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Haibin Zou,1 Fangfang Xi,1 Yuanyuan Fu,1 Jinhui Xu,1 Ping Zhang,1 Dongge Li,2 Heguo Luo1 1Department of Anesthesiology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, People’s Republic of China; 2The Third Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of ChinaCorrespondence: Heguo Luo, Department of Anesthesiology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +86 13807035516, Email ddjy121@163.comPurpose: Ciprofol, a new sedative anesthetic developed in China, offers rapid onset and recovery, reduced injection pain, and stable circulation. However, its effect on blood pressure during anesthesia induction in older adults remains unclear. To compare the effects of propofol and ciprofol on hypotension induced by general anesthesia in older adults.Patients and Methods: This prospective, single-center, double-blind, randomized, controlled clinical study enrolled 117 older adults undergoing surgery. Patients in the ciprofol group (group C) received an intravenous injection of ciprofol (0.3 mg/kg, n=57), while the propofol group (group P) received an intravenous injection of propofol (1.5 mg/kg, n=58). The primary outcome was the incidence of hypotension (mean arterial pressure (MAP) decreased by > 30% from baseline or MAP< 65 mmHg). Secondary outcomes included induction success rate (bispectral index (BIS) value ≤ 60 and Modified Observer’s Assessment of Alertness/Sedation Scale (MOAA/S) score ≤ 1), injection pain, number of drug additions, time to BIS 60, time to eyelash reflex disappearance, blood pressure changes, incidence of hypertension, tachycardia and BIS values before and after administration.Results: The incidence of induced hypotension was 26.3% (15/57) in group C and 48.3% (28/58) in group P (OR=0.383, 95% CI:175– 0.837, P =0.015). Group C had significantly lower injection pain incidence (5.3% vs 20.7%, OR=0.213, 95% CI: 0.057– 0.801, p=0.014). Both groups had a 100% induction success rate, with no significant difference in the number of additional doses. Post-intubation hypertension and tachycardia incidence were not significantly different. Group C showed less blood pressure decrease during induction and a deeper anesthesia level.Conclusion: Compared to propofol, ciprofol reduces the incidence of induced hypotension in older adults and maintains more stable blood pressure during induction. Additionally, ciprofol reduces injection pain and provides a good depth of anesthesia, making it a safe and effective option for anesthesia induction in older adults.Trial Registration ClinicalTrials.gov Identifier: ChiCTR2200066053.Keywords: ciprofol, propofol, bispectral index, BIS, hypotension

Yun Xiang,1,2,&ast; Dini Lin,1,&ast; Qiang Zhou,1 Hongyu Luo,1 Zixin Zhou,1 Shuyi Wu,2 Keyuan Xu,2 Xiaoting Tang,1 Pingping Ma,2 Chunyuan Cai,1 Xinkun Shen1 1Wenzhou Key Laboratory for the Diagnosis and Prevention of Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University (Ruian People’s Hospital), Wenzhou, 325016, People’s Republic of China; 2School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, 325027, People’s Republic of China&ast;These authors contributed equally to this work and share first authorshipCorrespondence: Xinkun Shen; Chunyuan Cai, Wenzhou Key Laboratory for the Diagnosis and Prevention of Diabetic Complications, The Third Affiliated Hospital of Wenzhou Medical University (Ruian People’s Hospital), Wenzhou, Zhejiang Province, 325016, People’s Republic of China, 108&num; Wansong Road, Email shenxinkun123@wmu.edu.cn; caichunyuan123@wmu.edu.cnBackground: Large-diameter titanium dioxide nanotubes (TNTs) have shown promise in preserving osteoblast function under oxidative stress (OS) in vitro. However, their ability to enhance osteogenesis in vivo under OS conditions and the underlying mechanisms remain unclear.Purpose: This study aimed to evaluate the osteogenic potential of 110 nm TNTs (TNT110) compared to 30 nm TNTs (TNT30) in an aging rat model exhibiting OS, and to investigate the mechanisms involved.Methods: Surface properties of TNTs were characterized, and in vitro and in vivo experiments were conducted to assess their osteoinductive effects under OS. Transcriptomic, proteomic analyses, and Western blotting were performed to investigate the protective mechanisms of TNT110 on osteoblasts. Protein adsorption studies focused on the roles of fibronectin (FN) and albumin (BSA) in modulating osteoblast behavior on TNT110.Results: In both in vitro and in vivo experiments, TNT110 significantly improved new bone formation and supported osteoblast survival under OS conditions. Subsequent ribonucleic acid sequencing results indicated that TNT110 tended to attenuate inflammatory responses and reactive oxygen species (ROS) expression while promoting endoplasmic reticulum (ER) stress and extracellular matrix receptor interactions, all of which are crucial for osteoblast survival and functionality. Further confirmation indicated that the cellular behavior changes of osteoblasts in the TNT110 group could only occur in the presence of serum. Moreover, proteomic analysis under OS conditions revealed the pivotal roles of FN and BSA in augmenting TNT110’s resistance to OS. Surface pretreatment of TNT110 with FN/BSA alone could beneficially influence the early adhesion, spreading, ER activity, and ROS expression of osteoblasts, a trend not observed with TNT30.Conclusion: TNT110 effectively protects osteoblast function in the OS microenvironment by modulating protein adsorption, with FN and BSA synergistically enhancing osteogenesis. These findings suggest TNT110’s potential for use in implants for elderly patients.Keywords: osteoporosis, oxidative stress, titania nanotube, protein adsorption, osteogenesis

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

Haoming Luo,1,2,&ast; Miao Guo,3,4,&ast; Mingxing Li,1 Yueshui Zhao,1 Jing Shen,1 Fukuan Du,1 Yu Chen,1 Shuai Deng,1 Yuhong Sun,1 Li Gu,1 Wanping Li,1 Xiaobing Li,1 Meijuan Chen,1 Zhangang Xiao,1,5,6 Shengpeng Wang,3,4 Xu Wu1,7 1Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China; 2Department of Pharmacy, Three Gorges University Hospital of Traditional Chinese Medicine & Yichang Hospital of Traditional Chinese Medicine, Yichang, Hubei, 443003, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China; 4Macao Centre for Research and Development in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China; 5Department of Pharmacy, Gulin County Hospital of Traditional Chinese Medicine, Luzhou, Sichuan, 646500, People’s Republic of China; 6School of Pharmacy, Sichuan College of Traditional Chinese Medicine, Mianyang, Sichuan, 621000, People’s Republic of China; 7Department of Paediatric Care, Luzhou People’s Hospital, Luzhou, Sichuan, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shengpeng Wang, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China, Email swang@um.edu.mo Xu Wu, Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China, Email wuxulz@swmu.edu.cnIntroduction: Rhodiola species have been utilized as functional foods in Asia and Europe for promoting health. Research has demonstrated that Rhodiola has the potential to alleviate inflammatory bowel disease (IBD) in animal models. However, the specific active components and the underlying mechanism for ameliorating intestinal damage remain unclear. This study aims to explore the relieving effect of Rosavin (Rov), a known active constituent of Rhodiola, in IBD and the regulatory mechanisms.Methods: The therapeutic effect of Rov was evaluated using a murine model of acute colitis induced by dextran sulfate sodium salt (DSS). Inflammatory cytokines and neutrophil activation markers were measured by corresponding kits. Immunohistochemistry, immunofluorescence, TUNEL, and EdU assays were applied to investigate the tight conjunction proteins expression, epithelial marker expression, number of apoptotic cells, and epithelial proliferation, respectively. The protection effect of Rov on gut epithelial injury was assessed using TNF-α-induced intestinal organoids. Additinally, RNA sequencing was applied to observe the genetic alteration profile in these intestinal organoids.Results: Oral administration of Rov significantly attenuated weight loss and restored colon length in mice. Notably, Rov treatment led to decreased levels of pro-inflammatory cytokines and neutrophil activation markers while increasing anti-inflammatory factors. Importantly, Rov restored intestinal despair by increasing the number of Lgr5+ stem cells, Lyz1+ Paneth cells and Muc2+ goblet cells in intestines of colitis mice, displaying reduced epithelial apoptosis and recovered barrier function. In TNF-α-induced intestinal organoids, Rov facilitated epithelial cell differentiation and protected against TNF-α-induced damage. RNA sequencing revealed upregulation in the gene expression associated with epithelial cells (including Lgr5+, Lyz1+ and Muc2+ cells) proliferation and defensin secretion, unveiling the protective mechanisms of Rov on the intestinal epithelial barrier.Discussion: Rov holds potential as a natural prophylactic agent against IBD, with its protective action on the intestinal epithelium being crucial for its therapeutic efficacy. Keywords: rosavin, colitis, inflammatory bowel disease, organoid, intestinal stem cell

Ying Yang,1– 3,&ast; Bixia Zhou,1,2,&ast; Min Li,4 Yishuai Sun,1,2 Xulei Jiang,1,2 Xinxin Zhou,1,2 Chengjun Hu,1,2 Dou Zhang,3 Hang Luo,3 Wuyuan Tan,1,2 Xinghua Yang,1,2 Shaorong Lei1,2 1Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, Hunan, People’s Republic of China; 3State Key Laboratory of Powder Metallurgy, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Oncology, Changsha Central Hospital, University of South China, Changsha, Hunan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaorong Lei, Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of China, Tel +86 73189753014, Email leishaorong@csu.edu.cn Xinghua Yang, Department of Plastic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of China, Tel +86 73189753014, Email yxhua8805@sina.comPurpose: The treatment of craniofacial bone defects caused by trauma, tumors, and infectious and degenerative diseases is a significant issue in current clinical practice. Following the rapid development of bone tissue engineering (BTE) in the last decade, bioactive scaffolds coupled with multifunctional properties are in high demand with regard to effective therapy for bone defects. Herein, an innovative bone scaffold consisting of GO/Cu nanoderivatives and GelMA-based organic-inorganic hybrids was reported for repairing full-thickness calvarial bone defect.Methods: In this study, motivated by the versatile biological functions of nanomaterials and synthetic hydrogels, copper nanoparticle (CuNP)-decorated graphene oxide (GO) nanosheets (GO/Cu) were combined with methacrylated gelatin (GelMA)-based organic-inorganic hybrids to construct porous bone scaffolds that mimic the extracellular matrix (ECM) of bone tissues by photocrosslinking. The material characterizations, in vitro cytocompatibility, macrophage polarization and osteogenesis of the biohybrid hydrogel scaffolds were investigated, and two different animal models (BALB/c mice and SD rats) were established to further confirm the in vivo neovascularization, macrophage recruitment, biocompatibility, biosafety and bone regenerative potential.Results: We found that GO/Cu-functionalized GelMA/β-TCP hydrogel scaffolds exhibited evidently promoted osteogenic activities, M2 type macrophage polarization, increased secretion of anti-inflammatory factors and excellent cytocompatibility, with favorable surface characteristics and sustainable release of Cu2+. Additionally, improved neovascularization, macrophage recruitment and tissue integration were found in mice implanted with the bioactive hydrogels. More importantly, the observations of microCT reconstruction and histological analysis in a calvarial bone defect model in rats treated with GO/Cu-incorporated hydrogel scaffolds demonstrated significantly increased bone morphometric values and newly formed bone tissues, indicating accelerated bone healing.Conclusion: Taken together, this BTE-based bone repair strategy provides a promising and feasible method for constructing multifunctional GO/Cu nanocomposite-incorporated biohybrid hydrogel scaffolds with facilitated osteogenesis, angiogenesis and immunoregulation in one system, with the optimization of material properties and biosafety, it thereby demonstrates great application potential for correcting craniofacial bone defects in future clinical scenarios. Keywords: nanomaterials, hybrid hydrogel, bone scaffolds, craniofacial bone defects, bone regeneration

Hailing Yu,1,&ast; Yongquan Huang,2,&ast; Zhisheng Nong,3,&ast; Xi Lin,1 Kexin Tang,1 Zeyu Cai,1 Kaichen Huang,4 Ting Yu,1 Huimin Lan,1 Qianqian Zhang,1 Qiang Wang,5 Lei Yang,6 Jingchuan Zhu,7 Lili Wu,8 Hui Luo1 1Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Ultrasound, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 3School of Materials Science and Engineering, Shenyang Aerospace University, Shenyang, Liaoning, People’s Republic of China; 4Department of Clinical laboratory, The Third People’s Hospital of Zhuhai, Zhuhai, Guangdong, People’s Republic of China; 5The Green Aerotechnics Research Institute of Chongqing Jiaotong University, Chongqing, People’s Republic of China; 6Center for Composite Materials and Structures, Harbin Institute of Technology, Harbin, Heilongjiang, People’s Republic of China; 7School of Materials Science and Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, People’s Republic of China; 8Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, School of Physics and Electronic Engineering, Harbin Normal University, Harbin, Heilongjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Luo; Lili Wu, Email luoh53@mail.sysu.edu.cn; wll790107@hotmail.comIntroduction: Traditional cancer treatment strategies often have severe toxic side effects and poor therapeutic efficacy. To address the long-standing problems related to overcoming the complexity of tumors, we develop a novel nanozyme based on the in situ oxidation of 2D Ti3C2 structure to perform simultaneous phototherapy and sonodynamic therapy on tumors. Ti3C2 nanozymes exhibit multi-enzyme activity, including intrinsic peroxidase (POD) activities, which can react with H2O2 in the tumor microenvironment. This new material can construct Ti3C2/TiO2 heterostructures in vivo.Methods: Photothermal (PTT), sonodynamic (SDT) effects, and photoacoustic (PA) image-guided synergy therapy can be achieved. Finally, anticancer immune responses occur with this nanozyme. In vivo experiments revealed that the Ti3C2/TiO2 heterostructure inhibited tumor growth.Results: Complementarily, our results showed that the Ti3C2/TiO2 heterostructure enhanced the immunogenic activity of tumors by recruiting cytotoxic T cells, thereby enhancing the tumor ablation effect. Mechanistic studies consistently indicated that Reactive Oxygen Species (ROS) regulates apoptosis of HCC cells by modulating NRF2/OSGIN1 signaling both in vitro and in vivo. As a result, Ti3C2 nanozyme effectively inhibited tumor through its synergistic ability to modulate ROS and enhance immune infiltration of cytotoxic T cells in the tumor microenvironment.Discussion: These findings open up new avenues for enhancing 2D Ti3C2 nanosheets and suggest a new way to develop more effective sonosensitizers for the treatment of cancer.Keywords: nanozyme, sonodynamic therapy, Ti3C2/TiO2, ROS

