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Analytical solution to incident angle quasi-phase-matching engineering for second harmonic generation in a periodic-poled lithium niobate crystal

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Chinese Physics B 2024年第2期33卷 115-123页

作者：洪丽红邱雅婷李晓霓陈宝琴李志远 State key Laboratory of High Field Laser Physics Shanghai Institute of Optics and Fine MechanicsChinese Academy of SciencesShanghai 201800China School of Physics and Optoelectronics South China University of TechnologyGuangzhou 510640China

Phase matching or quasi-phase matching(QPM)is of significant importance to the conversion efficiency of second harmonic generation(SHG)in artificial nonlinear crystals like lithium niobate(LN)crystal or microstructured nonlinear crystals like periodic-poled lithium niobate(PPLN)*** this paper,we propose and show that the incident angle of pump laser light can be harnessed as an alternative versatile tool to engineer QPM for high-efficiency SHG in a PPLN crystal,in addition to conventional means of period adjusting or temperature tuning.A rigorous model is established and analytical solution of the nonlinear conversion efficiency under the small and large signal approximation theory is obtained at different incident *** variation of phase mismatching and walk-off length with incident angle or incident wavelength are also *** simulations for a PPLN crystal with first order QPM structure are used to confirm our theoretical predictions based on the exact analytical solution of the general large-signal *** results show that the narrow-band tunable SHG output covers a range of 532 nm–552.8 nm at the ideal incident angle from 0°to 90°.This theoretical scheme,fully considering the reflection and transmission at the air-crystal interface,would offer an efficient theoretical system to evaluate the nonlinear frequency conversion and help to obtain the maximum SHG conversion efficiency by selecting an optimum incident wavelength and incident angle in a specially designed PPLN crystal,which would be very helpful for the design of tunable narrow-band pulse nanosecond,picosecond,and femtosecond laser devices via PPLN and other microstructured LN crystals.

关键词： nonlinear frequency conversion transmission reflection lithium niobate

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Cellulosomal hemicellulases:Indispensable players for ensuring effective lignocellulose bioconversion

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Green Carbon 2024年第1期2卷 57-69页

作者： Min Xiao Ya-jun Liu Edward A.Bayer Akihiko kosugi qiu Cui Yingang Feng CAS key Laboratory of Biofuels Qingdao Institute of Bioenergy and Bioprocess TechnologyChinese Academy of SciencesQingdao 266101China Shandong Provincial key Laboratory of Synthetic Biology Qingdao Institute of Bioenergy and Bioprocess TechnologyChinese Academy of SciencesQingdao 266101China Shandong Engineering Laboratory of Single Cell Oil Qingdao Institute of Bioenergy and Bioprocess TechnologyChinese Academy of SciencesQingdao 266101China Shandong Energy Institute Qingdao 266101China Qingdao New Energy Shandong Laboratory Qingdao 266101China University of Chinese Academy of Sciences Beijing 100049China Department of Biomolecular Sciences The Weizmann Institute of ScienceRehovot 7610001Israel Department of Life Sciences and the National Institute for Biotechnology in the Negev Ben-Gurion University of the NegevBeer-Sheva 8499000Israel Biological Resources and Post-harvest Division Japan International Research Center for Agricultural Sciences(JIRCAS)1-1 OhwashiTsukubaIbaraki 305-8686Japan

