Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

2015 Impact Factor: 1.863

Cover Story   2017, Volume 11 Issue 4
Similar to standard CAR-T cells, LAG-3 knockout CAR-T cells can eradicate tumor in murine xenograft model (Courtesy of Dr. Haoyi Wang. See pages 554-562 by Yongping Zhang et al. for more information.)
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, Volume 11 Issue 4 Previous Issue   
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REVIEW
Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses
Xiaohuan Wang, Peng Zou, Fan Wu, Lu Lu, Shibo Jiang
Front. Med.. 2017, 11 (4): 449-461.  
https://doi.org/10.1007/s11684-017-0589-5

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In recent years, unexpected outbreaks of infectious diseases caused by emerging and re-emerging viruses have become more frequent, which is possibly due to environmental changes. These outbreaks result in the loss of life and economic hardship. Vaccines and therapeutics should be developed for the prevention and treatment of infectious diseases. In this review, we summarize and discuss the latest progress in the development of small-molecule viral inhibitors against highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, Ebola virus, and Zika virus. These viruses can interfere with the specific steps of viral life cycle by blocking the binding between virus and host cells, disrupting viral endocytosis, disturbing membrane fusion, and interrupting viral RNA replication and translation, thereby demonstrating potent therapeutic effect against various emerging and re-emerging viruses. We also discuss some general strategies for developing small-molecule viral inhibitors.

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Human monoclonal antibodies as candidate therapeutics against emerging viruses
Yujia Jin, Cheng Lei, Dan Hu, Dimiter S. Dimitrov, Tianlei Ying
Front. Med.. 2017, 11 (4): 462-470.  
https://doi.org/10.1007/s11684-017-0596-6

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The emergence of new pathogens, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and Ebola virus, poses serious challenges to global public health and highlights the urgent need for novel antiviral approaches. Monoclonal antibodies (mAbs) have been successfully used to treat various diseases, particularly cancer and immunological disorders. Antigen-specific mAbs have been isolated using several different approaches, including hybridoma, transgenic mice, phage display, yeast display, and single B-cell isolation. Consequently, an increasing number of mAbs, which exhibit high potency against emerging viruses in vitro and in animal models of infection, have been developed. In this paper, we summarize historical trends and recent developments in mAb discovery, compare the advantages and disadvantages of various approaches to mAb production, and discuss the potential use of such strategies for the development of antivirals against emerging diseases. We also review the application of recently developed human mAbs against SARS-CoV, MERS-CoV, and Ebola virus and discuss prospects for the development of mAbs as therapeutic agents against emerging viral diseases.

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Universal influenza virus vaccines: what can we learn from the human immune response following exposure to H7 subtype viruses?
Daniel Stadlbauer, Raffael Nachbagauer, Philip Meade, Florian Krammer
Front. Med.. 2017, 11 (4): 471-479.  
https://doi.org/10.1007/s11684-017-0602-z

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Several universal influenza virus vaccine candidates based on eliciting antibodies against the hemagglutinin stalk domain are in development. Typically, these vaccines induce responses that target group 1 or group 2 hemagglutinins with little to no cross-group reactivity and protection. Similarly, the majority of human anti-stalk monoclonal antibodies that have been isolated are directed against group 1 or group 2 hemagglutinins with very few that bind to hemagglutinins of both groups. Here we review what is known about the human humoral immune response to vaccination and infection with H7 subtype influenza viruses on a polyclonal and monoclonal level. It seems that unlike vaccination with H5 hemagglutinin, which induces antibody responses mostly restricted to the group 1 stalk domain, H7 exposure induces both group 2 and cross-group antibody responses. A better understanding of this phenomenon and the underlying mechanisms might help to develop future universal influenza virus vaccine candidates.

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Immunological and virological characteristics of human immunodeficiency virus type 1 superinfection: implications in vaccine design
Yang Gao, Wen Tian, Xiaoxu Han, Feng Gao
Front. Med.. 2017, 11 (4): 480-489.  
https://doi.org/10.1007/s11684-017-0594-8

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Superinfection is frequently detected among individuals infected by human immunodeficiency virus type I (HIV-1). Superinfection occurs at similar frequencies at acute and chronic infection stages but less frequently than primary infection. This observation indicates that the immune responses elicited by natural HIV-1 infection may play a role in curb of superinfection; however, these responses are not sufficiently strong to completely prevent superinfection. Thus, a successful HIV-1 vaccine likely needs to induce more potent and broader immune responses than those elicited by primary infection. On the other hand, potent and broad neutralization responses are more often detected after superinfection than during monoinfection. This suggests that broadly neutralizing antibodies are more likely induced by sequential immunization of multiple different immunogens than with only one form of envelope glycoprotein immunogens. Understanding why the protection from superinfection by immunity induced by primary infection is insufficient and if superinfection can lead to cross-reactive immune responses will be highly informative for HIV-1 vaccine design.

