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Abstract
Introduction Anterior cruciate ligament injury seriously affects the motor function of patients. Currently, there are numerous rehabilitation methods after anterior cruciate ligament reconstruction (ACLR). The aim of this study was to investigate the rehabilitation effect of isokinetic muscle strength training combined with proprioceptive neuromuscular facilitation (PNF) technique in postoperative patients. A single-blind randomised controlled trial was conducted to compare the difference between this combined therapy and conventional rehabilitation, and to provide a scientific basis for optimising the rehabilitation strategy after ACLR, to promote faster and better recovery of knee joint function in patients.
Methods and analysis This study is a randomised controlled, assessor-blind trial. A total of 40 patients after ACLR were randomly divided into a control group and a test group. Conventional rehabilitation and isokinetic muscle strength training will be performed in the control group, while the test group will receive PNF techniques in addition to the interventions of the control group. These interventions were performed three times a week for 6 weeks. All interventions will be completed in the Department of Rehabilitation Medicine of the Second Affiliated Hospital of Xi'an Jiaotong University. The primary outcome measure will be assessed by knee proprioception. Secondary outcome measures will include knee isokinetic strength, balance ability and Lysholm knee function score. The above assessments will include a baseline assessment, an assessment after 6 weeks of intervention, and a follow-up visit at week 24.
Ethics and dissemination This study was approved by the Ethics Committee of the Second Affiliated Hospital of Xi'an Jiaotong University (Number: 2024059). Study results will be published in open access peer-reviewed journals and may be shared at relevant meetings and research meetings.
Trial registration number ChiCTR2400085897.
- Patients·
- REHABILITATION MEDICINE
- SPORTS MEDICINE
- Neuromuscular disease
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STRENGTHS AND LIMITATIONS OF THIS STUDY
Adopting a randomised controlled trial design, which can effectively reduce bias and improve the reliability of the study results.
Adoption of multidimensional assessment index: the primary outcome index is knee joint proprioception, and it also includes several secondary outcome indexes such as knee joint isometric muscle strength, balance ability, Lysholm knee function score, etc, which can comprehensively assess the rehabilitation effect.
Clearly defined interventions: in the control group, there will be routine rehabilitation and isokinetic training, while in the experimental group, proprioceptive neuromuscular facilitation will be added to the interventions of the control group, which will make it easy to implement and compare.
Due to the specific nature of the rehabilitation programme, the study cannot be double-blind, and only the evaluators will be blinded to the allocation of results.
Introduction
The anterior cruciate ligament (ACL) plays a key role in maintaining the static and dynamic stability of the knee joint and is one of the most common and serious injuries to the knee joint.1 In the USA, more than 200 000 people suffer from ACL tears every year.2 After an ACL injury, patients will experience swelling, pain, decreased muscle strength, decreased joint stability and proprioception abnormalities in the knee joint, causing a serious negative impact on the patient’s motor level and quality of life.3 4 After ACL rupture, arthroscopic anterior cruciate ligament reconstruction (ACLR) is one of the commonly selected options for most people after ACL rupture,5 which aims to restore the stability of the knee joint to restore normal knee joint motor physiological function.6 However, ACLR only restores the normal anatomy of the knee joint, and its motor function has not yet recovered. To restore to the pre-injury level or return to sports, scientific and reasonable rehabilitation training programmes are needed to promote the recovery of knee joint function.7 The quality of postoperative rehabilitation is directly related to the final recovery of knee joint function. An effective rehabilitation programme should accelerate tissue healing, enhance muscle strength, improve joint range of motion, restore proprioception, and reduce the occurrence of complications.7 At present, most patients with ACL injury after reconstruction receive rehabilitation treatment, including exercise therapy and physical factor therapy, all of which have achieved good results and greatly improve the daily life ability of patients. However, existing rehabilitation techniques are economically expensive and have a long treatment cycle, leaving some problems such as knee instability, poor control and proprioceptive abnormality.8 Therefore, the recovery of lower limb muscle strength, postural control ability and proprioception is the main treatment goal in the rehabilitation process after ACL injury reconstruction.