The bioconversion of lignocellulose has attracted global attention,due to the significant potential of agricultural and forestry wastes as renewable zero-carbon resources and the urgent need for substituting fossil *** cellulosome system is a multi-enzyme complex produced by anaerobic bacteria,which comprises cellulases,hemicellulases,and associated enzymatic and non-enzymatic components that promote biomass *** enhance their efficiency in degrading recalcitrant lignocellulosic matrices,cellulosomes have been employed to construct biocatalysts for lignocellulose bioconversion,such as consolidated bioprocessing and consolidated ***,the second most abundant polysaccharides in plant cell walls,hold valuable application potential but can also induce inhibitory effects on cellulose hydrolysis,thus highlighting the indispensable roles of hemicellulases within the cellulosome *** review evaluated current research on cellulosomal hemicellulases,comparing their types,abundance,and regulation,primarily focusing on eight known cellulosome-producing species of different *** also reviewed their growth conditions,their hemicellulose-degrading capabilities,and the inhibitory effects of hemicellulose on cellulosome-based lignocellulose ***,we proposed strategies for targeted enhancement of hemicellulase in cellulosomes to improve lignocellulose bioconversion in future studies.

关键词： Cellulosome Lignocellulose Hemicellulase Saccharification Biocatalyst

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基于半导体光放大器的纳秒脉冲串激光种子源系统

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中国激光 2024年第14期51卷 72-79页

作者：黄磊邱基斯齐耀东袁峰刘昊中国科学院空天信息创新研究院光学工程研究部北京100094 中国科学院大学光电学院北京100094

设计了一种基于半导体光放大器的纳秒脉冲串激光种子源系统。在该系统中,半导体光放大器具有40 dB以上的高消光比,可实现高信噪比的脉冲串激光输出。利用半导体光放大器腔外调制窄线宽连续激光光源,研究了不同重复频率下纳秒脉冲串激光... 详细信息

设计了一种基于半导体光放大器的纳秒脉冲串激光种子源系统。在该系统中,半导体光放大器具有40 dB以上的高消光比,可实现高信噪比的脉冲串激光输出。利用半导体光放大器腔外调制窄线宽连续激光光源,研究了不同重复频率下纳秒脉冲串激光的输出特性,通过调控触发信号实现了子脉冲重复频率为10~100 kHz、子脉冲脉宽为8.6~88.2 ns、单脉冲能量为0.892~6.124μj的高光束质量1064 nm脉冲串激光输出,最大平均功率为86.4 mW,输出不稳定度为1.66%,横向光束质量因子(M_(x)^(2))和纵向光束质量因子(M_(y)^(2))分别为1.12和1.16。该系统可作为高平均功率纳秒脉冲串激光器的种子源系统。

关键词：激光器半导体光放大器脉冲串激光激光器种子系统

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浒苔多酚对2型糖尿病小鼠降血糖功效研究

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食品工业科技 2024年第1期45卷 318-324页

作者：邱小明郭欣黄聪亮漳州职业技术学院食品工程学院福建漳州363000 农产品深加工及安全福建省高校应用技术工程中心福建漳州363000

目的:为探究浒苔多酚(Enteromorpha prolifera polyphenols,EPP)对2型糖尿病小鼠的降血糖功效,为浒苔多酚产品的开发提供理论依据。方法:以浒苔为材料,经乙醇溶液提取得到EPP粗提物,采用硅胶柱层析纯化EPP粗提物;用四氧嘧啶诱导建立2型... 详细信息

目的:为探究浒苔多酚(Enteromorpha prolifera polyphenols,EPP)对2型糖尿病小鼠的降血糖功效,为浒苔多酚产品的开发提供理论依据。方法:以浒苔为材料,经乙醇溶液提取得到EPP粗提物,采用硅胶柱层析纯化EPP粗提物;用四氧嘧啶诱导建立2型糖尿病小鼠模型,将实验小鼠分为空白对照组、模型对照组、EPP低剂量组(EPP-L)、EPP中剂量组(EPP-M)、EPP高剂量组(EPP-H)、阳性对照组,连续灌胃4周,测定小鼠基础指标,以及脂代谢和血清抗氧化指标。结果:在动物实验中,第4周时,EPP-H组小鼠体重达32.16±1.97 g,与阳性对照组无显著差异(P>0.05)。EPP-H组小鼠空腹血糖浓度为11.78±1.62 mmol/L,与阳性对照组无显著差异(P>0.05),且能显著提升小鼠葡萄糖耐受力(P<0.05),改善小鼠耐糖量异常。EPP-H组小鼠体内超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶、高密度脂蛋白胆固醇浓度及血清胰岛素水平分别为:157.36±6.71 U/mg,168.07±1.77 U/mg,378.14±9.74 U/mg,1.31±0.04 mmol/L,19.03±2.01 mU/L,与模型对照组相比极显著升高(P<0.01),且能显著降低丙二醛、甘油三酯、总胆固醇、低密度脂蛋白胆固醇的含量(P<0.05)。结论:浒苔多酚能有效改善2型糖尿病小鼠基础代谢情况及修复糖尿病小鼠的过氧化损伤,进而起到降血糖作用。

