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Xian He,1,2 Xin Ran,1 Dan Liang,2 Hongxia Fan,3 Yuping Ran1 1Department of Dermatovenereology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Department of Allergy, Chengdu First People’s Hospital, Chengdu, People’s Republic of China; 3Department of Ultrasonic, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Yuping Ran, Tel +8618980601697, Email ranyuping@vip.sina.comAbstract: An infantile hemangioma is a congenital benign tumor formed by the proliferation of vascular cells during the embryonic stage. It is more common in the skin but can also occur in the mucous membranes, liver, brain and muscle. Hepatic hemangioma appears to be a benign tumor; however, it may lead to poor outcomes because of severe complications, such as high-output cardiac failure. The main treatment of hepatic hemangioma in infants is oral drugs, such as propranolol and glucocorticoids, but the clinical response is not always satisfactory. We describe a rare case of a 2-month-old boy who presented with infantile cutaneous and hepatic hemangiomas. By using dermoscopy and observations of the abdominal color Doppler ultrasound, after 9 months of oral treatment with itraconazole solution, the infantile cutaneous hemangioma complicated with hepatic hemangioma was eventually cured. There was no liver or kidney function damage during the whole treatment period. Itraconazole oral solution for the treatment of infantile cutaneous hemangioma complicated with hepatic hemangioma showed good efficacy, compliance, and safety in this case.Keywords: infantile hemangioma, cutaneous, hepatic, itraconazole oral solution, dermoscopy, color ultrasonic

Mingzheng Yao,1 Dan Liang,2 Xiuli Zeng,1 Xiaomei Xie,1 Jiali Gao,1 Li’an Huang1 1Department of Neurology, The First Affiliated Hospital, Jinan University, Guangzhou, People’s Republic of China; 2Department of Neurology, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, People’s Republic of ChinaCorrespondence: Li’an Huang, Department of Neurology, The First Affiliated Hospital, Jinan University, Guangzhou, People’s Republic of China, Email huanglian1306@126.comPurpose: Galectin-3 is a key regulator of microglial proliferation and activation and may have dual and time-dependent effects on ischemic stroke. This study aimed to prospectively investigate the dynamic changes in Galectin-3 levels in patients with acute ischemic stroke receiving endovascular therapy and its clinical significance.Patients and Methods: A total of 105 patients with acute ischemic stroke who underwent endovascular therapy were prospectively enrolled. Plasma Galectin-3 was quantitatively detected by an enzyme-linked immunosorbent assay before the operation and at 1 day, 3 days and 7 days after the operation. A linear mixed-effect model, Pearson correlation analysis and receiver operating characteristic (ROC) curve analysis were used to evaluate the dynamic changes in the plasma Galectin-3 concentration and its relationship with clinical outcomes.Results: Increases in plasma Galectin-3 levels at 1 day and 3 days after surgery were associated with early neurological deterioration and death (both P < 0.05). Increased Galectin-3 levels before surgery and at 1 day and 3 days after surgery were associated with poor prognosis (P < 0.05). Pearson correlation analysis revealed that Galectin-3 levels before surgery (r =0.318, P =0.002), at 1 day (r =0.318, P =0.001), 3 days (r =0.429, P < 0.001) and 7 days after surgery (r =0.340, P =0.001) were positively correlated with NIHSS scores. The ROC curve results showed that Galectin-3 concentration had a certain predictive value for death at 1 day (AUC=0.707, P=0.013), 3 days (AUC=0.708, P=0.016) and 7 days after the operation (AUC=0.708, P=0.016), but this predictive value was lower than that of the NIHSS score.Conclusion: In acute ischemic stroke patients receiving endovascular therapy, an increase in the plasma Galectin-3 levels were associated with death, poor prognosis, and early neurological deterioration. Galectin-3 levels were significantly correlated with the NIHSS score and had a certain predictive value for death.Plain Language Summary: Galectin-3 is a key regulator of microglial proliferation and activation and may have dual and time-dependent effects on ischemic stroke. However, relevant clinical studies are less at present. In this study, we found that an increase in the plasma Galectin-3 levels had significant values in death, poor prognosis, and early neurological deterioration in acute ischemic stroke patients receiving endovascular therapy at various times.Keywords: ischemic stroke, Galectin-3, endovascular therapy, inflammation, dynamic change, outcome

Traumatic brain injury is followed by a cascade of dynamic and complex events occurring at the cellular level. These events include: diffuse axonal injury, neuronal cell death, blood-brain barrier break down, glial activation and neuroinflammation, edema, ischemia, vascular injury, energy failure, and peripheral immune cell infiltration. The timing of these events post injury has been linked to injury severity and functional outcome. Extracellular vesicles are membrane bound secretory vesicles that contain markers and cargo pertaining to their cell of origin and can cross the blood-brain barrier. These qualities make extracellular vesicles intriguing candidates for a liquid biopsy into the pathophysiologic changes occurring at the cellular level post traumatic brain injury. Herein, we review the most commonly reported cargo changes in extracellular vesicles from clinical traumatic brain injury samples. We then use knowledge from animal and in vitro models to help infer what these changes may indicate regrading cellular responses post traumatic brain injury. Future research should prioritize labeling extracellular vesicles with markers for distinct cell types across a range of timepoints post traumatic brain injury.

