Quality Markers of Traditional Chinese Medicine:Concept,Progress,and Perspective

As the most important complementary medication against a variety of diseases,traditional Chinese medicines(TCMs)have been extensively applied over thousands of years.Current quality control of herbal medicines,however,is in great dispute.Unlike chemical drugs,which have clear and validated quality standards,the content of only one(or a few)compounds of many herbs and preparations is currently assessed as an indicator of quality,even though the assessed compound(s)is neither closely associated with the efficacy nor representative of the medicine as a whole.Based on the clinical use,compatibility of multiple component prescriptions,and manufacturing process of TCM,the new concept of a TCM quality marker that was proposed in previous work is discussed further here.In addition,practical technological approaches are described for the qualitative analysis and quantification of TCMs including herbs,processed products,and preparations,which lead to the discovery and identification of specific chemicals as quality markers and new quality control patterns.The progress that has been made in TCM quality control is also addressed.This work provides useful information for the quality control of herbal medicines in the future.

Quality of life and survival analyses of breast cancer cases treated with integrated traditional Chinese and Western medicine

BACKGROUND Breast cancer(BC)is the second leading cause of tumor-related mortality after lung cancer.Chemotherapy resistance remains a major challenge to progress in BC treatment,warranting further exploration of feasible and effective alternative therapies.AIM To analyzed the quality of life(QoL)and survival of patients with BC treated with integrated traditional Chinese and Western medicine(TCM-WM).METHODS This study included 226 patients with BC admitted to the First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine between February 2018 and February 2023,including 100 who received conventional Western medicine treatment(control group)and 126 who received TCM-WM treatment(research group).The total effective rate,side effects(alopecia,nausea and vomiting,hepatorenal toxicity,and myelosuppression),QoL assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire(EORTC QLQ-C30),1-year overall survival(OS),recurrence and metastasis rates,and serum inflammatory factors[interleukin(IL)-6,IL-10,and tumor necrosis factor alpha]were comparatively analyzed.RESULTS The research group showed statistically better overall efficacy,EORTC QoL-C30 scores,and 1-year OS than the control group,with markedly lower side effects and 1-year recurrence and metastasis rates.Moreover,the posttreatment levels of serum inflammatory in the research group were significantly lower than the baseline and those in the control group.CONCLUSION Overall,TCM-WM demonstrated significantly improved therapeutic efficacy while ensuring drug safety in BC,which not only improved patients’QoL and prolonged survival,but also significantly inhibited the inflammatory response.

Prediction of quality markers of traditional Chinese medicines based on network pharmacology

Network pharmacology is a powerful tool to reflect the pharmacologically active effects,mechanism of action and toxic activity of traditional Chinese medicines(TCMs).The ingredients of TCMs,associated with quality control of TCM products,are those fundamental chemicals that exhibit biological activities.A great amount of effort has been made by scientists in that field in order to improve the quality of TCMs,though the approaches to determine their quality and the TCM theory and compatibility rules remain ambiguous.Now some methods and technologies must be applied to predict and explore the quality marker(Q-marker)for quality control,as well as to clarify the factors affecting the quality of TCM,which may give new insight into rational ground of establishment of appropriate quality control and assessment system.In this review paper,authors focus on the prediction of quality markers of TCMs by network pharmacology based on three aspects:(1)from network medicine to network pharmacology,(2)complex network system of traditional Chinese medicine,and(3)predicting TCM quality markers based on network pharmacology.Authors proposed the research pattern on network pharmacology based on biological and medical networks,and further TCM network pharmacology based on substantial basis of TCM formulae,and the idea of"effect-ingredient-target-fingerprint"to predict and recognize the TCM Qmarker was the ultimate goal.In addition,authors yet noted how to make full use of the advantages of network toxicology to provide new ideas for the toxicity study of complex TCM systems and the prediction of TCM toxicity markers.

