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Hui Ouyang,1 Hong Jiang,1 Jin Huang,2 Zunjing Liu1 1Department of Neuromedicine, Peking University People’s Hospital, Beijing, People’s Republic of China; 2Department of Emergency, Yiyang Central Hospital, Yiyang, Hunan, People’s Republic of ChinaCorrespondence: Zunjing Liu, Email 490644424@qq.comBackground: An international public health emergency has resulted from the emergence of the new coronavirus-2. Both direct and indirect influences have been felt on the treatment of acute stroke. However, no conclusive link between COVID-19 and the alleged decline in admissions for stroke-related reasons has been established, and the findings of recent studies are contentious. Most of those researches are not made use of authentic data. Therefore, the goal of this study is to examine how the COVID-19 pandemic has affected hospital admissions for stroke patients, to provide a basis for managing stroke patients in hospitals during COVID-19 pandemic.Methods: This retrospective study took place at the People’s Hospital of Peking University in Beijing, China. For each patient, interventions such as the application of tissue plasminogen activator (tPA) were examined. We recorded each patient’s outcomes. The stroke patients’ hospital admissions were compared to the average of the prior year. As the time span of interest, we selected the epidemic period (January 2020 to December 2020).Results: When compared to the previous year in the pre-COVID period, mean monthly stroke hospitalizations decreased during the pandemic by 54.42% (P< 0.001); average lengths of stay (ALOS) increased; and non-emergency admissions decreased by 78.8% (P< 0.001). The monthly volume of stroke patients exceeding the intravenous thrombolysis (IVT) window decreased by 25% and 59.73%, respectively (P < 0.001). There was a 5.3% increase in the percentage of IVT or within IVT time window in male stroke patients (p=0.019; p=0.049). During COVID-19, the proportion of non-local patients among male stroke patients decreased by 10% compared with the previous year (p=0.006).Conclusion: The COVID-19 epidemic has had a negative impact on stroke management in China, healthcare systems must work to assess and adapt to the new reality.Keywords: stroke, COVID-19, hospital management

Yuting Luo,1,&ast; Zhaowang Guo,2,&ast; Ying Li,1,&ast; Hui Ouyang,1 Shanfeng Huang,1 Yuanli Chen,3 Kenan Li,1 Yuxin Ji,1 Hongqiong Zhu,1 Wentao Luo,1 Xu Liu,1,4 Xinghua Li,1 Jinyu Xia,1 Xi Liu1 1Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, People’s Republic of China; 2Clinical Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, People’s Republic of China; 3Department of Hospital Infection Control, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xi Liu; Xinghua Li, Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, 52 Meihua East Road, Xiangzhou District, Zhuhai, 519000, People’s Republic of China, Tel/Fax +86-756-252-8592, Email liuxi26@mail.sysu.edu.cn; lixh79@mail.sysu.edu.cnObjective: The incidence of inappropriate and excessive empirical antibiotic therapy is unclear. The aim of this study was to determine the prevalence of different empirical antibiotic therapy prescriptions, related factors, and outcomes in hospitalized patients with bacterial infection.Methods: A retrospective cohort study was performed and patients with bacterial infection who were admitted between October 1, 2019, and September 30, 2020, were included. Multivariable analysis was performed by the logistic regression model.Results: A total of 536 (42.6%) of the 1257 included patients received inappropriate empirical antibiotic therapy (IEAT), and 368 (29.3%) patients received appropriate but unnecessarily broad-spectrum empirical antibiotic therapy (AUEAT). MDRO (adjusted OR 2.932 [95% CI 2.201~3.905]; p < 0.001) and fever on admission (adjusted OR 0.592 [95% CI 0.415~0.844]; p = 0.004) were correlates of IEAT; sepsis (adjusted OR 2.342 [95% CI 1.371~3.999]; p = 0.002), age (adjusted OR 1.019 [95% CI 1.008~1.030]; p < 0.001), MDRO (adjusted OR 0.664 [95% CI 0.469~0.941]; p = 0.021), and urinary tract infection (adjusted OR 0.352 [95% CI 0.203~0.611]; p < 0.001) were correlates of AUEAT. Patients who received AUEAT were more likely to have a poor prognosis (63 [17.8%] vs 101 [27.4%]; p = 0.002). Both IEAT (median [IQR], 24,971 [13,135– 70,155] vs 31,489 [14,894– 101,082] CNY; p = 0.007) and AUEAT (median [IQR], 24,971 [13,135– 70,155] vs 30,960 [16,475– 90,881] CNY; p = 0.002) increased hospital costs. 45.3% (570/1257) of patients were infected with MDRO and 62.9% of them received IEAT.Conclusion: Inappropriate and excessive empirical antibiotic use was widely prevalent among hospitalized patients. Either inappropriate or excessive use of antibiotics may increase the burden of healthcare costs, the latter of which may be associated with poor prognosis. Clinicians need to be more judicious in choosing antibiotic(s). The MDRO epidemic was severe, especially in patients who received IEAT. It is imperative to take effective measures to improve the current situation of antibiotic abuse and antimicrobial resistance.Keywords: antimicrobial resistance, bacterial culture-positive, empirical antibiotic therapy, patient outcome, multidrug-resistant organism

