, the patient developed drug-induced hepatotoxicity and gastrointestinal adverse reactions after six days of treatment. After a multidisciplinary team discussion, anti-tuberculosis therapy was stopped because of insufficient evidence of tuberculosis infection. A reduced dose of TMP-SMX with micafungin was used for PJP; however, symptoms persisted and repeated computed tomography showed extensive deterioration of bilateral pulmonary plaques. The PJP regimen was modified to include a combination of TMP-SMX and caspofungin. Due to the high fever and elevated infection indices, the patient was treated with teicoplanin to enhance the anti-infection effects. By Day 13, the patient’s temperature had normalized, and infection control was achieved by Day 30. CT revealed that the infection in both lung lobes fully resolved. Subsequently, lymphoma treatment commenced.Conclusion: BALF-NGS facilitates early and rapid diagnosis of PJP. mNGS reads of MTB bacillus < 5 may indicate a bacterial carrier state, warranting other detection techniques to support it. There is insufficient evidence for using TMP-SMX with micafungin to treat PJP; however, TMP-SMX combined with caspofungin is suitable.Keywords: bronchoalveolar lavage fluid, metagenomic next-generation sequencing, Pneumocystis jirovecii pneumonia, Mycobacterium tuberculosis, trimethoprim-sulfamethoxazole

Lu Li,1 Lin Li,1 Xianhui Cai,1 Zongfu Pan2 1Department of Clinical Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Zongfu Pan, Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China, Email panzongfu@163.comAbstract: Coronavirus disease 2019 (COVID-19)-induced new-onset diabetes has raised widespread concerns. Increased glucose concentration and insulin resistance levels were observed in the COVID-19 patients. COVID-19 patients with newly diagnosed diabetes may have worse clinical outcomes and can have serious consequences. The types and exact mechanisms of COVID-19-caused diabetes are not well understood. Understanding the direct effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pancreatic beta cells and insulin target metabolism organs, such as the liver, muscle, and adipose tissues, will provide new ideas for preventing and treating the new-onset diabetes induced by COVID-19.Keywords: COVID-19, SARS-CoV-2, new-onset diabetes, hyperglycemia

Yiling Lin,1,2 Yingneng Zhang,1,2 Xia Cai,3 Huashen He,2 Chuangzan Yang,2 Junfeng Ban,1,2,4 Bohong Guo1 1School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 2The Innovation Team for Integrating Pharmacy with Entrepreneurship, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 3Guangdong Institute for Drug Control, Guangzhou, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of ChinaCorrespondence: Junfeng Ban; Bohong Guo, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong, 51006, People’s Republic of China, Tel +86 20 39352309, Email banjunfeng@163.com; bohong-g@163.comBackground: Delayed wound healing in skin injuries has become a significant problem in clinics, seriously affecting and even threatening life and health. Recently, research interest has increased in developing wound dressings containing bioactive compounds capable of improving outcomes for complex healing needs.Methods: In this study, Puerarin-loaded nanoparticles (Pue-NPs) were prepared using the cell-penetrating peptide-poly (lactic-co-glycolic acid) (CPP-PLGA) as a drug carrier by the emulsified solvent evaporation method. Then, they were added into poly (acrylic acid) to obtain a self-assembled nanocomposite hydrogels (SANHs) drug delivery system using the co-polymerization method. The particle size, zeta potential, and micromorphology of Pue-NPs were measured; the appearance, mechanical properties, adhesive strength, and biological activity of SANHs were performed. Finally, the potential of SANHs for wound healing was further evaluated in streptozotocin-induced diabetic mice.Results: Pue-NPs were regularly spherical, with an average particle size of 134.57 ± 1.42 nm and a zeta potential of 2.14 ± 0.78 mV. SANHs was colorless and transparent with a honeycomb-like porous structure and had an excellent swelling ratio (917%), water vapor transmission rate (3077 g·m− 2·day− 1), mechanical properties (Young’s modulus of 18 kPa, elongation at break of 307%), and adhesive strength (15.5 kPa). SANHs exhibited sustained release of Pue over 48h, with a cumulative release of 55.60 ± 6.01%. In vitro tests revealed that the SANHs presented a 92.22% antibacterial rate against Escherichia coli after 4h, and a 61.91% scavenging rate of 1.1-diphenyl-2-trinitrophenylhydrazine (DPPH) radical. In vivo experiments showed that SANHs accelerated wound repair by reducing the inflammatory response at the wound site, promoting angiogenesis, and facilitating epidermal regeneration and collagen deposition.Conclusion: In conclusion, we successfully prepared SANHs. Our results show that SANHs have excellent performance and improves wound healing in diabetic mice model, indicating that it can be used to develop an effective strategy for the treatment of diabetic wounds. Keywords: Puerarin-loaded nanoparticles, nanocomposite hydrogel, drug delivery, wound healing

Yulin Chen,1 Yi Zhang,2 Jianjun Wang,3 Xiong Cai,1 Junzhang Chen,1 Xiaobo Min,1 Yunjie Xu,1 Qi Qin,1 Chidan Wan1 1Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Hubei Engineering Research Center of Tumor-Targeted Biochemotherapy, Wuhan, 430030, People’s Republic of China; 3Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, 621000, People’s Republic of ChinaCorrespondence: Qi Qin; Chidan Wan, Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277, Jiefang Avenue, Wuhan, 430022, People’s Republic of China, Email qinqi8441@163.com; wcdwhxhgdwk@163.comBackground: Hepatocellular Carcinoma (HCC) poses significant challenges due to limited effective treatments and high recurrence rates. Immunotherapy, a promising approach, faces obstacles in HCC patients due to T-cell exhaustion and immunosuppression within the tumor microenvironment.Methods: Using doxorubicin-loaded tumor-derived microparticles (Dox-TMPs), the mice with H22 ascites model and subcutaneous tumors model were treated. Following the treatment, mice were re-challenged with H22 cells to compare the therapeutic effects and recurrence among different groups of mice, alongside examining the changes in the proportions of immune cells within the tumor microenvironment. Furthermore, Dox-TMPs were combined with anti-PD-1 to further validate their anti-tumor efficacy. In vitro studies using various liver cancer cell lines were conducted to verify the tumor-killing effects of Dox-TMPs. Additionally, CD8+ T cells from the abdominal cavity of tumor-free mice were co-cultured with H22 cells to confirm their specific tumor-killing abilities.Results: Dox-TMPs demonstrate effective anti-tumor effects both in vitro and in vivo. In vivo, their effectiveness primarily involves enhancing CD8+ T cell infiltration, alleviating T cell immunosuppression, and improving the immune microenvironment to combat tumors. When used in combination with anti-PD-1, their anti-tumor effects are further enhanced. Moreover, some mice treated with Dox-TMPs developed anti-tumor immunity, displaying a self-specific T-cell immune response upon re-challenged with tumor cells. This suggests that Dox-TMPs also have the potential to act as a long-term immune response against tumor recurrence, indicating their capability as a tumor vaccine.Conclusion: Dox-TMPs exhibit a dual role in liver cancer by regulating T cells within the tumor microenvironment, functioning both as an anti-tumor agent and a potential tumor vaccine. Keywords: liver cancer, drug-loaded microparticles, tumor immune microenvironment, tumor vaccine

Haopeng Wang,1,&ast; Hua Zhao,1,&ast; Zheng Chen,1,&ast; Xiaomin Cai,1 Xuhui Wang,1 Ping Zhou,1 Yinda Tang,1 Tingting Ying,1 Xin Zhang,1 Yiman Shen,1 Baimiao Wang,1 Wanchun Zhu,1 Jin Zhu,1 Xinjun Wang,2 Shiting Li1 1Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, People’s Republic of China; 2Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shiting Li, Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, People’s Republic of China, Email lishiting@xinhuamed.com.cn Xinjun Wang, Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China, Email wangxj@zzu.edu.cnBackground: Facial nerves have the potential for regeneration following injury, but this process is often challenging and slow. Schwann cells (SCs) are pivotal in this process. Bone mesenchymal stem cells (BMSC)-derived exosomes promote tissue repair through paracrine action, with hypoxic preconditioning enhancing their effects. The main purpose of this study was to determine whether hypoxia-preconditioned BMSC-derived exosomes (Hypo-Exos) exhibit a greater therapeutic effect on facial nerve repair/regeneration and reveal the mechanism.Methods: CCK-8, EdU, Transwell, and ELISA assays were used to evaluate the functions of Hypo-Exos in SCs. Histological analysis and Vibrissae Movements (VMs) recovery were used to evaluate the therapeutic effects of Hypo-Exos in rat model. circRNA array was used to identify the significantly differentially expressed exosomal circRNAs between normoxia-preconditioned BMSC-derived exosomes (Nor-Exos) and Hypo-Exos. miRDB, TargetScan, double luciferase assay, qRT-PCR and WB were used to predict and identify potential exosomal cirRNA_Nkd2-complementary miRNAs and its target gene. The function of exosomal circRNA_Nkd2 in facial nerve repair/regeneration was evaluated by cell and animal experiments.Results: This study confirmed that Hypo-Exos more effectively promote SCs proliferation, migration, and paracrine function, accelerating facial nerve repair following facial nerve injury (FNI) compared with Nor-Exos. Furthermore, circRNA analysis identified significant enrichment of circRNA_Nkd2 in Hypo-Exos compared with Nor-Exos. Exosomal circRNA_Nkd2 positively regulates mediator complex subunit 19 (MED19) expression by sponging rno-miR-214-3p.Conclusion: Our results demonstrated a mechanism by which Hypo-Exos enhanced SCs proliferation, migration, and paracrine function and facial nerve repair and regeneration following FNI through the circRNA_Nkd2/miR-214-3p/Med19 axis. Hypoxic preconditioning is an effective and promising method for optimizing the therapeutic action of BMSC-derived exosomes in FNI. Keywords: hypoxic, BMSCs, exosomes, Schwann cells, facial nerve injury

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

Liao X, Shen M, Li T, et al. Int J Nanomedicine. 2023;18:5925–5942. The authors wish to advise, following publication of the article they identified errors were made during the collection and organization of data for Figures 3 and 4 on pages 5934 and 5935, respectively. The correct Figures 3 and 4 are as follows. Figure 3 Antioxidant properties of POM or hydrogel. (A) DCFH-DA assay showing intracellular ROS of MC3T3-E1 after incubation with POM in the presence of H2O2 (100 μM). (B) Quantification analysis of DCFH-DA staining (*And #Indicate p < 0.05 in comparison with the H2O2 group and GelMA group, respectively.) (C) Cell capacity of migration (scratch test). (D) Quantitative analysis of percent migration in scratch assay. (*And #Indicate p < 0.05 in comparison with the H2O2 group and GelMA group, respectively.) (E) Live/dead staining showing MC3T3-E1 cell viability after culturing on hydrogel in the presence of H2O2. (F) Quantification analysis of live cells. (*And #Indicate p < 0.05 in comparison with the H2O2 group and GelMA group, respectively.) (G) LSCM images showing MC3T3-E1 cultured on different hydrogels following H2O2 treatment. (n = 3, each group). (H2O2, cells cultured on the tissue culture plate with H2O2). Scale bar: 200 μm (A), 200 μm (C), 100 μm (E) and 100 μm (G). Figure 4 The osteogenesis properties of GelMA/POM hydrogel in vitro. In vitro assay of effects of hydrogel on ALP activity and extracellular calcium nodule production during osteogenesis differentiation of MC3T3-E1. (A) Alizarin red S staining. (B) Quantitative analysis of mineralized nodules. (C) Alkaline phosphatase activity. (D) Alkaline phosphatase staining. (*, # And a indicate p < 0.05 in comparison with the Control group, H2O2 group and GelMA group, respectively). (Control, cells cultured without H2O2). (n = 3, each group). Scale bar: 200 μm (A) and 200 μm (D). The authors advise these corrections do not significantly impact the overall findings and conclusions of the article or alter the interpretations or validity of the research. The authors apologize for any confusion these errors may have caused and appreciate the opportunity to rectify them.