Dongrui Liang,1 Xiaodong Li2 1 2nd Department of Ophthalmology, Baoding No.1 Central Hospital of Hebei Medical University, Baoding, Hebei, People’s Republic of China; 2Department of Nephrology, Baoding No.1 Central Hospital of Hebei Medical University, Baoding, Hebei, People’s Republic of ChinaCorrespondence: Xiaodong Li, Department of Nephrology, Baoding No.1 Central Hospital of Hebei Medical University, No. 320, Great Wall North Street, Baoding, Hebei, 071000, People’s Republic of China, Email lxd_765@sina.comBackground: Patients with primary nephrotic syndrome (PNS) are at an increased risk of developing various infections due to the long-term use of immunosuppressive agents. Cryptococcal meningitis (CM) is an uncommon but severe complication that can occur in patients with PNS, particularly those receiving immunosuppressive medications.Case Description: This case report describes a middle-aged female patient with PNS and type 2 diabetes mellitus (T2DM) who developed CM. She received a combination regimen of cyclophosphamide and prednisone, achieving partial remission of PNS. However, she later returned to the hospital with high fever and headache. At admission, her nasopharyngeal swab test was positive for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and she received therapy of dexamethasone and favipiravir, but her fever and headache were not improved. Following a lumbar puncture was performed for her and CM was diagnosed based on a positive Cryptococcus culture in the cerebrospinal fluid. The patient’s cyclophosphamides were temporarily discontinued, and antifungal therapy with amphotericin B liposome and fluconazole was initiated. Despite a noticeable increase in her blood glucose levels due to infection during her hospitalization, she showed improvement with intensified glycemic control treatment. The anti-infection showed significant effectiveness, and the patient’s proteinuria remained stable during follow-up.Conclusion: The patient with PNS and T2DM was concurrently diagnosed with both CM and coronavirus disease 2019 (COVID-19), marking the first reported case of such co-infections in these patients. Prompt diagnosis and appropriate antifungal therapy are crucial for improved outcomes of PNS patients with CM and COVID-19.Keywords: cryptococcal meningitis, primary nephrotic syndrome, type 2 diabetes mellitus, COVID-19

Dabin Liang,1,2,&ast; Zexuan Song,3,&ast; Xiaoyan Liang,1,2,&ast; Huifang Qin,1,2 Liwen Huang,1,2 Jing Ye,1,2 Rushu Lan,4 Dan Luo,5 Yanlin Zhao,3 Mei Lin1,2 1Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning, Guangxi, People’s Republic of China; 2Guangxi Key Laboratory of Major Infectious Disease Prevention and Control and Biosafety Emergency Response, Nanning, Guangxi, People’s Republic of China; 3National Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China; 4Department of Clinical Laboratory, Jiangbin Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, People’s Republic of China; 5School of Public Health and Management, Guangxi University of Chinese Medicine, Nanning, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanlin Zhao, National Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, No. 155 Chang Bai Road, Changping District, Beijing, 102206, People’s Republic of China, Email zhaoyl@chinacdc.cn Mei Lin, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, 530023, People’s Republic of China, Email gxlinmei@126.comBackground: Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a major public health issue in China. Nevertheless, the prevalence and drug resistance characteristics of isolates vary in different regions and provinces. In this study, we investigated the population structure, transmission dynamics and drug-resistant profiles of Mtb in Guangxi, located on the border of China.Methods: From February 2016 to April 2017, 462 clinical M. tuberculosis isolates were selected from 5 locations in Guangxi. Drug-susceptibility testing was performed using 6 common anti-tuberculosis drugs. The genotypic drug resistance and transmission dynamics were analyzed by the whole genome sequence.Results: Our data showed that the Mtb in Guangxi has high genetic diversity including Lineage 1 to Lineage 4, and mostly belong to Lineage 2 and Lineage 4. Novelty, 9.6% of Lineage 2 isolates were proto-Beijing genotype (L2.1), which is rare in China. About 12.6% of isolates were phylogenetically clustered and formed into 28 transmission clusters. We observed that the isolates with the high resistant rate of isoniazid (INH, 21.2%), followed by rifampicin (RIF, 13.2%), and 6.7%, 12.1%, 6.7% and 1.9% isolates were resistant to ethambutol (EMB), streptomycin (SM), ofloxacin (OFL) and kanamycin (KAN), respectively. Among these, 6.5% and 3.3% of isolates belong to MDR-TB and Pre-XDR, respectively, with a high drug-resistant burden. Genetic analysis identified the most frequently encountered mutations of INH, RIF, EMB, SM, OFL and KAN were katG_Ser315Thr (62.2%), rpoB_Ser450Leu (42.6%), embB_Met306Vol (45.2%), rpsL_Lys43Arg (53.6%), gyrA_Asp94Gly (29.0%) and rrs_A1401G (66.7%), respectively. Additionally, we discovered that isolates from border cities are more likely to be drug-resistant than isolates from non-border cities.Conclusion: Our findings provide a deep analysis of the genomic population characteristics and drug-resistant of M. tuberculosis in Guangxi, which could contribute to developing effective TB prevention and control strategies.Keywords: tuberculosis, Mycobacterium tuberculosis, drug-resistance, genetic diversity, whole genome sequencing

