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 Table of Contents  
RESEARCH ARTICLE
Year : 2018  |  Volume : 3  |  Issue : 3  |  Page : 66-73

Calcitonin plus calcium for viral cirrhosis with osteoporosis: a randomized, parallel, controlled clinical trial


1 Department of Pharmacy, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, Shandong Province, China
2 State-owned Assets Division, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, Shandong Province, China
3 Department of Osteoarthritis and Sports Medicine, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, Shandong Province, China
4 Emergency Department, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, Shandong Province, China

Date of Submission02-Jun-2018
Date of Decision13-Jul-2018
Date of Acceptance20-Jul-2018
Date of Web Publication10-Sep-2018

Correspondence Address:
Ai-Qun Li
Emergency Department, Yantai Affiliated Hospital, Binzhou Medical University, Yantai, Shandong Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-4157.240469

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  Abstract 

Background and objectives: In patients with osteoporosis and cirrhosis, the relative deficiency of vitamin D may result in osteomalacia and endocrine disorders. Few studies have investigated drug treatment for chronic liver disease combined with osteoporosis. This study will determine the efficacy and safety of salmon calcitonin combined with calcium in the treatment of viral cirrhosis with osteoporosis.
Methods: This prospective, single-center, open-label, randomized, parallel, controlled, 2-year follow-up clinical trial includes 102 outpatients and hospitalized patients with viral cirrhosis plus osteoporosis in Yantai Affiliated Hospital, Binzhou Medical University, China. The 102 patients are equally and randomly divided into two groups. The control group receives oral calcium, while the combination group will receive intramuscular salmon calcitonin plus oral calcium; both groups receives treatment for 24 months. This trial was approved by the Ethics Committee, Yantai Affiliated Hospital, Binzhou Medical University in July 2018 (approval No. 2018071601). The study protocol has been conducted in accordance with the Declaration of Helsinki, formulated by the World Medical Association. Written informed consent is obtained from all participants.
Results: The primary outcome measure is bone mineral density at L2–4 at 24 months after treatment commences. Secondary outcome measures include bone mineral density at L2–4 before treatment, and at 6 and 12 months after treatment commences; bone mineral density of the femoral neck and Ward’s triangle at 6, 12, and 24 months after treatment commences; serum calcium, phosphorus, 1,25(OH)2D3, parathyroid hormone, osteocalcin, interleukin-10, interleukin-6, tumor necrosis factor-alpha, and insulin-like growth factor 1 levels before treatment, and at 6, 12 and 24 months after treatment commences; adverse reaction rate at 6, 12, and 24 months after treatment commences. Our team obtained preliminary results from 2012 to 2016 for 64 patients. The 12-month follow-up results found that compared with the control group (n = 32), the combination group (n = 32) had significantly increased levels of serum calcium, 1,25(OH)2D3, interleukin-10, and insulin-like growth factor 1, and significantly increased bone mineral density at L2–4, femoral neck, and Ward’s triangle, but significantly reduced levels of serum phosphorus, parathyroid hormone, osteocalcin, interleukin-6, and tumor necrosis factor-alpha (all P < 0.05).
Conclusion: The results verify that salmon calcitonin combined with calcium is suitable for the treatment of viral cirrhosis with osteoporosis.
Trial registration: This trial was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR1800017732) on August 11, 2018. Protocol version (1.0).

Keywords: osteoporosis; viral cirrhosis; calcitonin; calcium; bone mineral density; phosphorus; 1,25(OH)2D3; interleukin-10; interleukin-6; parathyroid hormone; tumor necrosis factor-alpha; osteocalcin; insulin-like growth factor 1; bone metabolism


How to cite this article:
Wang JF, Liu T, Zhou BS, Li AQ. Calcitonin plus calcium for viral cirrhosis with osteoporosis: a randomized, parallel, controlled clinical trial. Clin Trials Orthop Disord 2018;3:66-73

How to cite this URL:
Wang JF, Liu T, Zhou BS, Li AQ. Calcitonin plus calcium for viral cirrhosis with osteoporosis: a randomized, parallel, controlled clinical trial. Clin Trials Orthop Disord [serial online] 2018 [cited 2018 Dec 12];3:66-73. Available from: http://www.clinicalto.com/text.asp?2018/3/3/66/240469


