This article has Open Peer Review reports available.
Effects of orthokeratology on the progression of low to moderate myopia in Chinese children
- Mengmei He†1,
- Yaru Du†1, 2,
- Qingyu Liu1,
- Chengda Ren1,
- Junling Liu1,
- Qianyi Wang1,
- Li Li1Email author and
- Jing Yu1Email author
© The Author(s). 2016
Received: 17 December 2015
Accepted: 13 July 2016
Published: 27 July 2016
To investigate the effectiveness of orthokeratology (ortho-k) in reducing the development of myopia in Chinese children with low to moderate myopia.
This was a retrospective study. In the ortho-k group, there were141 subjects, and the average age was (9.43 ± 1.10) years. The average spherical equivalent refractive error (SER) was (−2.74 ± 1.15)D, with examinations performed 1, 7, 30, and 90 days and 12 months after the patients started wearing ortho-k lenses. In the control group, there were 130 subjects, and the average age was (9.37 ± 1.00) years. The average SER was (−2.88 ± 1.39)D, with examinations performed every 6 months. Axial elongation, which is an important parameter reflecting the progression of myopia, was measured at baseline from the same IOLMaster each time by the same masked examiner and was compared between the groups after 1 year. The subjects were divided into two sub-groups according to age to further study the development of myopia at different ages. An unpaired t-test, paired t-test, Chi-square test and Spearman test were performed to analyze the data.
After 1 year, the average axial elongation was (0.27 ± 0.17) mm in the ortho-k lens group and (0.38 ± 0.13) mm in the control group, with a significant difference between the groups (P < 0.001). Axial elongation was not correlated with SER but had a negative correlation with initial age (ortho-k group: r s = −0.309, p < 0.01; control group: r s = −0.472, p < 0.01). The percentages of individuals with fast myopic progression (axial elongation > 0.36 mm per year) were 38.0 % among younger children (7.00 to 9.40 years) and 24.3 % among older children (9.40 to 12.00 years), whereas the respective percentages were 76.5 and 12.9 % in the control group. When SER ranged from -5.0D to −6.0D, the axial elongation in the ortho-k group was 57.1 % slower than that in the control group.
Ortho-k lenses are effective in controlling myopic progression in Chinese children, particularly in younger children and in children with higher myopia.
Myopic progression in children is of great concern in Asian countries, such as China, Hong Kong, and India [1–3], and it has even become prevalent in Europe . The incidence rate of refractive errors is the highest among the incidence rates of various eye diseases in the world . Because of significant axial elongation of the eyeball, high myopia poses increased risks of retinal and vitreous detachments as well as other disorders, such as glaucoma and macular degeneration [6–8]. Thus, obtaining a better understanding of the mechanisms of myopia is important. Zhu et al.  concluded that the following induced abnormal axial growth of the eye: near accommodation lag, mechanical tension created by the crystalline lens or ciliary body, and peripheral retinal signal domination. Clinicians have been searching for treatments based on these controversial hypotheses, but no significant treatment result has been demonstrated yet.
Orthokeratology (ortho-k lenses), a special type of contact lens that uses rigid materials, ensuring the best oxygen transmission rate , has become increasingly popular for controlling myopic progression. A number of studies have demonstrated that the use of an overnight ortho-k lens is effective for controlling the progression of myopia [11–13]. Nonrandomized controlled trials (non-RCTs) have reported that axial length elongation in subjects wearing ortho-k lenses was 36 to 56 % slower than that in subjects who wore spectacles [12, 13]. The purpose of the present retrospective study was to evaluate both the effectiveness of the ortho-k lens in Chinese children with varying ages and varying degrees of myopia and the factors that influence this effectiveness.