Increased use and improved methodology of carbonate clumped isotope thermometry has greatly enhanced our ability to interrogate a suite of Earth-system processes. However, interlaboratory discrepancies in quantifying carbonate clumped isotope (Δ47) measurements persist, and their specific sources remain unclear. To address interlaboratory differences, we first provide consensus values from the clumped isotope community for four carbonate standards relative to heated and equilibrated gases with 1,819 individual analyses from 10 laboratories. Then we analyzed the four carbonate standards along with three additional standards, spanning a broad range of δ47 and Δ47 values, for a total of 5,329 analyses on 25 individual mass spectrometers from 22 different laboratories. Treating three of the materials as known standards and the other four as unknowns, we find that the use of carbonate reference materials is a robust method for standardization that yields interlaboratory discrepancies entirely consistent with intralaboratory analytical uncertainties. Carbonate reference materials, along with measurement and data processing practices described herein, provide the carbonate clumped isotope community with a robust approach to achieve interlaboratory agreement as we continue to use and improve this powerful geochemical tool. We propose that carbonate clumped isotope data normalized to the carbonate reference materials described in this publication should be reported as Δ47 (I-CDES) values for Intercarb-Carbon Dioxide Equilibrium Scale.

Dongrui Liang,1 Xiaodong Li2 12nd Department of Ophthalmology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding, Hebei, People’s Republic of China; 2Department of Nephrology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding, Hebei, People’s Republic of ChinaCorrespondence: Xiaodong Li, Department of Nephrology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding Great Wall North Street No 320, Baoding, Hebei, 071000, People’s Republic of China, Tel +8618617789590, Email lxd_765@sina.com

Dongrui Liang,1,&ast; Shengnan Ma,1,&ast; Xiaodong Li2 12nd Department of Ophthalmology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding, Hebei, People’s Republic of China; 2Department of Nephrology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding, Hebei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaodong Li, Department of Nephrology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding Great Wall North Street No 320, Baoding, Hebei, 071000, People’s Republic of China, Tel +8618617789590, Email lxd_765@sina.com

Zhongbin Zhang,1,2,&ast; Jinqing Chen,1,&ast; Linghui Zou,1,&ast; Jing Tang,1 Jiaxin Zheng,1 Meijiao Luo,1 Gang Wang,1 Dan Liang,1,2 Yuyang Li,1 Ben Chen,1 Hongjun Yan,1 Wenya Ding1– 3 1Guangxi University of Chinese Medicine, Nanning, People’s Republic of China; 2Key Laboratory of Common Technology of Chinese Medicine Preparations, Guangxi University of Chinese Medicine, Nanning, People’s Republic of China; 3College of Veterinary Medicine, Northeast Agricultural University, Harbin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenya Ding, Guangxi University of Chinese Medicine, Nanning, People’s Republic of China, Tel +86-15045630868, Email DingWenYa666@163.comBackground and Purpose: Infections caused by Staphylococcus aureus (S. aureus) colonization in medical implants are resistant to antibiotics due to the formation of bacterial biofilm internal. Baicalein (BA) has been confirmed as an inhibitor of bacterial biofilm with less pronounced effects owing to its poor solubility and absorption. Studies have found that β-cyclodextrin-grafted chitosan (CD-CS) can improve drug efficiency as a drug carrier. Therefore, this research aims to prepare BA-loaded CD-CS nanoparticles (CD-CS-BA-NPs) for S. aureus biofilm elimination enhancement.Methods: CD-CS-BA-NPs were prepared via the ultrasonic method. The NPs were characterized using the X-ray diffraction (XRD), Thermo gravimetric analyzer (TGA), Transmission electron microscopy (TEM) and Malvern Instrument. The minimum inhibitory concentration (MIC) of the NPs were investigated. The biofilm models in vivo and in vitro were constructed to assess the S. aureus biofilm elimination ability of the NPs. The Confocal laser method (CLSM) and the Live/Dead kit were employed to explore the mechanism of the NPs in promoting biofilm elimination.Results: CD-CS-BA-NPs have an average particle size of 424.5 ± 5.16 nm, a PDI of 0.2 ± 0.02, and a Zeta potential of 46.13 ± 1.62 mV. TEM images revealed that the NPs were spherical with uniform distribution. XRD and TGA analysis verified the formation and the thermal stability of the NPs. The NPs with a MIC of 12.5 ug/mL exhibited a better elimination effect on S. aureus biofilm both in vivo and in vitro. The mechanism study demonstrated that the NPs may permeate into the biofilm more easily, thereby improving the biofilm elimination effect of BA.Conclusion: CD-CS-BA-NPs were successfully prepared with enhanced elimination of S. aureus biofilm, which may serve as a reference for future development of anti-biofilm agents.Graphical Abstract: Keywords: baicalein, β-cyclodextrin-grafted chitosan, nanoparticles, Staphylococcus aureus, biofilm elimination

