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STUDY PROTOCOL
Asia Pac J Clin Trials Nerv Syst Dis 2017,  2:15

Efficacy and safety of glucocorticoids combined with hyperbaric oxygen therapy in the treatment of delayed encephalopathy after acute carbon monoxide poisoning: study protocol for a randomized controlled trial


Department of Neurology, Baotou Central Hospital, Baotou, Inner Mongolia Autonomous Region, China

Date of Web Publication30-Jan-2017

Correspondence Address:
Bao-jun Wang
Department of Neurology, Baotou Central Hospital, Baotou, Inner Mongolia Autonomous Region
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3932.198961

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  Abstract 

Background: About half of patients with acute carbon monoxide (CO) poisoning suffer from delayed post-anoxic encephalopathy. Days or weeks after apparent recovery from acute CO poisoning, patients present with sudden onset neurophysiological symptoms, mainly symptoms of dementia, with a high risk of permanent disability or death. Glucocorticoids not only regulate the biosynthesis and metabolism of blood glucose, fat, and protein, but also inhibit the immune response and exhibit anti-inflammatory, anti-toxic, and anti-shock effects. Glucocorticoids can improve the clinical symptoms of delayed encephalopathy; however, the therapeutic effects of glucocorticoids combined with hyperbaric oxygen therapy (HBOT) on delayed encephalopathy after acute CO poisoning are poorly understood.
Methods/Design: This is a single-center, prospective, single-blind, randomized controlled trial, which will be performed at Baotou Center Hospital, China. A total of 120 eligible patients with delayed encephalopathy after acute CO poisoning will be randomly assigned to receive either basic treatment + HBOT + intravenous dexamethasone (trial group, n = 60) or basic treatment + HBOT (control group, n = 60). Intravenous injection of dexamethasone (10 mg, once a day, for 14 successive days) will be performed. HBOT (once a day, for 14 successive days) will be administered through a multi-place hyperbaric chamber that will be pressurized with 100% O 2 to 2-2.2 atmospheres absolute within 25 minutes, followed by 60 minutes of pressure stabilization, 10 minutes of resting, and 25 minutes of depressurization. The primary and secondary outcome measures of this study will be evaluated at baseline, 7, 14, 30, 60 and 90 days after treatment. The primary outcome measure is the Barthel Index of Activities of Daily Living change. The secondary outcome measures are Mini-Mental State Examination score, modified Ashworth Scale score and European Quality of Life-5 Dimensions questionnaire score, as well as adverse reactions and death rate.
Discussion: This study will be conducted to analyze the clinical therapeutic efficacy and safety of glucocorticoids combined with hyperbaric oxygen therapy in the treatment of delayed encephalopathy after acute CO poisoning.
Trial registration: This study protocol was registered with Chinese Clinical Trial Registry (registration number: ChiCTR-IPR-16009743) on 5 November 2016.
Ethics: This study protocol has been approved by the Ethics Committee, Baotou Central Hospital, China and will be performed in accordance with Declaration of Helsinki formulated by the World Medical Association.
Informed consent: Written informed consent will be obtained from patients' relatives prior to involvement in the clinical trial.

Keywords: acute carbon monoxide poisoning; delayed encephalopathy after acute carbon monoxide poisoning; glucocorticoids; hyperbaric oxygen; randomized controlled trial; therapeutic effects; safety; Mini-Mental State Examination; modified Ashworth Scale score; European Quality of Life-5 Dimensions questionnaire; adverse reaction


How to cite this article:
Xiang Wp, Xue H, Wang Bj. Efficacy and safety of glucocorticoids combined with hyperbaric oxygen therapy in the treatment of delayed encephalopathy after acute carbon monoxide poisoning: study protocol for a randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2017;2:15-22

How to cite this URL:
Xiang Wp, Xue H, Wang Bj. Efficacy and safety of glucocorticoids combined with hyperbaric oxygen therapy in the treatment of delayed encephalopathy after acute carbon monoxide poisoning: study protocol for a randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2017 [cited 2018 Dec 19];2:15-22. Available from: http://www.actnjournal.com/text.asp?2017/2/1/15/198961

Wen-ping Xiang, Hui Xue
These authors contributed equally to this paper.