关键词：浒苔多酚降血糖功效

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Research trends in exercise therapy for the treatment of pain in postmenopausal osteoporosis over the past decade:A bibliometric analysis

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World journal of Orthopedics 2024年第10期15卷 950-964页

作者： Zhao-qiu Dai Xiao-Yan Gong Rong Zhang Mei-Qin jin Wei Lu Wen Wen jie Chen Fang-jie Lu Yi-Fan Yang Lei Wang Xiao-jin He Changshu Hospital Affiliated with Nanjing University of Chinese Medicine Changshu 215500Jiangsu ProvinceChina Affiliated Hospital of Nanjing University of Chinese Medicine Jiangsu Province Hospital of Chinese MedicineNanjing 210029Jiangsu ProvinceChina Nanjing University of Chinese Medicine Nanjing 210023Jiangsu ProvinceChina

BACkGROUND Postmenopausal osteoporosis(PMOP)is the most common form of primary osteoporosis among women,and the associated pain often drives patients to seek clinical *** studies have highlighted the unique clinical benefits of exercise therapy(ET)in alleviating PMOP-related ***,bibliometric analyses examining collaboration,development trends,and research frontiers in the field of ET for PMOP pain remain *** To explore the research trends in ET for pain treatment in PMOP patients over the past *** All scholarly works were meticulously sourced from the Science Citation Index-Expanded within the prominent Web of Science Core *** the capabilities of CiteSpace 6.2.R5,we conducted a thorough analysis of publications,authors,frequently cited scholars,contributing nations,institutions,journals of significant citation,comprehensive references,and pivotal ***,our examination explored keyword cooccurrences,detailed timelines,and periods of heightened citation *** comprehensive search,from 2014 through 2023,was completed within a single day,on October 11,*** In total,2914 articles were ultimately included in the *** was a rapid increase in annual publication output in 2015,followed by stable growth in subsequent ***,Michael L,is the most prolific author,whereas Ware jE has the most *** United States’global influence is significant,surpassing all other *** University of California System and Harvard University are the most influential academic institutions.j Bone joint Surg Am is the most influential journal in this field.“Spinal cord injury”is the keyword that has garnered the most attention from *** developmental pattern in this field is characterized by interdisciplinary fusion,with different disciplines converging to drive *** The academic development of the field of ET for pain in PMOP has matured and stabili

关键词： Exercise therapy Pain Postmenopausal osteoporosis CiteSpace Bibliometric analysis Web of Science

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Pien Tze Huang Inhibits Migration and Invasion of Hepatocellular Carcinoma Cells by Repressing PDGFRB/YAP/CCN2 Axis Activity

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Chinese journal of Integrative Medicine 2024年第2期30卷 115-124页

作者： LUO Zhi-yi TIAN Qi CHENG Niang-mei LIU Wen-han YANG Ye CHEN Wei ZHANG Xiang-zhi ZHENG Xiao-yuan CHEN Ming-sheng ZHUANG qiu-yu ZHAO Bi-xing LIU Cong-sheng LIU Xiao-long LI Qin WANG Ying-chao The United Innovation of Mengchao Hepatobiliary Technology key Laboratory of Fujian Province Mengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhou(350025)China Fujian Pien Tze Huang Enterprise key Laboratory of Natural Medicine Research and Development Zhangzhou Pien Tze Huang Pharmaceutical Co.Ltd.ZhangzhouFujian Province(363099)China College of Biological Science and Engineering and Mengchao Med-X Center Fuzhou UniversityFuzhou(350116)China Department of Internal Medicine Mengchao Hepatobiliary Hospital of Fujian Medical UniversityFuzhou(350025)China