Changshui Wang,1,&ast; Shuzhen Zhao,2,&ast; Yuan Xu,3 Wenxue Sun,4 Yuanyuan Feng,2 Deshuai Liang,5 Yun Guan3 1Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, People’s Republic of China; 2Children’s Rehabilitation Center, Jining Maternal and Child Health Family Planning Service Center, Jining, 272000, People’s Republic of China; 3Department of Hematology, Jining NO. 1 People’s Hospital, Jining, 272000, People’s Republic of China; 4Institute of Clinical Pharmacy and Pharmacology, Jining NO. 1 People’s Hospital, Jining Medical University, Jining, 272000, People’s Republic of China; 5Department of pharmacy, Jining NO. 1 People’s Hospital, Jining, 272000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yun Guan; Deshuai Liang, Jining NO. 1 People’s Hospital, 6 Jiankang Road, Jining, Shandong, 272000, People’s Republic of China, Tel/Fax +86-0537 2087092, Email gyuanun1989@163.com; 13468322037@163.comPurpose: We designed this study to investigate the potential correlations between gut microbiota compositions and hepatic metabolomic disorders in mice with methotrexate (MTX)-induced hepatoxicity.Methods: We used MTX to induce hepatoxicity in healthy Kunming mice, and we determined plasma ALT and AST levels and assessed the liver tissue histopathology. We applied an integrated gas chromatography-mass spectrometry (GC-MS) and 16S ribosomal RNA (rRNA) gene sequencing approach to evaluate the effects of MTX on the gut microbiota and hepatic metabolic profiles of mice. We uncovered correlations between the gut microbiota and hepatic metabolomic profiles by calculating the Spearman correlation coefficient.Results: MTX caused ALT and AST level elevations and hepatoxicity in our mouse model. MTX disrupted amino acid metabolic pathways (including biosyntheses of valine, leucine, and isoleucine; and arginine; and, metabolism of alanine, aspartate, and glutamate; histidine; beta-alanine; and glycine, serine, and threonine); biosyntheses of aminoacyl-tRNA; and pantothenate, and CoA; and, metabolic pathways of energy, glutathione, and porphyrin; and chlorophyll. In addition, MTX increased the abundances of Staphylococcus, Enterococcus, Collinsella, Streptococcus, and Aerococcus, but decreased the amounts of Lactobacillus, Ruminococcus, norank_f_Muribaculaceae, unclassified_f_Lachnospiraceae, norank_f_Lachnospiraceae, A2, Eubacterium_xylanophilum_group, Phascolarctobacterium, Bifidobacterium, and Faecalibaculum. Our correlation analyses showed that different flora abundance changes including those of Phascolarctobacterium, Faecalibaculum, norank_f_Muribaculaceae, Streptococcus, Enterococcus, Staphylococcus, and Collinsella were associated with liver injury.Conclusion: We present evidence supporting the notion that MTX causes hepatoxicity by altering the gut microbiota and hepatic metabolite profiles, our findings provide new venues for the management of MTX-induced hepatoxicity.Keywords: gas chromatography-mass spectrometry, 16S ribosomal RNA, methotrexate, hepatoxicity

