Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B:A comprehensive review of phases II and III therapeutic agents

Chronic hepatitis B virus(HBV)infection affects over 295 million people globally and an estimated 1.6 million people in the United States.It is associated with significant morbidity and mortality due to cirrhosis,liver failure,and liver cancer.Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression,which in turn has been associated with a decreased risk of liver complications.However,current antiviral regimens are limited by concerns with adverse effects,adherence,resistance,long-term treatment,and ongoing risk for liver events.Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen(HBsAg)loss and suppression of HBV DNA.Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B,including core/capsid inhibitors,entry inhibitors,RNA interference(siRNA/ASO),HBsAg inhibitors,Toll-like receptor agonists,checkpoint inhibitors,and therapeutic vaccines.

Current status of outcome reporting in randomized controlled trials of traditional Chinese medicine for mammary gland hyperplasia: A systematic review

Objective:To assess outcome indicators in clinical trials and provide a reference for establishing a core outcome set to treat hyperplasia of mammary gland(HMG)with traditional Chinese medicine(TCM).Methods:Eight online databases were searched from their inception to December 31,2022,to assess outcomes reported in randomized controlled trials(RCTs)of HMG treated with TCM.The quality of the included studies was assessed according to the Cochrane Risk of Bias Assessment Tool.All outcomes were extracted,classified,and described.Results:A total of 8249 articles were initially retrieved.Of these,70 articles were eligible and involved 10618 participants with HMG.A total of 17 outcome indicators with a frequency of 271 times were involved and were collected according to six outcome domains.Conclusions:The core outcomes of RCTs of HMG treated with TCM are large and divergent.There are problems in evaluation standards,primary and secondary outcomes,TCM characteristic indicators,long-term prognosis,and standardization of reporting.It is recommended to strengthen the trial design and actively construct the core outcome sets with TCM characteristics for HMG.

Research on the Operation Mechanism of Claim in Civil Procedure Law and the Applications on Court Trial Way Reform

In this paper, we conduct research on the operation mechanism of claim in civil procedure law and the applications on the court trial way reform. The ultimate goal of the rule of law lies in identifying and protecting the rights of citizens. Way to protect the rights of citizens is diverse, but the judicial relief is the most basic and important form of insurance. Everyone can “into” the court and get the impartiality of the judicial relief, is a measure of a country judicial level height and the rule of law implementation degree of important yardstick. Judicial system and judicial procedure to build and build a better, if the subject of litigation rights are not being met and the safeguard, can’t get through the door and it is the legislators and legal scholars over the many efforts are meaningless, under this basic condition, we propose the new perspective on the corresponding issues that is necessary.

Usefulness of the clip-flap method of endoscopic submucosal dissection: A randomized controlled trial

AIM To prospectively investigate the efficacy and safety of clipflap assisted endoscopic submucosal dissection(ESD) for gastric tumors.METHODS From May 2015 to October 2016, we enrolled 104 patients with gastric cancer or adenoma scheduled for ESD at Shiga University of Medical Science Hospital. We randomized patients into two subgroups using the minimization method based on location of the tumor(upper, middle or lower third of the stomach), tumor size(< 20 mm or > 20 mm) and ulcer status: ESD using an endoclip(the clip-flap group) and ESD without an endoclip(the conventional group). Therapeutic efficacy(procedure time) and safety(complication: Gastrointestinal bleeding and perforation) were assessed. RESULTS En bloc resection was performed in all patients. Four patients had delayed bleeding(3.8%) and two had perforation(1.9%). No significant differences in en bloc resection rate(conventional group: 100%, clip flap group: 100%), curative endoscopic resection rate(conventional group: 90.9%, clip flap group: 89.8%, P = 0.85), procedure time(conventional group: 70.8 ± 46.2 min, clip flap group: 74.7 ± 53.3 min, P = 0.69), area of resected specimen(conventional group: 884.6 ± 792.1 mm^2, clip flap group: 1006.4 ± 1004.8 mm^2, P = 0.49), delayed bleeding rate(conventional group: 5.5%, clip flap group: 2.0%, P = 0.49), or perforation rate(conventional group: 1.8%, clip flap group: 2.0%, P = 0.93) were found between the two groups. Lessexperienced endoscopists did not show any differences in procedure time between the two groups.CONCLUSION For patients with early-stage gastric tumors, the clipflap method has no advantage in efficacy or safety compared with the conventional method.

