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 Table of Contents  
STUDY PROTOCOL
Year : 2016  |  Volume : 1  |  Issue : 2  |  Page : 51-57

Efficacy of Qingxin Huatan therapy in regulating cardiac autonomic nerve function in patients with chronic stable angina: study protocol for a randomized controlled trial


Department of Emergency, Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing, China

Date of Web Publication7-Jul-2016

Correspondence Address:
Hong-hao Ma
Department of Emergency, Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2468-5658.184744

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  Abstract 

Background: Coronary heart disease is a chronic degenerative disease of the coronary arteries characterized by atherosclerosis. Lianxia Ningxin granules, a traditional Chinese medicine, is a representative preparation of Qingxin Huatan therapy, which has been confirmed to be effective in improving autonomic nerve dysfunction in patients with coronary heart disease.
Methods/Design: We herein describe a prospective, single-center, randomized, double-blind, placebo-controlled trial to be performed by the Department of Cardiovascular Medicine, Third Affiliated Hospital of Beijing University of Chinese Medicine, China. Eighty patients with chronic stable angina will be randomly assigned to receive 4 weeks of treatment with either Western medicine plus Lianxia Ningxin granules (traditional Chinese medicine group) or Western medicine plus placebo (control group). All patients will be followed up for 8 weeks. The primary outcome is frequency of angina attacks. The secondary outcomes include heart rate variability, plasma catecholamine concentrations, nitroglycerin consumption, duration of angina, severity of angina pain, efficacy of traditional Chinese medicine treatment, and quality of life.
Discussion: This study is designed to assess the efficacy of Qingxin Huatan therapy in treating chronic stable angina, and simultaneously investigate the regulatory effects of this therapy on cardiac autonomic nerve function and related neurotransmitter concentrations. The outcomes will provide information concerning the clinical use of Qingxin Huatan therapy to treat chronic stable angina and its ability to regulate cardiac autonomic nervous function.
Trial registration : This protocol was registered at the Chinese Clinical Trial Registry (registration number: ChiCTR-TRC-14004699).
Ethics: Written approval has been obtained from the Medical Ethical Committee, Third Affiliated Hospital of Beijing University of Chinese Medicine, China (approval number: KTPJ-BZYSY-2003-003).
Informed consent: Written informed consent will be obtained from patients or their guardians prior to inclusion in this study.

Keywords: clinical trial; coronary heart disease; stable angina; phlegm-heat syndrome; heart rate variability; noradrenalin; adrenalin; dopamine; randomized controlled trial


How to cite this article:
Li P, Ma Hh. Efficacy of Qingxin Huatan therapy in regulating cardiac autonomic nerve function in patients with chronic stable angina: study protocol for a randomized controlled trial. Clin Trials Degener Dis 2016;1:51-7

How to cite this URL:
Li P, Ma Hh. Efficacy of Qingxin Huatan therapy in regulating cardiac autonomic nerve function in patients with chronic stable angina: study protocol for a randomized controlled trial. Clin Trials Degener Dis [serial online] 2016 [cited 2018 Dec 14];1:51-7. Available from: http://www.clinicaltdd.com/text.asp?2016/1/2/51/184744

Conflicts of interest
None declared.
Author contributions
HHM conceived and designed the protocol. PL wrote the manuscript, performed statistical analysis, and collected the data. All authors approved the final version of this manuscript for publication.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.