Kunping Cui,1 Yi Mao,2 Shuang Feng,3 Haixia Luo,2 Jiao Yang,2 Lang Bai1 1Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 2Intensive Care Unit, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, 610000, People’s Republic of China; 3Ultrasonic Medicine, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, 610000, People’s Republic of ChinaCorrespondence: Lang Bai, Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-18980602254, Email pangbailang@163.comPurpose: The mortality rate from pulmonary tuberculosis (PTB) complicated by severe community-acquired pneumonia (SCAP) in the intensive care unit (ICU) remains high. We aimed to develop a rapid and simple model for the early assessment and stratification of prognosis in these patients.Patients and Methods: All adult patients with PTB complicated by SCAP admitted to the ICU of a tertiary hospital in Chengdu, Sichuan, China between 2019 and 2021 (development cohort) and 2022 (validation cohort) were retrospectively included. Data on demographics, comorbidities, laboratory values, and interventions were collected. The outcome was the 28-day mortality. Stepwise backward multivariate Cox analysis was used to develop a mortality risk prediction score model. Receiver operating characteristic (ROC) and calibration curves were used to evaluate the model’s predictive efficiency. Decision curve analysis (DCA) was used to validate the model’s clinical value and impact on decision making.Results: Overall, 357 and 168 patients were included in the development and validation cohorts, respectively. The Pulmonary Tuberculosis Severity Index (PTSI) score included long-term use of glucocorticoid, body mass index (BMI) < 18.5 kg/m2, diabetes, blood urea nitrogen (BUN) ≥ 7.14 mmol/L, PO2/FiO2 < 150 mmHg, and vasopressor use. The area under the ROC curve (AUC) values were 0.817 (95% CI: 0.772– 0.863) and 0.814 for the development and validation cohorts, respectively. The PTSI score had a higher AUC than the APACHE II, SOFA, and CURB-65 score. The calibration curves indicated good calibration in both cohorts. The DCA of the PTSI score indicated the high clinical application of the model compared with the APACHE II and SOFA scores.Conclusion: This prognostic tool was designed to rapidly evaluate the 28-day mortality risk in individuals with PTB complicated by SCAP. It can stratify this patient group into relevant risk categories, guide targeted interventions, and enhance clinical decision making, thereby optimizing patient care and improving outcomes.Keywords: pulmonary tuberculosis, severe community-acquired pneumonia, mortality risk prediction, intensive care unit

Kexin Tong,1,&ast; Huating Luo,1,&ast; Haifeng Dai,2 Wenxiang Huang1 1Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haifeng Dai, Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86 15123192435, Email cqmudaihaifeng@163.com Wenxiang Huang, Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86 13883533808, Email wenxiang_huang@163.comAbstract: The escalating incidence of infective endocarditis (IE) caused by aminoglycoside-resistant Enterococcus is a growing concern for clinicians. This issue is particularly pronounced in elderly patients, who face an elevated risk of renal damage during antibiotic treatment, thereby limiting available pharmacological options. Furthermore, elderly patients often present with multiple comorbidities, leading to heightened mortality rates. In this article, we present a case involving an elderly male patient who sought medical attention on two separate occasions due to inflammation of the lower extremities and lumbosacral pain. Subsequent diagnosis revealed infective endocarditis (IE) caused by high-level gentamicin-resistant Enterococcus faecalis through blood culture and echocardiography. The patient also experienced peripheral and cerebral arterial embolism, secondary spine infection, and subsequent heart failure, highlighting the severity of the clinical situation. Following an initial 10-day course of vancomycin and ceftriaxone therapy, the patient developed renal impairment, necessitating a switch to bactericidal therapy with ampicillin in combination with ceftriaxone. Additionally, aortic valve replacement was performed during this period. Ultimately, the patient achieved clinical remission. This case underscores the critical importance of prompt and accurate diagnosis, appropriate antibiotic selection, and timely surgical intervention in enhancing the prognosis of elderly patients with IE.Keywords: endocarditis, bacterial, Enterococcus faecalis, aminoglycoside resistance, ampicillin plus ceftriaxone, geriatrics

Chuang Qin,1 Xiaofei Ye,1 Hongliang Luo,1 Hu Jin,1 Qiang Liu,1 Jiangfa Li2 1Hepatobiliary Surgery, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou City, Guangxi, People’s Republic of China; 2Hepatobiliary Surgery, The Affiliated Hospital of Guilin Medical University, Guilin City, Guangxi, People’s Republic of ChinaCorrespondence: Jiangfa Li, Hepatobiliary Surgery, The Affiliated Hospital of Guilin Medical University, No. 15, Lequn Road,Xiufeng District, Guilin City, Guangxi, 541001, People’s Republic of China, Email ljf.126@qq.comPurpose: This study contributes to the evolving understanding of the pivotal involvement of Sirtuins (SIRTs) in various human cancers, with a particular focus on elucidating their expression patterns and clinical relevance within the context of hepatocellular carcinoma (HCC). The investigation involves a comprehensive analysis of mRNA expression and prognostic implications associated with distinct SIRTs in HCC.Patients and Methods: Initial data pertaining to SIRT expression in HCC patients were collated from publicly accessible databases. Subsequently, the expression levels of select members of the SIRT family were validated using clinicopathological specimens from HCC patients. Additionally, HCC tissue microarray was employed to scrutinize the correlation between SIRT7 expression and HCC prognosis.Results: The findings indicated a substantial upregulation of SIRT2, SIRT3, SIRT4, SIRT6, and SIRT7 in HCC tissues. Survival analysis underscored a pronounced association between elevated mRNA levels of SIRT3, SIRT6, and SIRT7 and an adverse prognosis for HCC patients. Particularly, SIRT7 emerged as a potential independent risk factor for poor prognosis in HCC patients. Examination of the HCC tissue microarray revealed heightened expression of SIRT7 in 68 cases (54.8%) of HCC tissues. Multivariate analysis established high SIRT7 expression as an independent risk factor for diminished Disease-Free Survival (DFS) and Overall Survival (OS) in HCC patients.Conclusion: The aberrant expression of SIRT7 presents itself may be as a novel biomarker for predicting the prognosis of HCC patients.Keywords: HCC, microarray, prognosis, SIRT7, survivor

Han Luo,1,&ast; Xiaofei Wang,1,&ast; Mengqi Fang,1 Huifan Yu,1 Lili Gui,1 Zhengkun Wu,1 Jianyong Sheng,2 Fei Li1 1Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of China; 2Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fei Li, Hubei University of Medicine, 30 Renmin South Road, Shiyan, Hubei, 442000, People’s Republic of China, Email piaopodexinlifei@163.comIntroduction: Although flavonoid compounds exhibit various pharmacological activities, their clinical applications are restricted by low oral bioavailability owing to their poor solubility. Nanocrystals (NCs) represent an excellent strategy for enhancing the oral bioavailability of flavonoids. Hydroxyethyl starch (HES), a biomaterial compound used as a plasma expander, could be an ideal stabilizer material for preparing flavonoid NCs.Methods: HES was used to stabilize flavonoid nanocrystals (NCs), using luteolin (LUT) as a model drug. After full characterization, the freeze-drying and storage stability, solubility, intestinal absorption, pharmacokinetics, and in vivo anti-hyperuricemic effect of the optimized HES-stabilized LUT NCs (LUT-HES NCs) were investigated.Results: Uniformed LUT-HES NCs were prepared with mean particle size of 191.1± 16.8 nm, zeta potential of about − 23 mV, drug encapsulation efficiency of 98.52 ± 1.01%, and drug loading of 49.26 ± 0.50%. The freeze-dried LUT-HES NCs powder showed good re-dispersibility and storage stability for 9 months. Notably, compared with the coarse drug, LUT-HES NCs exhibited improved saturation solubility (7.49 times), increased drug dissolution rate, enhanced Caco-2 cellular uptake (2.78 times) and oral bioavailability (Fr=355.7%). Pharmacodynamic studies showed that LUT-HES NCs remarkably lowered serum uric acid levels by 69.93% and ameliorated renal damage in hyperuricemic mice.Conclusion: HES is a potential stabilizer for poorly soluble flavonoid NCs and provides a promising strategy for the clinical application of these compounds. LUT-HES NCs may be an alternative or complementary strategy for hyperuricemia treatment.Keywords: Hydroxyethyl starch, nanocrystals, stabilizer, luteolin, oral bioavailability, anti-hyperuricemia

Kun Wang,1 Wei Zhu,2 Wei Huang,3 Kangkang Huang,1 Huidan Luo,1 Lu Long,1 Bin Yi1 1Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 2Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 3Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of ChinaCorrespondence: Bin Yi, Tel +86-13707495781, Email xyyibin@163.comObjective: Ubiquitination is an important post-translational modification. However, the significance of the TRIM family of E3 ubiquitin ligases in head and neck squamous cell carcinoma (HNSCC) has not been determined. In this study, the roles of TRIM E3 ubiquitin ligases in lymphovascular invasion in head and neck squamous cell carcinoma (HNSCC) were evaluated.Materials and Methods: TRIM expression and related parameters were obtained from UbiBrowser2.0, UALCAN, TIMER, TISIDB, LinkedOmics, STRING, and GeneMANIA databases. Immunohistochemistry was used to confirm their expression.Results: TRIM2, TRIM11, TRIM28, and TRIM56 were upregulated in HNSCC with lymphovascular invasion. TRIM expression was strongly associated with immune infiltration, including key treatment targets, like PD-1 and CTL4. Co-expressed genes and possible ubiquitination substrates included tumor-related factors. The TRIMs had predicted roles in ubiquitination-related pathways and vital signaling pathways, eg, MAPK, PI3K-Akt, and JAK-STAT signaling pathways.Conclusion: Ubiquitination mediated by four TRIMs might be involved in the regulation of tumor immunity, laying the foundation for future studies of the roles of the TRIM family on the prediction and personalized medicine in HNSCC. The four TRIMs might exert oncogenic effects by promoting lymphovascular invasion in HNSCC.Keywords: ubiquitination, TRIM, head and neck squamous cell carcinoma, bioinformatic analysis, lymphovascular invasion

Kunping Cui,1,&ast; Yi Mao,2,&ast; Shuang Feng,3 Haixia Luo,2 Jiao Yang,2 Ruyi Xu,1 Lang Bai1 1Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 2Intensive Care Unit, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, 610000, People’s Republic of China; 3Ultrasonic Medicine, Public Health Clinical Center of Chengdu, Chengdu, Sichuan, 610000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lang Bai, Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-18980602254, Email pangbailang@163.comPurpose: Age is considered a vital factor in intensive care units (ICUs) because of its association with physiological frailty, comorbidities, and immune system function. Previous studies have examined the association between age and prognosis in patients with tuberculosis (TB) or sepsis; however, the association between age and prognosis in ICU patients with TB complicated by sepsis is rare. This study aimed to assess the association between age and the prognosis of patients in the ICU with TB complicated by sepsis.Patients and Methods: Data from the ICU of the Public Health Clinical Center of Chengdu were analyzed using the multivariable Cox regression model, stratified analysis with interaction, restricted cubic spline (RCS), and threshold effect analysis to investigate the association between age and 28-day all-cause mortality in patients with TB complicated by sepsis.Results: In total, 520 patients diagnosed with TB and sepsis were enrolled (120 women [23.1%]; median age, 64 years). The association between age and risk of death exhibited a J-shaped curve on the RCS (P for nonlinearity = 0.001). In the threshold analysis, the hazard ratio for the risk of death was 1.104 (95% confidence interval, 1.05– 1.16) in participants aged ≥ 66.2 years. The risk of death increased by 10.4% with every 1-year increase in age in patients with TB complicated by sepsis. No significant association was found between age and 28-day all-cause mortality in patients aged < 66.2 years.Conclusion: A nonlinear relationship was observed between age and short-term all-cause mortality in patients in the ICU with TB complicated by sepsis. Patients with a higher age at admission may have a higher risk of death and require focused attention, close monitoring, and early treatment to reduce mortality.Keywords: sepsis, tuberculosis, age, 28-day all-cause mortality, intensive care unit

Hongbiao Luo,1,2,&ast; Ji Luo,3,&ast; Ning Ding,1 Tao Zhang,1 Yongheng He1,4 1Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 2Department of Anorectal Surgery, Chenzhou NO. 1 People’s Hospital, Chenzhou, Hunan, 423000, People’s Republic of China; 3Hunan Key Laboratory of Chinese Medicine on Oncology, Affiliated Hospital of Hunan Academy of Chinese Medicine, Changsha, Hunan, 410006, People’s Republic of China; 4Department of Anorectal Surgery, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, Changsha, Hunan, 410006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongheng He, Department of Anorectal Surgery, Affiliated Hospital of Hunan Academy of Traditional Chinese Medicine, 58 Lushan Road, Yuelu District, Changsha, Hunan, 410006, People’s Republic of China, Tel +86-13517401858, Email 2320990685@qq.comBackground: Bicaudal-D (BICD) Family Like Cargo Adaptor 1 (BICDL1) is an essential component of the molecular mechanism during neuronal development. However, BICDL1 has not been reported in cancer. Using bioinformatics analysis, we systematically evaluated the potential role of BICDL1 in CRC.Methods: Colorectal cancer (CRC) and normal tissue samples were retrieved from the Gene Expression Omnibus (GEO), Genotype-Tissue Expression (GTEx), and Cancer Genome Atlas (TCGA) databases. Kaplan–Meier (K-M) analysis, nomogram, COX analysis, and receiver operating characteristic (ROC) curves were used to evaluate the prognostic power. Correlation analysis was also conducted to explore the correlation between mRNA expression and the methylation level of BICDL1 using cBioPortal, and the correlation between immune infiltration and BICDL1. RT-qPCR and Western blot assays were performed to analyze BICDL1 expression level between human colorectal cancer cell lines and normal colonic epithelial cells.Results: BICDL1 had a higher expression in CRC tissues than in normal tissues (p < 0.001) in TCGA and GES 74602 datasets. Kaplan-Meier survival analysis revealed that patients with high BICDL1 expression had lower overall survival (OS) (1.53, 95% confidence interval: 1.07– 2.17, p=0.019). The ROC curves demonstrated that BICDL1 has high specificity and efficiency in diagnosis (AUC=0.919, CI: 0.895– 0.943). The expression level of BICDL1 was significantly correlated with the infiltrating levels of Treg (R=0.146, p < 0.001), TFH (R=0.080, p=0.043), NK CD56bright cells (R=0.149, p < 0.001), aDC (R=0.095, p=0.016), and T helper cell infiltration (R=− 0.084, p=0.034). The correlation between BICDL1 expression and methylation levels was negative (R2=0.134, p < 0.001), and CRC patients had lower methylation levels than normal people (p=0.036). BICDL1 mRNA and its protein expression levels in CRC cell lines (SW620) was markedly increased compared with that of normal colonic epithelial cells (NCM460) (p < 0.001).Conclusion: BICDL1 may be a potential biomarker for evaluating immune infiltration levels and prognosis of CRC.Keywords: colorectal cancer, BICDL1, prognosis, biomarker, immune infiltration, methylation

