A protocol for systematic review and meta-analysis

h Abstract Background: Post-viral olfactory dysfunction (PVOD) have been reported in infections caused by several respiratory viruses, especially in COVID-19which influence severely the quality of life of affected subjects. Few study has been published on the treatment of PVOD. Traditional Chinese medicine (TCM) is an effective method for PVOD which effects and safety have been confirmed. Therefore, this study is aim to evaluate the effects of TCM on PVOD. Methods: A searching strategy will be carried out mainly in the following databases in English and Chinese, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, China Network Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), Chinese Biomedical and Medical Database (CBM), and Wanfang Database. Only randomized controlled trials related to TCM for PVODwill be included to enhance effectiveness. The primary outcome is the effective rate of PVOD. The secondary outcomes are included olfactory domain value examination, visual analogue scale (VAS), questionnaires of olfactory disorders (QOD), T&T olfactometer test, Sniffin ticks test, and any other clinical assessments. Two authors will independently perform study selection, data extraction, and quality assessment to ensure the quality of the systematic evaluation. Every disagreement will be deal with by the third author. Data synthesis and subgroup analysis will be performed in the Review Manager V 5.3.3. Results: This study is aim to evaluate the efficacy and safety of TCM in PVOD. Conclusion : Thismeta-analysis may providemore reliable evidence-basedmedical evidence for clinical practice to assist patient in relieving PVOD. Ethicsanddissemination: There is no need to acquire ethical approval for individuals come from literatures instead of recruiting directly. The findings of this review will be reported in peer-reviewed publications and/or presented at relevant conferences. Prospero registration number: CRD42021238977.


Introduction
Breast cancer is one of the most common malignant tumors in women worldwide. [1] About 75% of breast cancer patients are hormone receptor-positive and endocrine adjuvant therapy is usually used. Aromatase inhibitors (AIs) are the first-line drugs for endocrine therapy for postmenopausal breast cancer. Compared with tamoxifen, they can significantly reduce the absolute risk of recurrence after 10 years and improve the overall survival rate. [2] American Society of Clinical Oncology clinical practice guidelines recommended that the treatment of AIs in postmenopausal women with hormone receptor-positive breast cancer was extended to 10 years, especially those with nodepositive patients. [3] Despite its benefits in breast cancer treatment, its musculoskeletal impact cannot be ignored. Leonor et al found that time under AIs is an independent risk factor for joint pain and bone loss, with reduced disease-free survivalin patients. [4] In the IBIS-II prevention trial, patients who took anastrozole for 5 years had a significant decrease in bone mineral density. [5] Nearly 10% of breast cancer patients discontinued AIs due to aromatase inhibitor-associated musculoskeletal symptoms (AIMSS). [6] There are a variety of treatment methods for AIMSS, such as nonsteroidal anti-inflammatory drugs and vitamin D, [7] but the efficacy is not clear. There are also exercise therapies such as Tai Chi, yoga, and Pilates to treat AIMSS, but the symptoms of bone pain and joint pain have not been significantly improved. [8,9] At present, traditional Chinese medicine (TCM) has received more and more attention in the treatment of AIMSS. It is reported that Chinese herbs such as Rehmannia glutinosa, Corydalis, and Epimedium inhibit osteoclast formation, improve osteoporosis, and relieve bone pain. [10][11][12] In clinical studies, Chinese herbal decoction relieves pain and bone loss in patients with AIMSS. [13][14][15] However, the studies were scattered and the sample size was small. The authors report no conflicts of interest.
Declaration of Competing Interest: Yu Mingwei (e-mail: yumingwei@ccmu.edu.cn) and Wang Xiaomin (e-mail: wangxiaomin_bhtcm@126.com) contributed equally to this article as co-corresponding authors. All authors have no conflicts of interest.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Study Protocol Systematic Review
Medicine ®

OPEN
This study aimed to evaluate the efficacy and safety of TCM in the treatment of AIMSS and to provide an evidence-based basis for clinical treatment.

Registration
This protocol is based on the preferred reporting item for systematic review and meta-analysis protocols (PRISMA-P). [16] This study is registered in the Prospero Registry of the University of York with the registration number CRD42020192553 (URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID= CRD42020192553). The study used a population-based intervention comparative outcome study design framework (PICOS) to guide eligibility criteria.
2.2. Eligibility criteria 2.2.1. Types of study. This review will include randomized controlled trials from inception to October 2021 in English and Chinese. Cross-sectional studies, case reports, and cohort studies are not included. Figure 1 depicts the process of studies screening.