Synthesis of Au-Cu Nano-Alloy from Monometallic Colloids by Simultaneous Pulsed Laser Targeting and Stirring

Experimental work has been focused on the formation of alloyed Au-Cu nanoparticles under simultaneous laser exposure and mechanical stirring of mixed monometallic colloids, here referred to as dual procedure. As a feed for the dual procedure, Au and Cu monometallic nanoparticle colloids have been using a laser ablation technique. To accomplish this, bulk targets were ablated with 1064 nm wavelength Nd: YAG laser in a pure acetone(99.99%) environment. Ultraviolet-visible optical absorption spectrometry, transmission electron microscopy, X-ray diffraction and X-ray fluorescence technique have been used to characterize the nanoparticles. It has been found that experimental conditions such as stirring and laser parameters strongly affect the synthesized particle properties, including the size, shape, composition and stability of the nanoparticles. Alloy nanoparticles containing 39% Au – 61% Cu have also been prepared in the same process, but in two forms of a homogeneous alloy and a core-shell structure.

Evaluation of outcomes reported in randomized controlled trials for herbal remedies for adults with chronic hepatitis C

Background:Herbal remedies have been widely utilized in treating chronic hepatitis C (CHC) worldwide.Selecting appropriate outcomes to reflect both beneficial and harmful effects is a crucial step in designing randomized controlled trials (RCTs).This study evaluated the outcomes reported in RCTs on herbal remedies for CHC with comparison to the core outcomes recommended by the Cochrane Hepato-Biliary Group (CHBG),to check the consistency of the outcomes and to provide recommendation for future researches.Methods:A systematic literature search was conducted in Western and Chinese databases to identify RCTs on herbal remedies for adults with CHC.For each trial,all the outcomes reported in the results section were collected.Comparison between trial outcomes and CHBG core outcomes were evaluated and summarized with descriptive statistics.Results:A total of 116 RCTs involving 9154 participants were included;27 outcomes were identified.Commonly reported outcomes included alanine aminotransferase (64 trials,55.2%),adverse events (58 trials,50.0%),and end-of-treatment virological response (50 trials,43.1%).All trials indicated that the herbal remedies under investigation had a positive effect and was markedly more effective than the control.Nearly half of the trials reported that the combination of herbal medicine and antiviral drugs could ameliorate adverse events.Very few trials reported primary core outcomes relating survival and quality of life.The most frequently reported core outcomes are non-serious adverse events (54 trials,46.6%),viral response (27 trials,23.3%),and biochemical response (24 trials,20.7%).Conclusion:The variation and inconsistency in trial outcomes impedes research synthesis efforts,and indicate the need for comparable outcomes through the development of core outcome sets in CHC.The low concordance of outcome reporting could be improved by following CHBG core outcomes recommendation.

The Scientific School of Philosophical and Legal Thought in Criminal Proceedings of Marian Cieslak

The aim of the article is to show that Professor Cie?lak is the founder of the scientific school of philosophical and legal thought in criminal proceedings and five thoughts belonging to this school regarding the subject of the criminal process, the identity of a deed, participants in the process, the burden of the proof, the obligation of proving, and division the grounds for detention. Professor Cie?lak was one of the most distinguished Polish lawyers and scientists, and had a great influence on shaping views on the law, primarily in theory, but also in practice. His concepts result from his theoretical and philosophical research on the law and are also timeless, remotely dependent on the legislation currently in existence.

关于《刑事诉讼法》第四次修改的几点思考

近日,刑事诉讼法的第四次修改提上日程。学界对本次修改整体上较为积极,也有部分观点对修改存有隐忧。从整体上看,启动第四次刑事诉讼法修改有其必要性和重要的时代价值,应当抓住此次难得时机,同时,也要对实践中重打击轻保护的氛围保持高度警惕,牢牢把握人权保障和正当程序的目标和方向。刑事诉讼法第四次修改应当将刑事诉讼法典实质化作为目标,采取大修的立法模式,立足当下,着眼长远,系统规划,分步实施,迈出刑事诉讼法典实质化的关键一步。刑事诉讼法修改也要设定改革的亮点,这些亮点可以包括但不限于:重塑刑事诉讼法的篇章体例、以技术主义路径推进以审判为中心和庭审实质化、因应轻罪时代扩大附条件不起诉的适用范围、探索构建律师无效辩护制度、重塑强制措施体系、构建相对独立的涉案财物处置程序、完善证据制度等。

没收的正义——基于《监察法》没收违法所得条款之诠释

《监察法》中的违法所得没收条款,系任何人不得因自身的不法行为获得利益原理的具体体现,不让贪腐分子因腐败获益、补充常规监察手段不足以及加强国际反腐败合作是其价值基础。从属性上看,违法所得没收程序是让利益状态恢复到违法之前的保安处分,属于典型的对物程序和缺席审判程序。违法所得没收程序的适用须符合特定的罪名范围要求,被调查人的状态要求,案件重大、复杂且有必要继续调查,以及没收财产范围等要求。为确保没收程序的合法正当,应加强对监察机关提出没收违法所得申请、检察机关向人民法院提出没收违法所得申请、人民法院进行司法审查等三个阶段的程序控制。