Daniel Hsiang-Te Tsai,1,2 J Simon Bell,3 Shahab Abtahi,4 Brenda N Baak,5 Marloes T Bazelier,4 Ruth Brauer,6 Adrienne YL Chan,6– 9 Esther W Chan,9– 12 Haoqian Chen,13 Celine SL Chui,9,14,15 Sharon Cook,16 Stephen Crystal,16 Poonam Gandhi,13 Sirpa Hartikainen,17 Frederick K Ho,18 Shao-Ti Hsu,1 Jenni Ilomäki,3 Ju Hwan Kim,19 Olaf H Klungel,4 Marjaana Koponen,17 Wallis CY Lau,6,8,9 Kui Kai Lau,20,21 Terry YS Lum,22 Hao Luo,22 Kenneth KC Man,6,8,9 Jill P Pell,18 Soko Setoguchi,13,23 Shih-Chieh Shao,1,24 Chin-Yao Shen,1 Ju-Young Shin,19,25,26 Patrick C Souverein,4 Anna-Maija Tolppanen,17 Li Wei,6,9 Ian CK Wong,6,8,9,27 Edward Chia-Cheng Lai1 1School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Centre for Neonatal and Paediatric Infection, St George’s University of London, London, UK; 3Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia; 4Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; 5PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 6Research Department of Practice and Policy, UCL School of Pharmacy, London, UK; 7Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, ‐Epidemiology and ‐Economics, University of Groningen, Groningen, the Netherlands; 8Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 9Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong, Special Administrative Region, People’s Republic of China; 10Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 11Department of Pharmacy, the University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China; 12The University of Hong Kong Shenzhen Institute of Research and Innovation, Shenzhen, People’s Republic of China; 13Center for Pharmacoepidemiology and Treatment Science (PETS), Institute for Health, Rutgers University, New Brunswick, NJ, USA; 14School of Nursing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 15School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 16Center for Health Services Research, Rutgers University, New Brunswick, NJ, USA; 17Kuopio Research Centre of Geriatric Care and School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 18School of Health and Wellbeing, University of Glasgow, Glasgow, UK; 19School of Pharmacy, Sungkyunkwan University, Suwon, South Korea; 20Division of Neurology, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 21State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 22Department of Social Work and Social Administration, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 23Department of Medicine, Rutgers Robert Wood Johnson Medical School and Pharmacoepidemiology and Treatments Science, Institute for Health, Rutgers University, New Brunswick, NJ, USA; 24Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 25Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea; 26Department of Biohealth Regulatory Science, Sungkyunkwan University, Seoul, South Korea; 27Aston Pharmacy School, Aston University, Birmingham, UKCorrespondence: Edward Chia-Cheng Lai, School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Email edward_lai@mail.ncku.edu.twPurpose: To describe and categorize detailed components of databases in the Neurological and Mental Health Global Epidemiology Network (NeuroGEN).Methods: An online 132-item questionnaire was sent to key researchers and data custodians of NeuroGEN in North America, Europe, Asia and Oceania. From the responses, we assessed data characteristics including population coverage, data follow-up, clinical information, validity of diagnoses, medication use and data latency. We also evaluated the possibility of conversion into a common data model (CDM) to implement a federated network approach. Moreover, we used radar charts to visualize the data capacity assessments, based on different perspectives.Results: The results indicated that the 15 databases covered approximately 320 million individuals, included in 7 nationwide claims databases from Australia, Finland, South Korea, Taiwan and the US, 6 population-based electronic health record databases from Hong Kong, Scotland, Taiwan, the Netherlands and the UK, and 2 biomedical databases from Taiwan and the UK.Conclusion: The 15 databases showed good potential for a federated network approach using a common data model. Our study provided publicly accessible information on these databases for those seeking to employ real-world data to facilitate current assessment and future development of treatments for neurological and mental disorders.Keywords: meta-data, data repository, Neurological and Mental Health Global Epidemiology Network, NeuroGEN

Jiahui Wu,1,2 Huidan Luo,1,2 Kun Wang,1,2 Bin Yi1,2 1Department of Clinical Laboratory and Medical Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Bin Yi, Department of Clinical Laboratory and Medical Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China, Tel +86-13707495781, Fax +86-73189753200, Email xyyibin@163.comPurpose: The mortality rate of nasopharyngeal carcinoma (NPC) remains high due to the absence of quick and accurate diagnostic approaches at its early stage. Our aim is to evaluate the diagnostic value of the elevated expression of Aurora kinase A (AURKA) and the oxidative stress markers (such as glutathione, superoxide dismutase and malondialdehyde) in serum of NPC patients and to establish a nomogram model for predicting NPC on the ground of these biomarkers.Patients and Methods: Serum samples from 93 NPC patients and 94 healthy subjects were collected. Enzyme-linked immunosorbent assay (ELISA) was adopted to determine the AURKA level, while oxidative stress markers were measured by commercially available appropriate kits. Logistic regression was used for NPC predictor identification and nomogram construction. The training and validation cohorts (3:1) were randomly split up from the participants. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analyses (DCAs) were performed to validate the nomogram.Results: AURKA and malondialdehyde (MDA) levels were significantly high in the NPC population compared to the healthy controls (P < 0.0001). The nomogram resulted in an area under the curve (AUC) of 0.897 (95% confidence interval: 0.848– 0.947) in the training set and AUC of 0.770 (0.628– 0.912) in the validation set. The predicted probability and the actual probability matched well in the nomogram (P > 0.05). DCAs showed good results too.Conclusion: Serum levels of AURKA, SOD, and MDA have diagnostic values in NPC. The nomogram based on the identified biomarkers is favorable for NPC prediction.Keywords: nasopharyngeal carcinoma, AURKA, SOD, MDA, nomogram

Jiaojiao Gong,1,2 Renjie Yu,1 Xiaoxia Hu,1 Huating Luo,1 Qingzhu Gao,3 Yadi Li,1 Guili Tan,1 Haiying Luo,1 Bo Qin1 1Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Nephrology, Bishan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Bo Qin, Department of Infectious Diseases, Chongqing Key Laboratory of Infectious Diseases and Parasitic Diseases, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Email cqmuqb@163.comPurpose: The accurate prediction of non-cirrhotic hepatocellular carcinoma (NCHCC) risk facilitates improved surveillance strategy and decreases cancer-related mortality. This study aimed to explore the correlation between immunogenic cell death (ICD) and NCHCC prognosis using The Cancer Genome Atlas (TCGA) datasets, and the potential prognostic value of ICD-related genes in NCHCC.Methods: Clinical and transcriptomic data of patients with NCHCC patients were retrieved from TCGA database. Weighted gene co-expression network analysis was performed to obtain the NCHCC phenotype-related module genes. Consensus clustering analysis was performed to classify the patients into two clusters based on intersection genes among differentially expressed genes (DEGs) between cancer and adjacent tissues, NCHCC phenotype-related genes, and ICD-related genes. NCHCC-derived tissue microarray was used to evaluate the correlation of the expression levels of key genes with NCHCC prognosis using immunohistochemical staining.Results: Cox regression analyses were performed to construct a prognostic risk score model comprising three genes (TMC7, GRAMD1C, and GNPDA1) based on DEGs between two clusters. The model stratified patients with NCHCC into two risk groups. The overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. Univariable and multivariable Cox regression analyses revealed that these signature genes are independent predictors of OS. Functional analysis revealed differential immune status between the two risk groups. Next, a nomogram was constructed, which demonstrated the potent distinguishing ability of the developed model based on receiver operating characteristic curves. In vitro functional validation revealed that the migration and invasion abilities of HepG2 and Huh7 cells were upregulated upon GRAMD1C knockdown but downregulated upon TMC7 knockdown.Conclusion: This study developed a prognostic model comprising three genes, which can aid in predicting the survival of patients with NCHCC and guide the selection of drugs and molecular markers for NCHCC.Keywords: immunogenic cell death-related genes, non-cirrhotic hepatocellular carcinoma, risk stratification, nomogram

Ran Cheng,1 Ning Tan,2 Hao Luo,2 Qian Kang,2 Xiaoyuan Xu3 1Department of Infectious Diseases, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Infectious Diseases, Peking University First Hospital, Beijing, People’s Republic of China; 3Department of Gastroenterology, Peking University First Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xiaoyuan Xu, Department of Gastroenterology, Peking University First Hospital, 8 Xishiku Street, Beijing, 100034, People’s Republic of China, Tel +86-010-83575787, Fax +86-010-83575787, Email xiaoyuanxu6@163.comBackground and Aims: The performance of noninvasive assessments to rule-in or rule-out fibrosis may improve when combined. We aimed to evaluate the efficiencies of sequential algorithms based on the aspartate aminotransferase-to-platelet ratio index (APRI), the fibrosis index based on four factors (FIB-4), and transient elastography (TE) for the assessment of advanced fibrosis (AF) and cirrhosis.Methods: This study enrolled 179 CHB subjects who underwent liver biopsy (LB) before antiviral treatment.Results: AF and cirrhosis were identified in 71 (39.7%) and 28 (15.7%) patients, respectively. Compared with TE alone, sequential FIB-4-TE and APRI-TE algorithms saved a slightly higher number of liver biopsies for the identification of advanced fibrosis (69.3% or 68.2% vs 63.7%, P=0.263 or P=0.372, respectively). For the identification of cirrhosis, sequential FIB-4-TE and APRI-TE algorithms saved a significantly higher number of liver biopsies than TE alone (83.2% or 88.3% vs 69.8%, P=0.003 or P=0.000, respectively). No significant difference was found between the sequential algorithms and TE alone in the diagnostic accuracy for the detection of AF and cirrhosis.Conclusion: The sequential algorithms could significantly reduce the need for liver biopsy with high accuracy for diagnosis of AF and cirrhosis in CHB patients, which would be optimal especially in resource-limited areas.Keywords: noninvasive assessments, advanced liver fibrosis, cirrhosis, chronic hepatitis B

Jingyi Li,1,2 Haowen Luo,1 Yongsen Chen,1,2 Bin Wu,1,2 Mengqi Han,1,2 Weijie Jia,1,2 Yifan Wu,1,2 Rui Cheng,1,2 Xiaoman Wang,1,2 Jingyao Ke,1,2 Hongfei Xian,1,2 JianMo Liu,1 Pengfei Yu,1 Jianglong Tu,3 Yingping Yi1 1Department of Medical Big Data Research Centre, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2School of Public Health, Nanchang University, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang, People’s Republic of China; 3Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of ChinaCorrespondence: Yingping Yi, Department of Medical Big Data Research Centre, The Second Affiliated Hospital of Nanchang University, 1 MinDe Road, Nanchang, 330006, People’s Republic of China, Email yyp66@126.com Jianglong Tu, Department of Neurology, The Second Affiliated Hospital of Nanchang University, 1 MinDe Road, Nanchang, 330006, People’s Republic of China, Email Tujianglong85@126.comPurpose: To investigate the predictive value of various inflammatory biomarkers in patients with acute ischemic stroke (AIS) and evaluate the relationship between stroke-associated pneumonia (SAP) and the best predictive index.Patients and Methods: We calculated the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), prognostic nutritional index (PNI), systemic inflammation response index (SIRI), systemic immune inflammation index (SII), Glasgow prognostic score (GPS), modified Glasgow prognostic score (mGPS), and prognostic index (PI). Variables were selectively included in the logistic regression analysis to explore the associations of NLR, PLR, MLR, PNI, SIRI, SII, GPS, mGPS, and PI with SAP. We assessed the predictive performance of biomarkers by analyzing receiver operating characteristic (ROC) curves. We further used restricted cubic splines (RCS) to investigate the association. Next, we conducted subgroup analyses to investigate whether specific populations were more susceptible to NLR.Results: NLR, PLR, MLR, SIRI, SII, GPS, mGPS, and PI increased significantly in SAP patients, and PNI was significantly decreased. After adjustment for potential confounders, the association of inflammatory biomarkers with SAP persisted. NLR showed the most favorable discriminative performance and was an independent risk factor predicting SAP. The RCS showed an increasing nonlinear trend of SAP risk with increasing NLR. The AUC of the combined indicator of NLR and C-reactive protein (CRP) was significantly higher than those of NLR and CRP alone (DeLong test, P< 0.001). Subgroup analyses suggested good generalizability of the predictive effect.Conclusion: NLR, PLR, MLR, PNI, SIRI, SII, GPS, mGPS, and PI can predict the occurrence of SAP. Among the indices, the NLR was the best predictor of SAP occurrence. It can therefore be used for the early identification of SAP.Keywords: stroke-associated pneumonia, acute ischemic stroke, inflammation, prediction

Luo H, Hang Y, Zhu H, et al. Infect Drug Resist. 2023;16:2601–2609 Following a review of the paper post-publication, the authors realized the Funding statement on page 2607 was incorrect. The correct Funding statement is as follows: Funding This work was supported by the National Natural Science Foundation of China (82060391), the Natural Science Foundation of Jiangxi Province (No. 20202BAB216021), the Health Commission of Jiangxi Province (No. 20201034). The authors apologize for any inconvenience caused to the readers.