The role of proprioception in sensorimotor control is multifaceted, and to enable normal movement of the body, the central nervous system needs to understand the biomechanical and spatial properties of the body and this information is mainly provided by proprioceptors. During movement, proprioception is important for feedback control, feedforward control and regulation of muscle flexibility, normal proprioception is an important guarantee of postural stability, motor coordination and balance, and promoting proprioceptive recovery is a strategy to maintain postural stability.9 Many mechanoreceptors are attached to the ACL of the normal human knee joint, which are sensory neurons that transmit sensory inputs to the central nervous system and can detect changes in the speed, position and direction of the knee joint during normal movement of the knee joint.10 The ACLR is generally characterised by the reconstruction of an otherwise ruptured ACL by grafting muscles or tendons from other sites or using artificially created ligaments, to restore its original physiological function, but proprioceptive input is reduced in patients after ACL surgery. Reconstructed ligaments are not yet able to meet the normal motor function of the knee joint and one possible reason is that the reinnervation process of mechanoreceptors on the reconstructed ligaments and the central nervous system recovers more slowly.11 Thigh muscle strength is commonly diminished after ACL reconstruction and quadriceps muscle strength remains insufficient even in patients years after reconstruction.12 13 Patients with quadriceps muscle weakness are more likely to develop early degeneration of knee cartilage and knee osteoarthritis at subsequent times after return to exercise.14–17 Therefore, restoring thigh muscle strength after ACL reconstruction is essential for return to sports as well as preventing secondary injuries.
Proprioceptive neuromuscular facilitation (PNF) stimulates proprioceptors around the knee joint, enhances neuromuscular feedback mechanisms and improves joint stability and control ability through specific motor patterns and resistance training.18 19 The PNF is conducted through a spiral diagonal pattern, which effectively simulates functional activities encountered in daily life and enhances the overall rehabilitation of the knee joint. This mode of movement can activate the synergistic effects of multiple muscle groups, thereby improving overall movement efficiency.20 Isometric muscle contraction and relaxation techniques in the PNF techniques involve alternating contraction and relaxation of agonistic and antagonistic muscles. This process promotes balance and coordination of muscle strength while enhancing joint flexibility and stability.21 During the treatment, the PNF technology usually uses auxiliary methods such as visual and auditory cues to guide the patient’s movement pattern, thereby improving the treatment outcome.
The PNF technique has been shown to enhance neuromuscular function and proprioception in patients, while isokinetic strength training can improve muscle strength. However, it remains unclear whether the application of PNF techniques in patients following ACLR can effectively enhance their functional performance. Considering this uncertainty, the present study aims to integrate isokinetic strength training with PNF techniques during the rehabilitation process of the ACLR. This approach seeks to leverage the distinct advantages of both methodologies, thereby creating a synergistic effect that may further optimise rehabilitation outcomes. We hypothesise that the combined application of the PNF techniques and isokinetic strength training will lead to improvements in muscle strength and proprioception among ACLR patients, while also facilitating the recovery of their functional capabilities.
Study aims and objectives
The aim of this study was to investigate the safety, feasibility and acceptability of isokinetic muscle strength training combined with the PNF technique in the rehabilitation of ACLR patients and to develop a more scientific and effective rehabilitation programme for ACLR patients.
Primary objective
The ability of the PNF technique to increase proprioceptive function in ACLR patients will be clarified by comparing the changes in knee proprioceptive indexes before and after the intervention.
Secondary objective
The changes in knee muscle strength, balance function, Lysholm Knee Function Score and other related indexes before and after the intervention will be investigated to see whether PNF technology can promote the improvement of knee joint motor function in ACLR patients.
Methods and analysis
Trial design
This is a single-centre, prospective, single-blind (assessor-blinded), randomised controlled trial. We randomly divided the included subjects into the test group and the control group in a 1:1 ratio. Routine rehabilitation combined with isokinetic knee muscle strength training will be performed in the control group, and in the test group, in addition to the interventions in the control group, the proprioceptive neuromuscular stimulation technique will be applied. This study will be carried out in accordance with the Declaration of Helsinki. All adverse events will be recorded and reported. This trial protocol has been approved by the Ethics Committee of the Second Affiliated Hospital of Xi'an Jiaotong University (Number: 2024059). Only those subjects who agree to participate in this research protocol will be included, and they will sign a written informed consent form before enrolment (see online supplemental appendix A). This study protocol was written in accordance with the PREPARE trial guidelines22 and SPIRIT 2013 checklist.23 This research is scheduled to be officially launched on 1 August 2024 and is expected to be completed on 1 March 2026. The recruitment process is arranged to commence in January 2025 and is estimated to be successfully concluded in May 2025. After all the intervention measures have been fully implemented, it is planned to start the data analysis in February 2026.