Parhat Yasin,1 Muradil Mardan,2 Dilxat Abliz,3 Tao Xu,1 Nuerbiyan Keyoumu,4 Abasi Aimaiti,4 Xiaoyu Cai,1 Weibin Sheng,1 Mardan Mamat1 1Department of Spine Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People’s Republic of China; 2School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China; 3Department of Orthopedic, The Eighth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People’s Republic of China; 4Department of Anesthesiology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People’s Republic of ChinaCorrespondence: Mardan Mamat, Tel +86 0991-4365316, Email mardanmmtmx@163.comBackground: Pyogenic spondylitis (PS) and Brucella spondylitis (BS) are common spinal infections with similar manifestations, making their differentiation challenging. This study aimed to explore the potential of CT-based radiomics features combined with machine learning algorithms to differentiate PS from BS.Methods: This retrospective study involved the collection of clinical and radiological information from 138 patients diagnosed with either PS or BS in our hospital between January 2017 and December 2022, based on histopathology examination and/or germ isolations. The region of interest (ROI) was defined by two radiologists using a 3D Slicer open-source platform, utilizing blind analysis of sagittal CT images against histopathological examination results. PyRadiomics, a Python package, was utilized to extract ROI features. Several methods were performed to reduce the dimensionality of the extracted features. Machine learning algorithms were trained and evaluated using techniques like the area under the receiver operating characteristic curve (AUC; confusion matrix-related metrics, calibration plot, and decision curve analysis to assess their ability to differentiate PS from BS. Additionally, permutation feature importance (PFI; local interpretable model-agnostic explanations (LIME; and Shapley additive explanation (SHAP) techniques were utilized to gain insights into the interpretabilities of the models that are otherwise considered opaque black-boxes.Results: A total of 15 radiomics features were screened during the analysis. The AUC value and Brier score of best the model were 0.88 and 0.13, respectively. The calibration plot and decision curve analysis displayed higher clinical efficiency in the differential diagnosis. According to the interpretation results, the most impactful features on the model output were wavelet LHL small dependence low gray-level emphasis (GLDN).Conclusion: The CT-based radiomics models that we developed have proven to be useful in reliably differentiating between PS and BS at an early stage and can provide a reliable explanation for the classification results.Keywords: Brucella spondylitis, Pyogenic spondylitis, machine learning, radiomics, model interpretation

Jiawei Zhou,1 Xiaomeng Li,1 Xiang Li,2 Na Wang,3 Xu Cai,4 Lei Zhang,1 Chen Li,1 Wei Wang,1,&ast; Na Yu1,&ast; 1Department of Respiratory and Critical Care Medicine, The First Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Central Hospital Affiliated to Shenyang Medical College, Shenyang, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Tieling County Central Hospital, Tieling, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Wang; Na Yu, Email wwbycmu@126.com; yunacmu@163.com

Xintian Cai,1,&ast; Shuaiwei Song,1,&ast; Junli Hu,2 Lei Wang,2 Di Shen,1 Qing Zhu,2 Wenbo Yang,2 Qin Luo,2 Jing Hong,2 Nanfang Li2 1Graduate School, Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region, Hypertension Research Laboratory, Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang, 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, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region, Hypertension Research Laboratory, Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, No. 91 Tianchi Road, Urumqi, Xinjiang, 830001, People’s Republic of China, Tel +86 8564818, Email lnanfang2016@sina.comObjective: This study aimed to evaluate the relationship between the systemic inflammation response index (SIRI) and the risk of stroke and its subtypes in elderly patients with hypertension and to explore its predictive accuracy and any potential effect modifiers.Methods: The study included 4749 participants with no history of stroke at baseline. Cox regression was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CIs). Interaction tests and subgroup analyses were conducted. The predictive performance of various inflammatory indicators for stroke was compared using the area under the curve (AUC), continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI).Results: During a median follow-up period of 3.2 years, 640 strokes were recorded, of which 526 were ischemic and the remainder hemorrhagic. After adjustment for confounders, compared to the reference group, the HRs (95% CI) of stroke were 1.28 (95% CI, 1.01– 1.64) and 1.46 (95% CI, 1.14– 1.88) for participants in the second and third tertiles, respectively. We observed interactions between SIRI and homocysteine levels (< 15 vs. ≥ 15 μmol/L) (p for interaction = 0.014) on ischemic stroke risk. Furthermore, the AUC, NRI, and IDI analyses demonstrated that SIRI exhibited better predictive value for stroke risk when compared to other indicators. Similar results were observed for both ischemic and hemorrhagic strokes.Conclusion: Elevated SIRI levels were significantly associated with the risk of stroke and its subtypes in elderly patients with hypertension, suggesting its potential as a promising indicator for stroke risk in this population. However, larger prospective studies are needed to confirm these findings.Keywords: systemic inflammation response index, stroke, elderly, hypertension, inflammation, cohort study

Songting Li,1,2 Xiaolan Cai,3 Keyao Yu,1,2 Weihua Pan1,2 1Department of Dermatology, Second Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Molecular Medical Mycology, Shanghai, People’s Republic of China; 3Department of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Weihua Pan, Department of Dermatology, Second Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China, Tel +86-2188485495, Email panweihua9@sina.comBackground: Cutaneous metastasis is rare in clinical practice, especially that from primary hepatocellular carcinoma (HCC), which is even rarer.Case Presentation: This report describes a male patient with HCC with cutaneous metastases to the nasal tip. The patient developed a raised nodule at the nasal tip 5 years after surgery for HCC, with surface ulceration and crusting and no obvious symptoms. Abdominal computed tomography (CT) showed an obvious mass in the liver. The skin lesions on the nasal tip were confirmed to be cutaneous metastasis of HCC by histopathological and immunohistochemical examinations.Conclusion: The incidence of cutaneous metastasis of HCC is extremely low, and nasal tip cutaneous metastasis of HCC has no specific clinical manifestations; therefore, it needs to be distinguished from rosacea rhinophyma, fungal and atypical mycobacterial infections, tumours of vascular origin, and tumours of skin appendages that occur in the nasal tip and is prone to misdiagnosis and missed diagnosis, thus requiring clinical dermatologists and otolaryngologists to be aware of such metastasis.Keywords: primary, hepatocellular carcinoma, metastatic cancer, skin, nasal tip

Nan Sun,1 Dan Dai,1 Shihang Deng,2 Xun Cai,3 Ping Song1 1Department of Dermatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 2Department of Dermatology, Shenzhen Bao’an Authentic TCM Therapy Hospital, Shenzhen, 518126, People’s Republic of China; 3Department of Dermatology, The Fifth People’s Hospital of Suzhou, Suzhou, 215131, People’s Republic of ChinaCorrespondence: Nan Sun; Ping Song, Department of Dermatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China, Email dr-sue@foxmail.com; songping@vip.126.comBackground: Atopic dermatitis (AD) is an allergic inflammatory skin disease caused by aberrant and over-reactive immune response. Although circadian rhythm disruption is implicated in multiple immunoinflammatory conditions, including AD, the mechanisms at the molecular level underlying AD and circadian rhythms remain elusive.Methods: Bulk and single-cell RNA-sequencing data of AD patients were acquired from the Gene Expression Omnibus, including GSE121212, GSE120721, and GSE153760 datasets. A single-sample gene set enrichment analysis was performed to estimate circadian rhythm gene expression levels. A differential expression analysis was utilized to identify the key candidate genes in AD. CIBERSORT was used to quantify the proportions of immune cells, and the R package “Seurat” was utilized to investigate single-cell RNA-sequencing data.Results: Circadian rhythm gene expression levels were lower in AD skin samples than in normal skin samples. Dendritic cells were significantly upregulated and negatively correlated with circadian rhythm gene expression levels in AD patients. Compared with circadian rhythm-related genes in the control samples, ARNTL2, NOCT, and RORC were differentially expressed in AD; ARNTL2 and NOCT were significantly upregulated, whereas RORC was significantly downregulated in AD. ARNTL2, NOCT, and RORC also showed robust abilities to diagnose AD. We validated that the abundance of the dendritic cell was positively correlated with the ARNTL2 and NOCT expression levels using bulk RNA-sequencing data of the GSE121212 and single-cell RNA-sequencing data of the GSE153760. Moreover, the functional enrichment analysis showed that the IL-17 and NF-κB signaling pathways, Th1 and Th2 cell differentiations, and primary immunodeficiency, were enriched in AD patients.Conclusion: The findings of this study suggested that the circadian rhythm is involved in the progression of AD, and RNTL2, NOCT, and RORC as well as dendritic cells are differentially expressed in AD. These findings could be used to introduce diagnostic and chronotherapeutic modalities for AD.Keywords: atopic dermatitis, circadian rhythms, dendritic cells, ARNTL2, NOCT, RORC