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Current advances in the elimination of hepatitis B in China by 2030
Shuye Zhang, Fusheng Wang, Zheng Zhang
Front. Med.. 2017, 11 (4): 490-501.  
https://doi.org/10.1007/s11684-017-0598-4

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With its 78 million chronic carriers, hepatitis B virus (HBV) infection is still one of the leading public health challenges in China. Over the last two decades, China has made great progress on the prevention of HBV transmission through national vaccination programs. Zero transmission from mother to infant has been proposed as the current goal. Available anti-HBV therapy is efficacious in suppressing HBV replication; however, it fails to completely cure patients with chronic hepatitis B and even requires lifelong treatment. To reduce the costs and improve the efficacy, several trials have been recently conducted in China to optimize the current anti-HBV managements. Novel biomarkers were identified to predict treatment outcomes, and new promising treatment strategies were developed. Reports also indicate that coinfections of HBV with other hepatotropic viruses and human immunodeficiency virus are common in China and cause severe liver diseases, which should be recognized early and treated properly. Work is still needed to eliminate hepatitis B in China by 2030.

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Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos(t)ide analogs
Fengmin Lu, Jie Wang, Xiangmei Chen, Dongping Xu, Ningshao Xia
Front. Med.. 2017, 11 (4): 502-508.  
https://doi.org/10.1007/s11684-017-0590-z

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Although the efficacy of nucleos(t)ide analogue (NA) has been confirmed for treatment of chronic hepatitis B, long-term therapy has been recommended due to the high frequency of off-therapy viral DNA rebound and disease relapse. In this review, the RNA virion-like particles of hepatitis B virus (HBV) are integrated into the life cycle of HBV replication, and the potential significance of serum HBV RNA is systematically described. The production of HBV RNA virion-like particles should not be blocked by NA; in this regard, serum HBV RNA is found to be a suitable surrogate marker for the activity of intrahepatic covalently closed circular DNA (cccDNA), particularly among patients receiving NA therapy. Therefore, the concept of virological response is redefined as persistent loss of serum HBV DNA and HBV RNA. In contrast to hepatitis B surface antigen (HBsAg) that can originate from either the cccDNA or the integrated HBV DNA fragment, serum HBV RNA, with pregenomic RNA origination, can only be transcribed from cccDNA. Therefore, the loss of serum HBV RNA would likely be a promising predicator for safe drug discontinuation. The clinical status of consistent loss of serum HBV RNA accompanied with low serum HBsAg levels might be implicated as a “para-functional cure,” a status nearly close to the functional cure of chronic hepatitis B, to distinguish the “functional cure” characterized as serum HBsAg loss with or without anti-HBs seroconversion.

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Natural killer cells in hepatocellular carcinoma: current status and perspectives for future immunotherapeutic approaches
Min Yu, Zonghai Li
Front. Med.. 2017, 11 (4): 509-521.  
https://doi.org/10.1007/s11684-017-0546-3

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Hepatocellular carcinoma (HCC) is currently the fifth most common malignancy and the third leading cause of cancer-related mortalities worldwide. In the last few years, treatments for HCC have significantly improved from a mere surgical resection to a series of minimally invasive therapies and targeted drugs. However, recurrence frequently occurs even upon curative therapeutics, and drug therapies generally produce disappointing results, with the overall prognosis dismal. This challenging clinical scenario warrants new effective and life-prolonging strategies for patients with HCC. Compelling evidence suggests that NK cells play a critical role in the immune function of the liver and in the immune defenses against HCC, indicating that HCC might be an ideal target for NK cell-based immunotherapies. To obtain comprehensive insights into the putative influence of NK cells on HCC, this paper summarizes current knowledge on NK cells in HCC and discusses the usefulness and prospects of NK cell-based immunotherapies. Critical issues that require consideration for the successful clinical translation of NK cell-based therapies are also addressed. If appropriately used and further optimized, NK cell-based therapies could dominate important roles in the future immunotherapeutic market of HCC.