Supplemental material
Patient and public involvement
None.
Study setting
Subjects in this study will be mainly recruited from the Department of Rehabilitation Medicine and Orthopedic Outpatient Department and the Inpatient Department of the Second Affiliated Hospital of Xi'an Jiaotong University. We will release the recruitment information through posters, advertisement brochures, WeChat Moments, the official website of the Second Affiliated Hospital of Xi'an Jiaotong University, and other platforms with a wide user base. At the same time, we will actively use relevant medical forums and professional social groups to interact with professionals in the field of orthopaedic rehabilitation and patient groups, to expand the dissemination of the recruitment information. All tests and training will be completed in the Department of Rehabilitation Medicine of the Second Affiliated Hospital of Xi'an Jiaotong University.
Eligibility criteria
The study will plan to enrol unilateral leg ACL injury. The surgical approach will be arthroscopic hamstring tendon autograft ACL reconstruction surgery, with no other ligament combined injury, and the postoperative time will be 8 weeks. All patients will undergo ACLR surgery by the same team at the Department of Orthopedics of the Second Affiliated Hospital of Xi'an Jiaotong University, and the postoperative rehabilitation training will be completed by the same rehabilitation team. None of the patients had regular exercise habits prior to injury. Once it is found that subjects have regular exercise habits prior to injury, they will be excluded. (exercise habits: exercise at least 3 days per week for more than 30 min).
The following inclusion criteria will apply:
Aged 18–45 years old, male or female.
Unilateral leg ACL injury, the surgical method using arthroscopic hamstring ACL reconstruction surgery, no other ligament combined injury, postoperative time 8 weeks.
After the initial unilateral ACL injury reconstruction in the Second Affiliated Hospital of Xi'an Jiaotong University Department of Rehabilitation Medicine followed the same standardised rehabilitation programme.
The affected knee range of motion was normal.
The affected lower limb hip, knee and ankle did not undergo any other surgery.
Willing to sign the informed consent form for this study, can well cooperate with this rehabilitation evaluation.
The following exclusion criteria will apply:
Previous history of lower limb joint fracture ligament injury.
An acute attack of severe medical diseases, local skin infection, coagulation dysfunction, fever.
Existing musculoskeletal diseases affecting lower limb movement disorders.
Refuse to sign informed consent.
Interventions
This study will include the experimental group (isokinetic muscle strength training combined with PNF technique) and the control group (isokinetic muscle strength training group), and both groups will be given conventional rehabilitation training for 6 weeks.
Conventional rehabilitation included
Joint range of motion training: using joint mobilisation techniques and joint traction methods to alleviate stiffness in the affected knee joint, with each session lasting 20 min.
Muscle strength training: the therapist conducts manual muscle strength training or employs resistance tools such as elastic bands and sandbags based on the patient’s muscle strength assessment, with each session lasting 15 min.
Proprioception and balance training: in the initial phase, exercises focus on weight shifting. In the later phase, balance ball exercises are introduced where patients stand on a balance ball with one foot at a time while flexing their knees at approximately 60°, maintaining body balance for 1 min during each session of 5 min. This regimen is performed once daily, three times per week, over a total treatment duration of 6 weeks.
Conventional rehabilitation combined with isokinetic muscle strength training (control group)
The control group will undergo isokinetic muscle strength training using a multi-joint isokinetic testing and training system (Model A8-3 from Guangzhou Yikang Medical Equipment). Prior to training, participants will be seated in an adjustable chair that will be modified according to their height and body type following strict adherence to the equipment’s safety manual. During exercise setup, alignment will be ensured by positioning two planes so that the calf movement plane coincides with that of the knee/hip pad—specifically aligning the anterior tibia with the centre of this pad. Additionally, alignment points will be established whereby the lateral femoral condyle aligns with the rotational centre of the power head indicated by a laser point aimed at it.
Subsequently, adjustments will be made regarding length by setting up knee/hip accessories until they reach maximum extension along the calf segment. The fixation will involve securely attaching both legs—the patient’s lower leg will be firmly affixed to either knee or hip accessory while stabilising their thigh against the seating apparatus; if necessary, additional support will be provided for upper body stabilisation through appropriate fixtures positioned behind contralateral limbs.
The combination of conventional rehabilitation, isokinetic strength training and PNF (experimental group)
The PNF technique will be added to the control group. The specific method will be as follows:
D1 extension mode.