Objective:To investigate the effects of Pien Tze Huang(PZH) on the migration and invasion of HCC cells and underlying molecular ***:Cell counting kit-8(CCk-8) was applied to evaluate the cell viabilities of SMMC-7721,Sk-Hep-1,C3A and HL-7702(6 × 10^(3)cells/well) co-incubated with different concentrations of PZH(0,0.2,0.4,0.6,0.8 mg/mL) for 24 ***,wound healing assay,CCk-8and Annexin V-FITC/PI staining were conducted to investigate the effects of PZH on the migration,invasion,proliferation and apoptosis of Sk-Hep-1 and SMMC-7721 cells(650 μg/mL for Sk-Hep-1 cells and 330 μg/mL for SMMC-7721 cells),*** vivo,lung metastasis mouse model constructed by tail vein injection of HCC cells was used for evaluating the anti-metastasis function of ***-Hep-1 cells(10^(6)cells/200 μL per mice) were injected into B-NDG mice via tail *** 8 mice were randomly divided into PZH and control groups,4 mice in each *** 2-d inoculation,mice in the PZH group were administered with PZH(250 mg/kg,daily) and mice in the control group received only vehicle(PBS) from the 2nd day after xenograft to day *** analysis based on RNA-seq was subsequently used for deciphering anti-tumor mechanism of *** real-time polymerase chain reaction(qRT-PCR) and Western blot were applied to verify RNA-seq *** reporter assay was performed to examine the transcriptional activity of yes-associated protein(YAP).Results:PZH treatment significantly inhibited the migration,invasion,proliferation and promoted the apoptosis of HCC cells in vitro and in vivo(P<0.01).Transcriptome analysis indicated that Hippo signaling pathway was associated with anti-metastasis function of *** study showed PZH significantly inhibited the expressions of platelet derived growth factor receptor beta(PDGFRB),YAP,connective tissue growth factor(CCN2),N-cadherin,vimentin and matrix metallopeptidase 2(MMP2,P<0.01).Meanwhile,the phosphorylatio

关键词： PienTzeHuang hepatocellular carcinoma RNA-seq Hippo yes-associated protein

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面向数字人文研究的三星堆古城祭祀图谱构建与场景应用

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图书馆杂志 2024年第2期43卷 73-83页

作者：张云中邱璟上海大学文化遗产与信息管理学院上海200444

三星堆古城祭祀遗存是认识古蜀文明的实物例证,构建三星堆古城祭祀图谱能够为面向三星堆古城祭祀领域的数字人文研究提供数据基础设施的有力支撑。本文通过三星堆古城祭祀体系和数据体系的对照,确立了三星堆古城祭祀体系的研究维度,并... 详细信息

三星堆古城祭祀遗存是认识古蜀文明的实物例证,构建三星堆古城祭祀图谱能够为面向三星堆古城祭祀领域的数字人文研究提供数据基础设施的有力支撑。本文通过三星堆古城祭祀体系和数据体系的对照,确立了三星堆古城祭祀体系的研究维度,并依据其维度设计了三星堆古城祭祀体系本体模型,最后基于本体开展祭祀数字资源实体和关系的抽取,借助Neo4j图数据库完成知识图谱的存储和可视化。研究表明,构建的三星堆古城祭祀图谱能够有力地支撑观点呈现、知识发现和数据众包等数字人文研究场景应用,赋能三星堆古城祭祀相关的人文研究。