Yimin Chen,1 Thanh N Nguyen,2 James E Siegler,3 Mohammad Mofatteh,4 Jack Wellington,5 Rongshen Yang,6,7 Lihong Zeng,1 Jiale Wu,6,7 Xi Sun,6,7 Daiyu Liang,6,7 Qiubi Tang,8 Sijie Chen,6,7 Xisheng Huang,6,7 Shuiquan Yang,1 Xuxing Liao9,10 1Department of Neurology and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of China; 2Department of Neurology, Radiology, Boston University School of Medicine, Boston, MA, USA; 3Cooper Neurological Institute, Cooper University Hospital, Camden, NJ, USA; 4School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UK; 5School of Medicine, Cardiff University, Cardiff, UK; 6Medical Intern of Neurology Department, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of China; 7School of Medicine, Shaoguan University, Shaoguan, People’s Republic of China; 8Chronic Disease Department, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 9Dean Office and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of China; 10Department of Neurosurgery, First People’s Hospital of Foshan, Foshan, People’s Republic of ChinaCorrespondence: Shuiquan Yang, Department of Neurology and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, No. 16, Guanghaidadaoxi, Sanshui District, Foshan, People’s Republic of China, Email yangshuiquan1969@126.com Xuxing Liao, Dean Office and Advanced National Stroke Center, Foshan Sanshui District People’s Hospital, Foshan, People’s Republic of China, Email drliao210409@163.comPurpose: This study aimed to investigate the impact of characteristic ischemic stroke and outcomes during the first COVID-19 pandemic lockdown.Patients and Methods: A retrospective, observational cohort study of a comprehensive tertiary stroke center was conducted. Patients with ischemic stroke were divided into pre-COVID-19 lockdown (11/1/2019 to 1/30/2020) and COVID-19 lockdown (1/31/2020 to 4/30/2020) period groups. Patient data on stroke admission, thrombolysis, endovascular treatment, and 3-month routine follow-up were recorded. Data analysis was performed using SPSS according to values following a Gaussian distribution.Results: The pre-COVID-19 lockdown period group comprised 230 patients compared to 215 patients in the COVID-19 lockdown period group. Atrial fibrillation was more predominant in the COVID-19 lockdown period group (11.68% vs 5.65%, p=0.02) alongside patients who were currently smoking (38.8% vs 28.7%, p=0.02) and drinking alcohol (30.37% vs 20.00%, p=0.012) compared with that of the pre-COVID-19 lockdown period group. For patients receiving thrombolysis, the median door-to-CT time was longer in the COVID-19 lockdown period group (17.0 min (13.0, 24.0) vs 12.0 min (8.0, 17.3), p=0.012), median door to needle time was 48.0 minutes (35.5, 73.0) vs 43.5 minutes (38.0, 53.3), p=0.50, compared with that of the pre-COVID-19 lockdown period group. There were no differences for patients receiving mechanical thrombectomy. The median length of hospitalization (IQR) was no different. Discharge mRS scores (IQR) were higher in the COVID-19 lockdown period group (1.0 (1.0, 3.0) vs 1.0 (1.0, 2.0), p=0.022). Compared with the pre-COVID-19 lockdown period, hospitalization cost (Chinese Yuan) in the COVID-19 period group was higher (13,445.7 (11,009.7, 20,030.5) vs 10,799.2 (8692.4, 16,381.7), p=0.000). There was no difference observed in 3-month mRS scores.Conclusion: Patients presenting with ischemic stroke during the COVID-19 pandemic lockdown period had longer median door-to-CT time and higher hospitalization costs. There were no significant differences in 3-month outcomes. Multidisciplinary collaboration and continuous workflow optimization may maintain stroke care during the COVID-19 pandemic lockdown.Keywords: ischemic stroke, COVID-19 pandemic, thrombolysis, thrombectomy, hospitalization cost

Dongrui Liang,1 Xiaodong Li2 1Department of Ophthalmology, Baoding No. 1 Central Hospital of Hebei Medical Universtiy, Baoding, Hebei, People’s Republic of China; 2Department of Nephrology, Baoding No. 1 Central Hospital of Hebei Medical Universtiy, Baoding, Hebei, People’s Republic of ChinaCorrespondence: Xiaodong Li, Department of Nephrology, Baoding No. 1 Central Hospital of Hebei Medical Universtiy, Baoding Great Wall North Street No 320, Baoding, Hebei, 071000, People’s Republic of China, Tel +8618617789590, Email lxd_765@sina.com

This paper presents novel flux and source term treatments within a Godunov-type finite volume framework for predicting the depth-averaged shallow water flow and sediment transport with enhanced the accuracy and stability. The suspended load ratio is introduced to differentiate between the advection of the suspended load and the advection of water. A modified Harten, Lax and van Leer Riemann solver with the contact wave restored (HLLC) is derived for the flux calculation based on the new wave pattern involving the suspended load ratio. The source term calculation is enhanced by means of a novel splitting-point implicit discretization. The slope effect is introduced by modifying the critical shear stress, with two treatments being discussed. The numerical scheme is tested in five examples that comprise both fixed and movable beds. The model predictions show good agreement with measurement, except for cases where local three-dimensional effects dominate.