Initial posture: the patient will be placed in a supine position with legs straight and the therapist or assistant will hold the patient’s instep with one hand and the other hand fixed on the patient’s thigh. Action process: the therapist slowly pulls the patient’s instep upward while allowing the patient to actively contract the muscles on the anterior thigh to straighten the knee joint and flex the hip joint. This action helps the patient feel the contraction of the muscles on the front of the thigh and the extension of the knee joint. Hold this position for a few seconds, then slowly relax and return to the starting position.
D2 flexion mode.
Initial posture: the patient is placed in a supine position with legs straight and the therapist or assistant holds the heel of the patient with one hand and the thigh with the other hand.
Action process: the therapist slowly pulls the heel of the patient towards the buttock while allowing the patient to actively contract the muscles on the back of the thigh to flex the knee and extend the hip. This action helps the patient to feel the contraction of the posterior thigh muscles and flexion of the knee joint. Hold this position for a few seconds, then slowly relax and return to the starting position.
D1 flexion mode.
Initial posture: lateral decubitus with legs straight below and legs flexed above. The therapist or assistant holds the instep of the patient’s upper leg with one hand and the patient’s thigh with the other hand.
Action process: the therapist slowly pulls the instep of the upper leg of the patient upward, while allowing the patient to actively contract the muscles on the anterior thigh to flex the knee and hip joints. This action helps the patient to feel the contraction of the anterior thigh muscles and flexion of the knee joint. Hold this position for a few seconds, then slowly relax and return to the starting position.
D2 extension mode.
Initial posture: lateral decubitus, legs straight below, legs flexed above. The therapist or assistant holds the heel of the patient’s upper leg with one hand and the thigh with the other hand.
Action process: the therapist slowly pulls the heel of the upper leg of the patient towards the buttock while allowing the patient to actively contract the muscles on the posterior thigh to straighten the knee and extend the hip. This action helps the patient to feel the contraction of the muscles on the back of the thigh and the extension of the knee joint. Hold this position for a few seconds, then slowly relax and return to the starting position.
During the training process, the patients will be asked to pay high attention, carefully observe the movement of the limbs and carefully experience the movement sensation and position sensation produced when the limbs moved to different positions. The therapist comprehensively uses PNF principles such as manual contact, traction, maximum resistance, password communication, timing, enhancement and visual stimulation to give appropriate resistance according to the actual muscle strength status of each patient’s affected limb. When implementing the PNF technique, we will follow a standardised process, but we will adjust it according to those with different muscle strength. For those with weak muscle strength, the therapist will initially provide more guidance and assistance to ensure that the movements are standardised, and then gradually reduce the assistance to independent completion. For those who are strong, the therapist will focus on the quality and speed of the movement, encouraging a high standard of completion, but not exceeding the prescribed framework. And, as the patient’s limbs move continuously, the therapist needs to change the direction in which resistance is imposed. The above training mode will be randomly selected, with 10–15 movements in each group, and three groups will be performed each time. 3 times a week for 6 weeks.
Outcome measures
Table 1 shows outcome measures and time points. Testing will be performed prior to the start of training (week 0, T0), after the last intervention (week 6, T1), and at follow-up (week 24, T2). Each test will be performed at the same time each day, and all tests will be completed in the Department of Rehabilitation Medicine of the Second Affiliated Hospital of Xi'an Jiaotong University. All tests will be randomised to avoid differentiation caused by patient learning and familiarity.
Time schedule of enrolment, interventions, outcome measure and visits for participants
Primary outcome
The primary outcome will be knee proprioceptive function testing. Knee proprioception will be assessed using the multi-joint isokinetic muscle strength assessment and training system of Yikang Medical Equipment Industrial. Proprioception is divided into motion sense and position sense, and given experimental conditions, position sense is chosen to measure the subjects' knee proprioception in this study.
First, the patient will be placed in a sitting position. The upper edge of the affected knee will be fixed with a nylon band, and the popliteal fossa will be fitted to the edge of the seat so that the axis of the knee joint is consistent with the axis of the dynamic arm. The resistance pad at the end of the dynamic arm will be placed 3 cm above the medial malleolus, and the unaffected lower limb will be limited with a crossbar to prevent compensation. To test the subjects’ proprioception more precisely, we will ask them to wear eye shields to isolate external visual interference.