关键词：数字人文三星堆祭祀体系本体知识图谱

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Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis

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Acta Pharmaceutica Sinica B 2024年第2期14卷 682-697页

作者： Shuran Fan Ming Qi Qi Qi Qun Miao Lijuan Deng jinghua Pan Shenghui qiu jiashuai He Maohua Huang Xiaobo Li jie Huang jiapeng Lin Wenyu Lyu Weiqing Deng Yingyin He Xuesong Liu Lvfen Gao Dongmei Zhang Wencai Ye Minfeng Chen State key Laboratory of Bioactive Molecules and Druggability Assessment Jinan UniversityGuangzhou 510632China Guangdong Province key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research College of PharmacyJinan UniversityGuangzhou 510632China School of Medicine Jinan UniversityGuangzhou 510632China School of Traditional Chinese Medicine Jinan UniversityGuangzhou 510630China The First Affiliated Hospital of jinan University Guangzhou 510632China State key Laboratory of Chemical Oncogenomics Guangdong Provincial Key Laboratory of Chemical BiologyTsinghua Shenzhen International Graduate SchoolShenzhen 518055China

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer(LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha(FAPα) expression in LNM-CRC cells. Gain-or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis(CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

关键词： Lymphaticmetastasis Colorectal cancer Fibroblastactivation proteinα FAPα-activated prodrug Epithelial-mesenchymal

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Anti-PD1 antibody and not anti-LAG-3 antibody improves the antitumor effect of photodynamic therapy for treating metastatic breast cancer

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journal of Innovative Optical Health Sciences 2024年第1期17卷 87-103页

作者： Shan Long Yibing Zhao Yuanyuan Xu Bo Wang Haixia qiu Hongyou Zhao jing Zeng Defu Chen Hui Li jiakang Shao Xiaosong Li Ying Gu School of Medicine Nankai University Tianjin300072P.R.China Department of Laser Medicine The First Medical Center of Chinese PLA General Hospital Beijing 100853 P.R.China Department of Oncology The Seventh Medical Center of Chinese PLA General Hospital Beijing 100039 P.R.China School of Basic Medicine Guizhou Medical University Guiyang 550025GuizhouP.R.China College of Medical Technology Beijing Institute of Technology Beijing 100081P.R.China Medical School of Chinese PLA Beijing 100853 P.R.China

Photodynamic therapy(PDT)has limited effects in treating metastatic breast *** checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is *** study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and *** checkpoints on T cells were analyzed byflow cytometry after *** combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were *** HpD-PDT at 100 mW/cm2 and 40,60 and 80 j/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be *** checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT *** PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with ***-PDT could not combat metastatic breast ***1 and LAG-3 were upregulated after ***-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.

关键词： Photodynamic therapy anti-PD1 antibody anti-LAG-3 antibody anti-tumor im-mune effects metastatic breast cancer

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Vonoprazan-amoxicillin dual therapy for Helicobacter pylori eradication in Chinese population:A prospective,multicenter,randomized,two-stage study

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World journal of Gastroenterology 2024年第27期30卷 3304-3313页