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Application of liquid biopsy in precision medicine: opportunities and challenges
Junyun Wang, Shuang Chang, Guochao Li, Yingli Sun
Front. Med.. 2017, 11 (4): 522-527.  
https://doi.org/10.1007/s11684-017-0526-7

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Precision medicine for cancer patients aims to adopt the most suitable treatment options during diagnosis and treatment of individuals. Detecting circulating tumor cell (CTC) or circulating tumor DNA (ctDNA) in plasma or serum could serve as liquid biopsy, which would be useful for numerous diagnostic applications. Liquid biopsies can help clinicians screen and detect cancer early, stratify patients to the most suitable treatment and real-time monitoring of treatment response and resistance mechanisms in the tumor, evaluate the risk for metastatic relapse, and estimate prognosis. We summarized the advantages and disadvantages of tissue and liquid biopsies. We also further compared and analyzed the advantages and limitations of detecting CTCs, ctDNAs, and exosomes. Furthermore, we reviewed the literature related with the application of serum or plasma CTCs, ctDNAs, and exosomes for diagnosis and prognosis of cancer. We also analyzed their opportunities and challenges as future biomarkers. In the future, liquid biopsies could be used to guide cancer treatment. They could also provide the ideal scheme to personalize treatment in precision medicine.

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RESEARCH ARTICLE
Testing of tuberculosis infection among Chinese adolescents born after terminating the Bacillus Calmette--Guérin booster vaccination: subgroup analysis of a population-based cross-sectional study
Hengjing Li, Henan Xin, Shukun Qian, Xiangwei Li, Haoran Zhang, Mufei Li, Boxuan Feng, Qi Jin, Lei Gao
Front. Med.. 2017, 11 (4): 528-535.  
https://doi.org/10.1007/s11684-017-0573-0

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The prevalence of tuberculosis infection among adolescents born after terminating the Bacillus Calmette–Guérin (BCG) booster vaccination in China was estimated using tuberculin skin testing (TST) and QuantiFERON-TB Gold assay (QFT) to investigate the influence of neonatal BCG vaccination on the performance of TST. Data analysis was conducted for 2831 eligible participants aged 5–15 years from the baseline survey of a population-based multi-center prospective study. The prevalence rates of TST (induration≥10 mm) and QFT positivity were 9.3% (264/2827) and 2.5% (71/2831), respectively. The rate of QFT indeterminate result was 2.2% (62/2831). The overall agreement between TST and QFT was low (concordance= 88.0%; κ coefficient= 0.125). Only TST was positively associated with BCG vaccination with an adjusted odds ratio of 1.71 [95% confidence interval, 1.26–2.31]. A history of close contact with patients of active TB was significantly associated with positivity for TST and QFT. Our results suggested that BCG neonatal vaccination still affects TST performance, and a two-step approach might be considered for TB infection testing among adolescents in China.

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Irreversible phenotypic perturbation and functional impairment of B cells during HIV-1 infection
Jingjing Yan, Shuye Zhang, Jun Sun, Jianqing Xu, Xiaoyang Zhang
Front. Med.. 2017, 11 (4): 536-547.  
https://doi.org/10.1007/s11684-017-0592-x

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Human immunodeficiency virus type 1 (HIV-1) infection can damage humoral immunity. The knowledge of B cell perturbations during chronic HIV-1 infection and their recovery after combined antiretroviral therapy (cART) is not complete yet, and thus attempts to further improve humoral immunity are impeded. In this study, an HIV-1 chronically infected cohort with similar demographics, infection history, genetic background, and HIV-1 genotype was established to probe B cell perturbations. Results showed that the B cells from this cohort were highly activated and prone to cell death, and B cell compartments were altered significantly. Notably, although cART partially reversed the hyperactivation and reduced tissue-like memory B cells, other B cell perturbations, including impaired expression of survival factor Bcl-2, costimulatory molecules, and shrunken resting memory B cells, were irreversible. Further functional characterization revealed that the influenza HA-specific antibody-secreting cells were significantly lower during HIV-1 infection, whereas the recalled antibody response to HIV-1-specific antigens was decreased after cART. Finally, CpG plus R848 treatment increased the survival of B cells and memory B cells in vitro from HIV-1-infected patients. In conclusion, this study identified irreversible B cell immune perturbations in chronic HIV-1 infections regardless of cART and proposed the potential strategy to enhance B cell functions through the improvement of cell survival.