  Introduction Top


Research background

Chronic liver disease often leads to osteoporosis and is a risk factor for osteoporosis.[1],[2],[3] Patients with chronic liver disease and cirrhosis have a relatively decreased metabolic capacity of the liver, resulting in a relative lack of vitamin D, mineralization failure of normal trabecular bone, bone softening, trabecular bone fracture, and imbalances of osteocalcin, 1,25(OH)2D3, and parathyroid hormone.[4] There are currently few treatment options for osteoporosis associated with chronic liver disease, and many drugs used for the clinical treatment of osteoporosis have not been evaluated. Patients with osteoporosis often require oral calcium; however, the efficacy of calcium alone is limited.[5]

Calcitonin is an important calcium- and phosphorus-regulating hormone that can reduce blood calcium and blood phosphorus, and has a huge impact on bone tissue metabolism.[6],[7],[8],[9] Calcitonin not only regulates the proliferation and apoptosis of osteoclasts, but also stimulates the proliferation, differentiation, and mineralization of osteoblasts. The results of recent clinical studies evaluating the use of calcitonin for osteoporosis are summarized in [Table 1].[10],[11],[12]
Table 1: Most representative three clinical studies evaluating calcitonin as a treatment for osteoporosis between 2014– 2016

Click here to view


Main objective of this study

The effects of salmon calcitonin combined with calcium on bone biochemistry, metabolic parameters, cytokines, and bone mineral density (BMD) in patients with viral cirrhosis and osteoporosis will be observed in the expanded sample size of 102 cases during 2 years of follow-up.


  Subjects/Methods Top


Study design

This is a prospective, single-center, randomized, parallel, controlled 2-year follow-up clinical trial.

This trial was approved by the Ethics Committee, Yantai Affiliated Hospital, Binzhou Medical University in July 2018 (approval No. 2018071601) (Additional file 1 [Additional file 1]). This study follows the the Consolidated Standards of Reporting Trials (CONSORT) statement (Additional file 2 [Additional file 2]). Written informed consent is obtained from all participants (Additional file 3 [Additional file 3]). Protocol version (1.0).

Study setting

Yantai Affiliated Hospital, Binzhou Medical University, Yantai, Shandong Province, China.

Subjects

Recruitment

The ethics committee of Yantai Affiliated Hospital, Binzhou Medical University approved the study protocol and recruitment advertisements before the recruitment information was released.

The recruitment notice listing the study details is posted on the bulletin board of Yantai Affiliated Hospital of Binzhou Medical University in China. Recruitment information is also provided in relevant WeChat groups to recruit healthy volunteers into the control group.

Patients (or family members) who are interested in participating in the study directly contact the project leader to attain information about trial-related matters. Patients are included in the study after screening in accordance with the inclusion criteria described below.

After enrollment, patients undergo free blood biochemical tests during follow-up. The hospital reimburses the round-trip transportation expenses for follow-up.

Participant selection

This study includes 102 outpatients and hospitalized patients with viral cirrhosis combined with osteoporosis in Yantai Affiliated Hospital, Binzhou Medical University, China.

Inclusion criteria

  • Must meet the diagnostic criteria for viral cirrhosis presented at the National Conference on Viral Hepatitis in Xi’an[13]
  • Must meet the WHO diagnostic criteria for osteoporosis of bone loss of 2.5 SD or more[14]
  • Age between 45 and 75 years
  • No usage of antiosteoporotic drugs (such as estrogen, calcium, bisphosphonates, and vitamin D) or other drugs that affect bone metabolism in the previous 6 months
  • Provision of informed consent