Enhancing ulcerative colitis treatment with traditional Chinese medicine

Inflammatory bowel disease,particularly ulcerative colitis(UC),poses significant treatment challenges due to its chronic nature and potential for severe complications.This editorial reviews a recent network meta-analysis that evaluated the efficacy of and highlighted the superior outcomes achieved by combining each of five traditional Chinese medicine(TCM)formulations with mesalazine for the adjuvant treatment of UC.Clinical outcomes included enhanced mucosal healing,improved quality of life,and reduced recurrence rates.Additionally,the combination therapy resulted in a lower incidence of adverse reactions compared with mesalazine monotherapy.Despite these promising results,limitations such as variability in study quality and TCM dosage highlight the need for further highquality,large-sample,multicenter randomized controlled trials.This editorial underscores the potential of TCM in enhancing UC management and calls for more rigorous research to substantiate these findings and refine clinical guidelines.

Multimodal integrated strategy for the discovery and identification of quality markers in traditional Chinese medicine

With the modernization and internationalization of traditional Chinese medicine(TCM),the requirement for quality control has increased.The quality marker(Q-marker)is an important standard in this field and has been implemented with remarkable success in recent years.However,the establishment of Qmarkers remains fragmented and the process lacks systematicity,resulting in inconsistent quality control and insufficient correlation with clinical efficacy and safety of TCM.This review introduces four multimodal integrated approaches that contribute to the discovery of more comprehensive and accurate Qmarkers,thus aiding in the establishment of new quality control patterns based on the characteristics and principles of TCM.These include the whole-process quality control strategy,chemical-activity-based screening method,efficacy,safety,and consistent combination strategy,and TCM theory-guided approach.Furthermore,methodologies and representative examples of these strategies are described,and important future directions and questions in this field are also proposed.

Analysis of the Clinical Effect of Chinese Medicine Combined with Acupuncture and Moxibustion on Insomnia

Objective:To explore and analyze the clinical efficacy of Chinese medicine combined with acupuncture and moxibustion in the treatment of insomnia.Method:80 patients with primary insomnia were selected as the study sample,with 20 cases randomly selected as the control group and the rest as the observation group.The control group was treated with ordinary western medicine,while the observation group patients were treated with traditional Chinese medicine combined with acupuncture and moxibustion based on this syndrome differentiation.The comparison items were treatment effect,sleep quality,mental health,quality of life,specific sleep indicators,cerebral blood flow and neurotransmitters.Result:The treatment effectiveness showed that the observation group had a higher treatment effectiveness rate than the control group(P<0.05);The results of sleep quality showed that after treatment,the scores of the observation group were lower than those of the control group in seven dimensions:sleep quality,sleep time,sleep onset time,sleep efficiency,sleep disorders,hypnotic drugs,and daytime dysfunc‐tion score(P<0.05);The quality of life results showed that after treatment,the observa‐tion group had higher scores than the control group in eight dimensions:physiological function,physiological function,physical pain,health status,energy,social function,emotional function,and mental health(P<0.05);The results of slow wave sleep time and fast eye movement sleep time showed that after treatment,the HAMA and HAMD scores of the physiological mechanism in the observation group were lower than those in the control group(P<0.05);The results of cerebral blood flow and neurotransmitter indica‐tors show that after treatment,glutamateγ-The peak systolic blood flow velocity of ami‐nobutyric acid,vertebral artery,and basilar artery in the observation group was higher than that in the control group(P<0.05).Conclusion:The clinical treatment of Chinese medicine combined with acupuncture and moxibustion in the treatment of insomnia patients can significantly improve the clinical treatment effect,and improve the cerebral hemorrhage and neurotransmitter status of patients,promote the improvement of their physical and mental status,can more significantly improve the quality of sleep,reduce sleep difficulties,reduce the dosage of sleeping pills,which has important clinical application value.

The Influence of Integrated Chinese and Western Medicine Treatment on the Quality of Life and Laboratory Indicators of Patients with Novel Coronavirus Pneumonia