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

Yuan Wu,1,&ast; Xiaoli Liu,1,&ast; Xinhui Wang,2 Lihua Yu,1 Huiwen Yan,1 Yuqing Xie,1 Qing Pu,1 Xue Cai,1 Yaxian Kong,3 Zhiyun Yang1 1Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 2Department of Chinese Medicine, National Center for Children’s Health, Beijing Children’s Hospital, Capital Medical University, Beijing, 100045, People’s Republic of China; 3Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yaxian Kong, Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China, Email Kongyaxian@ccmu.edu.cn Zhiyun Yang, Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China, Email yangzhiyun2016@163.comObjective: CD8+T cells are essential components of the adaptive immune system and are crucial in the body’s immune system. This study aimed to investigate how the prognosis of patients with advanced hepatocellular carcinoma (HCC) was affected by their CD8+ T cell counts and age and established an effective nomogram model to predict the overall survival (OS).Methods: A total of 427 patients with advanced HCC from Beijing Ditan Hospital, Capital Medical University, were enrolled in this study and randomly divided into training and validation groups, with 300 and 127 individuals in each group, respectively. Cox regression analysis was used to screen for independent risk factors for advanced HCC, and the interactive relationship between CD8+T cells and patient age was examined to establish a nomogram prediction model.Results: Cox multivariate regression and interaction analyses indicated that tumor number, tumor size, aspartate aminotransferase (AST), C-reactive protein (CRP), relationship of CD8+T cell counts and age were independent predictors of 6-month OS in patients with advanced HCC, and the nomogram model was established based on these factors. The area under the receiver operating characteristic curve (AUC) of the nomogram model for predicting the 3-month, 6-month, and 12-month OS rates were 0.821, 0.802, and 0.756, respectively. Moreover, in clinical practice, patients with true-positive survival benefit more than true-positive death, therefore, we selected 25% as the clinical decision threshold probability based on probability density functions (PDFs) and clinical utility curves (CUCs), which can distinguish approximately 92% of patients who died and 37% of patients who survived.Conclusion: The nomogram model based on CD8+T cell counts and age accurately assessed the prognosis of patients with advanced HCC and suggested that high CD8+T cell levels are beneficial to the survival of patients with advanced HCC.Keywords: advanced hepatocellular carcinoma, nomogram, CD8+T cell counts, age, overall survival

Li Che,1,2 Zhefan Xie,2,3 Guangshu Chen,4 Wei Zhang,2 Tingting Xia,2,3 Jiaxin Lin,2 Wenzhi Luo,2 Li Chen,2 Wenguang Yin,1 Xingdong Cai,2 Shengming Liu2 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 3Affiliated Dongguan People’s Hospital, Southern Medical University, Donguan, People’s Republic of China; 4Department of Endocrinology, Guangzhou Red Cross Hospital, The Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of ChinaCorrespondence: Shengming Liu; Xingdong Cai, The First Affiliated Hospital of Jinan University, Guangdong, People’s Republic of China, Email tlsm@jnu.edu.cn; cxd19790920@sina.comBackground: The role of irreversible airway inflammatory damage in chronic obstructive pulmonary disease (COPD) progression is evident. Autophagy is an essential process in the cellular material metabolic cycle, and a family of resistant vegetative molecules may be involved in the COPD autophagic process. In this study, we investigated the mechanism of resistin-like molecule β (RELMβ) in COPD smoking-induced autophagy.Methods: Firstly, the expression differences of RELMβ and autophagy markers between COPD and control groups were analyzed in the Gene Expression Omnibus (GEO) datasets and clinical specimens. Secondly, in vitro and in vivo experiments were conducted using immunoblotting, immunofluorescence, immunohistochemistry, and other methods to investigate the mechanism by which RELMβ promotes airway inflammation through autophagy in a cigarette smoke extract-induced 16HBE cell inflammation model and a cigarette smoke-induced COPD-like mouse model. In addition, immunoprecipitation was used to analyze the binding of RELMβ to the membrane protein TLR4.Results: The expression of RELMβ and autophagy genes p62 and LC3B in lung tissue of COPD patients was significantly increased. RELMβ can mediate the activation of autophagy in 16HBE cells, and through autophagy, it increases the expression of inflammatory cytokines in a cigarette smoke extract-induced 16HBE cell inflammation model. RELMβ promotes cigarette smoke-induced COPD-like mouse airway inflammation through autophagy, and RELMβ can mediate signal transduction through the cell membrane receptor TLR4.Conclusion: The RELMβ binds to TLR4 to encourage signal transduction and that RELMβ can promote inflammation in smoky COPD lungs through autophagy.Keywords: autophagy, COPD, airway inflammation, cigarette smoke extract

Zeling Huang,&ast; Binjie Lu,&ast; Xianda Zhang,&ast; Jiangping Wang, Xuefeng Cai, Yujiang Liu, Jianxiong Mo, Yuwei Li, Bo Xu, Xiaofeng Shen Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, Jiangsu, 215008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Xu; Xiaofeng Shen, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, Jiangsu, 215008, People’s Republic of China, Tel +86 18359146790, Email xubo12080@163.com; 29240818@qq.comPurpose: The aim of this study was to investigate the effect of Zhiqiao Gancao decoction (ZQGCD) on hyperalgesia in lumbar disc herniation (LDH) and its mechanism.Methods: The potential mechanism of ZQGCD’s therapeutic effect on LDH was investigated through network pharmacology, which involved screening the targets of eight components that were absorbed into the bloodstream. The effects of CCR2 inhibitors and ZQGCD-containing serum on the excitability of the CCL2/CCR2 signaling pathway and dorsal root ganglion neurons (DRGn) were investigated in vitro. The effects of CCR2 inhibitors and ZQGCD on the expression of the CCL2/CCR2 signaling pathway and ASIC3 in the rat intervertebral disc and dorsal root ganglion (DRG), the degree of disc degeneration, the threshold of foot retreat, and the latency of foot retreat in LDH rats were examined in vivo. The binding affinities and interaction modes between CCR2 and the components absorbed into the blood were analyzed using the AutodockVina 1.2.2 software.Results: Network pharmacology revealed that ZQGCD could treat LDH through a mechanism involving the chemokine signaling pathway. It was observed that the CCR2 inhibitor and ZQGCD-containing serum downregulated CCR2 and ASIC3 expression and decreased cell excitability in DRGn. The CCL2/CCR2 signaling pathway was activated in the degenerated intervertebral disc and DRG of LDH rats, increased the expression of ASIC3, and decreased the mechanical allodynia domain and thermal hyperalgesia domain. However, a CCR2 inhibitor or ZQGCD could ameliorate the above changes in LDH rats. The target proteins, CCL2 and CCR2, exhibited a robust affinity for the eight components that were absorbed into the bloodstream.Conclusion: The CCL2/CCR2 pathway was activated in the intervertebral disc and DRG of LDH rats. This was accompanied by upregulation of ASIC3 expression, increased excitability of DRGn, and the occurrence of hyperalgesia. ZQGCD improves hyperalgesia in LDH rats by inhibiting the CCL2/CCR2 pathway and downregulating ASIC3 expression.Keywords: lumbar disc herniation, dorsal root ganglion neurons, hyperalgesia, traditional Chinese medicine, molecular docking

Yikuan Du,1,&ast; Xiaolin Cai,2,3,&ast; Bijun Xu,2,3 Yuqing Wu,2,3 Mianhai Chen,2,3 Jinjin Wang,2,3 Bing Yuan,2,3 Weichui Zhang,2,3 Jinfeng Zhu,2,3 Chun Yang2,3 1Central Laboratory, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, 523059, People’s Republic of China; 2Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523808, People’s Republic of China; 3Dongguan Key Laboratory of Stem Cell and Regenerative Tissue Engineering, Guangdong Medical University, Dongguan, 523808, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chun Yang, Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, People’s Republic of China, Tel +86 150 1915 9295, Email yangchunangel@163.comBackground: Fascial pathological pain is the main type of chronic pain in older adults today, and studying the relationship between fascia and pain can help in the clinical search for effective treatments. However, in the face of the vast amount of research findings, there is no systematic assessment of the relationship between fascia and pain in a bibliometric analysis. Therefore, the purpose of this study is to analyze studies on fascia and pain using CiteSpace and VOSviewer to identify research hotspots and future directions.Materials and Methods: A total of 744 papers related to fascia and pain from 2013 to 2022 were collected from the core collection database of Web of Science, and the authors, countries, institutions, keyword co-occurrence, keyword clustering, and keyword emergence were analyzed by CiteSpace and VOSviewer to construct a knowledge map.Results: Literature publication has shown an overall upward trend over the past decade, but there have been some fluctuations. Carmelo Pirri, Caterina Fede, and Raffaele De Caro are the top three authors with the most articles. The United States, China, and Spain are major contributors to fascial and pain research. The University of Padua, Universidad Complutense and Harvard Medical School are leading institutions in this field. However, it is noteworthy that the collaboration between authors, countries and institutions is not active. Keyword analysis showed that hot spots and trends in research on fascia and pain focused on hot diseases, major interventions, and mechanism exploration.Conclusion: This analysis identifies the most influential authors, institutions, and countries in the field of fascial and pain research and provides a reference for assessing their academic impact. The analysis of keywords and co-cited literature is useful for analyzing research hotspots and their evolution, as well as for predicting future trends.Keywords: fascia, pain, bibliometrics analysis, knowledge graph, research progress

Jinmeng Li, Xinjun Cai, Yingying Xu, Ruoying Zhang Department of Pharmacy, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310000, People’s Republic of ChinaCorrespondence: Ruoying Zhang, Department of Pharmacy, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310000, People’s Republic of China, Email hzhhzry@163.comAbstract: Aspergillus tubingensis spondylitis (AS) is a rare spinal infectious disease with severe clinical symptoms and a challenging diagnosis. Treatment of AS is challenging due to its prolonged duration, substantial side effects, and complex drug–drug interactions. However, there is a lack of experience in individualized pharmaceutical care of AS by clinical pharmacists, especially in the presence of rifampicin, which has sustained liver enzyme induction after discontinuation. Our case described an immunocompetent patient infected with Aspergillus tubingensis spondylitis. Clinical pharmacists proposed an individualized treatment regimen for AS, after considering the effects of sustained liver enzyme induction of rifampicin (after discontinuation) on voriconazole, and utilized caspofungin as a bridge-connection scheme. We also paid attention to changes in indicators during treatment and managed adverse reactions. Therapeutic drug monitoring of voriconazole was also used to optimize the dosing regimen. With the individualized pharmaceutical care of clinical pharmacists and the efforts of clinicians, the patient’s incision healed well after 33 days of hospitalization, and she was discharged with significant improvement. Therefore, individualized pharmaceutical care by a clinical pharmacist can help optimize the treatment of Aspergillus tubingensis spondylitis. In clinical practice, drug–drug and drug–diet interactions may affect voriconazole efficacy, and individualized dose adjustment using therapeutic drug monitoring (TDM) is critical to improve efficacy and reduce adverse reactions.Keywords: individualized pharmaceutical care, Aspergillus tubingensis spondylitis, enzyme-induction effect of rifampin, voriconazole, case report