  Background Top


Coronary heart disease is a chronic degenerative disease characterized by coronary artery atherosclerosis. Angina, the most common clinical manifestation of coronary heart disease, is a clinical syndrome characterized mainly by transient myocardial ischemia. Patients with coronary heart disease generally present with varying degrees of cardiac autonomic nerve dysfunction that manifests clinically as increased sympathetic activity and decreased vagus nerve activity (Fallen, 2005; Tang et al., 2006). Catecholamines secreted by sympathetic nerves initiate atherosclerosis and stimulate coronary artery constriction via multiple pathways (Bai, 2012). Treatment of coronary heart disease should therefore not only improve poor perfusion but also regulate autonomic nerve dysfunction, the latter manifesting clinically as chest pain or tightness and a choking sensation. From the perspective of traditional Chinese medicine (TCM), patients generally have the following symptoms: palpitations, dizziness, insomnia, anxiety, mental confusion, dry mouth, dry stools, oliguria, red tongue, and slippery pulse. In TCM, cardiac autonomic nerve dysfunction manifesting these symptoms belongs to the category of phlegm-heat syndrome of coronary heart disease, a syndrome that reportedly readily leads to cardiac autonomic nerve dysfunction (Wang et al., 2011; Bai, 2012). To the best of our knowledge, no clinical studies have been performed on the efficacy of Qingxin Huatan therapy in the treatment of cardiac autonomic nerve dysfunction in patients with chronic stable angina. Therefore, we planned to investigate the effects of Lianxia Ningxin granules, a representative preparation of Qingxin Huatan therapy, which comprises mainly heart-fire clearing and phlegm-removing preparations supplemented with blood circulation-promoting and qi-regulating preparations, on cardiac autonomic nerve function and plasma catecholamine concentrations in patients with chronic stable angina and phlegm-heat syndrome through a randomized, placebo-controlled trial.


  Methods/Design Top


Study design

A prospective, single-center, randomized, double-blind, placebo-controlled trial.

Study setting

Third Affiliated Hospital of Beijing University of Chinese Medicine, China.

Study procedure

This study protocol was registered at the Chinese Clinical Trial Registry (registration number: ChiCTR-TRC-14004699) on 23 May 2014. Eighty eligible patients with coronary heart disease and angina attending Third Affiliated Hospital of Beijing University of Chinese Medicine, China will be randomly assigned to receive 4 weeks of treatment with either Western medicine plus Lianxia Ningxin granules (TCM group, n = 40) or Western medicine plus placebo (control group, n = 40). All patients will be followed up for 8 weeks. A flow chart of the study protocol is shown in [Figure 1].
Figure 1: Flow chart of study protocol.
Note: TCM: Traditional Chinese medicine; HRV: heart rate variability; CA: catecholamine; wk: week(s).


Click here to view


Study participants

Eighty patients with coronary heart disease and chronic stable angina presenting with cardiac autonomic nerve dysfunction will be enrolled in this study according to the following inclusion and exclusion criteria.

Diagnostic criteria

The diagnostic criteria in this trial were derived from the following three sets of guidelines.

First, from the Guidelines for Diagnosis and Treatment of Chronic Stable Angina Pectoris (Chinese Society of Cardiology of Chinese Medical Association; Editorial Board of Chinese Journal of Cardiology, 2007): (1) A diagnosis of angina should be made according to the likelihood of coronary heart disease, this being evaluated based on occurrence of and characteristics of chest pain, age, sex, cardiovascular risk factors, and previous history of disease, findings on physical examination, and related examinations. (2) In patients with stenosis ≥ 50% in at least one main branch of a coronary artery experiencing physical or mental stress, coronary arterial blood flow does not completely meet the requirements for myocardial metabolism, leading to myocardial ischemia or hypoxia, which finally results in angina, the symptoms of which are mitigated by rest or oral nitroglycerin. (3) The severity, frequency and nature of, and predisposing factors for, chronic stable angina have not altered in the previous few weeks.

Second, from the American College of Cardiology/American Heart Association 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction (Braunwald et al., 2002): (1) Coronary heart disease diagnosis based on radiographic findings of stenosis > 70% in at least one main branch of a coronary artery or stenosis > 50% in the left main coronary artery. (2) Angina can occur even when vascular injury is less extensive than described in the previous criterion. Chronic stable angina of coronary heart disease is defined as angina where the severity, frequency, and nature of, and predisposing factors for, have not altered within the previous few weeks.