Exclusion criteria

  • Obviously abnormal liver and kidney function: Abnormal liver function: aspartate aminotransferase is greater than 50 M; glutamic pyruvic transaminase is greater than 40 M. Abnormal kidney function: Normal serum creatinine is 54–106 μM in males, and 44–97 μM in females. The subject whose level is not in this range is considered as having abnormal renal function
  • Metabolic bone disease, chronic liver and kidney diseases, and autoimmune diseases that interfere with bone metabolism
  • Secondary osteoporosis
  • Intake of drugs that affect cytokine production in the past 2 months, such as glucocorticoids, non-steroidal anti-inflammatory drugs, and immunomodulators
  • Other low bone mass metabolic diseases and other serious cardiovascular and cerebrovascular diseases, such as ischemic heart disease, peripheral vascular disease, cerebrovascular disease, and uncontrolled hypertension
  • Uterine and breast diseases
  • Allergy to salmon calcitonin


Withdrawal criteria

  • Compliance with the inclusion criteria, but failure to take the medication on time during the follow-up period
  • Complete loss of case follow-up data


Grouping and blinding

A random number table is generated using SAS 9.2 statistical software (SAS Institute Inc., Cary, NC, USA), and the subjects are numbered from 1–102. The RANUNI function is used to generate a random number (either 0 or 1) for each subject. Proc sort is used to sort these random numbers, and parallel grouping is done in a 1:1 ratio. The 102 patients are equally and randomly divided into two groups; those in the combination group receive intramuscular salmon calcitonin combined with oral calcium, while the control group receives oral calcium treatment. Treatment is given for 24 months in both groups.

This is an open-label trial, without double-blind grouping and allocation concealment. The clinicians examining the blood biochemical test results and the laboratory results are blinded to the trial protocol.

Treatment programs

Both groups are treated with conventional liver protection. The control group is given oral calcium carbonate D3 tablets (Caltrate; Wyeth Pharmaceutical Co., Ltd.; approval number: GYZZ H10950039; one 600 mg tablet once or twice daily), and supplemented by conventional rehabilitation exercises (walking and muscle training). The combination group is given the same treatment as the control group, and is also intramuscularly injected with salmon calcitonin (Hybio Pharmaceutical Co., Ltd., Shenzhen, China; approval number: GYZZ H20040302; specification: 1 mL = 50 IU); if the skin test shows a negative reaction, 50 IU will be given intramuscularly once a day for 2 weeks, and then once every 3 days from the 3rd week until the end of the 24-month follow-up period.

Outcome measures

Primary outcome measure

BMD at lumbar vertebrae 2–4 (L2–4) at 24 months after the start of treatment.

BMD at L2–4 is measured before and after treatment with XR-600 dual-energy X-ray absorptiometry (Norland, USA). The normal BMD values at L2–4 of Chinese adult males and females are 1.228 g/cm3 and 1.197 g/cm3, respectively. [15] BMD at L2–4 is measured at 24 months after the start of treatment in each group, and the difference between the BMD at L2–4 24 months after the start of treatment and the BMD at L2–4 at baseline is calculated.