Junli Hu,1– 5,&ast; Xintian Cai,1– 6,&ast; Qing Zhu,1– 6 Mulalibieke Heizhati,1– 5 Wen Wen,1– 6 Qin Luo,1– 5 Jing Hong,1– 5 Yujie Dang,1– 6 Wenbo Yang,1– 5 Nanfang Li1– 5 1Hypertension Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China; 2Xinjiang Hypertension Institute, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China; 3NHC Key Laboratory of Hypertension Clinical Research, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China; 4Key Laboratory of Xinjiang Uygur Autonomous Region, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China; 5Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China; 6Graduate School, Xinjiang Medical University, Urumqi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nanfang Li, Hypertension Center, 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.comObjective: To investigate the association between plasma aldosterone concentration (PAC) and non-alcoholic fatty liver disease (NAFLD) diagnosis in Chinese hypertensive patients.Methods: We conducted a retrospective study of all patients diagnosed with hypertension between January 1, 2010, and December 31, 2021. We included 3713 hypertensive patients based on the criteria for inclusion and exclusion. PAC measurement was performed using a radioimmunoassay. NAFLD was diagnosed using abdominal ultrasonography. Cox regression analysis was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for univariable and multivariable models. A generalized additive model was used to identify nonlinear relationships between PAC and NAFLD diagnosis.Results: A total of 3713 participants were included in the analysis. Over a median follow-up of 30 months, 1572 hypertensive individuals developed new-onset NAFLD. When PAC was used as a continuous variable, the risk of NAFLD increased by 1.04 and 1.24-fold for each 1 ng/dL and 5 ng/dL increase in PAC, respectively. When PAC was considered a categorical variable, the HR for tertile 3 was 1.71 (95% CI, 1.47– 1.98, P < 0.001) compared to tertile 1. Overall, there was a J-shaped relationship between PAC and new-onset NAFLD. By fitting a two-piecewise linear regression model and using a recursive algorithm, we identified a PAC inflection point at 13 ng/dL (log-likelihood ratio test, P = 0.005). In adjusted model 3, for PAC ≥ 13 ng/dL, a 5 ng/dL increase in PAC was associated with a 30% increase in the risk of new-onset NAFLD (95% CI, 1.25– 1.35, P < 0.001).Conclusion: The study revealed a non-linear relationship between elevated PAC levels and the incidence of NAFLD in hypertensive patients. Notably, the risk of new-onset NAFLD was significantly increased when PAC levels were ≥ 13 ng/dL. Larger, prospective studies are necessary to confirm these findings.Keywords: plasma aldosterone concentration, non-alcoholic fatty liver disease, hypertension, cohort study

Tianyu Yu,&ast; Jiangnan Dong,&ast; Qi Qi,&ast; Qiang Lv, Jun Li, Chaojun Huang, Xiaoyan Cai Department of General Surgery, Gongli Hospital of Shanghai Pudong New Area, Shanghai, 200135, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoyan Cai, Department of General Surgery, Gongli Hospital of Shanghai Pudong New Area, Shanghai, 200135, People’s Republic of China, Tel/Fax +86-21-58858730, Email cxy6429@163.comPurpose: The Omicron variant of SARS-CoV-2 has emerged as a significant global concern, characterized by its rapid transmission and resistance to existing treatments and vaccines. However, the specific hematological and biochemical factors that may impact the clearance of Omicron variant infection remain unclear. The present study aimed to identify easily accessible laboratory markers that are associated with prolonged virus shedding in non-severe patients with COVID-19 caused by the Omicron variant.Patients and Methods: A retrospective cohort study was conducted on 882 non-severe COVID-19 patients who were diagnosed with the Omicron variant in Shanghai between March and June 2022. The least absolute shrinkage and selection operator regression model was used for feature selection and dimensional reduction, and multivariate logistic regression analysis was performed to construct a nomogram for predicting the risk of prolonged SARS-CoV-2 RNA positivity lasting for more than 7 days. The receiver operating characteristic (ROC) curve and calibration curves were used to assess predictive discrimination and accuracy, with bootstrap validation.Results: Patients were randomly divided into derivation (70%, n = 618) and validation (30%, n = 264) cohorts. Optimal independent markers for prolonged viral shedding time (VST) over 7 days were identified as Age, C-reactive protein (CRP), platelet count, leukocyte count, lymphocyte count, and eosinophil count. These factors were subsequently incorporated into the nomogram utilizing bootstrap validation. The area under the curve (AUC) in the derivation (0.761) and validation (0.756) cohorts indicated good discriminative ability. The calibration curve showed good agreement between the nomogram-predicted and actual patients with VST over 7 days.Conclusion: Our study confirmed six factors associated with delayed VST in non-severe SARS-CoV-2 Omicron infection and constructed a Nomogram which may assist non-severely affected patients to better estimate the appropriate length of self-isolation and optimize their self-management strategies.Keywords: SARS-CoV-2, COVID-19, Omicron, viral shedding time, nomogram

Jian Lin,1,&ast; Tianpeng Shi,2,&ast; Yi Wang,1 Zhiqi He,1 Zhixiang Mu,1 Xiaojun Cai,1 Hui Deng,1 Jianliang Shen,3– 5 Fen Liu6 1School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Stomatology, PLA Strategic Support Force Medical Center, Beijing, People’s Republic of China; 3State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, People’s Republic of China; 5Department of Regenerative Medicine, Vision, and Brain Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), Wenzhou, People’s Republic of China; 6Department of Histology and Embryology, Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Deng; Fen Liu, Email dh0726@gmail.com; liufen6459@163.comBackground: Much attention has been paid to sustained drug release and anti-infection in wound management. Hydrogels, which are biocompatible materials, are promising tools for controlled drug release and infective protection during wound healing. However, hydrogels also demonstrate limitations in the highly efficient treatment of wounds because of the diffusion rate. In this work, we explored pH-sensitive hydrogels that enable ultra-long-acting drug release and sustained antibacterial properties.Methods: We constructed a hybrid gelatin methacrylate (GelMA) system with sustainable antibacterial properties combining hyaluronic acid (HA)-coated mesoporous silica nanoparticles (MSN), which loaded host-guest complexes of chlorhexidine (CHX) with β-cyclodextrins (β-CD) (CHX⊂CD-MSN@HA@GelMA). The release mechanism of CHX was explored using UV-vis spectra after intermittent diffusion of CHX. The hybrid hydrogels were characterized, and the drug content in terms of the release profile, bacterial inhibition, and in vivo experiments were investigated.Results: Except for dual protection from both hydrogels, MSN in the HA improved the drug loading efficiency to promote the local drug concentration. It showed that complicated CHX-loaded MSN releases CHX more gradually and over a longer duration than CHX-loaded MSNs. This demonstrated a 12-day CHX release time and antibacterial activity, primarily attributable to the capacity of β-CD to form an inclusion complex with CHX. Meanwhile, in vivo experiments revealed that the hydrogels safely promote skin wound healing and enhance therapeutic efficacy.Conclusion: We constructed pH-sensitive CHX⊂CD-MSN@HA@GelMA hydrogels that enable ultra-long-acting drug release and sustained antibacterial properties. The combination of β-CD and MSN would be better suited to release a reduced rate of active molecules over time (slow delivery), making them great candidates for wound dressing anti-infection materials.Keywords: mesoporous silica, cyclodextrin, pH-responsive, antibacterial property, wound healing

Kebing Zhou,1,&ast; Yu Zhou,2,&ast; Yuena Zeng,1,&ast; Jiahui Zhang,1 Xiaoyan Cai,1 Jieying Qin,1 Zhiying Li,1 Fengxia Yan1 1School of Nursing, Jinan University, Guangzhou, People’s Republic of China; 2Department of Rehabilitation, the First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fengxia Yan; Jiahui Zhang, School of Nursing, Jinan University, 601 Huangpu Avenue West, Tianhe District, Guangzhou, 510632, People’s Republic of China, Tel +86-20-85225836, Fax +86-20-8522227, Email yanfengxia0807@163.com; jiahuizhang051423@163.comPurpose: Transcranial direct current stimulation has been widely used in the clinical treatment of stroke. The purpose of this study was to perform a bibliometric analysis of scientific literature in this field.Methods: Articles and reviews regarding transcranial direct current stimulation in stroke from January 01, 2004 to May 31, 2022 were identified from the Science Citation Index-Expanded of the Web of Science Core Collection database. CiteSpace 6.1.R2, Bibliometrix and the Bibliometric Online Analysis Platform were used to analyze data.Results: A total of 905 papers were obtained, with the highest number of publications coming from the USA. The institutions and authors with the most publications were Harvard Medical School and Fregni F respectively. Nitsche MA had the most co-citations, followed by Fregni F. Neurosciences was the most fruitful research area and Brain Stimulation had the highest H-index. The research topics could be divided into three sections: mechanisms of treatment, comparison of efficacy with transcranial magnetic stimulation, clinical application of post-stroke dysfunction. The field of “walking”, “strength” and “virtual reality therapy” are the future research hotspots of transcranial direct current stimulation.Conclusion: The overall research showed a slow growth trend, and the outstanding contribution of the USA in this field cannot be ignored. Relevant researchers are suggested to focus on international collaboration and actively conduct high-quality randomized controlled clinical trials on research hotspots and frontiers in order to identify the optimal stimulation paradigm for clinical purposes.Keywords: stroke, transcranial direct current stimulation, bibliometric analysis, hotspots, frontier

Wenbo Yang,1,&ast; Xintian Cai,1,2,&ast; Junli Hu,1 Wen Wen,1 Heizhati Mulalibieke,1 Xiaoguang Yao,1 Ling Yao,1 Qing Zhu,1 Jing Hong,1 Qin Luo,1 Shasha Liu,1 Nanfang Li1 1Hypertension Center, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region, Xinjiang Clinical Medical Research Center for Hypertension Diseases, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China; 2Graduate School, Xinjiang Medical University, Urumqi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nanfang Li, Hypertension Center, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region, Xinjiang Clinical Medical Research Center for Hypertension Diseases, People’s Hospital of Xinjiang Uygur Autonomous Region, NO. 91 TianChi Road, Urumqi, 830001, People’s Republic of China, Tel +86 8564818, Email lnanfang2016@sina.comObjective: We aimed to evaluate the METS-IR (metabolic score for insulin resistance) index for the prediction of incident cardiovascular disease (CVD) and its subtypes (coronary artery disease and stroke) in patients with hypertension and obstructive sleep apnea (OSA).Methods: A retrospective cohort study was conducted with 2031 adults with hypertension and OSA, participants from the Urumqi Research on Sleep Apnea and Hypertension study (UROSAH). The hazard ratios and 95% CIs (credibility interval) for CVD and its subtypes were estimated using multivariate Cox proportional hazards regression models.Results: After a median follow-up of 6.80 years (interquartile range: 5.90– 8.00 years), a total of 317 (15.61%) participants developed new-onset CVD, including 198 (9.75%) incident coronary heart disease (CHD) and 119 (5.86%) incident stroke. After adjusting for as many relevant confounding factors as possible, each SD increase in METS-IR was associated with a 30% increased risk of new onset overall CVD events, a 32% increased risk of new onset CHD, and a 27% increased risk of new onset stroke. When METS-IR was assessed as tertiles, after adjustment for fully confounding factors, the highest tertiles versus the lowest tertiles were associated with a greater hazard of CVD (HR 2.05; 95% CI 1.52,-2.77), CHD (HR 1.96; 95% CI 1.35– 2.84), and stroke (HR 2.24; 95% CI 1.35– 3.72). The results of various subgroups and sensitivity analyses were similar. When METS-IR was added, CVD predictions were reclassified and identified more accurately than baseline models for the C-index, continuous net reclassification improvement, and integrated discrimination index. CHD and stroke showed similar results.Conclusion: METS-IR is a powerful predictor of CVD and its subtypes in patients with hypertension and OSA, which can facilitate the identification of high-risk individuals and provide individualized CVD prevention.Keywords: cohort study, METS-IR, cardiovascular disease, hypertension, obstructive sleep apnoea