Minxi Lao,1,2,&ast; Hui Ouyang,3,&ast; Nannan Li,1 Hao Li,1 Peiyin Dai,1 Zhongping Zhan,1 Dongying Chen1 1Department of Rheumatology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Geriatrics, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Department of Digestive Medicine Center, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongying Chen; Zhongping Zhan, Department of Rheumatology, the First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2 nd Road, Guangzhou, 510080, People’s Republic of China, Email chendy3@mail.sysu.edu.cn; zhanchuyue@163.comPurpose: To investigate the clinical features of infection, and associated factor for in-hospital mortality in a southern Chinese cohort with polymyositis/dermatomyositis (PM/DM).Patients and Methods: Clinical data were retrospectively reviewed from 2015 to 2022 from a tertiary hospital in southern China. Associated factors for infection and in-hospital mortality were analyzed by multivariate logistic regression analysis.Results: A total of 554 patients with PM/DM were included, and 35.6% (197/554) of them developed 404 episodes of infection. Half of the patients developed infection within 4 months after disease onset. Bacterial infection was predominant (249/404, 61.6%). Lung was the most involved (242/404, 59.9%). Gram-negative bacteria the leading pathogens (64/84, 76.2%). Patients with anti-MDA5 positive were prone to develop severe infections (35.1% vs 16.4%, P< 0.001) and had higher mortality (11.7% vs 3.4%, P=0.01). The in-hospital mortality was 6.5% (36/554). Infection was the leading cause of death (20/36, 55.6%). Older age (adjusted odds ratio (OR): 1.05, 95% confidential interval (CI): 1.02– 1.09, P=0.004), ILD (adjusted OR: 2.76, 95% CI: 1.11– 6.84, P=0.03), number of episodes of infection (adjusted OR: 1.91, 95% CI: 1.53– 2.38, P< 0.001), and elevated serum creatinine (Scr) (adjusted OR: 6.83, 95% CI: 1.77– 26.40, P=0.01) were associated with in-hospital mortality.Conclusion: Infection is an early complication in PM/DM with a high proportion of lung involvement and predominance of gram-negative bacteria. It is a major contributor to in-hospital mortality. Older age, ILD, and number of episodes of infection are associated with poor prognosis.Keywords: dermatomyositis, polymyositis, infection, MDA5, mortality