Na Yang,1,&ast; Qing-Yu Tao,1,&ast; Jing-Yi Niu,1 Hao Sun,1 Yan He,1,2 Yong-Bo Hou,1,2 Hong Luo,1 Zhi Zhang,3 Jun-Ma Yu1 1Department of Anesthesiology, the Third Affiliated Hospital of Anhui Medical University (The First People’s Hospital of Hefei), Hefei, Anhui, People’s Republic of China; 2Department of Anesthesiology, Wannan Medical College, Wuhu, Anhui, People’s Republic of China; 3Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhi Zhang; Jun-Ma Yu, Email zhizhang@ustc.edu.cn; majuny163@163.comPurpose: This study was conducted to explore whether incisional infiltration using a local anesthetic injection kit could better relieve postoperative pain and enhance the quality of recovery compared with ultrasound-guided rectus sheath block (RSB) or conventional local anesthetic infiltration in patients undergoing transumbilical single-incision laparoscopic cholecystectomy (SILC).Patients and Methods: A total of 60 patients undergoing SILC with American Society of Anesthesiology functional status scores of I-II were randomized into the rectus sheath block group (RSB group), conventional local wound infiltration group (LAI-I group) and incisional infiltration using a local anesthetic injection kit group (LAI-II group). The primary outcomes were the patient-controlled intravenous analgesia (PCIA) demand frequency within 48 hours after the operation and postoperative pain measured by a visual analog scale (VAS) at 2 h, 4 h, 8 h, 24 h, and 48 h after surgery. Secondary outcomes were the total procedure times, cumulative consumption of anesthetic drugs, duration of surgery, duration and awaking time of anesthesia, early recovery indicator and side effects.Results: The PCIA demand frequency in LAI-II group was significantly lower compared with patients in the RSB and LAI-I group (both P < 0.001). Moreover, the total procedure times in LAI-I and LAI-II group was significantly shorter than that in the RSB group (P < 0.001, respectively), but it was comparable between LAI-I and LAI-II group (P = 0.471). Though lower at 2h and 4h postoperative in LAI-II group, pain scores at each time point had no statistical differences among three groups. There were no significant differences among three groups for other outcomes as well.Conclusion: The effect of ultrasound-guided RSB and conventional local anesthetic infiltration in SILC patients were found to be similar in terms of relieving postoperative pain and promoting recovery. Incisional infiltration using a local anesthetic injection kit can significantly reduce the demand frequency of PCIA, which serves as a rescue analgesic.Keywords: laparoscopic cholecystectomy, rectus sheath block, local infiltration analgesia, recovery, pain

Weiqin Cheng,1 Ling He,1 Hechuan Luo,1 Yan Jiang,2 Chengbing Tan,2 Xiao Fan1 1Department of Radiology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, People’s Republic of China; 2Department of Neurology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, People’s Republic of ChinaCorrespondence: Xiao Fan, Department of Radiology, Children’s Hospital of Chongqing Medical University, No. 136 Zhongshan Er Road, Yuzhong District, Chongqing, 400014, People’s Republic of China, Tel +86 13637907710, Email fanxiao@cqmu.edu.cnObjective: To investigate and summarize the magnetic resonance imaging (MRI) manifestations of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy in children.Methods: We retrospectively analyzed data from 17 pediatric patients with autoimmune GFAP astrocytopathy confirmed by the detection of GFAP autoantibodies in cerebrospinal fluid in our single-center. Furthermore, we reviewed current literature and summarized previous findings on the MRI characteristics of this disease in children.Results: In these 17 patients, the clinical manifestations and results of CSF analysis were suggestive of autoimmune disorder, with a good improvement. The lesions on MRI were most commonly located in the bilateral basal ganglia (70.6%), thalamus (64.7%), cerebral white matter (29.4%). 93.3% of the cerebral lesions were relatively scattered and small, 80% of the spinal lesions presented as longitudinally extensive ones. Both periventricular radial linear (PVRL) (53.8%) and punctate or linear enhancement in basal ganglia and thalamus (53.8%) were commonly observed, followed by the leptomeningeal enhancement (46.2% in the brain and 62.5% in the spinal cord). We then included 55 pediatric patients with MRI data from current literature in our analysis (n = 72, 44 males). Our results revealed similar MRI findings but the enhancement pattern between our series and previously published cases, that is, leptomeningeal enhancement in the brain 46.2% vs 31.4%, in spinal cord 62.5% vs 18.4%, and PVRL enhancement 53.8% vs 11.2%. There were no detailed reports on punctate or linear enhancement.Conclusion: The MRI characteristics of autoimmune GFAP astrocytopathy in children could be suggestive. Scattered and small lesions (especially punctate or linear) in the bilateral thalamus, basal ganglia, and white matter, as well as longitudinally extensive spinal cord lesions (if present), with punctate, PVRL and leptomeningeal enhancement might be a distinct indication for the early diagnosis of this disorder.Keywords: glial fibrillary acidic protein, GFAP, astrocytopathy, autoimmune, magnetic resonance imaging, children

Youling Fang,1,2 Qiaoshi Zhong,1 Yanhui Chen,1 Yaping Hang,1 Xueyao Fang,1 Yanping Xiao,1 Xingwei Cao,1 Hongying Zhu,3 Hong Luo,1 Suqin Peng,1 Shumin Gu,1 Fuxing Li,1 Junqi Zhu,1 Jianqiu Xiong,4 Longhua Hu1 1Department of Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2School of Public Health, Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 3Clinical Laboratory of Ganzhou People’s Hospital, Ganzhou, Jiangxi, People’s Republic of China; 4Department of Nursing, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of ChinaCorrespondence: Longhua Hu; Jianqiu Xiong, Email longhuahu@163.com; 1773014059@qq.comObjective: To analyze the clinical characteristics, outcomes, and risk factors of patients treated with ceftazidime/avibactam, polymyxin, or tigecycline (CPT) compared with those receiving a conventional therapy (CT) (ie, imipenem, levofloxacin, or gentamicin).Methods: A single-center retrospective cohort study included patients with carbapenem-resistant Klebsiella pneumoniae bloodstream infection (CRKP-BSI) treated at one Chinese tertiary hospital between March 2012 and November 2022 was performed. Clinical characteristics, outcomes, and risk factors of patients treated with CPT or CT were compared. Predictors of 30-day mortality of patients with CRKP-BSI were also analysed in our study.Results: Among 184 recruited patients with CRKP-BSI, 39.7% (73/184) were treated with CPT, while 60.3% (111/184) were treated with CT. Compared to patients treated with CT, patients treated with CPT had worse conditions, as evidenced by a higher rate of underlying diseases and invasive procedures; however, they also had a better prognosis and lower rates of 14-day treatment failure (p = 0.024). In addition, univariate analysis and multivariate analysis showed that SOFA score [odds ratio (OR) = 1.310, 95% confidence interval (CI) 1.157– 1.483; p < 0.001] and cold weather (OR = 3.658, 95% CI 1.474– 9.081; p = 0.005) were independent risk factors for 30-day mortality.Conclusion: Compared to CRKP-BSI patients treated with CT, patients treated with CPT had worse conditions but better prognoses. CRKP-BSI occurred more frequently in hot weather; however, higher 30-day mortality was associated with cold weather. A randomized trial is needed to confirm these observational results.Keywords: carbapenem-resistantKlebsiella pneumoniae, polymyxin, tigecycline, ceftazidime/avibactam, bloodstream infection, hot weather, cold weather

Fengjun Xia,1,2,&ast; Xiaoyan Tao,2,3,&ast; Haichen Wang,1,2 Jian Shui,4 Changhang Min,1,2 Yubing Xia,1,2 Jun Li,1,2 Mengli Tang,1,2 ZhaoJun Liu,1,2 Yongmei Hu,1,2 Huidan Luo,1,2 Mingxiang Zou1,2 1National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 3Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, People’s Republic of China; 4Department of Clinical Laboratory, Changsha Central Hospital, Changsha, 410008, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingxiang Zou, National Clinical Research Center for Geriatric Disorders, Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People’s Republic of China, Tel/Fax +86-7384327440, Email zoumingxiang@csu.edu.cnPurpose: As an under-explored biomaterial, bacterial biofilms have a wide range of applications in the green synthesis of nanomaterials. The biofilm supernatant of Pseudomonas aeruginosa PA75 was used to synthesize novel silver nanoparticles (AgNPs). BF75-AgNPs were found to possess several biological properties.Methods: In this study, we biosynthesized BF75-AgNPs using biofilm supernatant as the reducing agent, stabilizer, and dispersant and investigated their biopotential in terms of antibacterial, antibiofilm, and antitumor activities.Results: The synthesized BF75-AgNPs demonstrated a typical face-centered cubic crystal structure; they were well dispersed; and they were spherical with a size of 13.899 ± 4.036 nm. The average zeta potential of the BF75-AgNPs was − 31.0 ± 8.1 mV. The BF75-AgNPs exhibited strong antibacterial activities against the methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase Escherichia coli (ESBL-EC), extensively drug-resistant Klebsiella pneumoniae (XDR-KP), and carbapenem-resistant Pseudomonas aeruginosa (CR-PA). Moreover, the BF75-AgNPs had a strong bactericidal effect on XDR-KP at 1/2 × MIC, and the expression level of reactive oxygen species (ROS) in bacteria was significantly increased. A synergistic effect was observed when the BF75-AgNPs and colistin were used for the co-treatment of two colistin-resistant XDR-KP strains, with fractional inhibitory concentration index (FICI) values of 0.281 and 0.187, respectively. Furthermore, the BF75-AgNPs demonstrated a strong biofilm inhibition activity and mature biofilm bactericidal activity against XDR-KP. The BF75-AgNPs also exhibited a strong antitumor activity against melanoma cells and low cytotoxicity against normal epidermal cells. In addition, the BF75-AgNPs increased the proportion of apoptotic cells in two melanoma cell lines, and the proportion of late apoptotic cells increased with BF75-AgNP concentration.Conclusion: This study suggests that BF75-AgNPs synthesized from biofilm supernatant have broad prospects for antibacterial, antibiofilm, and antitumor applications.Graphical Abstract: Keywords: multidrug resistant, green synthesis, colistin, metallic silver, melanoma

Shumin Gu,1,* Jianqiu Xiong,2,* Suqin Peng,1 Longhua Hu,1 Hongying Zhu,3 Yanping Xiao,1 Hong Luo,1 Yaping Hang,1 Yanhui Chen,1 Xueyao Fang,1 Xingwei Cao,1 Youling Fang,1 Fuxing Li,1 Junqi Zhu,1 Qiaoshi Zhong1 1Department of Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Departmentof Nursing, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 3Clinical Laboratory of Ganzhou People’s Hospital, Ganzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiaoshi Zhong, Department of Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Mingde Road No. 1, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +86151-8047-5673, Email zhong20000947@sina.comObjective: This study aimed to determine the clinical features, risk factors, and effective antimicrobial therapy for Carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infection (BSI).Methods: This was a retrospective analysis of data from patients with CRAB bacteremia in a Chinese tertiary hospital between January 2012 and October 2021. Risk factors, predictors of 30-day mortality, and effective antimicrobial therapy for CRAB BSI were identified using logistic and cox regression analyses.Results: Data from 276 patients with Acinetobacter baumannii (AB) BSI were included, of whom 157 (56.9%) had CRAB BSI. The risk factors that were significantly associated with CRAB BSI included previous intensive care unit (ICU) stay (P < 0.001), immunocompromised status (P < 0.001), cephalosporin use (P = 0.014), and fluoroquinolone use (P = 0.007). The 30-day mortality of the CRAB BSI group was 49.7% (78/157). ICU stay after BSI (P = 0.047), sequential organ failure assessment (SOFA) score ≥ 10 (P < 0.001), and multiple organ failure (MOF) (P = 0.037) were independent predictors of 30-day mortality. Among antibiotic strategies for the treatment of patients with CRAB BSI, we found that definitive regimens containing cefoperazone/sulbactam were superior to those without cefoperazone/sulbactam in reducing the 30-day mortality rate (25.4% vs 53.4%, P = 0.005). After propensity score matching, we observed a significant increase in the 30-day mortality (77.8%vs 33.3%, P = 0.036) in patients receiving tigecycline monotherapy compared to those receiving cefoperazone/sulbactam monotherapy. The mortality rate of patients receiving tigecycline with cefoperazone/sulbactam was also higher than that of patients receiving cefoperazone-sulbactam monotherapy; however, the difference was not significant (28.6%vs 19.0%, P = 0.375).Conclusion: The severity of patient conditions was significantly associated with mortality in patients with CRAB BSI. Those Patients treated with cefoperazone/sulbactam had better clinical prognoses, and tigecycline should be used with caution.Keywords: carbapenem-resistant, Acinetobacter baumannii, bacteremia, tigecycline, cefoperazone/sulbactam

Hong Luo,1 Yaping Hang,1 Hongying Zhu,2 Qiaoshi Zhong,1 Suqin Peng,1 Shumin Gu,1 Xueyao Fang,1 Longhua Hu1 1Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Clinical Laboratory of Ganzhou People’s Hospital, Ganzhou, Jiangxi, People’s Republic of ChinaCorrespondence: Longhua Hu, Email longhuahu@163.comBackground: Carbapenemase-producing Klebsiella pneumoniae is an unprecedented threat to public health, and its detection remains challenging. Analysis of microbial volatile organic compounds (VOCs) may offer a rapid way to determine bacterial antibiotic susceptibility.Purpose: The aim of this study was to explore the VOCs released by carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) using headspace solid-phase microextraction/gas chromatography-mass spectrometry (HS-SPME/GC-MS).Methods: Test bacteria were incubated in trypticase soy broth to the end of exponential growth phase, and imipenem was added in the middle time. Headspace VOCs were concentrated and analyzed using HS-SPME/GC-MS.Results: The compound 3-methyl-1-butanol was found to be a biomarker among the 26 bacterial isolates (10 KPC-positive, 10 NDM-positive, 2 IMP-positive, 2 carbapenemase-negative CRKP, and 2 carbapenem-susceptible K. pneumonoiae).Conclusion: This study explored a promising new strategy for the screening of carbapenemase-producing CRKP strains. Further research with larger sample sizes will potentially accelerate the application of biomarkers in routine microbiology.Keywords: carbapenem-resistantKlebsiella pneumoniae, volatile organic compounds, headspace solid-phase microextraction combined with gas chromatography-mass spectrometry