This paper describes an improved vector manipulation multislope monotone upstream-centred scheme for conservation laws (MUSCL) reconstruction for solving the shallow water equations on unstructured grids. This improved MUSCL reconstruction method includes a bigger stencil for the interpolation and saves time for determining the geometric relations compared to the original vector manipulation method, so it is computationally more efficient and straightforward to implement. Four examples involving an analytical solution, laboratory experiments and field-scale measurements are used to test the performance of the proposed scheme. It has been proven that the proposed scheme can provide comparable accuracy and higher efficiency compared to the original vector manipulation method. With the increasing of the number of cells, the advantage of the proposed scheme becomes more apparent.

Luoyang Ma,1,2 Xiaoyan Zheng,1,3 Rui Lin,1 Antonia RuJia Sun,4 Jintong Song,1 Zhiqiang Ye,1 Dahong Liang,1 Min Zhang,1 Jia Tian,1 Xin Zhou,2 Liao Cui,1 Yuyu Liu,1 Yanzhi Liu1,3,5 1Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang City, Guangdong Province, 524023, People’s Republic of China; 2Marine Medical Research Institute of Zhanjiang, Zhanjiang City, Guangdong Province, 524023, People’s Republic of China; 3Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang city, Guangdong province, 524045, People’s Republic of China; 4Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen City, Guangdong Province, 518055, People’s Republic of China; 5Shenzhen Osteomore Biotechnology Co., Ltd., Shenzhen city, Guangdong Province, 518118, People’s Republic of ChinaCorrespondence: Yanzhi Liu; Yuyu Liu, Tel +86-759-2388405 ; +86-759-2388588, Email liuyanzhi02@163.com; liuyuyu77@163.comAbstract: Drug delivery for osteoarthritis (OA) treatment is a continuous challenge because of their poor bioavailability and rapid clearance in joints. Intra-articular (IA) drug delivery is a common strategy and its therapeutic effects depend mainly on the efficacy of the drug-delivery system used for OA therapy. Different types of IA drug-delivery systems, such as microspheres, nanoparticles, and hydrogels, have been rapidly developed over the past decade to improve their therapeutic effects. With the continuous advancement in OA mechanism research, new drugs targeting specific cell/signaling pathways in OA are rapidly evolving and effective drug delivery is critical for treating OA. In this review, recent advances in various IA drug-delivery systems for OA treatment, OA targeted strategies, and related signaling pathways in OA treatment are summarized and analyzed based on current publications.Keywords: osteoarthritis, knee, drug delivery, intra-articular

Yangming Lin,1 Dabin Liang,2 Xiaoyan Liang,2 Minying Huang,2 Mei Lin,2 Zhezhe Cui2 1School of Public Health, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China; 2Guangxi Key Laboratory of Major Infectious Disease Prevention and Control and Biosafety Emergency Response, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning, Guangxi Zhuang Autonomous Region, 530028, People’s Republic of ChinaCorrespondence: Mei Lin; Zhezhe Cui, Guangxi Key Laboratory of Major Infectious Disease Prevention and Control and Biosafety Emergency Response, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning, Guangxi Zhuang Autonomous Region, 530028, People’s Republic of China, Tel +86-771-2518766 ; +86-771-2518785, Email gxlinmei@126.com; czz6997@163.comPurpose: Guangxi is a high prevalence area of tuberculosis (TB) in China, urgent needing of further TB reduction. Our purpose is to analyze the epidemiological characteristics of TB in Guangxi and analyze the relationship between socioeconomic factors and TB from the dimensions of time and space to provide evidence to effectively prevent and control TB.Patients and Methods: We performed a retrospective analysis of the epidemiology of TB. Moran’s index (I) was used for spatial autocorrelation analysis, and space-time scanning was used to detect temporal, space, and space-time clusters of TB. A Bayesian space-time model was used to analyze related factors of the TB epidemic at the county level in Guangxi.Results: From 2015 to 2019, a total of 233,623 TB cases were reported in Guangxi. The majority of TB cases were in males; the reported incidence of TB was the highest in people aged ≥ 65 years. By occupation, farmers were the most frequently affected. The overall reported incidence of TB decreased by 4.95% during this period. Tuberculosis occurs all year round, but the annual reporting peak is usually from March to July. Spatial autocorrelation analysis showed that the reported incidence of TB in 2015– 2019 was spatially clustered (Moran’s I > 0, P < 0.05); Kulldorff’s scan revealed that the space-time cluster (log-likelihood ratio = 2683.76, relative risk = 1.60, P < 0.001) was mainly concentrated in northern Guangxi. Using Bayesian space-time modeling, socioeconomic and healthcare factors are related to the high prevalence of TB.Conclusion: The prevalence of TB is influenced by a space-time interaction effect and is associated with socioeconomic and healthcare status. It is necessary to improve the economic development and health service in areas with a high TB prevalence.Graphical Abstract: Keywords: tuberculosis, space-time model, associated factors, Guangxi