Third, from the Standard for Traditional Chinese Medicine (TCM) Diseases and Syndromes Therapeutic Results (State Administration of Traditional Chinese Medicine, 1994), a national diagnosis standard for diagnosing phlegm-heat syndrome of coronary heart disease formulated in China: (1) Chest pain because of obstruction of qi in the chest, characterized by choking pain in the chest, sometimes referred to the back. (2) Phlegm-heat syndrome: a morbid condition marked by heart burn, feeling of fullness in the chest, cough and dyspnea, retention of phlegm, limb pain, depression and fatigue, dry mouth, bitter taste in the mouth, anger, irritability, insomnia, fat red tongue with a greasy yellow coat, and slippery pulse.

Inclusion criteria

All of following must be met for consideration for inclusion in the planned trial?

  • Coronary heart disease diagnosed by coronary arteriography or coronary computed tomography angiography, recurred myocardial infarction complicated by angina, or angina recurrence after percutaneous coronary intervention or coronary artery bypass
  • Stable disease (i.e., no electrocardiographic ST abnormality when chest pain or distress occurs) in the previous 3 months
  • Canadian Cardiovascular Society Classification class II-III (Campeau, 2002)
  • Coronary heart disease and chronic stable angina with phlegm-heat syndrome or stable coronary heart disease complicated by cardiac autonomous nerve dysfunction
  • Aged 45-75 years
  • Able to understand and sign written informed consent.


Exclusion criteria

Patients presenting with any of the following conditions will be excluded from the trial:

  • Acute coronary syndrome of coronary heart disease
  • Blood pressure > 24/14.67 kPa (180/110 mmHg), poor blood pressure control
  • Cardiac function grade III or above
  • Severe arrhythmias such as atrial fibrillation, atrial flutter, frequent ectopic beats, frequent ventricular tachycardia, and supraventricular tachycardia
  • Severe heart disease as evidenced by heart failure or sick sinus syndrome or serious comorbidities such as cardiomyopathy, diabetes mellitus accompanied by peripheral neuropathy, severe hepatic and renal inadequacy, chronic obstructive pulmonary disease, and asthma
  • Mental disorder
  • Climacteric syndrome


Withdrawal criteria

Patients will be withdrawn from the trial under any of the following circumstances:

  • Withdrawal of informed consent and refusal to continue treatment
  • Occurrence of serious adverse events related to the therapy
  • Medication not taken as prescribed
  • Incomplete records of medication
  • Misdiagnosis
  • Loss of contact with patients during follow-up


Randomization

Prior to treatment, one serial number will be randomly assigned using SAS9.1.3 software to each patient by a researcher who is not participating in the trial. After acquiring informed consent, another researcher will randomly allocate the patients to either the TCM or control group by telephone. The groups assigned will be preserved in opaque sealed envelopes by a researcher who will not participate in treatment and data analysis. After completion of baseline data collection, the groups assigned will be fully disclosed to a statistician for analysis.

Blinding

With the exception of nurses who will deliver the drugs, the physicians, patients, evaluators and statistician will be blinded to group assigned.

Sample size

According to a previous study (Zhang et al., 2014), the response rates in the TCM and control groups are expected to be 88.5% and 60%, respectively. The number required in each group to achieve a significance level of α = 0.05 with power (1-β ) = 0.80 was calculated by a two-sided chi-square test without continuity correction. The final effective sample size was determined to be n = 37 per group. We will include 80 patients in this study (n = 40 per group).

Recruitment

Patients in the wards or attending clinics will be informed about the trial by their attending physicians. Possible eligible patients will also be informed about the trial through recruitment advertisements on hospital and community posters, leaflets, newspapers, and radio. Those interested in participating will contact their attending physicians via telephone, E-mail or WeChat. After providing written informed consent, all potential participants will be screened according to the above inclusion and exclusion criteria.