Hailing Yu,1,&ast; Kexin Tang,1,&ast; Zeyu Cai,2,&ast; Xi Lin,1 Yongquan Huang,3 Ting Yu,1 Qianqian Zhang,1 Qiang Wang,4 Lili Wu,5 Lei Yang,6 Hong Shan,1 Hui Luo1 1Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 2Department of Radiology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 3Department of Ultrasound, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 4The Green Aerotechnics Research Institute of Chongqing Jiaotong University, Chongqing, People’s Republic of China; 5Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, School of Physics and Electronic Engineering, Harbin Normal University, Harbin, Heilongjiang, People’s Republic of China; 6Center for Composite Materials and Structures, Harbin Institute of Technology, Harbin, Heilongjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Luo; Hong Shan, Email luoh53@mail.sysu.edu.cn; shanhong@mail.sysu.edu.cnBackground: Nanomaterials exhibited intrinsic enzyme-like properties due to the unique properties compared with natural enzyme. Carbon dots (CDs) are an important kind of quantum-sized nanomaterials, which have enormous application potential in bio-imaging, drug carrier, and nanosystems. Carbon dots possess intrinsic enzyme-like properties, such as glutathione (GSH) oxidase or peroxidase activities.Methods: A co-delivery nanosystem that could carry siRNA and doxorubucin (DOX) simultaneously has been studied in this work. The co-delivery based on carbon dots was surface-modified with poly-ethylenimine (PEI) and loaded the siMRP1 with chemotherapeutics on the surface with pH-triggered drug release. The CD-PEI was synthesized by one-step microwave assisted method; the PEI was raw materials and passivator during the reaction process that makes CDs exhibit excellent optical property.Results: The CD-PEI was capable of loading and delivering siMRP1 and DOX to tumors and releasing them synchronously in cells in an acid-triggered manner. The particles exhibited GSH oxidase-like catalytic property, oxidizing GSH to oxidized glutathione with concomitant increase of reactive oxygen species (ROS). We found that silencing of MRP1 by co-delivery system antagonized chemoresistance by increasing DOX accumulation and significantly enhancing the inhibitory effect of cell viability induced by CD-PEI-DOX. The co-delivery system dramatically inhibited tumor growth in xenograft model, and CDs counteracted MRP1 function by siRNA-mediated knockdown of MRP1.Conclusion: Taken together, we uncover the potential role of CDs with a combination of siRNA and chemotherapeutics in overcoming chemoresistance of lung cancer by suppressing MRP1 and oxidation of GSH. Our findings imply its potential of antagonizing chemoresistance to enhance therapeutic efficiency of doxorubicin in clinical practices of lung cancer treatment.Keywords: carbon dots, chemoresistance, co-delivery, siRNA

Jisong Yan,1 Hong Luo,1 Qi Nie,1 Shengling Hu,2 Qi Yu,2 Xianguang Wang1 1Department of Respiratory and Critical Care Medicine, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China; 2Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of ChinaCorrespondence: Qi Yu, Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China, Email fishns123@163.com Xianguang Wang, Department of Respiratory and Critical Care Medicine, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China, Email 907395635@qq.comBackground: The growth of antibiotic resistance to Mycobacterium TB represents a major barrier to the goal of “Ending the global TB epidemics”. This study aimed to develop and validate a simple clinical scoring system to predict the unfavorable treatment outcomes (UTO) in multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) patients.Methods: A total of 333 MDR/RR-TB patients were recruited retrospectively. The clinical, radiological and laboratory features were gathered and selected by lasso regression. These variables with area under the receiver operating characteristic curve (AUC)> 0.6 were subsequently submitted to multivariate logistic analysis. The binomial logistic model was used for establishing a scoring system based on the nomogram at the training set (N = 241). Then, another independent set was used to validate the scoring system (N = 92).Results: The new scoring system consists of age (8 points), education level (10 points), bronchiectasis (4 points), red blood cell distribution width-coefficient of variation (RDW-CV) (7 points), international normalized ratio (INR) (7 points), albumin to globulin ratio (AGR) (5 points), and C-reactive protein to prealbumin ratio (CPR) (6 points). The scoring system identifying UTO has a discriminatory power of 0.887 (95% CI=0.835– 0.939) in the training set, and 0.805 (95% CI=0.714– 0.896) in the validation set. In addition, the scoring system is used exclusively to predict the death of MDR/RR-TB and has shown excellent performance in both training and validation sets, with AUC of 0.930 (95% CI=0.872– 0.989) and 0.872 (95% CI=0.778– 0.967), respectively.Conclusion: This novel scoring system based on seven accessible predictors has exhibited good predictive performance in predicting UTO, especially in predicting death risk.Keywords: multidrug- and rifampicin-resistant tuberculosis, treatment outcome, laboratory parameters, scoring system

Ming Shao,1,2,&ast; Fangting Yuan,1,2,&ast; Jingwen Liu,1,2 Hesheng Luo1,2 1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 2Hubei Key Laboratory of Digestive Diseases, Wuhan, 430060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hesheng Luo, Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China, Email whdxxhnklhs@whu.edu.cnPurpose: Ulcerative colitis (UC) patients have disturbances in the microbiota-gut-brain axis, and mast cells are important components of this axis. The mast cell-specific receptor Mrgprb2 has effects on host defense against bacterial infection and neurogenic inflammation, which may help mast cells act on the axis. This study analyzed how Mrgprb2 participates in the pathogenesis of UC by affecting the microbiota-gut-brain axis.Materials and Methods: Mrgprb2 knockout (b2KO) mice and wild-type (WT) mice were fed 2% (w/v) dextran sulfate sodium (DSS) in drinking water for 7 days, which was then replaced with normal water for 14 days. This cycle was repeated three times. Feces were collected on Days 21, 42, and 63 for intestinal microbiota analysis, and mice were euthanized on Day 64. Hypothalamus, amygdala and colon tissues were removed and analyzed.Results: Compared with WT mice, B2KO mice exhibited increased weight loss, colon shortening and colonic pathological damage after colitis induction. Analysis of the intestinal microbiota showed that b2KO mice with colitis had a significant decrease in the abundance and diversity, as well as an increase in Allobaculum and a decrease in norank_f__Muribaculaceae and Ileibacterium. In colon tissues, the expression of mucin 2 (MUC2) and junctional adhesion molecule A (JAM-A) in b2KO mice was reduced, and oxidative stress levels were higher. B2KO mice with colitis had higher corticotropin-releasing hormone (CRH), corticotropin-releasing hormone receptor 1 (CRHR1), neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) mRNA levels in hypothalamus tissues and glucocorticoid receptor mRNA levels in the amygdala.Conclusion: In the microbiota-gut-brain axis, Mrgprb2 was involved in regulating the intestinal microbiota composition, intestinal barrier and oxidative stress levels, and was related to stress regulation, which might help to explain the pathogenesis of UC.Keywords: ulcerative colitis, mast cells, Mrgprb2, microbiota-gut-brain axis

Zhiguo Zhang,1,2,&ast; Fangda Fu,1,2,&ast; Yishan Bian,1,2,&ast; Huihao Zhang,1,2 Sai Yao,1,2 Chengcong Zhou,1,2 Yuying Ge,2 Huan Luo,3 Yuying Chen,4 Weifeng Ji,1 Kun Tian,1 Ming Yue,5 Weibin Du,6 Hongting Jin,1 Peijian Tong,1 Chengliang Wu,1,2 Hongfeng Ruan1,2 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, People’s Republic of China; 2The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 5Department of Physiology, College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 6Research Institute of Orthopedics, The Affiliated Jiangnan Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongfeng Ruan; Chengliang Wu, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Fax +86 571 86613684, Email rhf@zcmu.edu.cn; wcl@zcmu.edu.cnBackground: With the rapid growth of the elderly population, the incidence of osteoarthritis (OA) increases annually, which has attracted extensive attention in public health. The roles of dietary intake in controlling joint disorders are perhaps one of the most frequently posed questions by OA patients, while the information about the interaction between dietary intake and OA based on scientific research is limited. α-Chaconine is the richest glycoalkaloid in eggplants such as potatoes. Previous evidence suggests that α-Chaconine is a toxic compound to nervous and digestive systems with potentially severe and fatal consequences for humans and farm animals, but its effect on OA development remains obscure.Objective: To determine whether α-Chaconine deteriorates OA progression through sensory innervation and chondrocyte pyroptosis via regulating nuclear factor-κB (NF-κB) signaling, providing evidence for a possible linkage between α-Chaconine and OA progression.Methods: We established a mouse OA model by destabilization of medial meniscus (DMM) surgery and then intra-articular injection of 20 or 100 μM α-Chaconine into the OA mice for 8 and 12 weeks. The severity of OA progression was evaluated by histological staining and radiographic analyses. The expressions of matrix metabolic indicators, Col2, Mmp3, and Mmp13, as well as pyroptosis-related proteins, Nlrp3, Caspase-1, Gsdmd, IL-1β, IL-18, were determined by immunohistochemistry. And the changes in sensory nerve ingrowth and activity of NF-κB signaling were determined by immunofluorescence.Results: We found that α-Chaconine could exacerbate mouse OA progression, resulting in subchondral sclerosis, osteophyte formation, and higher OARSI scores. Specifically, α-Chaconine could augment cartilage matrix degradation and induce chondrocyte pyroptosis and nerve ingrowth. Mechanistical analysis revealed that α-Chaconine stimulated NF-κB signaling by promoting I-κB α phosphorylation and p65 nuclear translocation.Conclusion: Collectively, our findings raise the possibility that α-Chaconine intake can boost chondrocyte pyroptosis and nerve ingrowth to potentiate OA progression by activating NF-κB signaling.Graphical Abstract: Keywords: α-Chaconine, osteoarthritis, pyroptosis, nerve ingrowth, NF-κB signaling

Yuying Ge,1,&ast; Yuying Chen,2,&ast; Chijiao Guo,1,&ast; Huan Luo,3 Fangda Fu,1,4 Weifeng Ji,1,4 Chengliang Wu,1,4 Hongfeng Ruan1,4 1The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China; 2The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengliang Wu, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Email wcl@zcmu.edu.cn Hongfeng Ruan, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Email rhf@zcmu.edu.cnAbstract: Low back pain (LBP) is a common problem worldwide, resulting in great patient suffering and great challenges for the social health system. Intervertebral disc (IVD) degeneration (IVDD) is widely acknowledged as one of the key causes of LBP. Accumulating evidence suggests that aberrant pyroptosis of IVD cells is involved in the pathogenesis of IVDD progression, however, the comprehensive roles of pyroptosis in IVDD have not been fully established, leaving attempts to treat IVDD with anti-pyroptosis approaches questionable. In this review, we summarize the characteristics of pyroptosis and emphasize the effects of IVD cell pyroptosis on the pathological progression of IVDD, including secretion of cytokines, nucleus pulposus cell apoptosis and autophagy, accelerated extracellular matrix degradation, annulus fibrosus rupture, cartilage endplate calcification, vascularization, sensory and sympathetic fiber neoinnervation, and infiltrating lymphatic vessels. Finally, we discuss several interventions used to treat IVDD by targeting pyroptosis. This review provides novel insights into the crucial role of IVD cell pyroptosis in IVDD pathogenesis, and could be informative for developing novel therapeutic approaches for IVDD and LBP.Keywords: low back pain, intervertebral disc degeneration, pyroptosis, inflammasome, anti-pyroptotic approach

Rui Wang,1,&ast; Huating Luo,2,&ast; Xiaojuan Xin,1 Bo Qin,1 Wenxiang Huang2 1Department of Infectious Diseases, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; 2Department of Geriatrics, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China&ast;These authors contributed equally to this workCorrespondence: Bo Qin, Department of Infectious Diseases, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China, Tel + 86 23 89012887, Email cqqinbo@126.com Wenxiang Huang, Department of Geriatrics, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China, Tel +86 13883533808, Email wenxiang_huang@163.comAbstract: Cryptococcus (C) neoformans infection mainly occurs in immunocompromised hosts, especially those with AIDS, and skeletal infection is a rare presentation of cryptococcosis. We report a rare case of disseminated cryptococcal infection of the lumbar spine in an immunocompetent man caused by Cryptococcus neoformans var. grubii. The lesion position first appeared on upper right lung and then spread to the fourth lumbar vertebra. The result of periodic acid–Schiff (PAS) and Gomori’s methenamine silver (GMS) staining of the tissue sample matched cryptococcal infection, but multiple culture was negative. Eventually, C. neoformans var. grubii was confirmed using next-generation sequencing (NGS). Current follow-up of 12 months indicated a stable condition after antifungal therapy (fluconazole 400 mg/day) combined with surgery. Our case reminds that physicians must consider the possibility of skeletal cryptococcosis in patients with bone lesions, and NGS might be an excellent option to obtain the most accurate diagnosis in clinical practice.Keywords: cryptococcosis, vertebral infection, immunocompetent, antifungal therapy, next-generation sequencing