In shallow water flow and transport modeling, the monotonic upstream-centered scheme for conservation laws (MUSCL) is widely used to extend the original Godunov scheme to second-order accuracy. The most important step in MUSCL-type schemes is MUSCL reconstruction, which calculate-extrapolates the values of independent variables from the cell center to the edge. The monotonicity of the scheme is preserved with the help of slope limiters that prevent the occurrence of new extrema during reconstruction. On structured grids, the calculation of the slope is straightforward and usually based on a 2-point stencil that uses the cell centers of the neighbor cell and the so-called far-neighbor cell of the edge under consideration. On unstructured grids, the correct choice for the upwind slope becomes nontrivial. In this work, 2 novel total variation diminishing schemes are developed based on different techniques for calculating the upwind slope and the downwind slope. An additional treatment that stabilizes the scheme is discussed. The proposed techniques are compared to 2 existing MUSCL reconstruction techniques, and a detailed discussion of the results is given. It is shown that the proposed MUSCL reconstruction schemes obtain more accurate results with less numerical diffusion and higher efficiency.

Current topographic survey technology provides high-resolution (HR) datasets for urban environments. Incorporating this HR information in models aiming to provide flood risk assessment is desirable because the flood wave propagation is depending on the urban topographic features, i.e. buildings, bridges and street networks. Conceptual, numerical and practical challenges arise from the application of shallow water models to HR urban flood modeling. For instance, numerical challenges are occurrence of wet-dry fronts, geometric discontinuities in the urban environment and discontinuous solutions, i.e. shock waves. These challenges can be overcome by using a Godunov-type scheme. However, the computational cost of this type of schemes is high, such that HR two-dimensional shallow water simulations with practical relevance have to be run on supercomputers. The porous shallow water model is an alternative approach that aims to reduce computational cost by using a coarse resolution and accounting for unresolved processes by means of the porosity terms. Usually, a speedup between two and three orders of magnitude in comparison to HR simulations can be obtained. This study reports preliminary results of a practical test case concerning pluvial flooding in a district of the city of Nice, France, caused by the intense rainfall event on October 3rd, 2015. HR topography data set on a 1 m resolution is available for the district, whereby street features of infra-metric dimensions have been included. A reference solution is calculated by a HR shallow water model on a 1 m by 1 m structured computational grid. The porous shallow water model is run on a 10 m by 10 m grid and the influence of the drag source term is studied. The model results show a large deviation, which is caused by the poor meshing strategy of the porous shallow water (AP) model. The study also summarizes practical challenges that arise during the application of the AP and HR models to a large urban catchment. The main difficulty is to obtain a good mesh. In smaller scale investigations, the mesh is currently constructed by hand such that the cell edges align with buildings. This approach is not feasible for large scale urban catchments with a large number of buildings. Future steps that have to be taken, such as a strategy for automatic mesh generation, are reported on.

Deku Liang,1,2 Min Hu,1 Qin Tang,1 Mao Huang,1 Liangdan Tang1 1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Obstetrics and Gynecology, Chengdu Women and Children’s Central Hospital Affiliated to University of Electronic Science and Technology of China, Chengdu, Sichuan Province, People’s Republic of ChinaCorrespondence: Liangdan Tang Email 201608@hospital.cqmu.edu.cnBackground: Endometrial carcinoma (EC) is one of the most common malignancies. Immunotherapy has shown promising effects in the treatment against specific subtypes of EC.Methods: The RNA and clinical information of patients with EC were acquired from The Cancer Gene Atlas (TCGA) database. Firstly, the differentially expressed pyroptosis-related lncRNAs (PRLs) were screened between the tumor and normal control tissue. Secondly, the PRLs closely related to survival were identified by univariate and multivariate regression analysis, based on which, we evaluated the risk score for each EC patient to construct a risk signature. Moreover, we assessed the prognostic value, clinical relevance immunity, and immunotherapy based on this signature.Results: We screened out 9 individual PRLs (AC087491.1, AL353622.1, AL035530.2, LINC02036, AL021578.1, AL390195.2, AC009097.2, AC004585.1, and AC244517.7) closely related to the prognosis of EC. Kaplan–Meier analyses showed a poorer prognosis for the patients in the high-risk FRLs signature (P < 0.001). The area under the curve (AUC) for 1 year, 2 years, 3 years was 0.693, 0.694, 0.750, respectively. Our risk model could be considered as an independent prognostic marker for EC (P < 0.001, HR:2.172, 95% CI:1.532– 3.079). Moreover, immune functions and checkpoints were generally different in the 2 groups. Simulation analysis by termed immunophenoscores hinted that immunotherapy might bring optimal therapeutic effect in the low-risk group.Conclusion: We successfully developed a novel signature with 9 lncRNAs related to pyroptosis, which may be used as biomarkers to evaluate the prognosis and immune treatment of EC.Keywords: endometrial carcinoma, pyroptosis, immunotherapy, lncRNAs, immune infiltration