In the test, the isokinetic instrument power head will perform automatic flexion and extension movement at a constant angular velocity (1°/s) to reach the preset knee flexion angles of 30° and 60° respectively. Following each movement, the instrument power head will immediately return to zero, and then the subject will be asked to actively move to the designated position. When the subject feels that the joint has moved to the designated position, they will press the stop button immediately, and the instrument will stop the movement. We will record the difference between the actual angle and the preset angle and perform three tests at each angle to obtain the average. In the test results, the smaller the difference between the actual angle and the preset angle, the stronger the subjects’ proprioceptive ability will be.
Secondary outcomes
Secondary outcomes will include knee isokinetic strength, balance ability and Lysholm knee function score.
Multi-joint isokinetic strength test and training instrument (Guangzhou Yikang, A8-3) will be used to test the maximum muscle strength and explosive power of knee flexor and extensor muscle groups. First, the patient will be placed in a sitting position. The upper edge of the affected knee will be fixed with a nylon band, and the popliteal fossa will be fitted to the edge of the seat to ensure that the axis of the knee joint is consistent with the axis of the dynamic arm. The resistance pad at the end of the dynamic arm will be placed 3 cm above the medial malleolus, the unaffected lower limb will be limited with a crossbar to prevent compensation, and then the centripetal - centripetal mode will be selected for testing. Gravity correction will be performed before testing to eliminate the effect of limb gravity on the test results, followed by three flexion and extension knee adaptability training sessions. The angular velocity of 60 °/s will be selected for the test, and the subjects will complete five consecutive repeated maximum contractions each time during the test. The peak torque (PT), relative peak torque (PT/BW) and flexion-extensor peak torque ratio (hamstrings/quadriceps) of active centripetal movement of knee flexion/extension will be recorded.
A quantitative assessment of static balance ability will be performed using a Tecnobody (PK254P, Italy) balance instrument. The patient’s foot will not be allowed to move during static postural stability testing. Before the test, the specific details of the test will be elaborated to the patient to familiarise them with the test procedure. At the end of each test, the force table will be reset and the body position will be adjusted. A total of three tests will be performed and the mean of each value will be included in the study. The maximum time for testing will be 120 s. The test indexes will be as follows: centre of pressure movement length and movement area. Smaller values will indicate greater control of static posture, which means that the patient’s knee will be better controlled.
The Lysholm score is a scoring system for assessing knee ligament injuries and has relatively high reliability and validity.24 This scoring system will focus on daily symptoms and mobility with a focus on knee stability. It will include pain (25 points), swelling (10 points), stair climbing (10 points), squatting (5 points), lameness (5 points), support (5 points), locking (15 points) and instability (25 points). The highest score patients can reach is 100 points. A score of more than 91 points is considered excellent; 84–90 points, is very good; 65–84 points, is fair and less than 65 points, is poor.
Sample size and power considerations
We use G Power (V.3.1.9.7) software for sample size calculations. Based on the previous randomised controlled trial study with knee joint proprioception as the main outcome, there is a clinically effective difference (Cohen’s d = 0.97) in joint position sense between the intervention group and the control group.25 We set the test level alpha to 0.05, Cohen’s d = 0.97 and power value (1-Bata) to 0.8 and calculated a total sample size of 36, which requires 40 subjects to account for a loss to follow-up rate of 10%.
Randomisation and blinding
The randomisation process will be performed by a statistician who is not involved in the assessment and data analysis. Patients who met the inclusion criteria 8 weeks after ACLR will be numbered 1–40 according to the order of enrolment, random numbers will be generated using SPSS (V.24.0) software, and groups will be sorted according to the resulting random numbers, generating treatment groups corresponding to 1–40. According to the grouping information, subjects were assigned to the corresponding test group or control group, and the corresponding interventions were started. Grouping information generated by randomisation will be documented and handled confidentially and only by statisticians not involved in the trial process.
Following randomisation, participants will be informed about the interventions they receive. Because this protocol cannot perform double-blind treatment for investigators and subjects due to intervention measures, only assessors (data collectors, statistical analysis experts) are blinded. All therapists involved in the intervention will receive in-depth training on standardised procedures to ensure consistency and objectivity of the intervention. Therapists are required to strictly follow the operation manuals, standardise their actions, control their strengths and standardise their speech to minimise any differences in treatment due to knowledge of grouping. In addition, a third-party monitoring mechanism will be introduced, whereby independent evaluators will conduct regular spot checks on the therapists’ operations, and any deviations found will be corrected immediately and documented. When the statistical analysis is completed, the person who keeps the blind code is responsible for unblinding to identify the test group and control group. Assessors will be responsible for collecting and analysing data, but remain blinded to group assignment throughout. They should work only according to pre-set assessment criteria and procedures and should not communicate relevant information to persons who are aware of the grouping.