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Impact of HBV replication in peripheral blood mononuclear cell on HBV intrauterine transmission
Xiaohong Shi, Xuefei Wang, Xixi Xu, Yongliang Feng, Shuzhen Li, Shuying Feng, Bo Wang, Suping Wang
Front. Med.. 2017, 11 (4): 548-553.  
https://doi.org/10.1007/s11684-017-0597-5

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This study determined the effect of hepatitis B virus (HBV) replication in peripheral blood mononuclear cell (PBMC) from HBsAg-positive mothers on HBV intrauterine transmission. A total of 150 HBsAg-positive mothers and their neonates were recruited in this study. Within 24 h after birth, HBV serological markers, serum HBV DNA, PBMC HBV relaxed circular DNA (rcDNA), and covalently closed circular DNA (cccDNA) were measured in the HBsAg-positive mothers and their neonates before passive-active immune prophylaxis. The relationship between HBV replication in PBMC and HBV intrauterine transmission was examined through Chi-square test and logistic regression. The rate of HBV intrauterine transmission was 8.00% (12/150) in the 150 neonates born to HBsAg-positive mothers. The positivities of PBMC HBV rcDNA and cccDNA in the HBsAg-positive mothers were 36.67% (55/150) and 10% (15/150), respectively. Maternal PBMC HBV cccDNA was a risk factor of HBV intrauterine transmission (OR= 6.003, 95% CI: 1.249–28.855). Maternal serum HBeAg was a risk factor of PBMC HBV rcDNA (OR= 3.896, 95% CI: 1.929–7.876) and PBMC HBV cccDNA (OR= 3.74, 95% CI: 1.186–11.793) in the HBsAg-positive mothers. Administration of hepatitis B immune globulin was a protective factor of PBMC HBV cccDNA (OR= 0.312, 95% CI: 0.102–0.954) during pregnancy. The positivity of PBMC HBV rcDNA was related to that of cccDNA in the HBsAg-positive mothers (c2=5.087, P= 0.024). This study suggests that PBMC is a reservoir of HBV and an extrahepatic site for virus replication and plays a critical role in HBV intrauterine transmission.

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CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells
Yongping Zhang, Xingying Zhang, Chen Cheng, Wei Mu, Xiaojuan Liu, Na Li, Xiaofei Wei, Xiang Liu, Changqing Xia, Haoyi Wang
Front. Med.. 2017, 11 (4): 554-562.  
https://doi.org/10.1007/s11684-017-0543-6

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T cells engineered with chimeric antigen receptor (CAR) have been successfully applied to treat advanced refractory B cell malignancy. However, many challenges remain in extending its application toward the treatment of solid tumors. The immunosuppressive nature of tumor microenvironment is considered one of the key factors limiting CAR-T efficacy. One negative regulator of T cell activity is lymphocyte activation gene-3 (LAG-3). We successfully generated LAG-3 knockout T and CAR-T cells with high efficiency using CRISPR-Cas9 mediated gene editing and found that the viability and immune phenotype were not dramatically changed during in vitro culture. LAG-3 knockout CAR-T cells displayed robust antigen-specific antitumor activity in cell culture and in murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates an efficient approach to silence immune checkpoint in CAR-T cells via gene editing.

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Propensity score-matched study and meta-analysis of cumulative outcomes of day 2/3 versus day 5/6 embryo transfers
Ye Yin, Ge Chen, Kezhen Li, Qiuyue Liao, Sijia Zhang, Nieying Ma, Jing Chen, Yan Zhang, Jihui Ai
Front. Med.. 2017, 11 (4): 563-569.  
https://doi.org/10.1007/s11684-017-0535-6

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The superiority of the cumulative outcomes of day 5/6 embryo transfer to those of day 2/3 embryo transfer in infertile couples has been debated. This retrospective study included data collected from 1051 patients from July 2011 to June 2014. Multiple maternal baseline covariates were subjected to propensity score matching analysis, and each day 5/6 group woman was matched to one day 2/3 group woman. A systematic meta-analysis was conducted to validate the results. After matching was completed, 217 patients on the day 2/3 group were matched with those on the day 5/6 group, and no significant differences in the baseline characteristics were observed between the two groups. The cumulative pregnancy rate (57.14% vs. 53.46%, OR 1.16, 95% CI 0.79–1.70) and cumulative live birth rate (53.00% vs. 49.77%, OR 1.14, 95% CI 0.78–1.66) of day 5/6 embryo transfers were higher than those of day 2/3 embryo transfers, but this difference was not significant. The mean cycles per live birth and mean days per live birth in the day 5/6 group were significantly lower than those in the day 2/3 group. This study demonstrated that day 5/6 embryo transfer is a more cost-effective and time-efficient policy than day 2/3 embryo transfer to produce a live baby.