Secondary outcome measures

  • BMD at L2–4 before treatment, and at 6 and 12 months after the start of treatment. The detection method is the same as above.
  • BMD of the femoral neck and Ward’s triangle at 6, 12, and 24 months after the start of treatment. BMD is measured with XR-600 dual-energy X-ray absorptiometry (Norland) before and after treatment. The differences between the BMD at the femoral neck and Ward’s triangle at 6, 12, and 24 months after the start of treatment compared with baseline are considered the observation results.
  • Serum calcium, phosphorus, 1,25(OH)2D3, parathyroid hormone, osteocalcin, interleukin-10, interleukin-6, tumor necrosis factor-alpha and insulin-like growth factor 1 levels before treatment, and at 6, 12 and 24 months after treatment. Osteoporotic patients present with low blood calcium and high blood phosphorus. Calcitonin inhibits intestinal calcium absorption, reduces plasma calcium and phosphorus concentrations, and inhibits calcium and phosphorus absorption. Parathyroid hormone promotes osteolysis of osteoclasts. 1,25(OH)2D3 promotes intestinal calcium and phosphorus absorption, and maintains calcium balance. Insulin-like growth factor 1 stimulates collagen formation and osteoblasts. Interleukin-10 is produced by monocytes, osteoblasts, and osteoclasts, and inhibits the development and formation of osteoclasts and affects bone metabolism. The synthesis of insulin-like growth factor 1 and interleukin-10 is reduced in osteoporosis, resulting in decreased numbers of osteoblasts, decreased activity, and bone loss. Inflammatory mediator interleukin-6 and tumor necrosis factor-alpha are strong bone resorption factors; increased levels of interleukin-6 and tumor necrosis factor-alpha can promote bone resorption by increasing the number of osteoclasts.
  • Detection of osteoporosis-related indicators. Fasting venous blood samples (10 mL) are obtained from each subject in the morning. One half of the blood sample (5 mL) is used for the detection of serum calcium and phosphorus levels using an ADVIA 2400 auto analyzer (Siemens, Germany) at the Clinical Laboratory of our hospital. The other half of the blood sample (5 mL) is centrifuged within 10 minutes of collection, and the serum is stored in a refrigerator for the later detection of 1,25(OH)2D3, calcitonin, and parathyroid hormone levels. Parathyroid hormone levels are measured by immunoradiometric assay with a kit (Diagnostic Products Corporation, Los Angeles, CA, USA). 1,25(OH)2D3 and calcitonin levels are determined by competitive radioreceptor assay with a kit (Diasorin, Stillwater, NJ, USA). The levels of serum interleukin-6, interleukin-10, tumor necrosis factor-alpha, and insulin-like growth factor 1 before and after treatment are measured by immunoluminescence with a kit (Pharmingen, San Diego, CA, USA).
  • Adverse reaction rates at 6, 12, and 24 months after the start of treatment. Drug-related adverse reactions (such as nausea, vomiting, fever, belching, constipation, anaphylaxis, hypercalcemia, alkalosis, and renal dysfunction) are recorded during follow-up, and the adverse reaction rate is calculated at each follow-up timepoint.


The schedule of outcome assessments is shown in [Table 2].
Table 2: Schedule of outcome assessments

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Adverse events

Definition

Any adverse medical event that occurs after a patient or subject receives a drug, regardless of whether there is a causal relationship with the treatment.

Severe adverse events

A severe adverse event is defined as any event that occurs during the clinical trial that results in hospitalization, prolonged hospitalization, disability, a life-threatening condition, or death.

Management of adverse events

Control Before the trial, the team members are familiarized with the prevention and treatment of potential adverse events, and the emergency plans. If a severe adverse event occurs, clinical physicians will report the details to the principle researcher and the drug clinical trial agency office within 2 hours. The drug clinical trial agency office will report to the provincial food and drug administration, ethics committee, and sponsor within 24 hours. Simultaneously, the clinical physician will record the adverse events, including at least a description of the adverse event, time of occurrence, time of termination, degree and frequency of episodes, whether treatment is needed, and what treatment was implemented (if any). The clinical physician will perform treatment in accordance with the patient’s condition, and will initiate a medical treatment plan to treat the adverse event (if necessary) and prevent its recurrence.

Trial procedure

A total of 102 subjects are included. [Figure 1] shows the flow chart of the study protocol.
Figure 1: Trial flow chart.
Note: BMD: Bone mineral density.


Click here to view


Sample size

According to our preliminary results and clinical experience, we assume that the mean BMD at the L2–4 in the combination group and the control group is 0.8 and 0.7 g/cm3, respectively, 24 months after treatment. Taking standard deviation = 0.15, β = 0.1 and power = 90% with a significance level of α = 0.05, the final effective sample size of n = 42 per group is calculated using PASS 11.0 software (PASS, Kaysville, UT, USA) with two-sample t-test. If we assume a loss rate of 20%, we require 51 cases per group and 102 cases in total.

Statistical considerations

Statistical description

Statistical analysis is performed using SPSS 22.0 software (IBM, Armonk, NY, USA) and SAS 9.2 software (SAS Institute Inc., Cary, NC, USA). In the statistical analysis, we first check the number of cases completed in each research center and the drop-out of cases. The demographic characteristics of the two groups at baseline are analyzed to compare the comparability between the combination group and the control group. Measurement data are expressed as the mean, median, standard deviation, the lower quartile (q1), upper quartile (q3), minimum and maximum. Enumeration data are presented as number and percentage.