Statistical analysis
Statistical methods for primary and secondary outcomes
All statistical analyses will be performed using IBM SPSS Statistics V.25 software (IBM). The level of significance was set at p<0.05. We will use the Shapiro-Wilk test for data distribution. The χ2 test will be used for gender comparisons. Age, height, weight and BMI will be compared by two independent samples t-test. Two-factor repeated measures analysis of variance (ANOVA) will be used to analyse the main effects at treatment and time and the interaction of these factors on the variables. We will use the Bonferroni correction method for post hoc multiple comparisons.26 If an interaction is observed, we will determine if there is a separate effect of time or treatment. Otherwise, we will determine if there is a main effect. CIs will be 95% and effects (η²) will be calculated in the ANOVA.
Cost–benefit analysis
We will conduct a cost-effectiveness analysis of both groups using device usage fees, associated personnel costs and patient functional recovery. (1) Equipment usage fees: the implementation of isokinetic muscle strength training requires specialised equipment which may involve an initial investment. However, given the potential for long-term use and service to multiple patients, the cost per patient can be amortised over time. We will base our cost calculations on price lists customised by countries in the region. (2) Staff costs: both technologies require trained professionals. (3) Functional recovery: the main measure of effectiveness is the improvement in the function of the ACL reconstruction knee. This can be assessed through a variety of objective measures, including muscle strength, proprioception, balance function and knee function. The combination of these two techniques has shown promising results in promoting functional recovery, which translates into better quality of life for patients.
Sensitivity analysis
To address uncertainty in cost and benefit estimates, a sensitivity analysis can be performed. This involves varying different critical parameters such as equipment costs, personnel salaries and treatment success rates to determine the robustness of cost-effectiveness results.
Data collection and management
The lead investigator or associate investigator of the project will explain the objectives, methods and potential impacts of the study in detail to the participants in clear and understandable written form and obtain their written consent. Case report forms will also carefully be prepared to ensure accurate recording of data. In addition, data will be stored in encrypted form in reliable digital storage devices such as mobile hard drives. After completion of the study, these data will be properly stored for 5 years in a specific safety locker at the Department of Rehabilitation Medicine of the Second Affiliated Hospital of Xi'an Jiaotong University. At the end of the 5 years period, the removable hard disk where data is stored will be physically destroyed according to strict safety procedures, and the consent form will also be securely destroyed.
Data monitoring
The monitoring manager has no conflicts of interest to declare. All adverse events should be recorded in the case report form, including the nature, onset time, severity, treatment measures taken and results of adverse events, and their severity should be assessed. A follow-up investigation will be performed if necessary. This study will be supervised and audited according to the policy of the Ethics Committee Office of the Second Affiliated Hospital of Xi'an Jiaotong University.
Ethics and dissemination
The trial will be conducted in full accordance with the Declaration of Helsinki, and the study is approved by the Medical Ethics Committee of the Second Affiliated Hospital of Xi'an Jiaotong University (Number: 2024059). All researchers participating in the trial will be trained in the training guidelines. All subjects signed an informed consent form. The results will be published in open-access peer-reviewed journals and may be shared at conferences and research meetings. Any changes to the protocol will be reported to the ethics committee and revised on the trial registration website in a timely manner.
Ethics statements
Patient consent for publication
Acknowledgments
Thanks to all participants of this study. Thanks to all the experts and scholars who provide guidance and suggestions for this study; your valuable opinions make our research more rigorous and scientific.
References
Footnotes
Contributors All authors (BW, QZ, PL, WL, YX, XL, KW, LL, XG, SZ, BM, PF and HQ) drafte the study protocol. BW, BM, QZ and HQ participated in designing the study and securing funding. BW and HQ coordinate the project and drafte the manuscript. XG and KW recruit and obtain consent from the patients. XL, LL, SZ and PF perform all subject evaluations. PL, WL and YX will perform the statistical analysis. HQ supervises the project. All authors have read and approved the final manuscript. HQ is responsible for the overall content as guarantor.
Funding This study was funded by The Second Affiliated Hospital of Xi'an Jiaotong University Foundation Free Inquiry (2020YJ (ZYTS) 449).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.