作者： Xue-Ping Huang Zhi-Hui Lin Yi-juan Liu Shao-Wei Lin Yan-Feng Shao Feng qiu Qing-Wu qiu Zhang-kun Xu jin-Xian Chen Liang-Huo Chen Zhen-Qun Lin Wen-Hua Dai Ming-Qing Zhang Qi jiang Zhong-Qin Xiao Xian-Xing Cheng Xiang-Fei Zhang Wen-Bin You Wei Chen Long-Qin Li Wei-Xing Lin Yong-Fu Wang Fu-jin Lai Long-Qun Chen Zhong-Hua Huang Wen-Qi Zheng jin-Qi Wei Department of Gastroenterology Shengli Clinical Medical College of Fujian Medical UniversityFuzhou 350000Fujian ProvinceChina Department of Gastroenterology Fujian Provincial HospitalFuzhou 350001Fujian ProvinceChina Department of Gastroenterology The First Affiliated Hospital of Fujian Medical UniversityFuzhou 350000Fujian ProvinceChina School of Public Health Fujian Medical UniversityFuzhou 350000Fujian ProvinceChina Department of Gastroenterology The Third People’s Hospital of Fujian ProvinceFuzhou 350000Fujian ProvinceChina Department of Gastroenterology Fujian Provincial Hospital North Brance Fujian Provincial Geriatric HospitalFuzhou 350000Fujian ProvinceChina Department of Gastroenterology Xiaoao HospitalFuzhou 350000Fujian ProvinceChina Department of Gastroenterology The General Hospital of Fujian Energy GroupFuzhou 350000Fujian ProvinceChina Department of Gastroenterology The Second Hospital of ZhangzhouZhangzhou 363000Fujian ProvinceChina Department of Gastroenterology Anxi Country HospitalQuanzhou 362000Fujian ProvinceChina Department of Gastroenterology Zhangzhou Municipal Hospital of TCMZhangzhou 363000Fujian ProvinceChina Department of Gastroenterology Zhangpu HospitalZhangzhou 363000Fujian ProvinceChina Department of Gastroenterology The Affiliated Dongnan Hospital of Xiamen UniversityZhangzhou 363000Fujian ProvinceChina Department of Gastroenterology First Hospital of Nanping CityNanping 353000Fujian ProvinceChina Department of Gastroenterology Fujian Nanping Second HospitalNanping 353000Fujian ProvinceChina Department of Gastroenterology Wuyishan Municipal HospitalNanping 353000Fujian ProvinceChina Department of Gastroenterology Fuzhou Changle District HospitalFuzhou 350000Fujian ProvinceChina Department of Gastroenterology Changle City Second HospitalFuzhou 350000Fujian ProvinceChina Department of Gastroenterology Jinjiang Municipal HospitalQuanzhou 362000Fujian ProvinceChina Department of Gastroenterology Fuding Hospital Affiliated to Fuj

BACkGROUND The efficacy of Vonoprazan-amoxicillin dual therapy(VAT)in the treatment of Helicobacter pylori(***)is *** To evaluate the efficacy of VAT in the Chinese *** This prospective,multicenter,randomized,open-label,and two-stage study was conducted at 23 centers in Fujian,China(May 2021-April 2022).***-infected patients were randomized to bismuth quadruple therapy(BQT),BQT-Vonoprazan(BQT-V),seven-day VAT(VAT-7),ten-day VAT(VAT-10),and fourteen-day VAT(VAT-14)*** primary endpoint was the *** eradication *** secondary endpoint was the frequency of adverse *** study was registered with the Chinese Clinical Trial Registry,*** In the first stage,VAT-7 and BQT-V groups were selected for early termination because less than 23 among 28 cases were *** the second stage,the eradication rates for BQT,VAT-10,and VA-14 were 80.2%[95%confidence interval(95%CI):71.4%-86.8%],93.2%(86.6%-96.7%),92.2%(85.3%-96.0%)in the intention-to-treat(ITT)analysis,and 80.9%(95%CI:71.7%-87.5%),94.0%(87.5%-97.2%),and 93.9%(87.4%-97.2%)in the per-protocol *** ITT analysis showed a higher eradication rate in the VAT-10 and VAT-14 groups than in the BQT group(P=0.022 and P=0.046,respectively).The incidence of adverse events in the VAT-10 and VAT-14 groups was lower than in the BQT group(25.27%and 13.73%vs 37.62%,respectively;P<0.001).CONCLUSION VAT with a duration of 10 or 14 days achieves a higher eradication rate than the BQT,with a more tolerable safety profile in ***-infected patients in *** XP et *** for *** eradication.

关键词： Helicobacter pylori Vonoprazan Amoxicillin Dual therapy Bismuth quadruple therapy

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