Qi Yu,1 Wujin Weng,2 Hong Luo,3 Jisong Yan,3 Xin Zhao4 1Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology; Hubei Clinical Research Center for Infectious Diseases; Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan, 430023, People’s Republic of China; 2Department of Oncology, Quzhou Hospital of Traditional Chinese Medicine, Zhejiang University of Chinese Medicine, Quzhou, 310053, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology; Hubei Clinical Research Center for Infectious Diseases; Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan, 430023, People’s Republic of China; 4Department of Pediatrics, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510799, People’s Republic of ChinaCorrespondence: Jisong Yan, Department of Respiratory and Critical Care Medicine, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China, Email Jisongyan163@163.com Xin Zhao, Department of Pediatrics, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510799, People’s Republic of China, Email 443608693@qq.comPurpose: This study was to explore the predictive value of monocyte to high-density lipoprotein cholesterol ratio (MHR), neutrophils to high-density lipoprotein cholesterol ratio (NHR), C-reactive protein-to-lymphocyte ratio (CLR), and C-reactive protein-to-albumin ratio (CAR) for type 2 diabetes mellitus (T2DM) in patients with active pulmonary tuberculosis (APTB).Patients and Methods: A total of 991 active pulmonary tuberculosis (APTB) patients (201 with T2DM) were hospitalized in the Department of Tuberculosis, Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology were included. The routine blood examination indicators and biochemical parameters were collected to calculate MHR, NHR, CLR, and CAR. The Pearson correlation analysis, Univariate Logistic regression analysis, and receiver operating characteristic (ROC) curve analysis were performed to assess the predictive value of MHR, NHR, CLR, and CAR for APTB-T2DM patients.Results: The levels of MHR, NHR, CLR, and CAR in the APTB-T2DM patients were significantly higher than in the APTB-no T2DM patients (P < 0.05). Additionally, the MHR, NHR, CLR, and CAR have a positive correlation with fasting blood glucose in the whole study population. However, in the APTB-T2DM patients, MHR, NHR, and CAR were not correlated with fasting blood glucose, and only CLR was positively correlated with fasting blood glucose. The area under curve (AUC) predicting APTB-T2DM patients of the MHR, NHR, CLR, and CAR was 0.632, 0.72, 0.715, and 0.713, respectively. Further, univariate logistic regression analyses showed that the higher MHR, NHR, CLR, and CAR were independent risk factors for APTB-T2DM (P < 0.01). The MHR, NHR, CLR, and CAR quartiles were used to divide the APTB patients into four groups for further analysis. The prevalence of T2DM was significantly higher in APTB individuals as MHR, NHR, CLR, and CAR values increased (P < 0.05).Conclusion: MHR, NHR, CLR, and CAR are simple and practicable inflammatory parameters that could be used for assessing T2DM in APTB. APTB patients have a greater possibility to be diagnosed with T2DM with the higher MHR, NHR CLR, and CAR values. Therefore, more attention should be given to the indicator in the examination of APTB.Keywords: active pulmonary tuberculosis, type 2 diabetes mellitus, MHR, NHR, CLR, CAR

Qin Zhou,1 Huanjun Luo,2 Xiaowei Wang,2 Peng Li,3 Haibo Kong,1 Baomei He1 1Center for Reproductive Medicine, Department of Pediatrics, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, People’s Republic of China; 2Bengbu Medical College, Bengbu, Anhui Province, People’s Republic of China; 3Department of Gastroenterology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of ChinaCorrespondence: Baomei He, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), No. 158 Shangtang Road, Hangzhou, Zhejiang Province, 310014, People’s Republic of China, Tel/Fax +86 13588008667, Email heyan916@126.comPurpose: Status epilepticus (SE) is a life-threatening condition causing brain damage, hippocampal necrosis and apoptosis. This study aimed to determine whether microRNA-210 regulates seizure and apoptosis by targeting the TLR4 /NF-κB1 associated signaling pathway.Methods: In a pilocarpine-induced epileptic rat model, the expressions of microRNA-210 (miR-210), TLR4, NF-κB1 and caspase-3 were assessed by a quantitative polymerase chain reaction and Western blotting. Tunel detects hippocampal neuron apoptosis.Results: We found that miR-210, TLR4, NF-κB1 and caspase-3 were upregulated in the hippocampus of the rat model compared with that of control. The knockdown of miR-210 significantly restored the expression levels of TLR4, NF-κB1 and caspase-3 and increased hippocampal apoptosis.Conclusion: These findings showed that the downregulation of miR-210 promoted apoptosis of hippocampal neurons by negatively regulating the TLR4/NF-&kcy;B1 signaling pathway.Keywords: apoptosis, microRNA, NF-κB1, status epilepticus, TLR4

Jin-Bao Ma,1 Ling-Cheng Zeng,2 Fei Ren,1 Li-Yun Dang,1 Hui Luo,1 Yan-Qin Wu,1 Xin-Jun Yang,1 Rong Li,1 Han Yang,3 You Xu1 1Department of Drug-Resistance Tuberculosis, Xi’an Chest Hospital, Xi’an, People’s Republic of China; 2Xi’an Center for Disease Control and Prevention, Xi’an, People’s Republic of China; 3Department of Clinical Laboratory, Xi’an Chest Hospital, Xi’an, People’s Republic of ChinaCorrespondence: Fei Ren; You Xu, Department of Drug-resistance tuberculosis, Xi’an Chest Hospital, West Section of HangTian Avenue, Yanta District, Xi’an, People’s Republic of China, Email doc.renfei@163.com; xuyou7575@126.comBackground: Long-term regimens are widely used for multidrug-resistant tuberculosis (MDR-TB) in North-West China; however, risk factors associated with the treatment outcomes are not well known.Methods: This was a retrospective cohort study of MDR-TB patients treated with longer regimen in Xi’an from 2017 to 2019. Risk factors associated with the treatment outcome were analyzed using multiple logistic regression.Results: Of the 446 patients with MDR-TB included, 215 were cured, 84 completed treatment, 23 failed treatment, 108 were lost to follow-up, and 16 died. Unfavorable outcome risk factors were age > 40 years (OR = 3.25, 95% CI = 2.12– 4.98), male sex (OR = 2.53, 95% CI = 1.52– 4.22), and re-treated tuberculosis (OR = 1.70, 95% CI = 1.11– 2.61), whereas poor treatment outcome risk factors were age > 40 years (OR = 5.51, 95% CI = 2.52– 12.07), fluoroquinolones not used in the regimen (OR = 3.31, 95% CI = 1.45– 7.51), and smear-positive (OR = 4.0, 95% CI = 1.47– 10.8).Conclusion: In Xi’an, MDR-TB treatments with long-term regimens had low success rates, and age, sex, and tuberculosis treatment history were risk factors of MDR-TB treatment outcomes.Graphical Abstract: Keywords: tuberculosis, multidrug-resistant, treatment outcomes, risk factors, China

Haixin Luo,1,&ast; Bo Xie,2,&ast; Jinhui Xu,2 Yuqi Zhu,1 Jiayi Sun,1 Yuqing Shen,1 Xiuzu Song2 1Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Dermatology, Hangzhou Third People’s Hospital; Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiuzu Song, Email songxiuzu@sina.comBackground: Vitiligo is an acquired skin depigmentation disease. It can be misdiagnosed at an early stage and tend to relapse. Serum markers are essential to monitoring the progression of vitiligo. Exosomal miRNAs act as the communication mediator between melanocytes and immune cells. Our study aimed to use serum exosomal miRNAs as a reference for evaluating vitiligo progression.Methods: The miRNAs were extracted from the serum exosomes of ten progressive vitiligo patients (before and after treatment) and ten healthy individuals. We profiled miRNAs expression by RNA sequencing and screened out potential miRNAs and plotted their receiver operating characteristic (ROC) curves to explore their sensitivity and specificity as prognostic biomarkers in vitiligo progression. We examined the correlation between miRNA expression and the lesion area. Different databases were used to predict gene targets of miRNAs, which were analyzed by gene ontology and Kyoto encyclopedia of genes and genomes (KEGG).Results: Our results showed that 141 miRNAs were differentially expressed in serum exosomes of progressive vitiligo patients, and 365 miRNAs were differentially expressed in these patients after treatment compared to healthy individuals. The expression of hsa-miR-487b-3p was significantly lower in these patients compared to healthy individuals. Still, there was no difference in its levels in patients after corticosteroid treatment compared to healthy controls. ROC curve analysis (area under curve = 0.840) indicated that hsa-miR-487b-3p could serve as a biomarker for the prognosis of vitiligo progression. Its expression positively correlated with the lesion area. A total of 41 target genes of hsa-miR-487b-3p were predicted via different databases. KEGG pathways were enriched in phenylalanine metabolism, glycan degradation, and protein export.Conclusion: Serum exosomal hsa-miR-487b-3p can be a biomarker to detect vitiligo progression. The predicted target genes of hsa-miR-487b-3p were enriched in catabolism. Thus, its in progressive vitiligo may accelerate catabolism in melanocytes and cause its impairment.Keywords: progressive vitiligo, exosome, miRNA, biomarker

Binyi Yang,1– 3,* Cheng Lei,1– 3,* Danhui Yang,1– 3 Chenyang Lu,1– 3 Yingjie Xu,1– 3 Lin Wang,1– 3 Ting Guo,1– 3 Rongchun Wang,1– 3 Hong Luo1– 3 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Hunan Diagnosis and Treatment Center of Respiratory Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongchun Wang; Hong Luo, Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China, Email 198202060@csu.edu.cn; luohonghuxi@csu.edu.cnBackground: OFD1 encodes a protein with 1012 amino acids, which is a component of basal bodies and centrioles, essential for cilia biogenesis. OFD1 was reported to be associated with X-chromosome linked dysmorphology syndrome in early studies and recent studies reported a few cases with primary ciliary dyskinesia (PCD) caused by OFD1 deficiency.Case Presentation: We report a 31-year-old man who suffered from recurrent respiratory infections with typical manifestations of primary ciliary dyskinesia. In addition to respiratory manifestations, the patient also had situs inversus, obesity, gastroesophageal reflux, and hearing impairment. Clubbing fingers and mild streblomicrodactyly were also observed.Examination Result: We performed whole-exome sequencing to identify a novel variant c.2795delA:p.(Lys932Argfs*3) in OFD1. The hemizygous variant was predicted to be likely pathogenic by bioinformatic analysis software and ACMG guideline. High-speed video microscopy (HSVM), transmission electron microscopy (TEM), and immunofluorescence were performed to analyze the respiratory cilia. A high beating frequency and a stiff beating pattern were observed under HSVM, while there were no significant abnormalities in TEM and immunofluorescence. The sperm flagella examinations were also generally normal.Conclusion: Our study identified a novel frameshift variant in OFD1 causing PCD, enriched the genetic spectrum of OFD1 variants, and verified that OFD1 mutation can lead to only a PCD characteristic phenotype, while other OFD1-associated syndromic symptoms such as dysmorphic features and renal symptoms were not present.Keywords: OFD1, primary ciliary dyskinesia, cilia, situs inversus

Jinqiang Wang,1 Hongtao Luo,2 Qi Wang,1 Xiaohui Zhu3 1Department of Emergency, Air Force Characteristic Medical Center, Beijing, 100142, People’s Republic of China; 2Department of Orthopaedics, Air Force Characteristic Medical Center, Beijing, 100142, People’s Republic of China; 3Department of Neurosurgery, Emergency Management Department Emergency General Hospital, Beijing, 100028, People’s Republic of ChinaCorrespondence: Hongtao Luo, Department of Orthopaedics, Air Force characteristic Medical Center, Beijing, 100142, People’s Republic of China, Tel +86 13701210368, Email luohongtaolht@126.comObjective: This study aimed to investigate the surgical outcomes in elderly (age ≥ 65) patients with hip fractures combined with hemiplegia and compare them with the surgical outcomes in elderly patients with hip fractures but no hemiplegia.Methods: A total of 761 elderly patients with hip fractures who were treated between January 2013 and December 2019 were enrolled in this study using a retrospective study design. The patients were divided into two groups: a hemiplegia group (77 cases, 10.1%) and a non-hemiplegia group (684 cases, 89.9%). Length of hospital stay, postoperative complications, 30-day and one-year mortalities, and one-year functional status were compared between the two groups.Results: The average length of hospital stay in the hemiplegia group (13.51 ± 10.17 days) was longer than in the non-hemiplegia group (12.60 ± 7.83 days), but the difference was not statistically significant (P = 0.354). The incidence of postoperative complications in patients with hemiplegia (28.6%, 22/77) was higher than in patients without hemiplegia (15.4%, 105/684), and the difference was statistically significant (P = 0.003). The 30-day and one-year mortalities in the hemiplegia group were higher than in the non-hemiplegia group (30 days after surgery: 10.4%, 8/77 vs 4.5%, 31/684; one year after surgery: 29.9%, 23/77 vs 15.2%, 104/684), and the difference was statistically significant (30 days after surgery: P = 0.027; one year after surgery: P = 0.001). One year after surgery, the average activity of daily living score was 56.02 ± 9.63 in the hemiplegia group and 76.89 ± 8.40 in the non-hemiplegia group, and the difference was statistically significant (P = 0.000).Conclusion: Hemiplegia can increase the incidence of postoperative complications and 30-day and one-year mortalities in patients with hip fractures.Keywords: hip fracture, hemiplegia, curative effect, elderly patients, comorbidity, recovery, complications

Hongying Zhu,1,&ast; Hong Luo,1,&ast; Qiaoshi Zhong,1 Xingwei Cao,1 Shumin Gu,1 Suqin Peng,1 Yanping Xiao,1 Yanhui Chen,1 Yaping Hang,1 Xueyao Fang,1 Shan Zou,1 Fangyou Yu,2 Longhua Hu1 1Department of Clinical Laboratory Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji UniversitySchool of Medicine, Shanghai, 200082, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Longhua Hu; Fangyou Yu, Email longhuahu@163.com; wzjxyfy@163.comIntroduction: The transmission of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible Staphylococcus aureus (MSSA) are great public health concern worldwide. To better understand S. aureus evolution and dissemination, we compared the molecular features of MSSA and MRSA isolates.Methods: In this study, 74 MSSA and 102 MRSA non-duplicate isolates were recovered from clinical samples between 2016 and 2020. Molecular epidemiology, antimicrobial resistance determinants, and virulence gene profiles were carried out by whole-genome sequencing (WGS).Results: Twenty distinct sequence types were identified in MRSA isolates, with the most common being ST59, ST630, and ST338. The major genotypes of MSSA were ST188 and ST7. The toxin genes clfA, sek, and seq were significantly associated with MRSA, while splA/B, clfB, map, sdrC/D, and sem-sen-seo-seu were detected more frequently in MSSA isolates than MRSA (P < 0.05). The tst positive isolates were more commonly identified in CC1 and CC72, whereas lukE/D was mainly found in the CC7, CC15, CC88, and completely absent in CC59 clones.Conclusion: Our results compared the genetic diversity between MRSA and MSSA strains, suggesting efforts to fight infections caused by MSSA need to be intensified due to MSSA isolates carrying wide range of virulence factors. Comparative epidemiological studies of large populations of MSSA and MRSA will be necessary in the future to understand how MSSA and MRSA populations may co-evolve and interact in the future.Keywords: methicillin-susceptible Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, virulence, resistance, molecular characteristics, whole-genome sequencing

