Accepted Manuscript

Kinesio Taping improves pain and function in patients with knee osteoarthritis: A
meta-analysis of randomized controlled trials

Zhijun Lu, Xiaoming Li, Rongchun Chen, Chaoyang Guo

PII: S1743-9191(18)31638-8
DOI: 10.1016/j.ijsu.2018.09.015
Reference: IJSU 4758

To appear in: International Journal of Surgery

Received Date: 2 August 2018

Revised Date: 5 September 2018
Accepted Date: 21 September 2018

Please cite this article as: Lu Z, Li X, Chen R, Guo C, Kinesio Taping improves pain and function in
patients with knee osteoarthritis: A meta-analysis of randomized controlled trials, International Journal of
Surgery (2018), doi: https://doi.org/10.1016/j.ijsu.2018.09.015.

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 ACCEPTED MANUSCRIPT

Zhijun Lu, MD, first author, Department of Spinal Surgery，People's

Hospital of Ganzhou City, Jiang Xi, China.

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Xiaoming Li, MD, corresponding author, Department of Spinal Surgery，

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People's Hospital of Ganzhou City, Jiang Xi, China. Email:

lixiaoming3353@126.com

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Rongchun Chen, MB, second author, Department of Spinal Surgery，
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People's Hospital of Ganzhou City, Jiang Xi, China.
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Chaoyang Guo, MB, third author, Department of Spinal Surgery，People's

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Hospital of Ganzhou City, Jiang Xi, China.

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1 Kinesio Taping improves pain and function in

2 patients with knee osteoarthritis: A meta-analysis
3 of randomized controlled trials
4

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5 Abstract
6 Objective: To perform a meta-analysis from randomized controlled trials (RCTs) to

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7 evaluate the efficacy of Kinesio Taping in reducing pain and increasing knee function

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8 in patients with knee osteoarthritis (OA).
9 Methods: The electronic databases include PubMed, Embase, web of science and the

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10 Cochrane Library up to August 2018. Studies searched were considered eligible if
11 they met the criteria as follows: Population: patients with knee OA; Intervention:
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12 intervention groups received Kinesio Taping for the treatment of knee OA;
13 Comparisons: Control group received sham taping; 3) Outcomes: visual analog scale
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14 (VAS), McMaster Universities Arthritis Index (WOMAC) scale, range of motion and
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15 muscle strength; Study design: RCTs. The Cochrane Collaboration’s tool was used to
16 assess risk of bias. We assessed statistical heterogeneity for each RCT with the use of
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17 a standard Chi2 test and the I2 statistic. STATA statistical software 15.0 was used for
18 meta-analysis.
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19 Results: Five RCTs involving 308 patients were included. The present meta-analysis
20 demonstrated that there were significant differences between Kinesio Taping groups
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21 and control groups in terms of visual analog scale (VAS), WOMAC scale and flexion
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22 range of motion. No significant difference was found regarding quadriceps femoris

23 muscle between groups.
24 Conclusion: Kinesio Taping is effective in improving for pain and joint function in
25 patients with knee OA. Due to the limited quality of the evidence currently available,
26 the results of our meta-analysis should be treated with caution.
27

28 Key words: Kinesio Taping, VAS, WOMAC, knee osteoarthritis, meta-analysis

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29 1. Introduction
30 Knee osteoarthritis (OA) is the most prevalent chronic joint disease. Cartilage is
31 the central tissue affected by OA and causes subsequent symptoms, including joint
32 pain, stiffness and joint swelling, which diminishes the range of motion [1, 2]. It is
33 one of the major causes of deformity, resulting in huge medical expense and poor

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34 quality of life. It affects nearly 34% of those ages 65 and older [3]. The number of
35 patients with knee OA has increased in tandem with population aging and it remains a

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36 huge healthcare challenge. Currently, no reliable treatment has been confirmed to
37 prevent progression of knee OA. The aim of treatment was to relieve pain and

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38 increase functional outcomes.
39 Numerous conservative methods for pain management, including modification
40

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of daily activities and peri-articular infiltration analgesia have been tested [4, 5], and
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41 the optimal method is currently still under debate. Among the different strategies used
42 in physiotherapy, the application of taping has showed improved outcomes to treat
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43 knee OA [6, 7]. Kinesio Taping was first introduced in 1979 in Japan (Fig 1). It is an
44 elastic woven-cotton strip with heat-sensitive acrylic adhesive which can increase
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45 muscle flexibility and strength [8, 9]. It is widely used in musculoskeletal disorder,
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46 such as shoulder impingement and sport injuries and it has become one of the
47 rehabilitation modalities [10, 11]. In 2011, guidelines from the American College of
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48 Rheumatology has recommended taping in patients with knee OA.