刑事案件二审开庭难的理论反思

刑事二审开庭范围是2012年《刑事诉讼法》修改的重点内容,但囿于个案的消极影响、考核的指标主导等,时至今日,它仍然是“未完成的改革”。刑事二审开庭问题受到制度因素、实践因素和观念因素的制约,需要在优化和调整审批程序、考核指标的基础上,确立程序公正优先的价值目标,指导制度改革。2023年9月开展的为期一年的“促进提高刑事案件二审开庭率专项工作”已取得显著成效,为了巩固专项工作成果,避免考核指导下的数字泡沫和虚假繁荣,《刑事诉讼法》再修改进程中需要及时作出制度回应,形成规范化、科学化的制度设计:首先,应当充分体现正当程序与诉讼构造的指引,进而突破刑事二审开庭问题中制度因素、实践因素和观念因素的制约;其次,在刑事二审开庭范围的具体制度设计上,可以考虑由列举应当开庭的案件范围转变为列举可以不开庭的案件范围,进一步明确“以开庭为原则,以不开庭为例外”;最后,还需要构建起针对二审不开庭的上诉人权利救济途径和法律监督机制,为刑事二审开庭问题提供具有刚性的程序保障。

我国执行回转的制度反思与程序重构——兼评《强制执行法(草案)》第91至94条

在《民事强制执行法》进入单独立法倒计时之际,全面审视与反思执行回转制度正当其时。作为一项移植于苏联的特色制度,我国的执行回转具有减轻当事人诉累、快速恢复原状、兼顾效率与公平等多重价值,但同时也存在背离审执分离与处分原则、缺乏体系建构与程序衔接等诸多问题。执行回转不属于执行救济,也不应内嵌于执行程序之中,而应定性为一种“简略式审判程序”,参照非讼程序原理进行设计。新的执行回转制度应该以判决的形式判定是否回转及其具体内容,取消法院依职权启动的路径,严格限定当事人的范围,适当扩大回转标的的范围,有效细化具体程序规则,理顺与执行程序、另诉程序、破产程序、国家赔偿程序等周边程序的关系。

法典化视角下刑事证明标准条款的完善

偏重哲学话语的理论争议无益于解决刑事证明标准的适用难题。在法典化改革的进程中,有必要厘清刑事证明标准条款自身的逻辑性和层次性,进而对现有法律文本的表述进行适当的调整和修改,明确证据收集的程序合法标准,明确证据查证属实的法定义务,确立定罪事实排除合理怀疑的程序规则,以实现发现案件真相和保障法官自由裁量权行使之间的价值平衡,最终实现刑事证明标准在程序规范下的合理适用。

中国刑事诉讼法治现代化的进程与展望

作为中国式法治现代化的重要维度,刑事诉讼法治在习近平法治思想的引领下实现了现代化的理念更新。以人民群众的新期盼为目标,中国刑事诉讼法治在司法体制改革中推进现代化,通过司法体制综合配套改革、国家监察体制改革、以审判为中心的诉讼制度改革,取得了影响深远的实践成就。在改革进程中,刑事诉讼的社会治理功能进一步发挥,人权保障作用更加凸显,国内法治、涉外法治得以统筹推进,执法司法中的顽瘴痼疾得到全面整治。但刑事诉讼法治仍然面临理论供给不足、诉讼资源分配制度不尽合理、权力监督制约架构相对薄弱、社会治理功能有待考察等现实困境。在未来需要从科学理论、知识增量、公正司法、能动司法等多个维度回应刑事诉讼法治现代化的需求。