Interventions

TCM group


Patients in this group will receive standard Western medicines, namely oral nitrates, statins, beta-blockers, and antiplatelet agents (Chinese Society of Cardiology of Chinese Medical Association, Editorial Board of the Chinese Journal of Cardiology, 2007) plus Lianxia Ningxin granules. Lianxia Ningxin granules contain Huang Lian (Golden Thread, Rhizoma Coptidis) 6 g, Jiang Ban Xia (pinellia tuber processed with ginger, Rhizoma Pinelliae) 6 g, Chen Pi (dried tangerine peel, Pericarpium Citri Reticulatae) 10 g, Fu Ling (Poria, Sclerotum Poroiae Cocos) 15 g, Zhu Ru (bamboo shavings, Caulis Bambusae in Taeniam) 10 g, Zhi Qiao (bitter orange, Fructus Aurantii) 10 g, Shi Chang Pu (grassleaf sweetflag rhizome, Rhizoma Acori Tatarinowii) 10 g, Yu Jin (turmeric tuber, Radix Curcumae) 15 g, and Shou Wu Teng (tuber fleeceflower stem, Caulis Polygoni Multiflori) 45 g.

The actions of each ingredient are shown in [Table 1].
Table 1: The actions of each ingredient of Lianxia Ningxin granules

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Control group

Patients in this group will receive standard Western medicines the same as in the TCM group plus an oral placebo. The placebo will comprise 10% Lianxia Ningxin granules and 90% starch and its shape, color, flavor, and wrapping will be the same as for full-strength Lianxia Ningxin granules. Both the Lianxia Ningxin granules and placebos will be prepared by Beijing Tcmages Pharmaceutical, China to the standards of good manufacturing practice (Zhu, 1998). Both Lianxia Ningxin granules and placebos will be dissolved in 100 mL of water at 30-37°C prior to use and the solution drunk on two occasions daily (once in the morning and once in the evening) for 4 successive weeks. One week prior to and during the study, other Chinese medicines for coronary disease will be withdrawn.

Outcome measures

Primary outcome


  • Frequency of angina attacks 2, 4 and 8 weeks after treatment


Secondary outcomes

  • Variability in heart rate. Four weeks after treatment, heart rate variability will be evaluated by 24-hour electrocardiographic recordings. An Oxford Medilog recorder will be used to analyze the following four heart rate variability indices: (1) standard deviation of all normal-to-normal intervals (SDNN), (2) standard deviation of means of normal-to-normal intervals (SDANN), measured from 288 successive 5-minute recording segments; (3) the square root of the mean of the sum of squares of differences between all adjacent normal-to-normal intervals (RMSSD); and (4) the percentage of normal-to-normal interval differences > 50 ms from the preceding interval (pNN50). Variability in heart rate is currently the only index that reflects cardiac autonomic nerve function and regulation. It closely reflects the severity of coronary heart disease (Zorin et al., 1999).
  • Plasma catecholamine concentrations. Four weeks after treatment, blood will be taken from the cubital vein, transferred to a tube containing an anticoagulant and centrifuged for measurement of epinephrine, norepinephrine and dopamine concentrations using an enzyme-linked immunosorbent assay kit (IBL, Hamburg, Germany). More severe coronary artery stenosis leads to more obvious cardiac autonomic dysfunction characterized by release of more catecholamines by the sympathetic nervous system, which increases the heart rate and thus ensures blood supply to the heart (Yang et al., 2008).
  • Nitroglycerin consumption. Evaluation 2, 4 and 8 weeks after treatment.
  • Duration of angina. Evaluation 2, 4 and 8 weeks after treatment.
  • Severity of angina pain. Evaluation 2, 4 and 8 weeks after treatment.
  • Efficacy of TCM therapy in the treatment of phlegm-heat syndrome. four-diagnosis assessments (Ma, 2015) will be performed 2 and 4 weeks after treatment. Higher scores indicate more severe symptoms. The symptoms will be evaluated according to the Guiding Principle of Clinical Research on New Drugs of Traditional Chinese Medicine (Trial Implementation) (Zheng, 2002) and will be graded as follows: (1) Obviously effective: clinical symptoms and physical signs have improved greatly as indicated by a curative effect index ≥ 70%, this index being calculated according to the patient's clinical symptoms and physical signs (scores prior to treatment − scores after treatment)/scores prior to treatment ×100%). (2) Effective: clinical symptoms and physical signs have improved slightly as indicated by a curative effect index between 30% and 70%. (3) Ineffective: clinical symptoms and physical signs have not improved or have worsened (curative effect index = 0) compared with prior to treatment, with curative effect index < 30%.
  • Quality of life. Evaluation 2 and 4 weeks after treatment using the Seattle Angina Questionnaire (Kimble et al., 2002), which consists of 11 questions covering five domains. Domain 1 (Question 1, comprising nine sub-questions) is designed to evaluate limitation in amount of movement; Domain 2 (Question 2) to evaluate the stability of angina; Domain 3 (Questions 3 and 4) to evaluate the frequency of angina; Domain 4 (Questions 5-8) to evaluate satisfaction with treatment; and Domain 5 (Questions 9-11) to evaluate the patient's perceptions. The questionnaire has a 100-point scale, higher scores indicating better quality of life.