Hongyu Chen,1 Jianxiang Liu,2 Qian Kang,1 Hao Luo,1 Ning Tan,1 Jiali Pan,1 Yuqing Yang,1 Min Yu,1 Dan Liu,1 Hongli Xi,1 Yifan Han,1 Ran Cheng,1 Yanyan Yu,1 Xiaoyuan Xu1 1Departments of Infectious Diseases, Peking University First Hospital, Beijing, People’s Republic of China; 2Department of Gastroenterology, Peking University First Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xiaoyuan Xu; Yanyan Yu, Email xiaoyuanxu6@163.com; yyy@bjmu.edu.cnBackground: Since oral direct-acting antiviral agents (DAAs) became available, the global hepatitis C treatment situation has undergone tremendous changes. However there are still many issues worthy of attention in treatment.Methods: We selected 53 HCV-infected patients who were treated and followed up in the Peking University First Hospital from December 2017 to January 2021 to detect the RASs in HCV. Pearson correlation analysis was used to analyze HCV RNA and HCV cAg, the Fisher exact test and chi-square test was used to compare the effects of RASs on the rate of decline of HCV RNA and HCV core antigen (cAg) during DAA treatment.Results: The RASs and its prevalence on the NS3 are mainly Y56F 2.56% (1/39), Q80K 23.08% (9/39), S122G 71.79% (28/39), and V170I 38.46% (15/39). On the NS5A were R30Q 10.53% (4/38), P32A 5.26% (2/38), P58S 2.63% (1/39), and Y93H 21.05% (8/38). On NS5B were C316N 71.05% (27/38), C451H 2.63% (1/38), and I585C 2.63% (1/38). There was no significant correlation between the RASs (Y93H, V179I, Q80K, S122G, C316N) and HCV genotype (p > 0.05). The baseline serum HCV RNA and HCV cAg had a significant medium-degree correlation (r = 0.601, p = 0.002). After 1 week of DAA treatment was weak correlation (r = 0.413, p = 0.032). Q80K, S122G, V170I, Y93H, and C316N had no effect on the clearance of HCV RNA and HCV cAg within the first week of DAA treatment (p> 0.05).Conclusion: The HCV genotype may have a limited impact on the presence of the five RASs (Y93H, V179I, Q80K, S122G, and C316N) as shown in this study. HCV RNA and HCV cAg have a correlation, especially at baseline is the highest; the appearance of some RASs has no effect on DAA treatment in most chronic hepatitis C patients.Keywords: hepatitis C virus, chronic hepatitis C, drug resistance, sequencing

Chu-Yun Cheng,1 Guan-Yin Zeng,1 Tong Wang,1 Yan-Hua Su,1 Feng-Dan Xu,2 Hong Luo,1 Hui-Ting Zhong,1 Xiu-Lan Chen1 1Department of Obstetrics, Dongguan Eighth People’s Hospital (Dongguan Children’s Hospital), Dongguan, Guangdong, 523325, People’s Republic of China; 2Department of Neonatal Clinic, Dongguan Eighth People’s Hospital (Dongguan Children’s Hospital), Dongguan, Guangdong, 523325, People’s Republic of ChinaCorrespondence: Chu-Yun Cheng, Department of Obstetrics, Dongguan Eighth People’s Hospital (Dongguan children’s Hospital), No. 68, West Lake 3rd Road, Shilong Town, Dongguan, Guangdong, 523325, People’s Republic of China, Tel +86 13688988412, Email chChu-Yun@126.comObjective: This study aimed to investigate the ability of serum cholic acid (CA) and lithocholic acid (LCA) in the diagnosis and perinatal prognosis assessment of intrahepatic cholestasis of pregnancy (ICP), and the relationship between both indicators and hypoxia-inducible factor-1α (HIF-1α).Methods: Between March 2020 and March 2021, pregnant women with high levels of total bile acid (TBA) in the late pregnancy with TBA ≥ 10 μmol/L and TBA < 10 μmol/L (control group) were included for the retrospective study. Those with TBA ≥ 10 μmol/L were divided into the ICP group and the asymptomatic hypercholanaemia of pregnancy (AHP) group based on ICP symptoms. The comparison of the bile acid profiles, the receiver operating characteristic (ROC) curve analysis, and Pearson correlation analysis were conducted successively.Results: Nine types of bile acids were significantly higher in ICP and AHP than in the control group, while CA and LCA serum levels in the AHP group were significantly lower than those in the ICP group (P < 0.05). The ROC curve analysis showed that LCA, CA, and LCA+CA were all diagnostic indicators for ICP, and LCA+CA displayed the greatest diagnostic value (area under the curve (AUC), 0.923). Subgroup analysis using the LCA+CA cut-off point (3.28 μmol/L) as the subgroup indicator proved that the incidence of adverse perinatal outcomes and the placental HIF-1α positivity were significantly higher in the high LCA+CA group than in the low LCA+CA group (P < 0.05). Pearson correlation analysis revealed significant positive correlations of HIF-1α expression levels to LCA, CA and LCA+CA (r = 0.473, 0.537, 0.619, respectively. P < 0.05 in all).Conclusion: This study confirmed that CA and LCA have a predictive diagnostic value for ICP in pregnant women, and the combined evaluation is associated with adverse perinatal outcomes, and LCA+CA positively correlates to placental HIF-1α expression levels.Keywords: cholic acid, lithocholic acid, intrahepatic cholestasis of pregnancy, hypoxia-inducible factor-1&#x03B1

Yingjie Xu,1– 3,* Binyi Yang,1– 3,* Cheng Lei,1– 3 Danhui Yang,1– 3 Shuizi Ding,1– 3 Chenyang Lu,1– 3 Lin Wang,1– 3 Ting Guo,1– 3 Rongchun Wang,1– 3 Hong Luo1– 3 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Hunan Diagnosis and Treatment Center of Respiratory Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongchun Wang; Hong Luo, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Furong District, Changsha, Hunan, 410011, People’s Republic of China, Email 198202060@csu.edu.cn; luohonghuxi@csu.edu.cnAbstract: Primary ciliary dyskinesia (PCD) is a rare genetic disease caused by mutations of genes coding motile-cilia-related proteins. CCDC40 variants can cause PCD via disrupting the assembling of inner dynein and dynein regulating complex in cilia and flagella, but none has been reported associated with multiple morphological abnormalities of the sperm flagella (MMAF). We identified and validated the disease-causing variants in our patient via whole-exome and Sanger sequencing. We used high-speed video microscopy analysis (HSVA) and immunofluorescence to analyze the functional and structural deficiency of respiratory cilia. Papanicolaou staining and scanning electron microscope was applied to analyze the morphological sperm defects resulted from the PCD associated variants. We identified novel compound variants (c.901C>T, p.(Arg301*); c.2065_2068dup, p.(Ala690Glyfs*67)) in CCDC40 in a male patient with male infertility. HSVA revealed the rigid and stiff ciliary beating pattern. Immunofluorescence indicated loss of inner dynein arm protein DNAH2 both in cilia and the sperms of the patient. Diagnosis of MMAF was confirmed through sperm Papanicolaou staining and scanning electron microscope. We first describe a patient with a combination of PCD and MMAF associated with novel compound heterozygous variants in CCDC40. Our results present initial evidence that CCDC40 associated with MMAF, which expands the genetic spectrum of PCD and MMAF and provides precise clinical genetic counseling to this family.Keywords: PCD, MMAF, CCDC40, male infertility

Bo Xie,1,&ast; Yi Chen,2,&ast; Yebei Hu,2 Yan Zhao,2 Haixin Luo,2 Jinhui Xu,1 Xiuzu Song1 1Department of Dermatology, Hangzhou Third People’s Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People’s Republic of China; 2Department of Dermatology, Hangzhou Third Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiuzu Song, Department of Dermatology, Hangzhou Third People’s Hospital, Affiliated Hangzhou Dermatology Hospital, Zhejiang University School of Medicine, West Lake Road 38, Hangzhou, 310009, People’s Republic of China, Tel +86-571-87823102, Email songxiuzu@sina.comObjective: The treatment of vitiligo is often challenging to dermatologists. There is ample evidence to suggest that hydroxychloroquine (HCQ) is effective for vitiligo treatment; nonetheless, the underlying mechanism remains unknown. In the present study, we sought to uncover the molecular targets of HCQ by an integrated network-based pharmacologic and transcriptomic approach.Methods: The potential targets of HCQ were retrieved from databases based on the crystal structure. Targets related to vitiligo were screened and intersected with potential targets of HCQ. A protein-protein interaction network of the intersected targets was generated. Interactions between the targets were verified by molecular docking. Moreover, human vitiligo immortalized melanocytes (PIG3V) were evaluated after treatment with HCQ (1μg/mL) for 24h. The total RNA of PIG3V was extracted and determined by RNA-seq transcriptomics for differential gene expression analysis. Network pharmacology was then used to identify the relationships between putative targets of HCQ and differentially expressed genes.Results: Molecular docking analysis revealed four putative key targets (ACHE, PNMT, MC1R, and VDR) of HCQ played important roles in vitiligo treatment. According to the transcriptomic results, the melanosomal biogenesis-related gene BLOC1S5 was upregulated 138005.020 fold after HCQ treatment. Genes related to protein repair (MSRB3) and anti-ultraviolet (UV) effect (UVSSA) were upregulated 4.253 and 2.603 fold, respectively, after HCQ treatment.Conclusion: The expression of the BLOC1S5 gene is significantly upregulated, indicating upregulated melanosomal biogenesis after HCQ treatment. In addition, HCQ yields a protective effect on melanocytes by upregulating genes associated with damaged protein repair (MSRB3) and anti-UV effect (UVSSA). The protective effects of HCQ are mediated by binding to putative targets ACHE, PNMT, MC1R, and VDR according to network pharmacology and docking verification.Keywords: vitiligo, hydroxychloroquine, treatment, pigmentation, melanocyte protection

Jian Li,1,&ast; Hui Luo,1,&ast; Ying-Ying Liu,1 Li-Xin Chen,1 Mei-Qin Zhu,2 Quan-Tong Deng,2 Dong-Mei Zhu,1,3 Zi-Mo Wang,1 Jin-Feng Xu1 1Department of Ultrasound, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, People’s Republic of China; 2Department of Medical Oncology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, People’s Republic of China; 3Department of Ultrasound, The Affiliated Nanchong Central Hospital of North Sichuan Medical College, Nanchong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Li; Jin-Feng Xu, Department of Ultrasound, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), No. 1077 of Dongmenbei Road, Luohu District, Shenzhen, 518020, People’s Republic of China, Tel +86 755 25533018, Fax +86 755 22945252, Email lijiandh@126.com; xujinfengsb4ke@126.comObjective: To explore the value of uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7)-161 single nucleotide polymorphism in predicting the occurrence of cardiotoxicity in Chinese human epidermal growth factor 2 (HER-2) positive breast cancer patients who underwent pertuzumab combined with trastuzumab Therapy.Methods: Fifty patients with HER-2 positive breast cancer who planned to receive trastuzumab and pertuzumab therapy for more than four cycles were enrolled in this study, and blood samples were collected. Thirty healthy volunteers of matching ages were selected as the control group. Myocardial parameters such as global work index, global effective work, and global wasted work were measured before treatment (M0) and at the end of four cycles of treatment month three (M3). Blood samples were collected from patients at the M0 stage, and polymorphisms of the UGT2B7-161 gene were detected to evaluate the predictive ability of different gene phenotypes on the myocardial drug toxicity injury.Results: There were 35 myocardial work decreased events among 50 patients. There were 24 (47.3%), 15 (40.8%), and 11 (11.8%) patients carrying UGT2B7-161 CC, CT, and TT genotypes, respectively. The occurrence of myocardial work decreased was decreased in UGT2B7-161 TT and CT genotypes (12.5%) compared with CC genotype (41.7%) with statistical significance (P < 0.001). Multivariate logistic regression model analysis exhibited that UGT2B7-161 genotypes, body mass index, and cardiac troponin I were independent factors influencing the risk of cardiotoxicity.Conclusion: UGT2B7-161 single nucleotide polymorphism is a potential predictive factor for cardiotoxicity in HER-2 positive breast cancer patients receiving trastuzumab and pertuzumab dual-targeted drug therapy.Keywords: breast cancer, uridine diphosphate-glucuronosyltransferase 2B7, pressure-strain loop, human epidermal growth factor 2, cardiotoxicity, trastuzumab, pertuzumab

Huihui Zeng,1– 3 Yiming Ma,1– 3 Xue He,1– 3 Shan Cai,1– 3 Ping Chen,1– 3 Yan Chen,1– 3 Hong Luo1– 3 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China; 2Research Unit of Respiratory Diseases, Central South University, Changsha, Hunan, People’s Republic of China; 3Hunan Centre for Evidence-Based Medicine Changsha, Hunan, People’s Republic of ChinaCorrespondence: Hong LuoDepartment of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital of Central South University, No. 139 Renmin Road, Changsha, Hunan, 410011, People’s Republic of ChinaEmail luohonghuxi@csu.edu.cnBackground: Organizing pneumonia (OP) is a secondary process in many diseases. Due to its low incidence and indistinct symptoms, there is limited information on OP associated with haematological malignancies. Therefore, the aim of this study was to discuss the characteristics and prognosis of OP associated with haematological malignancies.Methods: We observed and analysed pathologically confirmed OP cases associated with haematological malignancies in a hospital record database and excluded cases of OP with known causes, including chemotherapy, radiotherapy, targeted therapy, transplantation and infection.Results: There were five patients with OP underlying only haematological malignancies, including one case each of the following: myelodysplastic syndrome, acute myelogenous leukaemia, multiple myeloma, aplastic anaemia, and T cell lymphoma. Radiological findings did not show a distinct pattern, and two cases mimicked pulmonary aspergillosis with ground-glass opacity (GGO). The diagnosis of OP was confirmed by minimal invasive biopsy. Although all patients developed severe cases, steroids yielded favourable outcomes.Conclusion: This study demonstrates that haematological malignancies may be a cause of OP and that minimal invasive biopsy may be an effective and safe method to confirm the diagnosis. Although OP associated with haematological malignancies may more frequently develop into severe cases, the OP lesions were steroid-responsive during follow-up.Keywords: organizing pneumonia, haematological malignancies, characteristics, follow-up