Cong Wei,1,&ast; Xiaoting Zhang,1,&ast; Dan Liang,1 Jilong Yang,1 Jingwen Du,1 Chunyan Yue,1 Lan Deng1,2 1Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2Department of Hematology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lan DengDepartment of Hematology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of ChinaTel +86 13724862939Email denglan_76@126.comChunyan YueDepartment of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of ChinaTel +86 15521117300Email doctor_yy@126.comBackground: Graft-versus-host disease (GVHD) is a main complication following allogeneic hematopoietic stem cell transplantation and is a leading cause of non-relapse-related death. Unsatisfactory response to standard first-line therapy with glucocorticoids is a predictor of a poor prognosis in patients with GVHD. Ruxolitinib is a selective Janus kinases 1/2 inhibitor which has been shown to control acute (a) and chronic (c) GVHD while maintaining graft-versus-tumor effects.Objective: This study aims to evaluate the efficacy and safety of ruxolitinib in the treatment of steroid-refractory GVHD (SR-GVHD) in a population of Chinese patients.Methods: We report the results of 55 patients, including 23 patients with aGVHD and 32 patients with cGVHD, who were treated with ruxolitinib as salvage therapy between August, 2017 and December, 2020.Results: In patients with aGVHD, the overall response rate (ORR) was 86.9%, and the 1-year overall survival (OS) was 82.6% (95% CI, 67.1– 98.1%). The 1-year OS was significantly improved in responders than in non-responders (90.0% vs 33.3%, P=0.004). In patients with cGVHD, the ORR was 78.1%, and the 1-year OS was 81.3% (95% CI, 67.8– 94.8%). There was no significant difference in the 1-year OS between responders and non-responders (84.0% vs 71.4%, P=0.327). Cytopenia, cytomegalovirus-reactivation and infections were common adverse events, particularly in patients with aGVHD.Conclusion: Our real-world data from Chinese patients further confirm that ruxolitinib is a safe and effective treatment for SR-GVHD.Keywords: ruxolitinib, allogeneic hematopoietic stem cell transplantation, graft-versus-host disease, steroid-refractory

Yong Ling,1 Zhi-You Hao,2 Dong Liang,3 Chun-Lei Zhang,4 Yan-Fei Liu,5 Yan Wang6,7 1Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 2School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of China; 3State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, Guangxi, People’s Republic of China; 4State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China; 5State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 6HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; 7Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, People’s Republic of ChinaCorrespondence: Yan WangHEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanTel +92 21 111-222-292 ext 164Fax +92 21 34819018-9Email yan.wang@iccs.eduAbstract: Pyridine-based ring systems are one of the most extensively used heterocycles in the field of drug design, primarily due to their profound effect on pharmacological activity, which has led to the discovery of numerous broad-spectrum therapeutic agents. In the US FDA database, there are 95 approved pharmaceuticals that stem from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), abiraterone acetate (prostate cancer), tacrine (Alzheimer’s), ciclopirox (ringworm and athlete’s foot), crizotinib (cancer), nifedipine (Raynaud’s syndrome and premature birth), piroxicam (NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), and many more. Their remarkable therapeutic applications have encouraged researchers to prepare a larger number of biologically active compounds decorated with pyridine or dihydropyridine, expandeing the scope of finding a cure for other ailments. It is thus anticipated that myriad new pharmaceuticals containing the two heterocycles will be available in the forthcoming decade. This review examines the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the most recent developments from 2010 to date, highlighting the ever-expanding role of both scaffolds in the field of medicinal chemistry and drug development.Keywords: nitrogen heterocycles, pharmaceuticals, bioactive compounds, current trend, substituent effect

The shallow water model with anisotropic porosity conceptually takes into account the unresolved subgrid-scale features, e.g. microtopography or buildings. This enables computationally efficient simulations that can be run on coarser grids, whereas reasonable accuracy is maintained via the introduction of porosity. This article presents a novel numerical model for the depth-averaged equations with anisotropic porosity. The porosity is calculated using the probability mass function of the subgrid-scale features in each cell and updated in each time step. The model is tested in a one-dimensional theoretical benchmark before being evaluated against measurements and high-resolution predictions in three case studies: a dam-break over a triangular bottom sill, a dam-break through an idealized city and a rainfall-runoff event in an idealized urban catchment. The physical processes could be approximated relatively well with the anisotropic porosity shallow water model. The computational resolution influences the porosities calculated at the cell edges and therefore has a large influence on the quality of the solution. The computational time decreased significantly, on average three orders of magnitude, in comparison to the classical high-resolution shallow water model simulation.