Ting Duan,1,2,&ast; Xin Yang,3,&ast; Jingyu Kuang,4 Wenjie Sun,3 Jin Li,3 Juan Ge,3 Mohan Zhang,3 Xiaobo Cai,3 Peilin Yu,3 Jun Yang,5 Xinqiang Zhu6 1School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, People’s Republic of China; 2Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, School of Pharmacy, Hangzhou Normal University, Hangzhou, 311121, People’s Republic of China; 3Department of Toxicology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, People’s Republic of China; 4Department of Biology and Chemistry, College of Sciences, National University of Defense Technology, Changsha, Hunan, 410073, People’s Republic of China; 5Department of Nutrition and Toxicology, Hangzhou Normal University School of Public Health, Hangzhou, Zhejiang, 311121, People’s Republic of China; 6Medical Research Center, The Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, 322000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinqiang Zhu; Jun Yang, Email zhuxq@zju.edu.cn; gastate@zju.edu.cnPurpose: The uncoordinated-51 like kinase 1 (ULK1) is an important serine/threonine protein kinase involved in autophagy, especially for the initiation stage. Previous studies have shown that ULK1 could be used as a prognostic marker in predicting poor progression-free survival and a therapeutic target for hepatocellular carcinoma (HCC) when treated with sorafenib; however, its role during hepatocarcinogenesis remains to be elucidated.Methods: CCK8 and colony formation assay were used to detect cell growth ability. Western blotting was performed to determine expression level of protein. Data from public database were downloaded to analyze expression of ULK1 at mRNA level and predict survival time. RNA-seq was conducted to reveal disturbed gene profile orchestrated by ULK1 depletion. A diethylnitrosamine (DEN)-induced HCC mice model was used to uncover the role of ULK1 in hepatocarcinogenesis.Results: ULK1 was up-regulated in liver cancer tissues and cell lines, and knockdown of ULK1 promoted apoptosis and suppressed proliferation of liver cancer cells. In in vivo experiments, Ulk1 depletion attenuated starvation-induced autophagy in mice liver, reduced diethylnitrosamine (DEN)-induced hepatic tumor number and size, and prevented tumor progression. Further, RNA-seq analysis revealed a close relationship between Ulk1 and immunity with significant changes in gene sets enriched in the interleukin and interferon pathways.Conclusion: ULK1 deficiency prevented hepatocarcinogenesis and inhibited hepatic tumor growth, and might be a molecular target for the prevention and treatment of HCC.Keywords: hepatocellular carcinoma, ULK1, RNA-sequencing, apoptosis, autophagy

Bin Liang,1,&ast; Huiyu Chen,2,&ast; Donghong Yu,3,4 Wantong Zhao,1,3 Xiaoling Cai,1,3 Huahong Qiu,2 Liangpu Xu1 1Medical Genetic Diagnosis and Therapy Center, Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China; 2Laboratory Department, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China; 3Fujian Obstetrics and Gynecology Hospital, Fuzhou, Fujian, People’s Republic of China; 4Medical Research Center, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liangpu Xu; Huahong Qiu, Fujian Maternity and Child Health Hospital, Fuzhou, 350001, People’s Republic of China, Tel +86-0591-87554929 ; +86-0591-87604121, Email xiliangpu@fjmu.edu.cn; 722hhq@sina.comObjective: This study investigated the molecular epidemiology of Group B Streptococcus (GBS) in pregnant women with premature rupture of membranes (PROM) in Fuzhou region of China as a source of clinical reference.Methods: GBS isolates were obtained from pregnant women with PROM. All isolates were genotyped, serotyped, and tested for drug-resistance and virulence genes using PCR and DNA sequencing. Antibiotic susceptibility testing was performed using the Vitek® 2 automated system.Results: Among the 140 GBS isolates, seventeen sequence types (STs) were identified, of which ST19 (20.0%) was the most prevalent, followed by ST862, ST10, and ST12. Three clonal complexes (CC19, CC10 and CC1) were identified. The predominant serotype was III (45.7%), followed by V (23.6%), Ib (18.6%), Ia (7.1%), and II (3.6%). The prevalence of multidrug resistance was 72.8% (102/140). All isolates were susceptible to penicillin G, ampicillin, quinupristin, linezolid, vancomycin, and tigecycline. The majority of isolates were resistant to erythromycin (70.0%), clindamycin (72.1%), and tetracycline (81.4%), and 28.6% of isolates were resistant to levofloxacin and moxifloxacin. Of the 98 erythromycin-resistant strains, mreA, ermB, mefA, mefE, ermA, and ermTR were detected in 100%, 70.4%, 49.0%, 22.4%, 13.3%, and 9.2%, respectively. No linB was detected among 101 clindamycin-resistant strains. Of the 114 tetracycline-resistant strains, tetM, tetK, tetL and tetO were detected in 52.6%, 61.4%, 7.9%, and 23.7%, respectively. Regarding virulence genes, all strains carried rib and hylB, followed by scpB (98.6%), and bca (80.7%), whereas only one strain carried bac.Conclusion: ST19/III and ST862/III were the most prevalent GBS subtypes. Penicillin G remains a first-line antibiotic for intrapartum antibiotic prophylaxis and treatment of GBS infections. The prevalence of resistance to clindamycin, erythromycin, and tetracycline is high among GBS isolates in the Fuzhou region. ST862 and ST651 are emerging animal origin STs in human infections, and may become potential zoonotic threats.Keywords: Group B Streptococcus, molecular epidemiology, premature rupture of the membranes, antibiotic resistance, China

Xuezhou Cai,1,2,* Wei Li,1,* Jian Yang,1,3,* Guangjie Wu,1 Jianxin Song,4 Xuepeng Gong,1 Dong Liu,1 Yan He1 1Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pharmacy, Xianning Central Hospital, Hubei University of Science and Technology, Xianning, People’s Republic of China; 3Department of Pharmacy, General Hospital of Central Theater Command of Chinese People’s Liberation Army, Wuhan, People’s Republic of China; 4Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan He; Dong Liu, Email heyan_may@hotmail.com; ld2069@outlook.comBackground: There is a wide debate about the efficacy and safety of voriconazole in patients with impaired hepatic function at Child-Pugh C level.Objective: The purpose of this study was to investigate the safety and efficacy between the two groups treated with different dosages of voriconazole (400mg/day vs 200mg/day) in the treatment of invasive fungal infections (IFIs) in patients with hepatic dysfunction.Methods: A retrospective study enrolling patients with hepatic dysfunction receiving intravenous voriconazole for IFIs from January 1st, 2017, to December 30th, 2021 was conducted. Patients were enrolled in the 400mg per day dose group and 200mg per day dose group. In patients with the same degree of hepatic impairment, factors affecting prognosis were screened and differences in steady-state blood trough concentrations (Cmin) of voriconazole, positive G/GM tests and adverse effects (AEs) were compared between the two groups described above.Results: In total, 308 patients with IFIs were enrolled. For Child-Pugh C class, patients receiving the halved maintenance dose had a lower Cmin and AEs rate but higher recovered rate compared to those receiving maintenance dose, and significant predictors of recovery were dosage (OR, 5.131; 95% CI, 1.599– 16.464; p = 0.006) and diabetes (OR, 0.111; 95% CI, 0.020– 0.597; p = 0.010). For patients of Child-Pugh A & B class, chronic liver disease (OR, 0.334; 95% CI, 0.159– 0.704; p = 0.004) was a prognosis-related factor.Conclusion: Halving maintenance dose ensure the efficacy and safety of voriconazole in patients suffering from invasive fungal infections with serious hepatic dysfunction.Keywords: hepatic dysfunction, invasive fungal infections, voriconazole, through concentration, Child-Pugh

Mengru Wang,1,&ast; Menghui Wang,1,&ast; Qing Zhu,1,2 Xiaoguang Yao,1 Mulalibieke Heizhati,1 Xintian Cai,1,2 Yue Ma,1 Run Wang,1 Jing Hong,1 Ling Yao,1 Le Sun,1 Na Yue,1 Yingli Ren,1 Nanfang Li1 1Hypertension Center, Xinjiang Hypertension Institute, National Health Committee Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region, Xinjiang Clinical Medical Research Center for Hypertension Diseases, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China; 2Graduate School, Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nanfang Li, Hypertension Center, Xinjiang Hypertension Institute, National Health Committee Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region, Xinjiang Clinical Medical Research Center for Hypertension Diseases, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China, Email lnanfang2016@sina.comPurpose: To develop and validate a risk prediction model for coronary heart disease (CHD) in snorers with hypertension, including traditional and new risk factors.Patients and Methods: Twenty factors were evaluated in the records of 2810 snorers with hypertension. Training (70%) and validation (30%) sets were created by random allocation of data, and a new nomogram model was developed. The model’s discrimination and calibration were measured by calculating the area under the receiver operating curve (AUC) and creating calibration charts. The performance of the nomogram model was compared with that of the Prediction for ASCVD Risk in China (China-PAR) and Framingham models by decision curve analysis. An optimal cutoff point for the risk score in the training set was computed to stratify patients.Results: In the nomogram model, the AUCs for predicting CHD at 5, 7 and 9 years in the training set were 0.706 (95% confidence interval [CI] 0.649– 0.763), 0.703 (95% CI 0.655– 0.751) and 0.669 (95% CI 0.593– 0.744), respectively. The respective AUCs were 0.682 (95% CI 0.607– 0.758), 0.689 (95% CI 0.618– 0.760) and 0.664 (95% CI 0.539– 0.789) in the validation set. The calibration chart showed that the predicted events from the nomogram score were close to the observed events. Decision curve analysis indicated that the nomogram score was slightly better than the Prediction for ASCVD Risk in China (China-PAR) and Framingham models for predicting the risk of CHD in snorers with hypertension. A cutoff point was identified for being CHD-free (a nomogram score of ≤ 121), which could be helpful for the early identification of individuals at high-risk of CHD.Conclusion: The nomogram score predicts the risk probability of CHD in snorers with hypertension at 5, 7 and 9 years, and shows good capability in terms of discrimination and calibration. It may be a useful tool for identifying individuals at high risk of CHD.Keywords: snorer, hypertension, coronary heart disease, prediction model