  Background Top


Carbon monoxide (CO) is the most common cause of toxic death (Zazzeron et al., 2016). Acute CO poisoning occurs after breathing in a high-concentration CO within a short period. CO has a greater affinity for hemoglobin than oxygen, which decreases the oxygen-carrying capacity of hemoglobin, resulting in decreased function of ion pumps located in the cell membrane and increased vascular permeability (Azarov et al., 2016; Oh et al., 2016; Rose et al., 2016). The brain is much more sensitive to hypoxia than other organs (Deng et al., 2015) and a decrease in the concentration of oxygen leads to an increase in cerebrovascular permeability and increased risks of cerebral edema and softening foci. This can result in a central nervous system disorder termed delayed encephalopathy after acute CO poisoning (DEACMP) that is clinically manifested by delayed psychiatric symptoms, such as cognitive and memory impairments and extracorticospinal tract symptoms (Fujiwara et al., 2016; Wang et al., 2016). DEACMP symptoms arise days to weeks and generally within 2 months after apparent recovery from acute CO poisoning (Yoshiike et al., 2016). The incidence of DEACMP is currently reported to be up to 47% of acute CO poisoning cases in China and its clinical manifestations mainly include intellectual impairment, psychiatric symptoms, tremor, dystonia, urinary and fecal incontinence and paralysis, while epilepsy, autonomic nerve disorder and impaired vision are often seen (Wang et al., 2014; Watanuki et al., 2014). There is no effective treatment for DEACMP and this disease has high mortality and disability rates (Chen et al., 2015). Therefore, it is very urgent to develop effective methods to treat this disease.

The pathological mechanism underlying DEACMP remains unclear. Ischemia/hypoxia, free radical generation, excitatory amino acid release, and apoptosis after acute CO poisoning are the main pathological mechanisms that impair cerebral function. Persistent excitatory amino acid release, apoptosis, and microcirculation disturbance play an important role in the occurrence of DEACMP (Hansen et al., 2014; Ochi et al., 2014; Xiang et al., 2014).

Hormones exhibit therapeutic effects on many diseases (Wells et al., 2016; Zieliρska et al., 2016). There is strong evidence that hormones can improve the clinical symptoms of delayed encephalopathy (Deng et al., 2013; Geraldo et al., 2014; Kudo et al., 2014).

Furthermore, dexamethasone, as a kind of hormone, has been proven to attenuate the inflammation that plays a key role in delayed encephalopathy induced by acute CO poisoning through protecting myelin from the damage of inflammatory response (Xiang et al., 2014). Lee et al. (2001) reported that immediate administration of HBO during acute CO poisoning may prevent against neuropsychiatric symptoms including consciousness disturbance, motor dysfunction, chorea, aphasia and agnosias. To our knowledge, the use of hormones in combination with hyperbaric oxygen therapy to treat DEACMP has not been studied. In this randomized controlled study, we will use dexamethasone in combination with hyperbaric oxygen therapy to treat DEACMP and we will evaluate the clinical efficacy and safety of this method.

Objective

To investigate the efficacy and safety of combined hormone and hyperbaric oxygen therapy in the clinical treatment of DEACMP.


  Methods/Design Top


Inclusion criteria

Patients with DEACMP will be considered for admission to this study after screening against the inclusion criteria below, and after written informed consent has been provided.

  • Meeting the diagnosis criteria of DEACMP formulated by the World Health Organization-Examination of the head by CT or MRI
  • Age 18 years or older
  • Time from onset to enrollment < 1 month


Exclusion criteria

Patients presenting with one of the following conditions will be excluded from this study:

  • Acute cerebrovascular disease or encephalopathy caused by other factors
  • Poisoning by toxic substances
  • Previous dementia or mental disorder
  • Burning or trauma
  • Severe heart, lung, liver, kidney and blood system diseases and hematopoietic system diseases
  • Gastrointestinal disorders or gastrointestinal surgery that may affect gastrointestinal absorption
  • No intervention of severe infection
  • Lactating or pregnant
  • Malignant tumor or undergoing treatment for tumor
  • Participated (within 3 months prior to provision of informed consent) or participating in other interventional clinical study
  • Upon the request of the sponsor for safety reasons


Rejection criteria

Patients presenting with one of the following conditions will be rejected for this study:

  • No mediation or no medical record regarding therapeutic effects after randomization
  • Non-compliance with inclusion/exclusion criteria


Withdrawal criteria

  • If a patient presents with an allergic response, worsened symptoms, or a severe adverse reaction related to the therapy, the clinical study participation of this patient should be terminated upon the physician's determination
  • If some co-morbidities, complications or special physiological changes occur during the study, because of which a patient will be not suitable for future participation in the study, the clinical study participation of this patient should be terminated upon the physician's determination
  • If the patients decline to continue to participate in clinical study, they can apply for withdrawal from the study


Study design

This is a randomized controlled study that includes 120 subjects scheduled to undergo 3 months of treatment.

Eligible patients with DEACMP will be randomly assigned to a trial group and a control group to receive 3-month treatments. On days 7, 14, 30, 60 and 90 post-treatment, follow-up evaluations will be performed to provide data regarding curative effects and safety of long-term hormone use.

Sample size

According to a previous study (Xiang, 2015), based on the primary outcome measures and the seasonal nature of CO poisoning, 120 patients [including possible lost patients (10%)] are scheduled to be involved in this study.

Randomization

120 random numbers will be generated by SAS software and assigned to a trial group and a control group with a 1:1 ratio. The allocation sequence will be placed in sequentially numbered, opaque sealed and stapled envelops. Eligible patients will be assigned to corresponding groups according to the allocation sequence.

Prohibition of combined drugs

Edaravone, Urinary Kallidinogenase, Pyrrolidinones, Donepezil, Nootropics, Ziprasidone, Bromocriptine, Baclofen, Haloperidol.

Concomitant diseases

If concomitant diseases occur during the treatment period, then drugs used for treatment of concomitant diseases should be recorded in detail on Case Report Forms (including drug category, medication start and end time).

Study drugs



Drug usage and dosage

During days 1-14, intravenous administration of dexamethasone sodium phosphate will be performed using non-PVC infusion sets, one injection ≥ 50 minutes.



Study procedure

Written informed consent will be provided prior to enrollment and each patient will be evaluated as follows:

  • Demographic data and other information: name, sex, birth date, body height, body weight
  • Previous disease history, complications and concomitant drugs
  • Current disease history
  • DEACMP onset time, onset situation, time interval from symptom onset to initial treatment
  • Mini-Mental State Examination (MMSE) score (Yatawara et al., 2016)
  • Barthel Index of Activities of Daily Living (ADL) (Hong et al., 2016)
  • Determination of muscular tension
  • Head MRI or CT examination
  • Electrocardiography
  • Laboratory examinations: routine blood tests, routine urine tests, plasma biochemical tests
  • Vital signs: blood pressure, heart rate, respiratory rate, body temperature


Treatment period

  • Vital signs including body temperature, blood pressure, heart rate, respiratory rate will be examined once on days 14 (±2), 30 (±7), 60 (±7), and 90 (±7).
  • MRI examination will be performed on day 7 after treatment.
  • Laboratory examination: Routine blood tests, routine urine test, plasma biochemical tests, and electrocardiography will be performed on day 7 after treatment.
  • MMSE score, Barthel Index of ADL, modified Ashworth Scale score, and European Quality of Life-5 Dimensions (EQ-5D) questionnaire score will be measured on days 14 (±2), 30 (±7), 60 (±7) and 90 (±7) after treatment.
  • Combined drug application and adverse events will be also recorded.


Evaluation methods

Efficacy evaluation


  • Barthel Index of ADL: Comparison of change in Barthel Index of ADL between the day of enrollment and day 90 of treatment between trial and control groups
  • Measurement of cognitive function: Comparison of change in MMSE score between the enrollment and day 90 of treatment between trial and control groups
  • Modified Ashworth Scale score: Comparison of change in modified Ashworth Scale score between the day of enrollment and day 90 of treatment between trial and control groups


Safety evaluation

  • Hormone safety and tolerance relative to basic medication in DEACMP
  • Evaluation indices: Mortality, adverse events, severe adverse events, clinical biochemical and blood tests, vital signs, and electrocardiogram


Records and reports of adverse events

Association of adverse events with investigational drugs


The association of adverse events (as defined in Appendix 1), regardless of severity, with investigational drugs, will be evaluated according to the following criteria ([Table 1]).
Table 1: Associations of adverse events with investigational drugs