Yudan Liang,1,2,&ast; Qinghuo Kong,1,&ast; Huiwen Luo,1 Jinhua Tan,1 Huizheng Zhu3 1Department of Acupuncture and Rehabilitation, The Affiliated Jiangmen Traditional Chinese Medicine Hospital of Jinan University, Jiangmen, Guangdong, People’s Republic of China; 2Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Traditional Chinese Medicine, The 2nd Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, Shenzhen, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huizheng ZhuDepartment of Traditional Chinese Medicine, The 2nd Clinical Medical College (Shenzhen People’s Hospital) of Jinan University, No. 1017, Dongmen North Road, Luohu District, Shenzhen, Guangdong, 518020, People’s Republic of ChinaEmail zhuhuizheng@jnu.edu.cnPurpose: Chronic spontaneous urticaria (CSU) pathogenesis involves mast cell degranulation induced by the inositol 1,4,5-trisphosphate/diacylglycerol (IP3/DAG) pathway, but the condition lacks specific biomarkers. This study was performed to investigate long non-coding RNA (lncRNA) expression profiles, identify those associated with IP3/DAG pathway, and assess their diagnostic and prognostic value for CSU.Methods: Ten samples were selected from CSU and control groups, and microarray was performed to screen differentially expressed (DE) lncRNAs and mRNAs. Bioinformatic and co-expression network analyses were used to identify lncRNAs associated with IP3/DAG pathway. Quantitative real-time polymerase chain reaction was used to validate lncRNA expression levels. Combined with disease characteristics and serum indices detected with enzyme-linked immunosorbent assays, Spearman analysis and logistic regression were applied to analyze lncRNA-associated disease risk. Receiver operating characteristic (ROC) curves and 2-year follow-up data were applied to evaluate lncRNA diagnostic and prognostic value.Results: A total of 678 up- and 573 downregulated DE lncRNAs and 609 up- and 176 downregulated DE mRNAs were identified. Seven lncRNAs (upregulated T264761, T280622, ENST00000587970, T224062, ENST00000562459, and his-1_RNA_dna; downregulated ENST00000417930) were associated with the IP3/DAG pathway. D-dimer and histamine levels were significantly different between the two groups. Correlation analysis showed that his-1_RNA_dna positively correlated with the frequency of symptom appearance, while his-1_RNA_dna, ENST00000417930, T264761, and T280622 negatively correlated with the maximum wheal diameter. Regression analysis showed T264761 was associated with CSU risk. ROC analysis showed that the specificity of T264761 was 90%, with an area under the curve of 0.666. In follow-up, the rate of well-controlled disease in the low T264761 expression group was 82.61%.Conclusion: This study established lncRNA and mRNA expression profiles in CSU and identified lncRNAs associated with IP3/DAG pathway, which is mechanistically involved in this disease. T264761 may be a novel biomarker for CSU, but further study is needed to confirm its specific mechanism.Keywords: lncRNA, biomarker, urticaria, mRNA, microarray

Huihao Zhang,1,&ast; Sai Yao,1,&ast; Zhiguo Zhang,1,&ast; Chengcong Zhou,1 Fangda Fu,1 Yishan Bian,1 Huan Luo,2 Yan Li,1 Shuxin Yan,1 Yuying Ge,1 Yuying Chen,3 Kunyu Zhan,4 Yanzhi Ge,1 Zuxiang Chen,1 Ming Yue,5 Xiaofeng Li,6 Weibin Du,1,7 Hongting Jin,1 Peijian Tong,1 Hongfeng Ruan,1,8 Chengliang Wu1 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 3The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 5Department of Physiology, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 6Department of Orthopedics and Traumatology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 7Research Institute of Orthopedics, The Affiliated JiangNan Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 8Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongfeng Ruan; Peijian TongInstitute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of ChinaEmail rhf@zcmu.edu.cn; peijiantongzjtcm@163.comPurpose: To explore the pharmacological mechanisms of Liuwei Dihuang Decoction (LWDHD) against intervertebral disc (IVD) degeneration (IVDD) via network pharmacology analysis combined with experimental validation.Methods: First, active ingredients and related targets of LWDHD, as well as related genes of IVDD, were collected from public databases. The protein–protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed to predict the core targets and pathways of LWDHD against IVDD. Secondly, the IVDD model of mice treated with LWDHD was selected to validate the major targets predicted by network pharmacology.Results: By searching the intersection of the active ingredient targets and IVDD targets, a total of 110 targets matched the related targets of 30 active ingredients in LWDHD and IVDD were retrieved. PPI network analysis indicated that 17 targets, including Caspase-3, IL-1β, P53, etc., were hub targets. GO and KEGG enrichment analyses showed that the apoptosis pathway was enriched by multiple targets and served as the target for in vivo experimental study validation. The results of animal experiments revealed that LWDHD administration not only restored the decrease in disc height and abnormal degradation of matrix metabolism in IVDD mice but also reversed the high expression of Bax, Caspase-3, IL-1β, P53, and low expression of Bcl-2, thereby inhibiting the apoptosis of IVD tissue and ameliorating the progression of IVDD.Conclusion: Using a comprehensive network pharmacology approach, our findings predicted the active ingredients and potential targets of LWDHD intervention for IVDD, and some major target proteins involved in the predictive signaling pathway were validated experimentally, which gave us a new understanding of the pharmacological mechanism of LWDHD in treating IVDD at the comprehensive level.Keywords: intervertebral disc degeneration, Liuwei Dihuang decoction, network pharmacology, pharmacological mechanisms, apoptosis

Chenyang Lu,1– 3,* Danhui Yang,1– 3,* Cheng Lei,1– 3 Rongchun Wang,1– 3 Ting Guo,1– 3 Hong Luo1– 3 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Research Unit of Respiratory Disease, Central South University, Changsha, People’s Republic of China; 3Hunan Diagnosis and Treatment Center of Respiratory Disease, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Luo; Ting GuoDepartment of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Furong District, Changsha, Hunan, 410011, People’s Republic of ChinaEmail luohonghuxi@csu.edu.cn; guotingxy@csu.edu.cnBackground: Dynein axonemal assembly factor 2 (DNAAF2) is involved in the early preassembly of dynein in the cytoplasm, which is essential for motile cilia function. Primary ciliary dyskinesia (PCD) associated with DNAAF2 variants has rarely been reported in females with infertility. Moreover, there is no report linking DNAAF2 to scoliosis in human.Materials and Methods: We recruited patients from two consanguineous families with a clinical diagnosis of PCD and collected their clinical history, laboratory tests, and radiographic data. Sequencing and bioinformatics analysis were then performed. Immunofluorescence and high-speed microscope analysis were used to support the pathogenicity of the variant.Results: Proband 1, a 26-year-old female from family I, exhibited scoliosis, bronchiectasis, sinusitis, situs inversus, and infertility. We found a novel homozygous missense variant in DNAAF2, c.491T>C, p.(Leu164Pro) in this patient. Subsequent immunofluorescence indicated the absence of outer dynein arm and inner dynein arm of cilia, and high-speed microscopy analysis showed that the most of the cilia are static, which support the pathogenicity of this variant. Proband 2, a 53-year-old female, presented with bronchiectasis, sinusitis, and infertility. In this patient, a new homozygous frameshift variant DNAAF2, c.822del, p.(Ala275Profs*10) was identified. The disease-causing variants mentioned above are not included in the current authorized genetic databases.Conclusion: Our findings expand the spectrum of DNAAF2 variants and link DNAAF2 to female infertility and likely scoliosis in patients with PCD.Keywords: primary ciliary dyskinesia, scoliosis, DNAAF2, bronchiectasis, situs inversus, female infertility

Wantai Dang,1,&ast; Xiaohui Xu,2,&ast; Danling Luo,2 Hui Luo,2 Jin Hu,2 Jingguo Zhou,1 Jian Liu,2 Lanlan You2 1Department of Rheumatism and Immunity, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, People’s Republic of China; 2Department of Ultrasound, Clinical Medical College and The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lanlan You Email 17027279@qq.comObjective: To explore the effects of different blood uric acid levels in gout patients on the two-dimensional image of the kidney and the risk factors for gout-related kidney damage for providing clinical evidence to enable early prevention and treatment of gout-related kidney damage.Methods: We obtained information of 227 patients with primary gout and estimated the association between two-dimensional kidney images and clinical indicators using binary logistic regression.Results: Our study showed that different uric acid levels, age, disease course, cystatin C (CysC) level, and γ-glutamyl transpeptidase level were correlated with echo of the renal medulla (P < 0.05). CysC level was correlated with the renal cortex thickness and kidney stones in different uric acid-level groups (P < 0.05). Disease course, aspartate transaminase (AST) level, creatinine (CREA) level, and tophi were risk factors for renal cortex thinning in gout patients (P = 0.045, 0.026, 0.004, 0.006, respectively). The disease course, platelet (PLT) count, and high-density lipoprotein (HDL-C) level were risk factors for kidney stone formation in gout patients (P = 0.037, 0.022, 0.023, respectively), while CysC level and C-reactive protein (CRP) level were risk factors for increased renal medulla echo in these patients (P = 0.022, 0.028, respectively).Conclusion: Our study revealed disease course, AST level, CREA level, tophi, PLT count, HDL-C level, CysC level and CRP level may be important predictors of renal image changes.Keywords: gout, two-dimensional ultrasound, renal medulla, renal cortex, kidney stones

Yan Hu, Jingjing Li, Haifeng Luo, Wenli Song, Jiyuan Yang Department of Oncology, The First People’s Hospital of Jingzhou, Jingzhou, Hubei, 434000, People’s Republic of ChinaCorrespondence: Yan HuDepartment of Oncology, The First People’s Hospital of Jingzhou, Jingzhou, Hubei, 434000, People’s Republic of ChinaTel +86 716 8513623Email yanhu_dr@outlook.comBackground: Gastric cancer (GC) is among the most prevalent cancers globally. As such, there is a need to explore the mechanism underlying its pathogenesis and identify potential biomarkers for its prognosis.Methods: ONCOMINE was used to screen differentially expressed genes between GC and normal gastric mucosa. GEPIA was used to analyze the expression and correlation of candidate genes in tumor node metastasis (TNM) stage. STRING was used to construct protein interaction network. Kaplan–Meier plotter was used to analyze survival. TIMER was used to evaluate the association between candidate genes and immune cell infiltration.Results: From the ONCOMINE database, we found COL1A1, COL1A2, COL6A3, and SULF1 genes were significantly upregulated in stomach adenocarcinomas. There was a considerable correlation between the expression of COL1A1 (p = 0.029), COL1A2 (p = 0.004), COL6A3 (p = 0.002), SULF1 (p = 0.001), and the TNM stage. COL1A1 was positively correlated with ERBB2 (R = − 0.037, p = 0.46), while the other three genes were negatively correlated with ERBB2 (p > 0.05). The Kaplan–Meier plotter showed that low transcriptional levels of COL1A1 (p = 0.0020), COL1A2 (p = 0.0015), COL6A3 (p = 0.0015), and SULF1 (p = 0.0016) in gastric cancer patients were remarkably related to longer overall survival. In addition, there was a close relationship between chemokine expression and infiltration of the six immune cell types: B cells, macrophages, CD4+ T cells, CD8+ T cells, dendritic cells, and neutrophils, implying that the genes acted as indicators of both prognosis and immune status.Conclusion: Our findings implicate COL1A1, COL1A2, COL6A3, and SULF1 as candidate biomarkers for the prognosis of gastric cancer.Keywords: gastric cancer, biomarker, prognosis

Xingwei Cao,1,&ast; Qiaoshi Zhong,1,&ast; Yinjuan Guo,2,3 Yaping Hang,1 Yanhui Chen,1 Xueyao Fang,1 Yanping Xiao,1 Hongying Zhu,1 Hong Luo,1 Fangyou Yu,2,3 Longhua Hu1 1Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200082, People’s Republic of China; 3Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200082, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Longhua Hu; Fangyou Yu Email longhuahu@163.com; wzjxyfy@163.comIntroduction: Polymyxin resistance caused by the plasmid-mediated mcr-1 gene in gram-negative bacilli poses a huge threat to our health. In recent years, many regions have reported that mcr-1 and β-lactamase genes can coexist in a single strain.Methods: In this study, 107 nonduplicate Klebsiella pneumoniae (K. pneumoniae) isolates were collected from a tertiary hospital in Jiangxi, China. Antimicrobial susceptibility testing of isolates was performed using gram-negative susceptibility cards on the VITEK system. The minimum inhibitory concentrations (MICs) of polymyxin B was detected using the microdilution broth method. The presence of resistance genes was assessed using polymerase chain reaction (PCR). We subjected isolates to genotyping using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) and analyzed the transferability of plasmids with filter mating and electroporation. Subsequently, whole-genome sequencing was performed for plasmids.Results: Of the 107 K. pneumoniae isolates, 15 (14.0%) were resistant to polymyxin B. All polymyxin B-resistant isolates harbored at least one of the extended-spectrum β-lactamase genes tested. Only one isolate simultaneously harbored mcr-1, blaNDM− 5, blaCTX-M-55, and blaSHV-27 genes. MLST results showed that 15 carbapenem-resistant K. pneumoniae isolates belonged to five sequence types (STs). PFGE results displayed nine different PFGE clusters. Conjugation and transformation experiments and sequencing analysis showed that the strain had three plasmids, and mcr-1, blaNDM− 5, and blaCTX-M-55 were located on different plasmids.Conclusion: The present study demonstrated for the first time the coexistence of mcr-1, blaNDM− 5, and blaCTX-M-55 in a K. pneumoniae ST485 isolate. The three plasmids carrying the mcr-1, blaNDM− 5, and blaCTX-M-55 genes can be transmitted in Enterobacteriaceae strains, which may lead to more severe bacterial resistance.Keywords: Klebsiella pneumoniae, polymyxin B, mcr-1, blaNDM-5, blaCTX-M-55, plasmid