Statistical methods

The difference of the BMD at the L2–4, femoral neck and Ward’s triangle between after treatment and the baseline, serum calcium, phosphorus, 1,25(OH)2D3, parathyroid hormone, osteocalcin, interleukin-10, interleukin-6, tumor necrosis factor-alpha and insulin-like growth factor 1 levels is compared using two-sample t-test (normal distribution) or Mann-Whitney U test (non-normal distribution). The intragroup comparison of the above data at each time point is performed by repeated measures analysis of variance and least significant difference test. Adverse reaction rate in both groups is analyzed using Pearson X2 test. Correlation analysis between BMD index, osteoporosis index and inflammatory factor index is performed by linear correlation analysis (normal distribution) and Spearman correlation analysis (non-normal distribution). The significance level (two-sided) is α = 0.05.

Data sets

Included subjects are assigned to the per protocol set. Per protocol set refers to the set of subjects who complete the study without major protocol deviations, and provide tight enough compliance. The situation of the violation that obviously affects the efficacy is finalized at the time of data review, and may include the following cases (but not limited to these cases): the subject does not meet the inclusion criteria; interference therapy after the inclusion; poor compliance; and the follow-up beyond the window period.

Data collection and management

Data collection

The investigator records all collected data in the case report form. All records are verified by the principal investigator, who signs. All changes are made by the principal investigator or his authorized personnel, who sign and date.

Data management

According to the item in the case report form, Epi-Data 3.0 software is used to establish the corresponding entry procedure, and the logical review qualification conditions are set at the time of entry. Thus, the database is tested and the database system dedicated to this trial is established. The data are automatically entered by the data administrator using the double-entry method, and are checked item by item.

Audits

Data monitoring committee composition

The data monitoring committee is composed of experts in medical science (professional doctor), clinical pharmacology and/or toxicology, epidemiology, statistics, clinical trial management and ethics

Investigator qualification

Doctors who evaluate imaging and laboratory examination indicators have received medical professional training and have extensive experience.

Auditing

The monitor visits the trial unit on a regular basis or according to the actual situation to conduct clinical quality audit. The data monitoring committee reports the progress of the trial to the Ethics Committee every 2 months and updates the status of the trial in the registration database.

Compensation to study participants

During the clinical trial, patients learn about and obtain the most recent treatment information and are followed up closely by the professional medical team for free. There is no test or registration fees at follow-up.

Quality control

All clinical observation indices are checked by the same medical staff. All doctors and nurses receive unified and strict training in advance, and perform repeated testing.

In accordance with the design created by statisticians, computer-generated random numbers are used to determine the patient grouping in a balanced manner, ensuring that the patients are evenly distributed into the two groups, and that the two groups have comparable baseline characteristics.

The researchers formulate a detailed test process plan, and uniformly train the participating medical personnel to ensure that the test is carried out in strict accordance with the study design.


  Results Top


We have obtained 1-year follow-up results from 64 patients with viral cirrhosis combined with osteoporosis who have been treated with salmon calcitonin plus calcium from 2012 to 2016.

A total of 64 patients were randomly divided into the treatment group (n = 32) who received intramuscular salmon calcitonin plus oral calcium, and the control group (n = 32) who received oral calcium alone. The two groups were comparable in sex, age, and Child-Pugh classification of liver function (P > 0.05; [Table 3]).
Table 3: Comparison of baseline data between the two groups (n=32)

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The 1-year follow-up results: The treatment group had significantly increased levels of serum calcium, 1,25(OH)2D3, interleukin-10, and insulin-like growth factor, and significantly increased BMD at L2–4, the femoral neck, and Ward’s triangle, but significantly decreased levels of serum phosphorus, parathyroid hormone and osteocalcin, interleukin-6, and tumor necrosis factor-alpha compared with the control group (all P < 0.05; [Table 4]).
Table 4: Comparison of 1-year follow-up results between the two groups

Click here to view



  Discussion Top


Contributions and problems of previous studies in this field

A previous study showed that chronic liver disease is strongly associated with osteoporosis.[3],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24] Therefore, it is of great importance to effectively reduce bone loss, improve bone metabolism, protect the bone health of patients with chronic liver disease, and reduce the risk of fracture in those with chronic liver disease with osteoporosis.[25],[26],[27] Calcitonin reduces blood calcium and blood phosphorus, and has a huge impact on bone tissue metabolism.[28] However, few studies have evaluated the treatment of viral cirrhosis with osteoporosis.