49 Although previous studies have demonstrated Kinesio Taping was effective in
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50 knee disease, there was still a lack of reliable evidence and the effect of Kinesio
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51 Taping in knee OA was still controversial. Therefore, we performed a meta-analysis

52 of randomized controlled trials (RCTs) to evaluate the efficacy of Kinesio Taping in
53 reducing pain and increasing knee function in patients with knee OA.
54

55 2. Methods
56 This study was reported according with the guideline of PRISMA statement and
57 AMSTAR (Assessing the methodological quality of systematic reviews) Guidelines.
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58 Ethical approval or patient consent was not required since the present study was a
59 review of previous published literatures.

60 2.1 Search strategy

61 Two reviewers performed an electronic literature search for RCTs assessing the
62 outcome of treatment of knee OA with Kinesio Taping. The electronic databases

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63 include PubMed, Embase, web of science and the Cochrane Library up to August
64 2018. No language or date restrictions was applied. The following terms were used as

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65 key words: “Kinesio Taping”, “knee osteoarthritis” and “randomized controlled trial”.
66 In addition, further articles that may have been missed in the electronic databases

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67 were manually searched from selected articles. The detail retrieval process is shown in
68 Figure 2.

69
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70 2.2 Inclusion criteria
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71 Studies searched were considered eligible if they met the PICOS criteria as
72 follows: Population: patients with knee OA; Intervention: intervention groups
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73 received Kinesio Taping for the treatment of knee OA; Comparisons: Control group
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74 received sham taping; 3) Outcomes: visual analog scale (VAS), McMaster

75 Universities Arthritis Index (WOMAC) scale, range of motion and muscle strength;
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76 Study design: RCTs were considered as potential included studies. Studies excluded
77 from the present meta-analysis were comprised of incomplete data, case reports,
conference abstracts, or review articles.
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78
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79

80 2.3 Data extraction

81 Two reviewers retrieved the relevant data from articles using a standard data
82 extraction form independently. The extracted data included publication date, authors,
83 study design, inclusion and exclusion criteria, number and demographics of
84 participants, intervention of each group, duration of follow-up, and outcomes. For
85 missing data, such as standard deviations, we tried to get it by contacting with the
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86 original author first. Two reviewers extracted the data independently, and any
87 disagreement was discussed until a consensus was reached.
88

89 2.4 Risk of bias and quality assessment

90 The methodological bias and quality of included RCTs were assessed by The

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91 Cochrane Collaboration’s tool for assessing risk of bias according to the Cochrane
92 Handbook for Systematic Reviews of Interventions. It is a two-part tool with seven

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93 specific domains: sequence generation, allocation concealment, blinding of
94 participants and personnel, blinding of outcome assessment, incomplete outcome data,

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95 selective outcome reporting and other sources of bias. Disagreements were by
96 consensus after discussion, and if necessary, the third reviewer was consulted.
97

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98 2.5 Statistical analysis
99 STATA statistical software 15.0 was used for meta-analysis. The continuous
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100 variables would be conducted by weighted mean difference (WMD) and 95%
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101 confidence interval (CI). For the dichotomous outcome, we calculated the odds ratios
102 (ORs) and 95% CIs. The chi-squared statistic and the I2 statistic were used for the test
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103 of heterogeneity. A P<0.05, I2 >50% was considered a significant heterogeneity, and a

104 random-effect model was applied. Otherwise, a fixed-effect model was used if there
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105 was no significant heterogeneity (P≥0.05, I2 ≤50%). Publication bias was showed by
106 the funnel plot.
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107
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108 3. Result
109 3.1 Study selection
110 The flow path of how to search, exclude, and include papers in this meta-analysis
111 were displayed in Fig 2. In the primary search, a total of 214 studies (PubMed: 66,
112 EMBASE: 57, Cochrane Library: 36 and Web of Science: 55) were identified. Full
113 texts of reference list were also manually searched from selected articles. Finally, five

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114 full-text RCTs [12-16] associated with Kinesio Taping and control in patients with
115 knee OA were finally included in the meta-analysis. No more studies were retrieved
116 through review articles and references of included studies.
117