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

Mingcheng Huang,1,* Keping Wu,1,* Shan Zeng,2,* Wenfen Liu,1 Tianjiao Cui,1 Zhiqing Chen,1 Lian Lin,1 Dongying Chen,3 Hui Ouyang1 1Department of Nephrology, Kidney and Urology Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, ShenZhen, Guandong, People’s Republic of China; 2Department of Rheumatology, The First Affiliated Hospital of Jinan University, Guangzhou, Guandong, People’s Republic of China; 3Department of Rheumatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongying Chen; Hui Ouyang Email chendy3@mail.sysu.edu.cn; ouyh23@mail.sysu.edu.cnBackground: The aggressive phenotype of fibroblast-like synoviocytes (FLSs) is essential in the synovitis and bone destruction in rheumatoid arthritis (RA). Punicalagin is a natural polyphenol extracted in pomegranate juice, which possesses antioxidant, anti-inflammatory and anti-tumor properties suggesting it may be a potent drug for RA therapy. However, there is paucity of information on its effect in RA.Objective: To investigate the effects of punicalagin on synovial inflammation and bone destruction in RA.Methods: FLSs were isolated from synovial tissue of RA patients. The mRNA levels were evaluated by quantitative real-time PCR. Western blot was used for protein level measurements. The secretion of pro-inflammatory cytokines and metalloproteinases (MMPs) was detected by ELISA assays. Edu staining assays were carried out to investigate the proliferation of FLSs. Cell migration was assessed by Boyden chambers, wound scratch assays and F-actin staining in vitro. The intracellular translocation of nuclear factor kappa B (NF-κB) was investigated using immunofluorescence. The effects of punicalagin in vivo were measured by using collagen-induced arthritis (CIA) mice.Results: Punicalagin treatments significantly reduced the TNF-α induced expressions of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and IL-17A) and MMPs (MMP-1 and MMP-13) of RA FLSs. Punicalagin also suppressed the proliferation and migration of RA FLSs. Moreover, punicalagin (50mg/kg/d) alleviated arthritis severity and bone destruction, and decreased serum IL-6 and TNF-α in CIA mice. Further mechanism studies indicated that punicalagin blocked NF-κB activation via suppressing phosphorylation of IKK and IkBα, and preventing the translocation of 65.Conclusion: Our findings suggested that punicalagin might be one of natural therapeutic compounds for relieving RA progress via suppressing FLSs inflammation and migration through modulating NF-κB pathways.Keywords: rheumatoid arthritis, punicalagin, fibroblast-like synoviocytes, migration, pro-inflammatory cytokines

Meichen Qian,1 Na Wu,1,2 Ling Li,1 Wenshu Yu,1 Hong Ouyang,1 Xinyan Liu,1 Yujing He,1 Abdulrahman Al-Mureish2 1Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110004, People’s Republic of China; 2Clinical Skills Practice Teaching Center, Shengjing Hospital of China Medical University, Shenyang 110004, People’s Republic of ChinaCorrespondence: Na WuDepartment of Endocrinology, Clinical Skills Practice Teaching Center, Shengjing Hospital of China Medical University, Shenyang 110004, People’s Republic of ChinaEmail 3441535223@qq.comAbstract: Ketone bodies are one of the products of fat metabolism which can be used as an alternative energy source for the human body in states of glucose deficiency. Normal pregnant women may develop ketosis due to physiological changes during pregnancy, while pregnant women with abnormal glucose metabolism are more likely to develop ketosis due to abnormal insulin secretion. Animal experiments and clinical studies have shown that exposure to high-ketone environments during pregnancy is closely related to adverse maternal and infant outcomes. However, there is no unified conclusion on whether ketone bodies should be routinely monitored during pregnancy. This review summarizes the existing studies on ketone body levels and pregnancy outcomes in the case of abnormal blood glucose during pregnancy, elaborates the current guidelines on the level of ketone bodies, provides the detection and treatment of ketosis in pregnant women with abnormal blood glucose in the clinical practice.Keywords: diabetic ketoacidosis, gestational diabetes mellitus, ketoacidosis, pregestational diabetes mellitus, diabetes mellitus