Click here to view


- Definitely related

If five or more of the following items occur, adverse events will be considered definitely related to the investigational drugs:

  • An adverse event that has a timely relationship to the administration of the investigational drug
  • An adverse event that cannot be fully explained by the known disease, environmental or toxic factors, or by the use of other treatments
  • An adverse event that follows a known pattern of responses for which no alternative cause is present
  • The symptoms of an adverse event will disappear or alleviate after drug withdrawal or drug dose decreases (note: With the exception that the adverse events of some drugs will not disappear after withdrawal, for example bone marrow depression and tardive dyskinesia)
  • An adverse event that is consistent with the suspected adverse drug reaction
  • Reappearance of adverse events after readministration of the investigational drugs
  • Exclusion of external factors


- Probably related

If three of the following conditions occur, adverse events will be considered probably related to the investigational drugs:

  • An adverse event that has a timely relationship to the administration of the investigational drug
  • An adverse event that cannot be fully explained by the known disease, environmental or toxic factors, or by the use of other treatments
  • The symptoms of an adverse event will disappear or alleviate after drug withdrawal or drug dose decreases (note: With the exception that the adverse events of some drugs will not disappear after withdrawal, for example bone marrow depression and tardive dyskinesia)
  • An adverse event that is consistent with the suspected adverse drug reaction
  • Reappearance of adverse events after readministration of the investigational drugs


- Possibly related

If two of the following conditions occur, adverse events will be considered possibly related to the investigational drugs:

  • An adverse event that has a timely relationship to the administration of the investigational drug
  • An adverse event that cannot be fully explained by the known disease, environmental or toxic factors, or by the use of other treatments
  • An adverse event that is consistent with the suspected adverse drug reaction


- Likely unrelated

If two of the following conditions occur, adverse events will be considered possibly related to the investigational drugs:

  • An adverse event that does not have a timely relationship to the administration of the investigational drug
  • An adverse event that is definitely caused by a patient's disease, environmental or toxic factors, or by the use of other treatments
  • An adverse event that is not consistent with the suspected adverse drug reaction
  • Absence or no aggravation of adverse events after readministration of the investigational drugs


- Unrelated

An adverse event that is definitely caused by external factors (e.g. disease or environment) and does not meet the criteria (likely unrelated, possibly related, probably related) for evaluating the association of adverse events with the investigational drugs.

- Cannot be assessed

There is no defined relationship between the adverse events and the investigational drugs because of insufficient or contradictory data as well as no possibility to provide supplementary information or supportive data.

Severity of adverse events

The severity of adverse events will be graded as mild, moderate, or severe according to the following criteria.

  • Mild: Asymptomatic or mild symptoms; do not affect daily activity or function; intervention not indicated for alleviating clinical symptoms
  • Moderate: Obviously uncomfortable; affect daily activity and function; clinical or diagnostic observations; intervention indicated
  • Severe: Greatly uncomfortable; symptoms-cause loss of function and greatly affect daily activity; termination of study if necessary; symptomatic treatment and/or hospitalization


Evaluation of severity of adverse events should be according to clinical outcomes (for example abnormal laboratory indices) rather than patient's direct perception.

Management of adverse events

  • If severe adverse events occur, necessary measures will be administered immediately to protect the patients. All adverse events should be followed up with a detailed record of the process and results until they are properly resolved or symptoms are stable. Patients with abnormal laboratory test results should be followed up until indices return to normal. Follow-up should be performed via hospitalization, clinic visits, home visits, telephone, or other communication means depending on the severity of adverse events.
  • After adverse events occur, relevant information will be reported to the Safety Supervision Department of the Food and Drug Administration (China), the principal investigator, and the institutional review board within 24 hours via telephone or fax.


Study termination and patient dropout

Study termination


If one or more of the following conditions occur, the clinical study can be terminated:

  • Patients cannot abide by the clinical study protocol because of the abovementioned reasons
  • Upon the request of the researchers for safety reasons
  • Upon the request of the State Drug Administration
  • Significant deviations in the design or implementation of the clinical research program have made it difficult to evaluate drug effects


Note: Advance termination of the clinical study should be known by the study center.