Objective: To investigate the influence of integrated Chinese and Western medicine treatment on the quality of life and laboratory indicators of patients with novel coronavirus pneumonia (COVID-19). Methods: A prospective, self-controlled study was conducted to analyze the changes in corresponding laboratory indicators and quality of life in 75 confirmed COVID-19 patients treated with integrated Chinese and Western medicine in our hospital during the early stage, middle stage, recovery period, and two weeks after discharge. The effectiveness and safety of the treatment regimen were evaluated in conjunction with the time for 2019-nCoV nucleic acid conversion, disease progression, and adverse reactions. Results: The PLT levels in the initial stage were significantly lower than those in the recovery period in 75 patients. The CRP levels in the initial stage were significantly lower than those after discharge for 2 weeks. The TBIL, IBTL, and DHIL levels in the initial stage were significantly lower than those in the middle stage. The K+ levels in the initial stage were significantly lower than those in the recovery period and after discharge for 2 weeks. The LYMGH levels in the initial stage were significantly lower than those in the recovery period and after discharge for 2 weeks. The TP and ALB levels in the initial stage were higher than those in the middle stage and the recovery period. The LDH levels, scores of daily activity limitation, scores of respiratory distress symptoms, scores of psychological emotions, CT imaging scores, and positive rate of nucleic acid were significantly lower than those in the recovery period and after discharge for 2 weeks. The AG, CK, CK-MB, and α-HBDH levels in the initial stage were significantly higher than those in the recovery period. However, the AMY level in the initial stage was significantly lower than that in the recovery period and after discharge for 2 weeks (p Conclusion: Integrated Chinese and Western medicine treatment has a significant impact on laboratory indicators such as PLT, LYMGH, CRP, TBIL, IBTL, DHIL, TP, ALB, K+, AG, LDH, CK, CK-MB, α-HBDH, AMY, CT imaging, and 2019-nCoV nucleic acid in COVID-19 patients. It has good clinical efficacy and safety, and can improve the quality of life of patients.

Nursing outcomes of traditional Chinese medicine adjunctive therapy on osteofascial compartment syndrome:a review

The rate of disability due to acute osteofascial compartment syndrome(OCS)is high,and the therapeutic effect of decompressive fasciotomy is not ideal.This paper retrospectively reviews the modern treatment of OCS,including Western medicine and Traditional Chinese medicine(TCM),mainly in the context of the advantages of TCM in the treatment process of decompressive fasciotomy or conservative treatment to the patients who are suffering from OCS.It was found that TCM treatment reduced the levels of serum creatine kinase(CK),lactate dehydrogenase(LDH),and aspartate aminotransferase(AST);it is beneficial to the elimination of swelling and pain.TCM adjunctive therapy promotes patients’postoperative functional recovery and decreases the occurrence of fasciotomy in patients;TCM can relieve tissue hypoxia of compartments and prevent necrosis of muscle and nerve tissue.TCM treatment improves the quality of medical service and ensures the safety of OCS patients.This paper aims to summarize the function of TCM in the treatment of OCS,provide reference for the clinical treatment of OCS,and improve the nursing/medical outcomes of OCS.

A holistic strategy for quality and safety control of traditional Chinese medicines by the “iVarious” standard system

An effective quality control system is the key to ensuring the quality, safety and efficacy of traditional Chinese medicines(TCMs). However, the current quality standard research lacks top-level design and systematic design,mostly based on specific technologies or evaluation methods. To resolve the challenges and questions of quality control of TCMs, a brand-new quality standard system, named "iVarious", was proposed. The system comprises eight elements in a modular format. Meaning of every element was specifically illustrated via corresponding research instances. Furthermore, frankincense study was taken as an example for demonstrating standards and research process, based on the "i Various" system. This system highlighted a holistic strategy for effectiveness,security, integrity and systematization of quality and safety control standards of TCMs. The establishment of"i Various" integrates multi-disciplinary technologies and progressive methods, basis elements and key points of standard construction. The system provides a novel idea and technological demonstration for regulation establishment of TCMs quality standards.

Development of chromatographic technologies for the quality control of Traditional Chinese Medicine in the Chinese Pharmacopoeia

As an important branch of medicine, Traditional Chinese Medicine(TCM) has been applied for the treatment of diseases for thousands of years in China and other countries in East Asia. The Chinese Pharmacopoeia(ChP) is a drug code formulated by the Chinese government, and it includes a special volume for the monographs of TCM, which plays an important role in ensuring the quality of drugs. The use of quality control technology has always been a complex and important factor in TCM. Owing to the chemical diversity of TCM, chromatography technology has been proven to be a comprehensive strategy for the assessment of the overall quality of TCM and has become the main analytical method in the ChP.This article provides an overview of the classical and modern chromatographic technologies applied in the ChP, and summarizes the advantages and disadvantages of each technique in the TCM monographs.In 2020, the new edition of the Ch P(the 2020 edition) has been implemented at the end of 2020. This paper also contains a brief introduction about the application of chromatographic technologies in the new edition of the ChP.