118 3.2 Study and patient characteristics

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119 Detailed characteristics of five eligible studies are represented in Table 1. The
120 meta-analysis involved 156 participants who received Kinesio Taping and 152 who

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121 received a control intervention. The papers had similar distributions of sex, age, BMI,
122 intervention and all of them were published between 2016 and 2018. The sample size

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123 ranged from 39 to 94, and the mean age of patients ranged from 51 to 70 years. The
124 follow up duration ranged from 1 to 6 weeks.
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126 3.3 Quality Assessment
127 Seven aspects of the RCTs related to the risk of bias were assessed, following the
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128 instructions in the Cochrane Handbook for Systematic Reviews of Interventions [17]
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129 (Table 2 and 3). All studies were randomized and mentioned that the lists of random
130 numbers were generated through computers. All RCTs used sealed envelopes for
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131 allocation concealment. None article reported double blinding to the surgeons and
132 participants and three RCTs [13-15] reported blinding to assessors. Low risk of bias
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133 due to incomplete outcome data and selective outcome reporting was detected.
134
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135 3.4 Outcome of meta-analysis

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136 3.4.1 VAS at rest

137 Five [12-16] studies reported VAS at rest. No significant heterogeneity was found
138 in the pooled outcomes, so a fixed-effect model was utilized in our study (χ2 = 2.57,
139 df = 4, I2 = 0%, P = 0.631). As shown in Figure 3, the pooled results showed
140 significant difference between the two groups (WMD = −0.394; 95% CI = −0.759 to
141 -0.029; P = 0.034).

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142

143 3.4.2 VAS during walking

144 All included [12-16] studies showed VAS during walking. A low heterogeneity
145 among studies was found (χ2= 5.11, df = 4, I2 = 21.8%, P = 0.276), so we used a
146 fixed-effect model. The overall estimate indicated that the difference was statistically

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147 significant, and VAS during walking was higher in control group (WMD = -0.429, 95%
148 CI: -0.752 to -0.105, P =0.009; Fig 4).

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149

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150 3.4.3 WOMAC scale
151 All RCTs [12-16] provided data on WOMAC scale. There was no significant

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152 heterogeneity (χ2= 4.89, df = 4, I2 = 18.2%, P = 0.299); therefore, a fixed-effect
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153 model was used. The overall pooled results indicated that Kinesio Taping was
154 associated with an improved WOMAC scale compared with control groups (WMD =
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155 -5.026, 95% CI: -7.649 to -2.403, P <0.001; Fig 5).

156
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157 3.4.4 Flexion range of motion

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158 Four studies [12-15] reported flexion range of motion. Heterogeneity existed
159 between the included studies (χ2 = 10.46, df = 3, I2 = 71.3%, P = 0.015). Thus, a
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160 random-effect model was performed. The present meta-analysis revealed that the
161 application of Kinesio Taping could significantly improve knee flexion range of
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162 motion (WMD = 6.193, 95% CI: 2.678 to 9.709, P =0.001; Fig 6).
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164 3.4.5 Muscle strength

165 Quadriceps femoris muscle strength was reported in three RCTs [13-15]. There
166 was no significant heterogeneity, and a fixed-effect model was adopted (χ2 = 1.07, df
167 = 2, I2 = 0%, P = 0.584). The present meta-analysis indicated that there was no
168 significant difference in quadriceps femoris muscle in patients with knee OA (WMD
169 = 3.205, 95% CI: -3.141 to 9.550, P =0.322; Fig 7).
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170

171 3.4.6 Evidence level

172 The overall evidence is low, which indicates that further research is likely to
173 significantly alter confidence in the effect estimate and to change the estimate (Table
174 4). This finding may lower the confidence in any recommendations.

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175

176 4. Discussion

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177 Up to now, the systematic review and meta-analysis of comparative studies about

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178 Kinesio Taping in patients with knee OA have not yet been performed. Thus, we
179 performed this meta-analysis from recent published RCTs and found that Kinesio