中医药治疗功能性消化不良随机对照试验结局指标现状分析

目的分析中医药治疗功能性消化不良(Functional dyspepsia,FD)的随机对照试验(Randomized controlled trial,RCT)结局指标研究现状,为中医药治疗功能性消化不良核心指标集的构建奠定基础。方法计算机检索中国知网(CNKI)、万方(WanFang)、维普(VIP)、中国生物医学文献服务系统(SinoMed)、EMbase、PubMed、Cochrane Library数据库收录的中医药治疗FD的RCT,检索时限为2017年1月1日—2022年1月1日,2名研究者根据纳入、排除标准独立进行文献筛选与资料提取。结果共纳入了285项RCTs,28061例患者,涉及117个结局指标及28种中医证型,单项RCT指标数最多12个,最少1个,平均5个。各指标共计使用1275次,结局指标使用频次排列前5位的指标为临床总有效率(81.40%),中医症候积分(54.04%),不良反应(47.02%)、胃动素(MTL)(30.18%),症状积分(23.1%)。根据结局指标的功能属性将其分为6大指标域,其中,症状/体征(38.51%)及理化检测(28.94%)类指标应用较多。结论目前中医药治疗FD的RCT中结局指标存在指标选择差异过大、结局指标主次不分、中医疗效评价指标不一致、总有效率指标缺乏规范、指标测量时点差异大、缺乏远期预后指标、指标测量工具种类偏多且适用性差、未纳入经济学评价指标及安全性事件报告简单化等问题,亟须构建规范、标准的中医药治疗功能性消化不良核心指标集研究,解决结局指标存在的诸多问题。

Central endoscopy reads in inflammatory bowel disease clinical trials:The role of the imaging core lab

Clinical trials in inflammatory bowel disease(IBD)are evolving at a rapid pace by employing central reading for endoscopic mucosal assessment in a field that was,historically,largely based on assessments by local physicians.This transition from local to central reading carries with it numerous technical,operational,and scientific challenges,many of which can be resolved by imaging core laboratories(ICLs),a concept that has a longer history in clinical trials in a number of diseases outside the realm of gastroenterology.For IBD trials,ICLs have the dual goals of providing objective,consistent assessments of endoscopic findings using central-reading paradigms whilst providing important expertise with regard to operational issues and regulatory expectations.This review focuses on current approaches to using ICLs for central endoscopic reading in IBD trials.

中医药治疗脓毒症性急性肺损伤/急性呼吸窘迫综合征临床试验结局指标分析与思考

背景中医药治疗脓毒症性急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)的疗效确切,但大多数已发表的临床试验设计中缺乏标准、统一的结局指标,造成同类研究结果难以合并、对比,无法产生高质量的循证证据指导临床决策。目的分析2017—2022年中医药治疗脓毒症性ALI/ARDS临床试验结局指标的使用情况。方法检索中国知网(CNKI)、万方数据知识服务平台、中国生物医学文献服务系统、PubMed、Web of Science、Embase、Cochrane Library数据库中有关脓毒症性ALI或ARDS的随机对照试验,其中干预组措施为中医药联合其他药物或常规治疗方案,对照组不做限制。采用Cochrane研发的ROB.2工具进行文献质量评价并总结结局指标分类情况。结果经筛选后纳入39篇文献,其中文献偏倚风险评估为低风险1篇(2.56%),高风险3篇(7.69%),可能存在风险35篇(89.74%)。5篇(12.82%)文献结局指标报告质量评分≥5分,为结局指标报告完整。共报告106种结局指标,累计使用443次,包括理化检测(55种,51.89%)、中医症状/证候(2种,1.89%)、症状/体征(13种,12.26%)、远期预后(19种,17.92%)、生活质量(7种,6.60%)、安全性事件(8种,7.55%)和经济学评估(2种,1.89%)。使用率>50%的结局指标有4个,分别是氧合指数(82.05%)、急性生理与慢性健康状况评分系统Ⅱ(58.97%)、机械通气时间(51.28%)和白介素6(51.28%)。21篇文献使用有效率和/或中医证候疗效的复合结局指标,包括总有效率12次,中医证候积分8次和中医症状疗效6次。由于各结局指标差异较大,对106种指标进行合并和依次归类,最终总结出3个大类,分别为:整体评价指标(36种,33.96%)、共性指标(36种,33.96%)及不同关注重点指标(34种,32.08%)。结论目前中医药治疗脓毒症性ALI/ARDS临床试验结局指标的选择尚不规范,主要表现为主次结局指标区分不明确、复合结局指标标准不统一、轻视终点指标、缺少随访数据和中医特色指标等。未来应构建脓毒症性ALI/ARDS的中医药核心结局指标集,推动中医药的高质量发展。