Patients' baseline and clinical characteristics are shown in [Table 2] and the schedule for assessments of outcomes is shown in [Table 3].
Table 2: Patient's baseline and clinical characteristics

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Table 3: Schedule for assessments of outcomes

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Adverse events

To investigate the safety of Qingxin Huatan therapy, routine blood tests including hepatic and renal function tests and electrocardiograms will be monitored throughout the trial. Possible adverse events include any unexpected or uncomfortable symptoms, signs, or other evidence of disease. If adverse events occur, their details will be recorded in case report notes and reported to the Ethics Committee, Third Affiliated Hospital of Beijing University of Chinese Medicine, China.

Data collection, management, analysis and open access

All data will be recorded on case report forms and the collated data input into an electronic database by a professional member of staff using a double-data entry strategy. The accuracy of the data will be checked when all recruited patients have completed follow-up. The database will be locked by the researcher in change and will not be altered. All information regarding this trial will be preserved by Third Affiliated Hospital of Beijing University of Chinese Medicine, China. The full electronic database will be supplied to a professional statistician for statistical analysis. Anonymized trial data will be published at http://www.figshare.com.

Statistical analysis

All data will be statistically processed by a statistician blind to grouping using SPSS 17.0 software. The statistical analysis of this study will follow intention-to-treat principles. Normally distributed data will be expressed as the mean ± SD. Numeration data will be expressed as percentages. P < 0.05 will be considered statistically significant. Repeated measures analysis of variance will be used for comparison of measurement data between the TCM and control groups at baseline and 2, 4, and 8 weeks after treatment. Tukey test will be used for pairwise comparisons if significant differences between these two groups are identified. The chi-square test will be used for comparison of numeration data between the two groups.

Auditing

Trial progression will be reported to the ethics committee of Third Affiliated Hospital of Beijing University of Chinese Medicine, China every 3-6 months and the trial's status will be updated in the registration database.

Confidentiality

All trial data, including medical case notes, will be preserved in a dedicated password-protected computer and managed by a data management professional. Data recorded on paper will be preserved in a secure, locked place for future viewing.


  Discussion Top


The outcomes from this study will provide novel clinical data-based evidence for use of Qingxin Huatan therapy in treating chronic stable angina in coronary heart disease with phlegm-heat syndrome and will further investigate the mechanism(s) of this therapy.

This will be the first randomized placebo-controlled trial to investigate the efficacy of Qingxin Huatan therapy in treating chronic stable angina in coronary heart disease with phlegm-heat syndrome and the first trial protocol regarding Qingxin Huatan therapy for phlegm-heat chronic stable angina from the perspectives of cardiac autonomic nerve function and related neurotransmitter concentrations.