An ultra-robust fingerprinting method for quality assessment of traditional Chinese medicine using multiple reaction monitoring mass spectrometry

Chromatographic fingerprinting has been perceived as an essential tool for assessing quality and chemical equivalence of traditional Chinese medicine.However,this pattern-oriented approach still has some weak points in terms of chemical coverage and robustness.In this work,we proposed a multiple reaction monitoring(MRM)-based fingerprinting method in which approximately 100 constituents were simultaneously detected for quality assessment.The derivative MRM approach was employed to rapidly design MRM transitions independent of chemical standards,based on which the large-scale fingerprinting method was efficiently established.This approach was exemplified on QiShenYiQi Pill(QSYQ),a traditional Chinese medicine-derived drug product,and its robustness was systematically evaluated by four indices:clustering analysis by principal component analysis,similarity analysis by the congruence coefficient,the number of separated peaks,and the peak area proportion of separated peaks.Compared with conventional ultraviolet-based fingerprints,the MRM fingerprints provided not only better discriminatory capacity for the tested normal/abnormal QSYQ samples,but also higher robustness under different chromatographic conditions(i.e.,flow rate,apparent pH,column temperature,and column).The result also showed for such large-scale fingerprints including a large number of peaks,the angle cosine measure after min-max normalization was more suitable for setting a decision criterion than the unnormalized algorithm.This proof-of-concept application gives evidence that combining MRM technique with proper similarity analysis metrices can provide a highly sensitive,robust and comprehensive analytical approach for quality assessment of traditional Chinese medicine.

Pharmacological intervention of traditional Chinese medicine for the quality of life in patients with colorectal cancer： a systematic review and meta-analysis

Objective： The objective of this study is to evaluate the impact of various traditional Chinese medicine （TCM）approaches on the quality of life in patients with colorectal cancer. Methods： In this study, we systematically performedthe screening of randomized controlled trials from Cochrane Library, Pubmed, Embase, Medline, and Web of Science.The data were extracted by two reviewers independently, and then risk assessment was performed. All the analyses wereconducted using Review Manager 5.3. Results： A total of 18 eligible studies containing 1312 patients were included.Experimental group were treated with TCM combined with Western medicine or TCM alone （N = 688） and controlgroup were treated with Western medicine treatment alone （N = 624）. The results showed that the recent clinicalefficiency between the two groups was not statistically significant （P = 0.06）. KPS scores of the experimental group werehigher than those in the control group [P 〈 0.001, WMD = 9.60, 95%CI = （5.62, 13.57）]. The toxicity comparisonshowed that the occurrence of toxicities, such as leucopenia, thrombocytopenia, nausea and vomiting, diarrhea, andneurotoxicity in the experimental group was lower than that in the control group [P 〈 0.001, OR = 0.31, 95%CI = （0.19,0.50）], [P = 0.003, OR = 0.49, 95%CI = （0.31, 0.78）], [P 〈 0.001, OR = 0.30, 95%CI = （0.16, 0.54）], [P 〈 0.001, OR =0.40, 95%CI = （0.27, 0.58）], and [P 〈 0.001, OR = 0.43, 95%CI = （0.30, 0.61）]. The immunological test comparisondemonstrated that the immunological parameters （CD3, CD4, and CD4/CD8） showed higher values in the experimentalgroup than those in the control group [P 〈 0.001, MD = 5.55, 95%CI = （4.83, 6.28）], [P 〈 0.0001, MD = 6.75, 95%CI =（5.25, 8.26）], and [P = 0.001, MD = 0.26, 95%CI = （0.10, 0.41）]. Conclusions： TCM did not show significant recentclinical efficiency. However, treatment with TCM showed increase in KPS scores in patients with colorectal cancer,alleviation of toxicity associated with chemotherapy, regulation of autoimmunity, and improvement in the quality of lifeof patients.

Study on the Quality of Traditional Chinese Veterinary Medicine and Discussion on the Problems

In this paper,the study on the quality of traditional Chinese veterinary medicine and its existing problems are discussed,which mainly include the research techniques and research thoughts of traditional Chinese veterinary medicine,and the problems in its research progress,at the same time,the causes for the quality problems of traditional Chinese veterinary medicine are analyzed,and the solutions for the problems are put forward. The quality research of traditional Chinese veterinary medicine should refer to traditional Chinese medicine,then inherit,carry forward and innovate it based on the modern research. Solving the problems in the development of traditional Chinese veterinary medicine and putting forward the thinkings conforming to the development of traditional Chinese veterinary medicine using advanced instruments and devices as well as science and technology are urgent affairs.