The date and causes of drug withdrawal and treatment change will be recorded on case report forms. After drug withdrawal, drug efficacy and safety will be evaluated within the limited period.

Patient dropout

Definition: All eligible participants who provide written informed consent and enter the trial but cannot complete the observation scheduled by the study protocol because of any causes at any time will be considered dropouts.

The possible causes of patient dropout are listed as follows:

  • Poor patient compliance: Drug compliance < 80% or > 120%, or taking drugs forbidden by the current study protocol, or withdrawal from or change of drug regimens or administration of new drugs by patients or their relatives without the physician's permission
  • Lost to follow up: Patients receive effective treatment, but cannot complete the entire trial, resulting in incomplete data for the judgment of drug efficacy and safety


Management of patient dropout: When patients drop out of the study, a review will be made via home visits, telephone, e-mail, or WeChat communication to determine dropout causes and the last time of medication, which will help to provide more evaluation items.

For patients who drop out of the study because of allergy, adverse reaction or ineffective treatment, corresponding interventions will be given according to the situation.

Efficacy evaluation items on the Case Report Form (CRF) will be filled in.

Dropout cause items on the CRF will be also filled in: The time of and cause of study termination: The CRFs of dropout patients will be recorded and preserved for both documentation and intention-to-treat analysis.

Study quality control and assurance

Study quality control


  • Laboratory quality control

    Standard operating and quality control procedures of laboratory observation indicators will be developed. The International System of Units will be used for hospital laboratory tests. The laboratory test reports will provide a full list of items, signed by an inspection physician, examiner and review physician and printed.

    Prior to the study, researchers should provide the laboratory name and normal reference range of tested items. If any information (the name of laboratory, experimental methods, unit, or normal reference range of items tested) changes, the sponsor will be informed. In addition, suitability of any alteration for subjects scheduled for subsequent laboratory examinations will be explained. If not, possible causes will be given.
  • Pre-treatment researcher training

    Researchers participating in this study should have professional skills, qualifications and abilities. Prior to starting the study, investigators will be trained to make them fully understand and recognize each index. The symptoms that patients feel will be described objectively without inference or bias. Monitoring of subjective indices scheduled in the study protocol will be performed at prescribed sites and using scheduled methods. The recording of symptoms, physical signs and quantitative criteria will be conducted consistently. If patients cannot visit for reviews, investigators should inform them for further reviews or follow ups. Adverse events or non-expectant adverse and side effects should be observed and once occurred, patients will be closely followed up. Investigators should sign a declaration regarding their obligations and responsibilities during the trial.
  • Measures taken to improve patient's compliance

    Investigators should ensure patients fully understand the study objectives and that they cooperate with clinical research to accomplish the aims of the study. An electronic medication monitor will be used to monitor adherence to medication regimens.


Study quality assurance

  • Establishment of Research Coordination Committee

    The author WPX is responsible for coordinating the entire study and resolving all problems.
  • Establishment of quality control and insurance system

    The project manager will train investigators to record uniformed scoring criteria. The investigators who pass the tests will be qualified for scoring the patients.


The sponsor will designate a clinical research associate to supervise, monitor, and support the administration and progression of the clinical trial. The clinical research associate will ensure the rights and interests of the patients are upheld and that accurate, complete and correct records and reports are kept and that the study follows the approved program, guidelines for good clinical practice (GCP) for trials on pharmaceutical products, and relevant laws and regulations. The visiting times of the clinical research associate should meet the requirements of clinical study quality control.

Data management

Requirement for clinical records


CRFs of all cases will be carefully recorded by physicians at clinical visits. All items in the CRFs should be filled in, including the patient's name, address, telephone, and inpatient medical record number. Any changes to be made in the CRFs should be made by crossing out old data and placing the altered data in the side notes. In addition, the altered data will be fully explained, signed and dated by a clinical physician. The original record cannot be erased or covered. All original laboratory reports should be pasted to the simple medical notes (a copy is permitted if the original paper is lost). Data that are greatly higher (over 100%) than normal clinical reference values should be re-checked, and necessary explanations will be made by clinical physicians.