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COMMENTARY
New medical risks affecting obstetrics after implementation of the two-child policy in China
Qiang Li, Dongrui Deng
Front. Med.. 2017, 11 (4): 570-575.  
https://doi.org/10.1007/s11684-017-0552-5

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China recently instituted a two-child policy in response to its aging population, declining workforce and demographic dividend, and the need to develop asocial economy. Additionally, women generally delay having a second child because of the overwhelming pressure in their lives. With the improvements in assisted fertility technologies in recent years, the number of elderly women attempting to bear children has increased. The quality of woman’s eggs and a man’s sperm declined dramatically with increasing age, leading to an increased risk of pregnancy-related complications among older women. Therefore, the types of fertility problems experienced by elderly females must be provided with considerable attention by obstetricians. This commentary article focuses on the medical problems faced by older second-child pregnant women. This work discusses their increased rates of infertility, spontaneous abortion, fetal malformation, gestational diabetes, cesarean section, placenta previa, postpartum hemorrhage, postpartum depression, and hypertensive disorders, which complicate pregnancy.

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Strategies of minimally invasive treatment for intrahepatic and extrahepatic bile duct stones
Zongming Zhang, Zhuo Liu, Limin Liu, Mengmeng Song, Chong Zhang, Hongwei Yu, Baijiang Wan, Mingwen Zhu, Zixu Liu, Hai Deng, Haiming Yuan, Haiyan Yang, Wenping Wei, Yue Zhao
Front. Med.. 2017, 11 (4): 576-589.  
https://doi.org/10.1007/s11684-017-0536-5

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Cholelithiasis is a kind of common and multiple diseases. In recent years, traditional laparotomy has been challenged by a minimally invasive surgery. Through literature review, the therapeutic method, effect, and complications of minimally invasive treatment of intrahepatic and extrahepatic bile duct stones by combining our practical experience were summarized as follows. (1) For intrahepatic bile duct stones, the operation may be selected by laparoscopic liver resection, laparoscopic common bile duct exploration (LCBDE), or percutaneous transhepatic cholangioscopy. (2) For concomitant gallstones and common bile duct stones, the surgical approach can be selected as follows: laparoscopic cholecystectomy (LC) combined with endoscopic sphincterotomy (EST) or endoscopic papillary balloon dilatation, LC plus laparoscopic transcystic common bile duct exploration, LC plus LCBDE, and T-tube drainage or primary suture. (3) For concomitant intrahepatic and extrahepatic bile duct stones, laparoscopic liver resection, choledochoscopy through the hepatic duct orifice on the hepatectomy cross section, LCBDE, EST, and percutaneous transhepatic cholangioscopic lithotripsy could be used. According to the abovementioned principle, the minimally invasive treatment approach combined with the surgical technique and equipment condition will be significant in improving the therapeutic effect and avoiding the postoperative complications or hidden dangers of intrahepatic and extrahepatic bile duct stones.

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Application of Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to the guideline development for clinical practice with acupuncture and moxibustion
Hong Zhao, Fengxia Liang, Yigong Fang, Baoyan Liu
Front. Med.. 2017, 11 (4): 590-594.  
https://doi.org/10.1007/s11684-017-0537-4

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Grading of Recommendations Assessment, Development, and Evaluation (GRADE) offers a worldwide approach to guideline development for clinical practice. For the clinical practice of acupuncture therapy, 18 evidence-based guidelines have been developed in China using GRADE. In this study, we review the advantages and limitations of the GRADE approach in the guideline development for acupuncture and moxibustion and propose some solutions to these limitations. Scientific advantages of rating the quality of evidence, outcome-centric direction, overall progression to develop recommendations, and strength of recommendations providing specific clinical guidance are the advantages of GRADE. The limitations of GRADE in the development of guidelines for acupuncture and moxibustion include rating the quality of evidence for ancient literature and literature on famous traditional Chinese medicine experts’ experiences and specific guidelines for formulating recommendations from evidence. In the guideline development for clinical practice with acupuncture and moxibustion, we suggest that a specific method should be explored based on the GRADE approach and the characteristics of acupuncture therapy.

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16 articles