Effects of Traditional Chinese Medicine Five-element Music Combined with Acupoint Application on Perioperative Sleep Quality in Patients Undergoing Joint Replacement Surgery

OBJECTIVE: To explore the effects of traditional Chinese medicine(TCM) five-element music combined with acupoint application on perioperative sleep quality in patients undergoing joint replacement surgery. METHODS: In this study, a total of 122 patients with joint replacement surgery in Beijing Jishuitan Hospital were targeted from 2015 to 2018. All patients were grouped by random number table method. Among them, 61 patients with routine nursing were included in the control group. On this basis, the other 61 patients with acupoint application and TCM five-element music therapy were included as the observation group. 2 weeks later, the Pittsburgh Sleep Quality Index(PSQI) was used to evaluate sleep quality in all patients. The sleep improvement of the 2 groups was evaluated, and the patient was assessed for anxiety and depression, and the curative efficacy was evaluated. RESULTS: After 2 weeks of nursing, the PSQI of the patients improved significantly. The PSQI of the observation group was only 6.6 ± 2.4, and the control group decreased to 9.9 ± 2.7. The observation group was better than the control group, and the difference was statistically significant(P < 0.05). Comparing the 2 groups, the anxiety score of the observation group decreased to 4.8 ± 1.6, which was significantly lower than that of 6.9 ± 2.2 in the control group. The depression score of the observation group decreased to 4.6 ± 1.3, which was significantly lower than that of 6.8 ± 2.3 in the control group. In the control group, the negative emotion scores after nursing were better than those before nursing, and the difference was statistically significant(P < 0.05). Comparing the 2 groups, the effective rate of sleep improvement in the observation group was 96.6%, and the cure rate was as high as 49.1%. The control group was 82.0%, and the cure rate was 18.0%. The observation group was better than the control group, and the difference was statistically significant(P < 0.05). CONCLUSION: The combination of TCM five-element music with acupoint application can improve the perioperative sleep quality of patients undergoing joint replacement surgery, and it can help patients to relieve negative emotions. It is worth promoting.

Discussion on the Quality Evaluation Method of Traditional Chinese Medicine Compound Preparations

As an important representative of the modernization of the Chinese medicine industry,traditional Chinese medicine(TCM)compound preparations are an indispensable part of the development of TCM.The complex ingredients and unclear action mechanism of TCM compound preparations restrict the development of TCM.In line with this problem,the modern TCM research has made extensive remarkable achievements.From the single indicator in the past to multiple indicator,the research on the combination of TCM fingerprints and pharmacodynamics also has made great progress.The introduction of quality evaluation methods such as the"quantitative analysis of multi-components by a single marker","dose-effect"indicator,"Bioactive Equivalent Combinatorial Components"(BECCs)and TCM quality markers have brought new ideas for quality control of TCM compound preparations.

Investigation of Heavy Metal Contents in Traditional Chinese Herbal Medicine Peristrophe roxburghiana Collected from Northwest of Guangxi

Objective] This study was conducted to evaluate the product quality and safety of Peristrophe roxburghiana_ col ected from different places in Hechi City, northwest of Gunagxi, so as to provide basic data for further development and uti-lization of the characteristic plant resource P. roxburghiana. [Method] Contents of 9 kinds of heavy metals including Cd, Mn, Pb, Zn and Cu in the herb were deter-mined by the method of wet digestion-flame atomic absorption spectrophotometry and atomic fluorescence spectrometry, respectively. [Results] Heavy metal contents of Cd, Mn, Pb, Fe, Cu, Zn, As, Hg and Se were 1.62-17.25, 8.93-142.53, 4.37-18.43, 103.7-242.81, 2.55-5.35, 85.40-146.30, 0.07-0.54, 0.00-0.08 and 0.00-0.47 mg/kg, respectively. According to the national food safety standards and Green Trade Standards of lmporting ＆amp; Exporting Medicinal plants ＆amp; Preparations, the heavy metal contents of the P. roxburghiana_samples col ected from different coun-ties in Hechi City exceeded standards or at the critical values. Among which, Cd, Pb and Zn contents of the samples are seriously higher than the standards. [Con-clusion] Therefore, the impact of soil heavy metal pol ution on the safety of edible plants in the northwest of Guangxi should be highly concerned.