Yujing He,1 Na Wu,1,2 Wenshu Yu,1 Ling Li,1 Hong OuYang,1 Xinyan Liu,1 Meichen Qian,1 A Al-Mureish1 1Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 2Clinical Skills Practice Teaching Center, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of ChinaCorrespondence: Na WuDepartment of Endocrinology, Shengjing Hospital of China Medical University, 36 Sanhao Road, Heping District, Shenyang, Liaoning Province 110004, People’s Republic of ChinaTel +86 18940258445Email 3441535223@qq.comAbstract: Gestational diabetes mellitus (GDM) refers to different degrees of abnormal glucose metabolism during pregnancy, where blood glucose levels do not reach the level of overt diabetes, accounting for 80– 90% of pregnancy with hyperglycemia. Hyperglycemia affects the pregnancy process, leading to a series of adverse maternal outcomes that have a profound impact on the future of the offspring. The establishing of an appropriate GDM model will provide theoretical basis for study GDM pathogenesis involves, the choice of resonable drugs and the observation the disease trends and outcomes. At present, there are many methods for establishing experimental GDM animal models and animal choices. This paper examines the different GDM models and their induction methods.Keywords: gestational diabetes mellitus, animal model, chemical induction, high-sugar and high-fat diet, genetic manipulation

Wenshu Yu,1 Na Wu,1 Ling Li,1 Hong OuYang,1 Meichen Qian,1 Haitao Shen2 1Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, People’ s Republic of China; 2Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Na WuDepartment of Endocrinology, Shengjing Hospital of China Medical University, 36 Sanhao Road, Heping District, Shenyang, Liaoning Province 110004, People’ s Republic of ChinaTel +86 18940258445Email 3441535223@qq.comAbstract: Gestational diabetes mellitus (GDM) is associated with many adverse obstetric outcomes and neonatal outcomes, including preeclampsia, Cesarean section, and macrosomia. Active screening and early diabetes control can reduce the occurrence of adverse outcomes. Glycosylated hemoglobin (HbA1c) only reflects average blood glucose levels, but not glycemic variability (GV). Studies have shown that GV can cause a series of adverse reactions, and good control of GV can reduce the incidence of adverse pregnancy outcomes in patients with GDM. In order to provide clinicians with a better basis for diagnosis and treatment, this study reviewed the measurement, evaluation, and control of GV, the importance of GV for patients with GDM, and correlations between GV and maternal and neonatal outcomes.Keywords: gestational diabetes mellitus, glycemic variability, outcomes, self-monitoring of blood glucose, continuous glucose monitoring