Weiyuan Ma,1 Ruyu Zhan,2 Changlin Sui,3 Fushan Zhou,2 Haidong Liu,4 Xiuwen Zhang,5 Zhenqiang Ruan,6 Yukun Wang,7 Xiaolan Cai8 1Department of Dermatology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, People’s Republic of China; 2Scientific Research Center, Anxi County Hospital, Quanzhou, Fujian, People’s Republic of China; 3Department of Dermatology, Yantai Yuhuangding Hospital, Yantai, Shandong, People’s Republic of China; 4Department of Dermatology, Liaocheng People’s Hospital, Liaocheng, Shandong, People’s Republic of China; 5Department of Dermatology, Weihai Municipal Hospital, Weihai, Shandong, People’s Republic of China; 6Department of Dermatology, Jinan Dermatosis Prevention and Control Hospital, Jinan, Shandong, People’s Republic of China; 7Department of Dermatology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China; 8Department of Otolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Weiyuan Ma, Department of Dermatology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, People’s Republic of China, Email fymaweiyuan@wfmc.edu.cnPurpose: The clinical and pathological data of patients with rhinofacial ulcers were retrospectively reviewed and analyzed to lay the foundation for standardized clinical treatment.Patients and Methods: We retrospectively analyzed the clinical data, etiology, pathological features, treatment methods, and prognosis of 243 patients with rhinofacial ulcers treated in the Departments of Otorhinolaryngology and Dermatology at six hospitals in Shandong Province, China from July 2014 to October 2021. The clinical characteristics and treatment methods of the rhinofacial ulcers were summarized to provide a basis for standardizing patients’ diagnosis and treatment.Results: The male-to-female ratio of the 243 patients was 2.04:1, and their ages ranged from 25 to 91 years. The most common sites were the cheek, nasal dorsum, and upper lip. The common primary diseases were basal-cell carcinoma, squamous-cell carcinoma, and odontogenic fistula, but rare triggers played important roles in some cases, such as infection, autoimmune diseases, and adverse drug reactions. Surgical treatment was feasible for tumor ulcers; 71 patients with basal-cell carcinoma and 50 with squamous-cell carcinoma were treated with Mohs micrographic surgery. During the follow-up period of 1– 84 months, most of the rhinofacial ulcers were cured, while natural killer/T-cell lymphoma, angiosarcoma, and melanoma were important causes of death.Conclusion: Various causes may lead to rhinofacial skin ulcers, and some cases lacking specificity of clinical manifestations are easily misdiagnosed in clinical practice. Histopathological biopsy is valuable for confirming the diagnosis, after which correct etiological treatment is very important.Keywords: skin, diagnosis, treatment, otorhinolaryngology, dermatology

Xiaoying Sun,1,2 Liu Liu,1,2 Siting Chen,1,2 Jiao Wang,1,2 Xiaoce Cai,1,2 Jiankun Song,3 Mi Zhou,1,2 Dongjie Guo,1,2 Le Kuai,1,2 Xiaojie Ding,1,2 Bin Li,2,4 Xin Li1,2 1Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Dermatology of TCM, Shanghai Skin Diseases Hospital, Shanghai, People’s Republic of China; 4Department of Dermatology, Shanghai Skin Diseases Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Xin Li, Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, People’s Republic of China, Tel +8613661956326, Email 13661956326@163.com Bin Li, Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, 110 Ganhe Road, Hongkou District, Shanghai, 200437, People’s Republic of China, Tel +8618930568129, Email 18930568129@163.comBackground: Psoriasis is an immune-mediated chronic systemic inflammatory skin disease whose diagnosis and severity assessment pose challenges for clinicians worldwide. The use of serum biomarkers facilitates the early diagnosis and treatment of psoriasis.Methods: This case–control study compared tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-17, IL-10, and fibrinogen-like protein 1 (FGL1) levels of 139 untreated psoriasis patients and 140 healthy controls. Serum samples were collected, and enzyme-linked immunosorbent assays were performed to quantify their levels. Subgroups were analyzed according to abnormal lipid metabolism status.Results: Compared to controls, patients with psoriasis exhibited lower concentrations of serum TNF-α, IL-17, and FGL1 (P < 0.05). A correlation analysis showed that FGL1 was inversely correlated with high-density lipoprotein cholesterol and IL-17 in the psoriatic state. Stepwise multiple regression analysis revealed that FGL1 and total cholesterol were the independent determinants of Psoriasis Area and Severity Index (PASI) score in psoriasis patients. The area under the receiver operating characteristic curve of FGL1 assessing moderate-to-severe psoriasis and mild psoriasis was 0.70, while the area under the curve (AUC) assessing severe psoriasis and mild-to-moderate psoriasis was 0.67, better than that of IL-17. In addition, FGL1, but not IL-17, was able to identify psoriasis with abnormal lipid metabolism to a certain extent (AUC = 0.60).Conclusion: In conclusion, serum FGL1 may be a promising biomarker for diagnosing and staging psoriasis. It may also be involved in its progression and comorbid abnormal lipid metabolism.Keywords: psoriasis, disease severity, biomarker, fibrinogen-like protein 1, lipid metabolism

Wenlong Shen, Xingzhi Cai, Xiaohui Liu, Zongwang Zhang, Xuxiang Wang, Ailan Yu Department of Anesthesiology, Liaocheng People’s Hospital, Liaocheng, Liaocheng, Shandong, People’s Republic of ChinaCorrespondence: Ailan Yu; Xingzhi Cai, Department of Anesthesiology, Liaocheng People’s Hospital, Liaocheng, Shandong, 252000, People’s Republic of China, Tel +86 13563530309, Email yuercai@126.com; xingzhicai2015@126.comPurpose: Endoscopic submucosal dissection (ESD) has become the primary treatment for early upper gastrointestinal tract lesions. During endoscopic surgery, endotracheal intubation is generally performed in the patients’ supine position, and patients are shifted to the left lateral position for endoscopic surgery. This study compared the efficacy of flexible bronchoscope-guided intubation with that of video laryngoscope-guided intubation in the left lateral position.Patients and Methods: Forty-eight patients receiving ESD were randomly divided into the flexible bronchoscope group (group F) or the video laryngoscope group (group V). Tracheal intubation was performed by a trained anesthetist with a flexible bronchoscope (group F) or unchanneled video laryngoscope (group V) in the left lateral position. Primary outcomes included the intubation duration and success rate. Secondary outcomes included the ease of intubation technique and the occurrence of complications.Results: Twenty-four (100%) patients in group F and twenty-three (95.8%) in group V were successfully intubated (P = 1.000). The median intubation time in group F was 37s (interquartile range, 33.0, 44.5), which was significantly shorter compared to group V (53s [45.5, 66.5]; P < 0.001). The flexible bronchoscope was significantly easier to manage than the video laryngoscope, as reflected by the users scoring system (9 [9, 10] vs 8 [7, 8]; P < 0.001). The presence of perioperative adverse events and complications were comparable between the two groups.Conclusion: Both flexible bronchoscope- and video laryngoscope-guided intubation in patients’ left lateral position achieved high success rates and comparable complication rates. However, intubation with the flexible bronchoscope was completed more quickly.Keywords: intubation, bronchoscope, laryngoscope, endoscopic submucosal dissection, left lateral position

Xueping Chen,1,2 Xiaoxue Liang,2 Jun Zhang,1,2 Liujing Chen,1,2 Jingping Sun,2 Xueli Cai2 1Zhejiang University, School of Medicine, Hangzhou, Zhejiang, 310005, People’s Republic of China; 2Department of Neurology, Lishui Hospital of Zhejiang University (Lishui Municipal Central Hospital), Lishui, Zhejiang, 323000, People’s Republic of ChinaCorrespondence: Xueli Cai; Jingping Sun, Department of Neurology, Lishui Hospital of Zhejiang University (The Central Hospital of Lishui), No. 289, KuoCang Street, Lishui, Zhejiang, 323000, People’s Republic of China, Tel +8613967059836 ; +860578-2285330, Email xueli_cai_official@126.com; lszxyysunjingping@yeah.netPurpose: Stroke-associated infection (SAI) is one of the most common post-stroke complications, which may lead to a relatively poor prognosis. This study aims to explore the potential relationship between serum calcium levels and SAI.Patients and Methods: This is a cross-sectional study involving 395 participants. SAI is a term that covers stroke-associated pneumonia (SAP), urinary tract infection (UTI), as well as other infections diagnosed during the first week after a stroke. Serum calcium levels were measured within 24 hrs of admission. To determine the association of serum calcium levels with the SAI, logistic regression models were calculated. An adjusted spline regression model was used to further confirm the relationship between the two.Results: Among the total patients, SAI occurred in 107 (27.1%) patients. Serum calcium was associated with SAI and was independent of the SAI risk factors for age, admission NIHSS score, and intravascular therapy [adjusted OR 0.040 (95% CI = 0.005– 0.291), p = 0.002]. Remarkably, this trend applies predominantly to serum calcium levels less than 2.25mmol/L (p= 0.005 for linearity).Conclusion: Serum calcium levels are associated with the risk of SAI, when serum calcium is below normal (2.25mmol/L), the risk of SAI increases as serum calcium levels decrease.Keywords: calcium homeostasis, stroke-associated infection, pneumonia, risk factors