International expert consensus on clinical application of traditional Chinese medicine formula granules

Guided by the theory of traditional Chinese medicine(TCM),TCM formula granules are made through the optimal process of extraction,concentration,drying,and granulation by combining modern new preparation technologies and pharmaceutical technologies.TCM formula granules are stable,safe,convenient,and effective.Compared with TCM decoction pieces,TCM formula granules can achieve the full process control of its industry chain from field to workshop and standardize the management of the origin of medicinal materials,processing of decoction pieces,processing technology,quality inspection,sales,and products distribution.TCM formula granules can partially replace Chinese patent medicines.Only available for around 800 common varieties of TCM,TCM formula granules cannot replace decoction pieces for many types which are not commonly used in clinical practice.A large number of formula granules are used in clinical and animal studies so that investigators no longer need to extract and control the quality of TCM decoction pieces.How to improve the production process,establish the quality standard,perfect the regulatory system,and expand the clinical application are the problems we need to solve as soon as possible for the better development of formula granules.

Quality 4.0 technologies to enhance traditional Chinese medicine for overcoming healthcare challenges during COVID-19

The Quality 4.0 concept is derived from the industrial fourth revolution,i.e.,Industry 4.0.Quality 4.0 is the future of quality,where new digital and disruptive technologies are used to maintain quality in organizations.It is also suitable for traditional Chinese medicine(TCM)to maintain quality.This quality revolution aims to improve industrial and service sectors’quality by incorporating emerging technologies to connect physical systems with the natural world.The proposed digital philosophy can update and enhance the entire TCM treatment methodology to become more effective and attractive in the current competitive structure of the pharmaceutical and clinical industries.Thus,in healthcare,this revolution empowers quality treatment during the COVID-19 pandemic.There is a major requirement in healthcare to maintain the quality of medical tools,equipment,and treatment processes during a pandemic.Digital technologies can widely be used to provide innovative products and services with excellent quality for TCM.In this paper,we discuss the significant role of Quality 4.0 and how it can be used to maintain healthcare quality and fulfill challenges during the pandemic.Additionally,we discuss 10 significant applications of Quality 4.0 in healthcare during the COVID-19 pandemic.These technologies will provide unique benefits to maintain the quality of TCM throughout the treatment process.With Quality 4.0,quality can be maintained using innovative and advanced digital technologies.

Translational Chinese Medicine: A Way for Development of Traditional Chinese Medicine

Translational Chinese medicine is one of the latest developing fields in traditional Chinese medicine. In this paper, we discuss the “3 w” namely, “what is”, “why to advance”, “how to carry out” and the significance of translational Chinese medicine. To overcome the innate drawbacks of traditional Chinese medicine (TCM), the basic theory of TCM had better be refreshed. The safety and efficacy of classic formulae and therapy experience of TCM should be evaluated based on strict quality control and reaffirmed with evidence based medicine. The significance of translational Chinese medicine is to transform Chinese medicine into a balanced, personalized medicine with sound safety, good efficacy and strict quality control.

Quality Evaluation on Traditional Chinese Medicine Nursing Plan for Stroke in Acute and Recovery Phases

OBJECTIVE: To formulate the quality evaluation questionnaire of Traditional Chinese Medicine(TCM) nursing plan for stroke in acute and recovery phases, and to evaluate the quality of TCM nursing plan for stroke by clinical nurses. METHODS: The questionnaire was designed by referring to the Applicability Questionnaire of TCM Clinical Diagnosis and Treatment Guideline, and the expert consultation was used to assess the content validity. In addition, the results of the questionnaire were processed and analyzed with SPSS20.0 software. RESULTS: The content validity of the self-designed questionnaire was 0.94 for the S-CVI/Ave score. The results of the questionnaire demonstrated that the overall content of the plan was "better than the original routine nursing plan"(59.18%); the recognition degree of "common symptoms"(36.70%) and "syndrome classification"(36.70%) of the plan was the lowest. CONCLUSION: The plan is supposed to be further improved in the future in order to be coincident with clinical reality.