中医药治疗胃癌前病变近20年疗效评价指标分析

[目的]系统分析中医药治疗胃癌前病变相关随机对照试验(RCT)的疗效评价指标。[方法]检索中医药治疗胃癌前病变相关的RCT,检索数据库包括中国知网、万方数据知识服务平台、维普数据库、PubMed及Embase数据库,检索时限为2001—2022年。参考Cochrane手册的干预性试验研究评价标准,结合专家意见确定研究的入选标准,提取疗效评价方法,建立数据库,并进行统计分析。[结果]共纳入887项RCT,涉及胃镜下黏膜表现、病理、症状、证候、血清学、生存质量、安全性7个指标域,其中病理(71.36%)和胃镜下黏膜表现(37.54%)类指标应用较多。包含20种积分方法,分属于胃镜、病理、症状、证候4个部分,使用较高的积分方法依次为有效率(43.63%)、总积分(11.99%)、单一症状积分(25.86%)。部分研究(胃镜46篇,5.19%;病理135篇,15.22%;症状105篇,11.84%)在积分时仅指出使用的积分方法,却未具体说明如何进行积分。[结论]目前,胃癌前病变疗效的评价指标存在对胃镜及病理指标重视程度不足、单一指标选择缺乏严谨性、复合指标应用缺乏规范化、指标积分方法不统一、安全性指标不足、生活质量指标缺乏适用性等问题。今后在设计胃癌前病变的疗效评价方案时,应多个方面综合考虑,建立以病理组织学指标为核心,结合胃镜指标、患者症状、生活质量等指标的综合评价体系,使临床疗效的试验设计更加规范化和标准化,提高研究结果的真实性和可靠性。

针刺治疗膝骨关节炎随机对照试验结局指标现状分析

背景中医针刺已被广泛用于膝骨关节炎(KOA)治疗且疗效突出,但缺乏公认、统一的结局指标,无法使研究结果转化为高质量的临床证据,构建针刺治疗KOA的核心结局指标集有利于提高中医临床研究方案的科学性、合理性和可行性,为临床研究提供更高质量循证依据。目的通过分析目前针刺治疗KOA随机对照试验(RCT)结局指标的使用现状,为针刺治疗KOA的临床疗效评价方法提供依据。方法检索PubMed、Cochrane Library、Embase、Web of Science、中国知网(CNKI)、万方数据知识服务平台、维普中文期刊全文数据库(VIP)、中国生物医学文献数据库(SinoMed)中有关针刺方法治疗KOA的临床RCT,检索时间为2003—2022年。由2名研究者筛查文献,提取文献特征,并分析针灸治疗KOA的RCT指标域、测量工具、测量时点。结果共纳入131篇文献,样本量22726例,共使用89个结局指标,将结局指标进行分类:症状体征类40项(44.9%)、理化检查类22项(24.7%)、生活质量类5项(5.6%)、心理状态指标5项(5.6%)、满意度评价3项(3.4%)、安全性指标2项(2.2%)、其他指标12项(13.5%)。131篇文献中,共包含23个测量时间点,研究时间跨度为治疗后1 h~3年;106篇(80.9%)文献使用了“临床疗效”作为结局指标;23篇(17.6%)文献进行了安全性评价及不良事件报告。结论针刺治疗KOARCT结局指标存在使用差异大、不分主次结局、指标组合随意性高、复合指标使用欠规范、安全性指标使用欠缺、结局指标测量时间点欠规范、远期预后评价不足、没有体现针刺的中医药干预治疗特色等问题。之后相关研究应结合中医药辨证论治特色,选用科学合理的结局指标来评价针刺治疗KOA的疗效,并且亟须建立中医药治疗KOA的核心指标集,构建规范公认的中医药核心指标集。

中医药治疗老年单纯收缩期高血压的临床研究结局指标分析

[目的]梳理中医药治疗老年单纯收缩期高血压(ISH)的随机对照试验(RCT)的评价指标,构建中医药治疗老年ISH临床试验核心指标集。[方法]检索PubMed、CoChrane library、Embase、中国知网数据库、万方数据库、维普数据库中应用中药联合长效钙拮抗剂(CCB)或肾素-血管紧张素-醛固酮系统阻断剂(ACEI或ARB)干预老年ISH的随机对照临床研究,检索时限均为建库至2019年12月31日。[结果]纳入38篇RCT,共计2848例患者,涉及396个指标,频次排列前16位的指标依次为:诊室收缩压(7.04%)、降压有效率(6.31%)、中医证候疗效(6.31%)、诊室舒张压(5.56%)、肝功能(4.29%)、肾功能(4.29%)、血常规(4.04%)、尿常规(3.79%)、不良反应发生率(3.54%)、夜间平均收缩压(3.28%)、24小时平均收缩压(3.03%)、日间平均收缩压(3.03%)、中医证候积分(3.03%)、诊室脉压差(2.78%)、日间平均舒张压(2.78%)及夜间平均舒张压(2.78%)。[结论]中医药治疗老年ISH的指标选择存在较多的问题,如差异性较大、指标测量时点差异大、缺乏中医药特色等,需加快研制老年ISH;核心指标集。