Junli Hu,1– 5,&ast; Xintian Cai,1– 5,&ast; Nanfang Li,1– 5 Qing Zhu,1– 5 Wen Wen,1– 5 Jing Hong,1– 5 Delian Zhang,1– 5 Xiaoguang Yao,1– 5 Qin Luo,1 Le Sun1– 5 1Hypertension Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China; 2Xinjiang Hypertension Institute, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China; 3National Health Committee Key Laboratory of Hypertension Clinical Research, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China; 4Key Laboratory of Xinjiang Uygur Autonomous Region, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China; 5Xinjiang Clinical Medical Research Center for Hypertension Diseases, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nanfang Li, Hypertension Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of China, Tel/Fax +86 991-8564818, Email lnanfang2016@sina.comPurpose: This study aimed to investigate the association between triglyceride glucose index-waist circumference (TyG-WC) and the risk of first myocardial infarction (MI) in Chinese hypertensive patients with obstructive sleep apnoea (OSA).Methods: This study was an observational cohort study. A total of 2224 Chinese hypertensive patients with OSA without a history of MI were included in this study. Hazard ratio (HR) and 95% confidence interval (CI) were estimated using multivariable Cox proportion hazard models. A generalized additive model was used to identify nonlinear relationships. Additionally, we performed hierarchical analysis and test for interaction.Results: During a median follow-up of 7.15 years, 85 incidents of MI developed. Overall, there was a positive association between TyG-WC and the risk of first MI. In the multivariable-adjusted model, the risk of MI increased with quartiles of the TyG-WC, the HR in quartile 4 versus quartile 1 was 4.29. A generalized additive model and a smooth curve fitting showed that there existed a similar J-shaped association between TyG-WC and the risk of first MI, with an inflection point at about 785.Conclusion: Elevated levels of the baseline TyG-WC are associated with an increased risk of first MI. This finding indicates that the TyG-WC might be useful to identify the high risk of first MI in Chinese hypertensive patients with OSA.Keywords: triglyceride glucose index-waist circumference, myocardial infarction, hypertension, obstructive sleep apnoea, cohort study

Qinglin Li,1,&ast; Xiaoyan Cai,2,&ast; Guanggang Li,3 Hongyan Ju,3 Dawei Li,4 Feihu Zhou1,5 1Department of Critical Care Medicine, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 2Department of Nephrology, the Second Medical Center, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 3Department of Critical Care Medicine, the Seventh Medical Center, Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China; 4Department of Critical Care Medicine, the Sixth Medical Center, Chinese PLA General Hospital, Beijing, 100048, People’s Republic of China; 5Chinese PLA General Hospital National Clinical Research Center for Geriatric Diseases, Beijing, 100853, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Feihu Zhou, Department of Critical Care Medicine, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China, Tel +86– 10– 66938148, Fax +86– 10– 88219862, Email feihuzhou301@126.comPurpose: Acute kidney injury (AKI) in elderly patients is associated with higher hospital mortality. However, the relationship between AKI and peri-intubation complications is unclear.Methods: This retrospective, observational, multicenter cohort study enrolled 3271 consecutive elderly patients (≥ 75 years) who received invasive mechanical ventilation (MV) in four medical centers of Chinese PLA General Hospital from 2008 to 2020. AKI was diagnosed according to the 2012 KDIGO criteria by an absolute increase in serum creatinine of ≥ 26.5 μmol/L within the first 48 hours of MV. We recorded subsequent in-hospital complications, including incident gastrointestinal bleeding, new-onset electrolyte imbalances, severe hypoxemia, hypoalbuminemia, cardiovascular instability and all-cause 90-day mortality.Results: A total of 1292 patients were included in the final evaluation, with 29.1% presenting AKI (stage 1: 31.4%, stage 2: 35.1%, stage 3: 33.5%). Multiple regression analyses show that more advanced AKI increased the risk of MAP < 65 mmHg (stage 1: OR=1.833, P=0.002; stage 2: OR= 4.653, P< 0.001; stage 3: OR=4.834, P< 0.001) and SBP < 90 mmHg (stage 1: OR=1.644, P=0.014; stage 2: OR=3.701, P< 0.001; stage 3: OR=5.750, P< 0.001), a new need for or requiring an increased dose of vasopressors (stage 1: OR=1.623, P=0.014; stage 2: OR=3.250, P< 0.001; stage 3: OR=12.132, P< 0.001), gastrointestinal bleeding (stage 1: OR=1.102, P=0.669; stage 2: OR=1.471, P=0.060; stage 3: OR=2.377, P< 0.001), severe hypoxia (stage 1: OR=1.213, P=0.399; stage 2: OR=1.449, P=0.077; stage 3: OR=2.214, P< 0.001) and all-cause 90-day mortality (stage 1: OR =0.935; P=0.741; stage 2: OR=1.888; P=0.001; stage 3: OR=12.584; P< 0.001).Conclusion: Our study suggests that the presence of AKI within the first 48 hours of MV in geriatric patients is associated with a higher risk for postintubation complications and 90-day mortality. Moreover, the risk of complications was greater for patients with more severe AKI.Keywords: mechanical ventilation, aged, complications, acute kidney injury, electrolyte imbalance

Dongying Chen,1,&ast; Xiaoyan Cai,2,&ast; Hui Ouyang,3,&ast; Shiwen Yuan,2 Xiaodong Wang,4 Lian Lin,5 Zhiqing Chen,5 Mingcheng Huang5 1Department of Rheumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guandong, People’s Republic of China; 2Department of Rheumatology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guandong, People’s Republic of China; 3Department of Digestive Medicine Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, ShenZhen, Guandong, People’s Republic of China; 4Department of Ultrasound, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guandong, People’s Republic of China; 5Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, ShenZhen, Guandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingcheng Huang, Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, ShenZhen, Guandong, People’s Republic of China, Email huangmch6@mail.sysu.edu.cnObjective: Aggressive phenotype and abnormal glycolytic metabolism of fibroblast-like synoviocytes (FLSs) are essential to joint inflammation and damage in rheumatoid arthritis (RA). Eukaryotic elongation factor-2 kinase (eEF2K) is a negative regulator of protein synthesis and has been shown to play an important role in regulating various cellular processes and promoting glycolysis in tumor cells. However, the role of eEF2K in regulating the pathogenic FLS behaviors is unknown.Methods: A specific inhibitor of eEF2K, NH125, and siRNA were used to evaluate the role of eEF2K on RA FLSs in vitro. Collagen-induced arthritis (CIA) mice were used to evaluate the in vivo effect of eEF2K. Cell migration, invasion of RA FLSs were assessed by transwell or wound healing assays. Relative changes of cytokines were analyzed by quantitative real-time PCR, western blot and ELISA.Results: Herein, we found an increased expression of eEF2K in synovial tissues and FLSs of RA patients. eEF2K knockdown by siRNA or treatment with NH125, an inhibitor of eEF2K, significantly reduced inflammation, migration/invasion, glucose uptake and lactate productions. eEF2K knockdown suppressed TNF-α-induced activation of NF-κB and AKT pathways in RA FLSs. Lactate reversed the inhibitory effect of eEF2K knockdown on inflammation and migration of RA FLSs. Moreover, lactate was also involved in eEF2K-mediated activation of NF-κB and AKT. NH125 treatment attenuated the severity of arthritis in collagen-induced arthritis mice.Conclusion: eEF2K inhibition suppressed glycolysis and aggressive behaviors of RA FLS, which indicated that targeting eEF2K may be a new strategy for the treatment of RA.Keywords: rheumatoid arthritis, fibroblast-like synoviocytes, eukaryotic elongation factor-2 kinase, glycolysis, migration, invasion

Yunxiao Zhong,1,&ast; Xiaodong Cai,2,&ast; Li Ding,3,&ast; Jinchi Liao,1 Xu Liu,1 Yiying Huang,1 Xiaohong Chen,1 Ling Long1 1Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510600, People’s Republic of China; 2Department of Neurology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510655, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling Long; Xiaohong ChenDepartment of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, 510600, People’s Republic of China, Tel +86-20-85253275Email longl3@mail.sysu.edu.cn; chenxh5@mail.sysu.edu.cnObjective: Parkinson’s disease (PD) is associated with dysregulated neural cell death, such as pyroptosis, but its regulatory mechanisms are poorly understood. This study investigated roles of nuclear factor E2-related factor 2 (Nrf2) in regulating pyroptosis and PD development.Methods: Cellular and rat PD models established by 6-OHDA exposure were subjected to Nrf2 overexpression. Neurobehavioral functions were assessed by the traction test, Morris Water Maze, and open field test. Cell proliferation was analyzed by MTS assay, while flow cytometry was applied to quantify levels of reactive oxygen species (ROS) and apoptosis. Nissl bodies in rat brains were detected by Nissl staining, and cell apoptosis in brain tissues was assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Differential expression of lncRNA and mRNA was characterized by deep sequencing.Results: A cellular PD model was successfully established by inducing PC12 cell differentiation with nerve growth factor-β and exposing differentiated cells to 6-OHDA. Cells exhibited significantly increased ROS levels, enhanced pyroptosis, and inhibited Nrf2 phosphorylation. The rat PD model exhibited impaired muscle strength, increased pyroptosis, and repressed Nrf2 phosphorylation. Nrf2 overexpression effectively repressed pyroptosis in both cellular and rat PD models. Marked alterations of lncRNA and mRNA profiles were induced by Nrf2 overexpression in the cellular PD model, which involved multiple signaling pathways. Silencing of the lncRNA AABR07032261.5 significantly promoted pyroptosis in the cellular PD model.Conclusion: Nrf2 suppressed PD pathogenesis in cellular and animal models by promoting AABR07032261.5, which repressed pyroptosis.Keywords: Nrf2, lncRNAs, AABR07032261.5, oxidative stress, pyroptosis, Parkinson’s disease

Xintian Cai,1,2 Nanfang Li,1 Junli Hu,1 Wen Wen,1,2 Xiaoguang Yao,1 Qing Zhu,1,2 Mulalibieke Heizhati,1 Jing Hong,1 Le Sun,1 Guzailinuer Tuerxun,1 Delian Zhang,1 Qin Luo1 1Hypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, National Health Committee Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region, Xinjiang Clinical Medical Research Center for Hypertension Diseases, Urumqi, Xinjiang, People’s Republic of China; 2Graduate School, Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of ChinaCorrespondence: Nanfang LiHypertension Center of People’s Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, National Health Committee Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region, Xinjiang Clinical Medical Research Center for Hypertension Diseases, Urumqi, Xinjiang, People’s Republic of China, Email lnanfang2016@sina.comPurpose: We aimed to investigate the relationship between the Chinese visceral adiposity index (CVAI) and the risk of new-onset myocardial infarction (MI) in patients with hypertension and obstructive sleep apnoea (OSA) and to inspect possible modifiers of the effect.Methods: The Cox regression model was used to evaluate the relationship between baseline CVAI and risk of new-onset MI. A generalized additive model was used to identify the nonlinear relationship. Besides, we conducted subgroup analyses and interaction tests.Results: A total of 2177 patients with hypertension and OSA undergoing polysomnography were enrolled in this study. During a median follow-up period of 87 months, 82 participants developed new-onset MI. Overall, CVAI was positively related to the risk of new-onset MI (per 1 SD increase; HR = 1.54, 95% CI: 1.28– 1.85). In multivariable-adjusted models, the risk of new-onset MI increased with quartiles of CVAI, with an HR of 3.64 (95% CI: 1.94– 6.83) for quartile 4 compared with quartile 1. The generalized additive model and smoothed curve fit revealed a nonlinear relationship between CVAI and risk of new-onset MI with an inflection point of approximately 112. None of the stratification variables had a significant effect on the relationship between CVAI and new-onset MI. Similar outcomes were observed in the sensitivity analysis. The addition of CVAI significantly improved reclassification and discrimination over the conventional model, with a category-free NRI of 0.132 (95% CI 0.021 to 0.236, P = 0.021) and an IDI of 0.012 (95% CI 0.005 to 0.023, P < 0.001).Conclusion: This study demonstrated a nonlinear relationship between CVAI and the risk of new-onset MI in patients with hypertension and OSA. Higher CVAI was significantly associated with the risk of new-onset MI when CVAI was ≥ 112.Keywords: Chinese visceral adiposity index, myocardial infarction, hypertension, obstructive sleep apnoea, cohort study