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180 Taping was associated with a significantly improved in VAS, WOMAC scale and
181 knee range of motion. No significant difference was found between groups in
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182 quadriceps femoris muscle strength.
183 Osteoarthritis is the most common form of arthritis. It is a slowly progressive,
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184 which may cause pain, stiffness and disability, decreasing quality of life. With the
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185 aging population, the incidence of OA has increased year by year. It is reported that
186 nearly 35% of those ages 65 and older suffered OA and it has been a severe social
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187 problem all around the world [18]. Recent study indicated that OA also affected
188 young people. The weight-bearing joints are most frequently affected, such as knees
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189 and hips. Nonpharmacological includes exercise, weight control and physical therapy.
190 Degeneration of arthrodial cartilage and chronic inflammation of the synovium may
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191 lead to pain. The goal of treatment is to improve joint function, prevent progression
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192 and reduce pain. Kinesio Taping was developed by Kase et al and it is an elastic
193 cotton strip with an acrylic adhesive that is used with the intent of treating pain and
194 disability from athletic injuries and a variety of other physical disorders. Huang et al
195 [19] reported that Kinesio Taping could improve pain during functional activities as
196 well as the performance. Anandkumar et al [20] investigated the effects of Kinesio
197 Taping on people with knee OA. They compared an intervention group who received
198 Kinesio Taping to a placebo group received sham Taping. VAS scale was adopted to
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199 measure pain and it was considered a subjective method. They showed that there was
200 a decreased pain in Kinesio Taping groups while climbing stairs. The present
201 meta-analysis indicated that Kinesio Taping was associated with a significantly
202 reduction in VAS scale at rest, as well as at movement in patients with knee OA. This
203 pain reduction can be attributed to neurological suppression, due to stimulation of

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204 cutaneous mechanoreceptors. However, the VAS scale among included studies were
205 recorded at different time points, so this may cause significant heterogeneity, which

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206 should be taken into consideration when analyzing the results.
207 Articular cartilage can be damaged by normal wear and abnormal mechanical

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208 loading which may cause abnormal cellular activities in cartilage and synovium,
209 resulting in stiffness, loss of range of motion [21]. Joint function is an important

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210 parameter to evaluate the effectiveness of treatment in knee OA, and the WOMAC is
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211 one of the most commonly used functional and disability scores. Kinesio Taping can
212 be a cheap and convenient option that aims to reduce symptoms and improve function.
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213 Intra-articular aseprtic inflammation can be reduce by the use of Kinesio Taping. Our
214 study demonstrated that Kinesio Taping was associated with an improved WOMAC
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215 compared with sham Taping. Lysholm knee scoring scale is also a well validated
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216 functional score designed for knee disorders. However, only Wageck et al [13]
217 showed the outcome of Lysholm scale, thus we failed to perform a meta-analysis, and
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218 further study was required.

219 Quadriceps femoris muscle weakness is a common symptoms in knee OA and
this may affect joint function and accelerate progress of degeneration [22, 23]. It is
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221 well recognized that it was crucial to enhance the quadriceps femoris muscle strength
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222 in knee OA. Kinesio Taping has become an effective rehabilitation modality used in
223 musculoskeletal system [24]. Currently, there remains controversial on improving
224 quadriceps strength in knee OA, although lots of articles has been published. Aydogdu
225 et al [15] concluded that Kinesio Taping was associated with a statistically significant
226 improvements in quadriceps muscle strength in knee OA. However, Lemosa et al [25]
227 reported that the use of Kinesio Taping did not change muscle strength. Therefore, we
228 performed the present meta-analysis and showed that there was no significant
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229 difference in quadriceps femoris muscle in patients with knee OA. Published articles
230 have hypothesized that placebo effect could be a major attributing factor. Although
231 efforts has been made in assessing the contribution of placebo to the effect of Kinesio
232 Taping, evidence investigating the quantity of placebo effects is still very limited. This
233 should be considered when analyzing the results.

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234 The limitations of this study were as follows: (1) our study included five RCTs
235 with a sample size ranging from 39 to 94, so the outcome should be treated cautiously;

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236 (2) the analysis of some outcome measures, such as flexion range of motion was
237 based on a relatively small sample size with high heterogeneity, so firm conclusion

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238 cannot be derived; (3) the comparison of Kinesio Taping and traditional drug was still
239 unclear, further study was necessary; (4) short-term follow-up caused the

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240 underestimation of complications; (5) Although there was no obvious publication bias
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241 among studies, it was still unavoidable.

242
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243 5. Conclusion
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244 Kinesio Taping is effective in improving for pain and joint function in patients
245 with knee OA. Due to the limited quality of the evidence currently available, the
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246 results of our meta-analysis should be treated with caution.

247
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248 Provenance and peer review

249 Not commissioned, externally peer-reviewed
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250
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251 Reference
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282 12. Cho HY, Kim EH, Kim J, Yoon YW: Kinesio taping improves pain, range of motion, and
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284 American journal of physical medicine & rehabilitation 2015, 94(3):192-200.