Characteristics of this study protocol

A previous study investigated the effect of the absence or reduction of calcitonin on bone loss and fracture acceleration in patients with primary biliary cirrhosis and primary sclerosing cholangitis after liver transplantation.[29] Calcitonin treatment for the first 6 months after liver transplantation reportedly cannot prevent or reduce accelerated bone loss or spontaneous fracture in the first year after transplantation.[29] Furthermore, parenteral injections of calcitonin for 6 months did not effectively prevent bone loss in 25 patients with primary biliary cirrhosis-related metabolic bone disease, while calcium supplementation may have had a short-term beneficial effect.[30] The present study aims to evaluate the use of oral calcium combined with intramuscular salmon calcitonin in patients with viral cirrhosis and osteoporosis. Thus, it involves different subjects and treatment methods compared with the abovementioned studies.

Our previous study determined the efficacy of salmon calcitonin combined with calcium in the treatment of viral hepatitis cirrhosis with osteoporosis over a 12-month period,[5] but there is as yet no report on the efficacy during longer follow-up or on the occurrence of adverse drug reactions during follow-up. In addition to observing the efficacy and safety of salmon calcitonin combined with calcium in the treatment of viral cirrhosis with osteoporosis for 2 years, this study will further evaluate the relationships between BMD, osteoporosis indices, and inflammatory factors, and provide quantitative data for further exploration of its therapeutic mechanisms.

Limitations of this study

The study limitations are the lack of a double-blind design and the lack of an analysis of stratification factors (such as the type of virus in patients with viral cirrhosis and the impact of disease typing on the study results). These limitations impact the accuracy and reliability of the study results. We plan to conduct a multi-center, large-sample, randomized, controlled study in the future.

Significance of this study

Our results further clarify the efficacy and safety of salmon calcitonin combined with calcium in the treatment of patients with viral cirrhosis and osteoporosis over a 2-year period. This trial clarifies whether salmon calcitonin combined with calcium can regulate bone metabolism through inflammatory factors and improve BMD. The study results thus provide a reference for the protection of bone health in patients with viral cirrhosis.


  Trial Status Top


Registration date: August 11, 2018.

Recruitment date: August 2018 to October 2019.

Completion date: February 2022.

Current status: undergoing recruitment.

Additional files

Additional file 1: Hospital ethics approval (Chinese).

Additional file 2: CONSORT checklist.

Additional file 3: Informed consent form (Chinese).

Author contributions

Study design: JFW and BSZ. Subject recruitment: TL. Data collection and analysis: BSZ and AQL. All authors approved the final version of this manuscript for publication.

Conflicts of interest

None declared.

Financial support

None.

Institutional review board statement

The study protocol has been conducted in accordance with the Declaration of Helsinki, and ethical requirements for human research of Yantai Affiliated Hospital, Binzhou Medical University, China. This trial was approved by the Ethics Committee, Yantai Affiliated Hospital, Binzhou Medical University, China in July 2018 (approval No. 2018071601). Written informed consent is obtained from all participants. This trial was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR1800017732). Protocol version (1.0).

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for patients’ images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity.

Reporting statement

The writing and editing of the article are performed in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement.

Biostatistics statement

The statistical methods of this study are reviewed by the biostatistician of Yantai Affiliated Hospital, Binzhou Medical University.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

No individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be in particular shared. Study protocol and informed consent form will be available. The data will be available immediately following publication without end date.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Peer-review started: June 8, 2018

First decision: July 5, 2018

P-Reviewer: Zammit K; C-Editor: LWW, Zhao M; S-Editor: Wang J, Li CH; L-Editor: Qiu Y; T-Editor: Jia Y

 
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