Yanglong Zhu,1 Kuan Liu,2 Jianjian Deng,1 Jing Ye,1 Fanrong Ai,3 Huan Ouyang,4 Tianlong Wu,1 Jingyu Jia,1 Xigao Cheng,1 Xiaolei Wang21Department of Orthopedic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China; 2Institute of Translational Medicine, Nanchang University, Nanchang 330088, People’s Republic of China; 3School of Mechanical & Electronic Engineering, Nanchang University, Nanchang 330031, People’s Republic of China; 4Department of Vascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of ChinaBackground: Nowadays, zirconia ceramic implants are widely used as a kind of hip prosthesis material because of their excellent biocompatibility and long-term wear resistance. However, the hip joint is one of the major joints with complex 3D morphological structure and greatly individual differences, which usually causes great material waste during the process of surgical selection of prosthesis.Methods: In this paper, by combining ceramic 3D printing technology with antibacterial nano-modification, zirconia ceramic implant material was obtained with precise 3D structure and effective antibacterial properties. Among which, two technical problems (fragile and sintering induced irregular shrinkage) of 3D printed ceramics were effectively minimized by optimizing the reaction conditions and selective area inversing compensation. Through in vivo and in vitro experiments, it was confirmed that the as prepared hip prosthesis could precisely matched the corresponding parts, which also exhibited good biocompatibility and impressive antibacterial activities.Results: 1) Two inherent technical problems (fragile and sintering induced irregular shrinkage) of 3D printed ceramics were effectively minimized by optimizing the reaction conditions and selective area inversing compensation. 2) It could be seen that the surface of the ZrO2 material was covered with a layer of ZnO nano-particles. A universal testing machine was used to measure the tensile, bending and compression experiments of ceramic samples. It could be found that the proposed ZnO modification had no significant effect on the mechanical properties of ZrO2 ceramics. 3) According to the plate counting results, ceramics modified with ZnO exhibited significantly higher antibacterial efficiency than pure ZrO2 ceramics, the ZrO2-ZnO ceramics had a significant killing effect 8 hours. 4) The removed implants and the tissue surrounding the implant were subjected to HE staining. For ZrO2-ZnO ceramics, inflammation was slight, while for pure ZrO2 ceramics, the inflammatory response could be seen that the antibacterial rate of the ZrO2-ZnO ceramics was significantly better than that of the pure ZrO2 ceramics group. 5) It could be seen that the cytotoxicity did not increase proportionally with the increase of concentration, all of viability were still above 80%. This suggested that our materials were safe and could be applied as a type of potential biomaterial in the future. 6) Further animal studies demonstrated that the implant was in good position without dislocation. This resulted implied that the proposed method can achieve accurate 3D printing preparation of ceramic joints. In addition, the femurs and surrounding muscles around the implant were then sectioned and HE stained. Results of muscle tissue sections further showed no significant tissue abnormalities, and the growth of new bone tissue was observed in the sections of bone tissue.Conclusion: 1) The ceramic 3D printing technology combined with antibacterial nano-modification can quickly customize the ideal implant material with precise structure, wear-resistant and effective antibacterial properties. 2) Two inherent technical problems (fragile and sintering induced irregular shrinkage) of 3D printed ceramics were effectively minimized by optimizing the reaction conditions and selective area inversing compensation. 3) ZnO nano-materials were modified on the ceramic surface, which could effectively killing pathogenic bacteria.Keywords: zirconia, 3D printing, antibacterial, surface modification, implant material

Nonlinear structural identification is essential in engineering. As new materials are being used andstructures become slender and lighter, nonlinear behaviour of structures becomes more important. There have been many studies into the development and application of system identification methods for structural nonlinearity based on changes in natural frequencies, mode shapes and damping ratios. A great challenge is to identify nonlinearity in large structural systems. Much work has been undertaken in the development of nonlinear system identification methods (e.g. Hilbert Transform, NARMAX, and Proper Orthogonal Decomposition), however, it is arguable that most of these methods are cumbersome when applied to realistic large structures that contain mostly linear modes with some local nonlinearity (e.g. aircraft engine pylon attachment to a wing). In this paper, a multi-shaker force appropriation method is developed to determine the underlying linear and nonlinear structural properties through the use of the measurement and generation of restoring force surfaces. One undamped mode is excited in each multi-shaker test. Essentially, this technique is a derivative of the restoring surface method and involves a non-linear curve fitting performed in modal space. A reduced finite element model is established and its effectiveness in revealing the nonlinear characteristics of the system is discussed. The method is demonstrated through both numerical simulations and experiments on a simple jointed laboratory structure with seeded faults, which represents an engine pylon structure that consists of a rectangular wing with two stores suspended underneath.

Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis. Zhang et al. report p16INK4a as a downstream integrator of diverse signals, such as inherited genetic risk, age, and intraocular pressure, in the pathogenesis of glaucoma. They demonstrate that upregulation of SIX6 upon stress directly increases p16INK4a, leading to retinal ganglion cell senescence and death.

Asthma is an inflammatory disease where the balance between Th1/Th2 and Th17/Treg plays a crucial role in its pathogenesis. Shikonin is used to treat a variety of autoimmune diseases due to its good anti-inflammatory activity. However, the effect and mechanism of shikonin on asthma remain unknown.