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321 25. Lemos TV, Júnior J, Santos M, Rosa M, Silva L, Matheus J: Kinesio Taping effects with
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Number of Female
Mean age BMI
Author Year Design participants patient Intervention Outcomes Follow up (M)
(KT/Control) (KT/Control) (KT/Control) (KT/Control)

Intervention：an I-shaped KT starting at the

VAS scale

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origin of the rectus femoris and a Y-shaped KT WOMAC scale
Cho 2016 RCT 23/23 58/58 17/16 25/22 2
proximal to the superior patellar boarder Range of motion

Control：sham tape

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Intervention：three KT elements applied
VAS scale

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Wageck 2017 RCT 38/38 70/69 35/31 30/31 simultaneously WOMAC scale 6
Range of motion
Control：sham tape
Muscle strength
10-m Walk Test

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Intervention：KT on their quadriceps VAS scale

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WOMAC scale
Mutlu 2017 RCT 20/19 54/57 16/17 31/31 femoris and hamstring muscle 1
Range of motion
Control：sham tape Muscle strength

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10-m Walk Test

Intervention：KT on quadriceps and hamstring

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VAS scale
muscles was performed with Y-shaped
Aydogdu 2017 RCT 28/26 53/51 24/22 31/32 WOMAC scale 1.5

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technique
Range of motion
Control：sham tape Muscle strength
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Intervention：KT on their quadriceps
VAS scale
Rahlf 2018 RCT 47/47 65/65 24/26 29/28 femoris and hamstring muscle WOMAC scale 2
10-m Walk Test
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Control：sham tape
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Table 1 Characteristics of the included studies

KT: kinesio taping, RCT: randomized controlled trial

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Random Sequence Allocation Blinding of participates Blinding of outcome Incomplete
Study Selective Reporting Other bias
Generation Concealment and personal assessment Outcome Data
Cho low risk low risk high risk unclear risk low risk low risk low risk

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Wageck low risk low risk unclear risk low risk low risk low risk low risk
Mutlu low risk low risk unclear risk low risk low risk low risk low risk
Aydogdu low risk low risk high risk low risk low risk low risk low risk

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Rahlf low risk low risk unclear risk high risk low risk low risk low risk

Table 2 Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

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Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

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Other bias

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0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

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Table 3 Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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Quality assessment Sample size

Outcome measures Quality Importance
Number of RCT Limitations Inconsistency Indirectness Imprecision KT Control

VAS at rest

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serious no serious no serious
4 serious limitations 156 152 WMD= -0.394; 95% CI = -0.759 to -0.029 Low critical
inconsistency indirectness imprecision

VAS during walking

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serious no serious no serious
4 serious limitations 156 152 WMD = -0.429, 95% CI: -0.752 to -0.105 Low critical
inconsistency indirectness imprecision

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WOMAC scale
serious no serious no serious
4 serious limitations 156 152 WMD = -5.026, 95% CI: -7.649 to -2.403 Low critical

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inconsistency indirectness imprecision

Flexion range of motion

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serious no serious no serious
4 serious limitations 109 105 WMD = 6.193, 95% CI: 2.678 to 9.709 Low critical
inconsistency indirectness imprecision

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Muscle strength
serious no serious no serious
3 serious limitations 86 83 WMD = 3.205, 95% CI: -3.141 to 9.550 Low critical

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inconsistency indirectness imprecision

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Table 4 Evidence level
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Fig 1 The Kinesio taping metod a -Y shaped quadriceps technique
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Identification

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Records identified through Additional records identified
database searching through other sources
(n =214) (n = 0)

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Records after duplicates removed
(n =103)
Screening

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(n =80)
Records screened
(n =88)
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Full-text articles excluded for

1. Unsuitable control group (n = 1)
Full-text articles assessed 2. Non-RCT (n=2)
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Eligibility

for eligibility
(n = 8)
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Studies included in
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qualitative synthesis
(n = 5)
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Included

Studies included in
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quantitative synthesis
(meta-analysis)
(n = 5)

Fig 2. PRISMA flow diagram for search strategy and study selection
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Study %

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ID WMD (95% CI) Weight

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Cho (2016) -0.60 (-1.93, 0.73) 7.48

Wageck (2017) -0.20 (-0.85, 0.45) 31.28

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Mutlu (2017) -0.90 (-1.65, -0.15) 23.45