Trial status

Recruiting is ongoing at the time of submission. [16]

 
  References Top

1.
Bai FF (2012) Assessment of Anxiety and Plasma Catecholamine Level in Patients with Coronary Heart Disease and Angina with Phlegm Heat Syndrome. Beijing: China Academy of Chinese Medical Sciences.  Back to cited text no. 1
    
2.
Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE 3rd, Steward DE, Theroux P, Gibbons RJ, Alpert JS, Faxon DP, Fuster V, Gregoratos G, et al. (2002) ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction--2002: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 106:1893-1900.  Back to cited text no. 2
    
3.
Campeau L (2002) The Canadian Cardiovascular Society grading of angina pectoris revisited 30 years later. Can J Cardiol 18:371-379.  Back to cited text no. 3
    
4.
Chinese Society of Cardiology of Chinese Medical Association, Editorial Board of Chinese Journal of Cardiology (2007) Guidelines for diagnosis and treatment of chronic stable angina pectoris. Zhonghua Xinxueguan Bing Zazhi 35:195-206.  Back to cited text no. 4
    
5.
Fallen EL (2005) Vagal afferent stimulation as a cardioprotective strategy? Introducing the concept. Ann Noninvasive Electrocardiol 10:441-446.  Back to cited text no. 5
    
6.
Kimble LP, Dunbar SB, Weintraub WS, McGuire DB, Fazio S, De AK, Strickland O (2002) The Seattle angina questionnaire: reliability and validity in women with chronic stable angina. Heart Dis 4:206-211.  Back to cited text no. 6
    
7.
Ma NN (2015). Qingxin Huatan Therapy for Phlegm-Heat Syndrome in Coronary Heart Disease. Beijing: Beijing University of Chinese Medicine   Back to cited text no. 7
    
8.
State Administration of Traditional Chinese Medicine (1994) Standard for Traditional Chinese Medicine (TCM) Diseases and Syndromes Therapeutic Results.   Back to cited text no. 8
    
9.
Tang WH, Zhang Q, Sun ZB, Chen XJ (2006) Effects of varying degrees of coronary artery disease on heart rate variability. Guangxi Yixue 28:1517-1520.   Back to cited text no. 9
    
10.
Wang LH, Li P, Ma HH, Bai FF, Liu WN (2011) Explorative research on heart rate variability of coronary heart disease of differenct Chinese medicine syndromes. Shijie Zhongxiyi Jiehe Zazhi 6:119-121.  Back to cited text no. 10
    
11.
Yang DH, Xu XQ, Zhu XL (2008) Effects of coronary artery stenosis and PCI on heart rate variability in patients with coronary heart disease. Zhongxiyi Jiehe Xin Nao Xueguan Bing Zazhi 6:1351-1352.  Back to cited text no. 11
    
12.
Zhang HN (2014) Berberine-pinellia formula′s prevention and treatment of sudden death in malignant cardiac event by a intervention in autonomic nervous remodeling after myocrdial infarction. Beijing: Guang′anmen Hospital, China Academy of Chinese Medical Sciences.  Back to cited text no. 12
    
13.
Zhang Z, Zhang F, Wang Y, Du Y, Zhang H, Kong D, Liu Y, Yang G (2014) Traditional Chinese medicine for stable angina pectoris via TCM pattern differentiation and TCM mechanism: study protocol of a randomized controlled trial. Trials 15:422.  Back to cited text no. 13
    
14.
Zheng XY(2002) Guiding Principle of Clinical Research on New Drugs of Traditional Chinese Medicine (Trial Implementation). Beijing: China Medical Science and Technology Publishing House.  Back to cited text no. 14
    
15.
Zhu YP (1998) Chinese Material Medical: Chemistry, Pharmacology, and Applications. Amsterdam: Harwood Academic.  Back to cited text no. 15
    
16.
Zorin AV, Noeva EA, Khaspekova NB, Fedorova VI, Oknin VIu, Shchennikov AV (1999) Defects in autonomic regulation in myocardial ischemia. Ter Arkh 71:57-61.  Back to cited text no. 16
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]


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