Types of participants.
We will include studies of evaluation for pathological diagnosis of hormone receptorpositive postmenopausal breast cancer patients.

Types of interventions.
Both nondrug therapy and drug therapy will be included in the study. Aerobic exercise, yoga, Taiji, and acupuncture are nondrug therapy. Drug therapy includes analgesics, hormonal drugs, bisphosphonates, vitamin D, omega-3 fatty acids, and Chinese herbal medicine.

Comparisons.
The treatment of the control group will include placebo, blank control, routine nursing. There is no limit to the duration of treatment.
2.2.5. Outcomes. Pain: Evaluating the change of joint pain degree before and after treatment against the Numerical Rating Scale, the Visual Analogue Scale, the Verbal Rating Scale (VRS), or Western Ontario and McMaster universities. [17] Quality of life: The functional assessment of cancer therapy breast cancer-specific is used to evaluate the change of quality of life after treatment and at baseline.
Bone mineral density and bone metabolism markers: The indicators of bone metabolism markers include bone alkaline phosphate, osteocalcin, [18] and tartrate-resistant acid phosphatase.

Information sources
We will search the following databases from January 2010 to October 2021: PubMed (MEDLINE), the Cochrane Library, Web of Science, the Cochrane Controlled Register of Trials . English and Chinese studies will be included.

Search strategy
The search strategy of PubMed is as follows in Table 1.

Data collection
Two reviewers will read the abstract to screen the initial eligible studies, and then determine the final included studies through reading the full text, and finally, the 2 reviewers cross-checked the screening result. If the 2 reviewers have different opinions about the selection of studies, they can solve the problem through discussion with a third reviewer to make a decision. If the information is insufficient, we will contact the author via email for more comprehensive information. Data extraction contents include the author's name, year of publication, tumor stage, intervention measures, treatment, time, follow-up time, sample size. The flow chart is shown in Figure 1.

Quality of Methodological assessment
The risk assessment criteria for bias provided by Cochrane System Reviewers manual 5.1.0 will be used to evaluate the quality of the included studies, including random methods, blind method, allocation concealment, the integrity of data results, and selective reporting. Accordingly, the quality of the included literature will be divided into three: low bias (Grade A)-meet all quality standards; moderate bias (Grade B)-≥1 quality standards are partially met; high bias (Grade C)-≥1 quality standards are not met. Two reviewers will conduct quality evaluation independently and conclude the discussion with a third reviewer in case of any differences.

Assessment of heterogeneity
x 2 test will be used to assess the heterogeneity of the included studies, and the degree of heterogeneity will be expressed by I 2 ; heterogeneity is acceptable if I 2 50%. If the test for heterogene-ity result is P > .10, indicating that the homogeneity of the included studies is high, we will use the fixed-effect model for analysis. If the heterogeneity test results P .10, we will analyze the cause of heterogeneity and conduct a subgroup analysis. If heterogeneity exists after the above methods, a random-effect model or no meta-analysis will be selected.

Data analysis
The Rev Man 5.3 statistical software will be used for metaanalysis. We will assess the differences between the experimental group and the control group, and the differences between the same group before and after treatment will also be assessed. Relative risk will be used as the statistic for dichotomous data, and weighted mean difference will be used for continuous data, 95% confidence interval and P value are required for all analytical data.
For studies with high heterogeneity, we will look for possible sources of heterogeneity, such as intervention methods, regional differences, and so on, and conduct subgroup analysis to reduce such heterogeneity.
We will assess publication bias for outcomes with ≥10 included studies by funnel plots, try our best to reduce publication bias, excluding low-quality studies, and test the stability of the effect size estimation through sensitivity analysis. If the bias affects the system evaluation, we will report faithfully.

Discussion
Musculoskeletal symptoms such as bone pain, arthralgia, and bone loss are common adverse effects of AIs in breast cancer patients. The incidence of AI-associated joint pain or stiffness approaches 50%. [19] Patients taking AIs for 5 years have a fracture rate of 18% to 20%. [20] This seriously affects the patients' quality of life, and they will stop taking AIs because of the above reasons, which will affect the treatment of breast cancer. Therefore, AIMSS are of increasing concern to physicians and patients. The most common clinical treatment for AIMSS are NSAIDs, exercise, yoga, omega-3 fatty acids, and acupuncture, [21][22][23] but there is no clear curative effect. TCM has been widely used in clinical practice; especially, TCM decoction is very common. We designed this study to integrate the methods of TCM treatment of AIMSS and provide a reliable basis for the optimal treatment strategy of TCM treatment of AIMSS.