Monitoring of clinical records


During the study process, the clinical research associate will check each patient's informed consent, screening and inclusion at regular intervals. All CRFs will be correctly filled. All errors or missing information will be corrected or noted and signed and dated. Drug dose alteration, treatment alteration, drug combination, concomitant diseases, lost to follow up, and missing information of each patient will be confirmed and checked. Patient dropouts and missed appointments will be re-checked and recorded in CRFs. All adverse events will also be recorded in CRFs. The severe adverse events will be reported in the prescribed time. Complete information regarding use of investigated drugs will be recorded. The following notes should be included: (1) meeting disease diagnostic criteria, patient's inclusion and exclusion criteria; (2) in the original medical notes, the name, dosage and usage of the investigated drugs will be recorded; (3) no use of drugs forbidden by the study protocol; (4) re-checking the judgments of disease severity, curative effects and safety; (5) ensuring correct information in the original records, including patient's name, address, telephone number and inpatient medical record number. The clinical research associate will review the medical notes of each participant and fill in related forms person-by-person.

Record preservation


The original medical records for each patient will be preserved by Baotou Central Hospital, China.

Statistical analysis

Statistical analysis will be performed using professional statistical software.

Study ends and summary

CRF acceptance


At the end of the observation period for each patient, the CRF will be delivered to the project manager of Baotou Central Hospital, China for acceptance and archiving within 7 working days.

The project manager will authorize all clinical data and sign. The first link of the CRF (including report table regarding patient rejection and dropouts) will be delivered to Baotou Central Hospital, China. Then the data will be statistically processed using professional software by statistical personnel.

Data summary and conclusion

The statistical personnel will be responsible for establishing a database and data processing. Statistical analyzers will summarize and integrate all data. The project manager will make a final clinical summary report and stamp it. Several copies of the final report will be delivered to the sponsor.

Ethical principle

The study protocol will not be performed until it is approved by the ethics committee of Baotou Central Hospital, China. If the study protocol is altered during the clinical trial, it should be approved again by the ethics committee. If some important criteria regarding the investigated drugs changes, then written informed consent will be obtained again from patients and approved again by the ethics committee.

Before starting the clinical trial, the investigators will provide detailed information, including the nature and objective of the study, potential benefits and risks, alternative treatments, and describe the obligations and responsibilities to patients required the Declaration of Helsinki.

The clinical trial will not be initiated until patients provide written informed consent after fully understating the study objective and procedure. Each patient will provide detailed information of simplified medical notes, including the patient's address, telephone and identity number. At the same time, the physicians should give their telephone numbers to the patients to facilitate communication if a disease condition occurs. This helps physicians to follow disease condition changes and reminds patients to attend clinical appointments and not to be lost to follow up.


  Trial Status Top


Recruitment of patients is currently underway. This study is expected to be completed in December 2017.


  Discussion Top


Significance of this study

In this study, HBOT for treatment of DEACMP can increase plasma O2 solubility and alleviate brain edema, contributing to recovery of injured brain cells. In addition, hormone therapy in combination with HBOT can prevent brain cell degeneration and necrosis. This is the first study to perform a prospective single-blind trial, which can effectively reduce study bias.

Strengths and limitations of this study

Results from this study hope to provide clinical evidence that HBOT in combination with hormone therapy can reduce a patient's physical and mental suffering, ensure medical safety and improve medical rehabilitation. This combined method is of important clinical significance in developing an effective method to treat DEACMP and decreasing mortality and fatality rates. However, this study is limited to a small sample size. In addition, evaluation indices are affected by patients' subjectivity. Studies involving larger sample sizes and long-term follow up should be performed. In addition, the optimal treatment option with the most satisfactory therapeutic effects should be investigated in future studies.

Appendix 1 Definitions of (severe) adverse events

Adverse events


Any medical abnormalities occurring from recruitment to the end of the observation period, regardless of whether they are directly associated with the investigational drugs, will be considered adverse events.

Severe adverse events

Any adverse event occurring during the clinical trial that is fatal or life threatening, is permanently disabling, requires inpatient hospitalization or prolongs hospitalization, or results in a congenital anomaly or birth defect will be considered serious. [23]

 
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Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the form the patients will give their consent for their 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, but anonymity cannot be guaranteed.
Conflicts of interest
None declared.
Author contributions
Study design and manuscript writing: WPX; trial evaluation, data collection and management: HX; trial evaluation and manuscript authorization: BJW. All authors approved the final version of this manuscript.
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.



 
 
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