Song Liu,1,&ast; Xiaojun Cai,1,&ast; Tao Wang,1 Jiwen Xu,2 Weilun Cheng,3 Xuling Wang,1 Gangjie Wei,4 Shuang Yan5 1Endocrinology Department, Traditional Chinese Medicine Academy of Heilongjiang, Harbin, Heilongjiang Province, People’s Republic of China; 2Anatomy, Histology and Embryology Teaching and Research Section, School of Basic Medicine, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, People’s Republic of China; 3Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 4Medical Department, Traditional Chinese Medicine Academy of Heilongjiang, Harbin, Heilongjiang Province, People’s Republic of China; 5Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuang Yan, Email yan8028397483@126.comPurpose: Skeletal muscle insulin resistance (IR) is an important etiology of type 2 diabetes mellitus (T2DM); however, its molecular mechanism is yet to be fully defined. This study attempted to identify the gene expression patterns and molecular disorders in T2DM patients’ skeletal muscle samples.Methods: First, the difference in genetic expression among GSE25462 data was analyzed. Next, PPI network analysis of differential genes was carried out, after which the maladjustment module was identified. Then, an enrichment analysis and gene set enrichment analysis (GSEA) were carried out. Finally, the transcription factors that regulate the modular genes by raid were predicted.Results: Most differentially expressed genes were found to be able to form an interaction network and cluster into 9 modules. These modular genes were shown to possess a significant correlation with immune inflammation and metabolic response. Importantly, the top 15 genes of area under receiver operating characteristic curve (AUC) were identified, and the expression of 10 genes by GSE12643, GSE18732 and GSE29221 was confirmed. The expression and AUC value of ALDH6A1 were then verified according to three sets of data, where ALDH6A1 was found to be negatively correlated with follicular helper T cells. However, among the predicted transcription regulators, HDAC was shown to have a better regulatory effect.Conclusion: The findings highlight that the dysregulation of ALDH6A1 expression in IR of T2DM may serve as a potential therapeutic target. ALDH6A1 is involved in the immune inflammation and metabolic pathways.Keywords: type 2 diabetes mellitus, ALDH6A1, immune inflammatory response, metabolic pathway, HDAC

Li Wang, Na Zhao, Li Zhou, Juan Tong, Lei Xue, Lei Zhang, Yongsheng Han, Xingbing Wang, Liangquan Geng, Baolin Tang, Huilan Liu, Weibo Zhu, Xiaoyan Cai, Xin Liu, Xiaoyu Zhu, Zimin Sun, Changcheng Zheng Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of ChinaCorrespondence: Changcheng ZhengDepartment of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Lujiang Road No. 17, Hefei, 230001, People’s Republic of ChinaTel/Fax +86-551-62284476Email zhengchch1123@ustc.edu.cnBackground: There is great uncertainty in the treatment of elderly patients with acute myeloid leukemia (AML), which leads to great challenges in treatment decision. The aim of this study is to find more suitable induction therapy and consolidation therapy for elderly AML patients.Methods: A total of 149 consecutive newly diagnosed elderly AML patients (aged ≥ 60 years) who received induction chemotherapy in our medical center from January 2015 to December 2019 were retrospectively analyzed.Results: After the first induction treatment, the complete remission/or complete remission with incomplete hematologic recovery (CR/CRi) rates in the standard-intensity chemotherapy group was significantly higher than that in the low-intensity chemotherapy group (58.2% vs 32.9%, p = 0.003). Compared with the low-intensity chemotherapy, the incidence of severe infection in the standard-intensity chemotherapy was significantly increased (p < 0.001), but the early mortality was comparable. One hundred and seven patients received minimal residual disease (MRD) examination after the first induction treatment; and MRD was negative accounting for 51.9% in the standard-intensity chemotherapy group, while only 32.7% in the low-intensity group (p = 0.05). The 2-year-overall survival (OS) of patients in standard-intensity induction chemotherapy group (37.2%) was slightly higher than that in low-intensity induction chemotherapy group (23.4%) (p = 0.075). Eighty-one CR/CRi patients received intermediate or high dose cytarabine (n = 35) or sequential chemotherapy regimens (n = 46) as consolidation treatment. The 2-year OS and event-free survival (EFS) of patients in the intermediate or high-dose cytarabine group were significantly higher than those in the sequential chemotherapy regimens group (73.0% vs 38.5%, p = 0.002; 54.8% vs 35.0%, p = 0.035).Conclusion: Our results showed that standard-intensity induction chemotherapy can significantly improve the CR rate for elderly AML patients, and does not increase the early mortality; consolidation therapy with intermediate or high-dose cytarabine can significantly improve EFS and OS for elderly AML patients achieved CR.Keywords: acute myeloid leukemia, elderly patients, minimal residual disease, standard-intensity chemotherapy, intermediate or high dose cytarabine

Jiao Zhou,1,2 Yunlong Dong,3 Xiang Cai,1,2 Hongbo Yang,1,2 Tao Guo1,2 1Department of Cardiology, Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 2Department of Cardiology, Fuwai Yunnan Cardiovascular Hospital, Kunming, Yunnan, People’s Republic of China; 3Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of ChinaCorrespondence: Tao GuoDepartment of Cardiology, Affiliated Cardiovascular Hospital of Kunming Medical University, 1168 Chunrong West Road, Yuhua Street, Chenggong New City, Kunming, Yunnan, People’s Republic of ChinaTel +86 13888988986Fax +86 0871 65199777Email 1785875598@qq.comBackground: Autophagy is an evolutionary conserved important process for the turnover of intracellular substances in eukaryotes and is closely related to the development of atrial fibrillation (AF). The aim of this study is to identify and validate potential autophagy-related genes (ARGs) of AF through bioinformatics analysis and experimental validation.Methods: We downloaded two data sets from the Gene Expression Omnibus (GEO) database, GSE14975 and GSE31821. After merging the data of the two microarrays, adjusting the batch effect, and integrating the differentially expressed genes (DEGs) with ARGs to obtain differentially expressed autophagy-related genes (DEARGs). Functional and pathway enrichment analyses were carried out based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Use the STRING database to construct a protein–protein interaction (PPI) network. Finally, mRNA expression levels of DEARGs were validated in right atrial tissue samples from AF patients and non-AF controls by qRT-PCR.Results: Through bioinformatics analysis, we finally identified 11 DEARGs (CDKN1A, CXCR4, DIRAS3, HSP90AB1, ITGA3, PRKCD, TP53INP2, DAPK2, IFNG, PTK6, and TNFSF10) in AF using [log2 (fold change)] > 0.5 and P < 0.05. In the pathway enrichment analysis, the most significantly enriched pathway was the autophagy pathway. The results of validation showed that the expression levels of CXCR4, DAPK2, and TNFSF10 corroborating with our computational findings, and the results were statistically significant (P< 0.05).Conclusion: Our study demonstrates that these 11 potential crucial ARGs, especially CXCR4, DAPK2, and TNFSF10, may be potential biomarkers and therapeutic targets in AF, which will help the personalized treatment of AF patients.Keywords: autophagy, AF, Gene Expression Omnibus, hub genes

Jianyun Long, Xupin Xie, Dong Xu, Changpin Huang, Yongchang Liu, Xiaohu Meng, Xuchao Cai, Xin Fang Department of Vascular Surgery, Affiliated Hangzhou First People’s Hospital, ZheJiang University School of Medicine, Hangzhou, Zhejiang, 310014, People’s Republic of ChinaCorrespondence: Xin FangDepartment of Vascular Surgery, Affiliated Hangzhou First People’s Hospital, ZheJiang University School of Medicine Hangzhou, Zhejiang, 310014, People’s Republic of ChinaTel +86 571-56005600Email hzfhfx@126.comObjective: Red blood cell distribution width (RDW) is a predictor of adverse outcomes in aortic aneurysms. Recent recommendations suggest that combining RDW with other biomarkers could yield better results. We, therefore, propose evaluating the biomarker of vascular aging, albumin with RDW to predict the risk of aortic aneurysms. This study aims to explore whether the combination of RDW with albumin can effectively predict the prognosis of aortic aneurysm patients.Methods: This retrospective cohort study was conducted among adults (age > 18) with aortic aneurysms in the Medical Information Mart for Intensive Care Database III V1.4 (MIMIC-III). RAR was measured according to the red blood cell distribution width and albumin. The primary outcome was the 30-day mortality rate, and the secondary outcome was the 90-day and one-year mortality rates. Estimation of hazard ratios (HR) was obtained from Cox regression models for all-cause mortality related to red cell distribution width-to-albumin ratio (RAR) values.Results: In total, 312 patients were involved, with an average age of 74.9 ± 10.9 years and an average RAR value of 5.4 ± 1.6 mL/g. In 30 days for all-cause mortality, the HR (95% CI) in the highest RAR group (> 5.8 mL/g) in tertiles was 2.54 (1.25, 5.14) in the unadjusted model, with a significant difference compared with the reference group (P < 0.05). After adjusting for race, gender and age, there was still a correlation (P < 0.05), and the HR (95% CI) was 2.51 (1.23, 5.10). Further adjustment of possible covariates showed similar correlation in model 3 (P < 0.05), and HR (95% CI) was 2.66 (1.17, 6.01). Multivariable logistic regression shows that RAR is an independent risk factor for the outcome of aortic aneurysms after adjusting the covariates. In the subgroup analysis, we analyzed the patient’s complications, and no significant interaction was observed.Conclusion: RAR is a risk factor for patients with aortic aneurysms. However, more in-depth research is warranted to further analyze and substantiate our findings on the role of RAR in aortic aneurysm patients.Keywords: red blood cell distribution width–albumin ratio, aortic aneurysms, retrospective cohort study, MIMIC-III