Aydogdu (2017) -0.20 (-1.03, 0.63) 19.38

Rahlf (2018) -0.20 (-1.05, 0.65) 18.42

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Overall (I-squared = 0.0%, p = 0.631) -0.39 (-0.76, -0.03) 100.00
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-1.93 0 1.93
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Fig. 3 Forest plot of comparison: VAS score at rest

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Study %

ID WMD (95% CI) Weight

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Cho (2016) -0.10 (-0.71, 0.51) 28.31

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Wageck (2017) -0.80 (-1.28, -0.32) 45.94

Mutlu (2017) -0.50 (-1.86, 0.86) 5.69

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Aydogdu (2017) -0.50 (-2.10, 1.10) 4.08

Rahlf (2018) 0.10 (-0.71, 0.91) 15.98

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Overall (I-squared = 21.8%, p = 0.276) AN -0.43 (-0.75, -0.11) 100.00

-2.1 0 2.1
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Fig. 4 Forest plot of comparison: VAS score during walk

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Study %

ID WMD (95% CI) Weight

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Cho (2016) -5.00 (-11.65, 1.65) 15.54

Wageck (2017) -5.00 (-9.52, -0.48) 33.69

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Mutlu (2017) 1.00 (-6.86, 8.86) 11.13

Aydogdu (2017) -10.00 (-16.15, -3.85) 18.16

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Rahlf (2018) -4.00 (-9.66, 1.66) 21.47

Overall (I-squared = 18.2%, p = 0.299) -5.03 (-7.65, -2.40) 100.00

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-16.2 0 16.2
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Fig. 5 Forest plot of comparison: WOMAC scale

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Study %

ID WMD (95% CI) Weight

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Cho (2016) 7.00 (-2.41, 16.41) 13.96

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Wageck (2017) 3.00 (-5.21, 11.21) 18.36

Mutlu (2017) -3.00 (-9.61, 3.61) 28.30

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Aydogdu (2017) 14.00 (8.40, 19.60) 39.39

Overall (I-squared = 80.7%, p = 0.001) 6.19 (2.68, 9.71) 100.00

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-19.6 0 19.6
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Fig. 6 Forest plot of comparison: flexion range of motion

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Study %

ID WMD (95% CI) Weight

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Wageck (2017) 7.00 (-2.93, 16.93) 40.81

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Mutlu (2017) 2.00 (-9.34, 13.34) 31.34

Aydogdu (2017) -1.00 (-13.02, 11.02) 27.85

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Overall (I-squared = 0.0%, p = 0.584) 3.20 (-3.14, 9.55) 100.00

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-16.9 0 16.9

Fig. 7 Forest plot of comparison: quadriceps femoris muscle strength

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Kinesio Taping is effective in improving for pain

and joint function in patients with knee OA.

No significant differences were found regarding

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quadriceps femoris muscle or 10-m walk test
between groups.

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Due to the limited quality of the evidence

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currently available,AN the results of our
meta-analysis should be treated with caution.
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International Journal of Surgery Author Disclosure Form

The following additional information is required for submission. Please note that
failure to respond to these questions/statements will mean your submission will be
returned. If you have nothing to declare in any of these categories then this should be
stated.

Please state any conflicts of interest

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No conflicts of interest

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SC
Please state any sources of funding for your research

No
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AN
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Please state whether Ethical Approval was given, by whom and the relevant
Judgement’s reference number
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Ethical approval or patient consent was not required since the present study
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was a review of previous published literatures.

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Research Registration Unique Identifying Number (UIN)

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Please enter the name of the registry and the unique identifying number of the study.
You can register your research at http://www.researchregistry.com to obtain your UIN
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if you have not already registered your study. This is mandatory for human studies
only.

Unique Identifying Number (UIN): reviewregistry585

1
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If you are submitting an RCT, please state the trial registry number – ISRCTN

No application

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Author contribution
Please specify the contribution of each author to the paper, e.g. study design, data

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collections, data analysis, writing. Others, who have contributed in other ways should
be listed as contributors.

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Zhijun Lu: write manuscript

Xiaoming Li :finish the table and figure

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Rongchun Chen study design
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Chaoyang Guo: data analysis
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Guarantor
The Guarantor is the one or more people who accept full responsibility for the work
and/or the conduct of the study, had access to the data, and controlled the decision to
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publish.
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Xiaoming Li