Inclusion and exclusion criteria
• 7.0 to 11.5 years old
• SE: >−0.50D and < −6.00D in both eyes
• With-the-rule astigmatism (axes 180 ± 30) < 1.50D
• BCVA:(logMAR) of 0.10 or better in both eyes
• Had an IOP of <21 mmHg
• Maintained regularly scheduled visits and completed the 1-year follow-up
• Discontinued lens wear for a total of 30 days or less during the 1 year (criterion only for ortho-k group)
• Previous experience withcontact lens wear or other treatment for myopia control
• Strabismus at distance or near ornystagmus
• Contraindication for ortho-k lens(e.g., limbus-to-limbus corneal cylinder and dislocated corneal apex)
• Previous history of ocular surgery, trauma, or chronic ocular disease
• Concurrent use of medications that may affect tear quality
• Systemic or ocular conditions that may affect tear quality or contact lens wear (e.g., allergy and concurrent medication) or that may affect refractive development (e.g., Down syndrome, ptosis)
Baseline data of subjects who completed the one-year follow-up examination in the ortho-k lens and control groups
N = 141
N = 130
9.43 ± 1.10
9.37 ± 1.00
P = 0.643
P = 0.362
−2.74 ± 1.15
−2.88 ± 1.39
P = 0.380
24.71 ± 0.72
24.82 ± 0.77
P = 0.234
The ortho-k lenses (Ortho-K LK Lens; Lucid, Korea) were spherical 4-zone lenses that were made of gas-permeable lens material (Boston XO) with a nominal Dk of 100 × 10–11 (cm2.mLO2)/(sec. ml. mmHg). The nominal central thickness of the lenses was 0.22 mm (central lens thickness: 0.24 mm), and the diameter was 10.6 mm. All of the subjects in the ortho-k group were fitted with the lenses by a certified ophthalmic technician based on the manufacturer’s instructions. Subsequently, the lenses were dispensed to the patients. The patients were advised to wear the lenses for at least seven consecutive hours every night, and a cleaning procedure was necessary every time that they removed the lenses. In the control group, the patients wore single-vision glasses made of plastic lens material. These spectacles were prescribed by the same technician who fitted the subjects in the ortho-k lens group and were modified according to visual acuity (VA) and refractive changes during the follow-up period. Myopic progression was estimated based on changes in axial length in both groups, which were evaluated using a noncontact optic biometric device (IOLMaster (IOL: intraocular lens); Carl Zeiss Meditec AG, Jena, Germany). The axial length measurements were taken from the same IOLMaster each time by the same masked examiner.
Before the subjects in the two groups started wearing the lenses, their axial length, best-corrected VA(BCVA), VA, intraocular pressure (IOP), noncycloplegic manifest refraction, cycloplegic manifest refraction, corneal topography(Oculus, Wetzlar, Germany),corneal curvature, and corneal endothelial cells were assessed. The axial length was used to estimate the myopic progression, and the other examinations were just used to evaluate the health status of the patients before they started wearing the lenses and during their follow-up visit. Subjects in the ortho-k group were examined 1, 7, 30, and 90 days and 6 and 12 months after they started wearing the ortho-k lenses. The examinations were performed 3 h after removing the lenses and included measurements of the subjects’ VA, refraction, IOP, axial length, corneal integrity, and corneal topography and fluorescein staining of the corneal epithelium. Whenever any abnormal symptoms, such asphotophobia, redness, eye pain, or tearing occurred, wearing of the ortho-k lenses was stopped for an average of 1 month. If the symptoms were severe, the subjects received treatment. The subjects could not restart wearing the lenses until they were completely recovered because lens wearing may make keratitis more severe. In the control group, the examinations were performed every 6 months and included measurements of the subjects’ VA, IOP, and axial length. The ortho-k lenses and the spectacles were refitted according to VA and refractive changes to ensure the best visual quality for the patients.
The data analysis was performed using SPSS software ver. 17.0 (SPSS Inc., Chicago, IL, USA). All data were distributed normally (Kolmogorov-Smirnov test, P > 0.05). The data are presented as the mean ± standard deviation. The difference in the M/F ratio between the groups was assessed using the Chi-square test. Unpaired t-tests were used to compare other baseline data between the groups to determine myopic progression over 1 year. Additionally, a paired t-test with Bonferroni correction was performed to compare the difference in axial length between the two groups, and an unpaired t-test was used to compare the difference in axial elongation between the groups. Factors that may affect axial elongation were examined using Spearman analysis. P < 0.05 was considered to be statistically significant.
Axial length in the ortho-k and spectacle groups during the study period
Before wearing the lens(mm)
24.71 ± 0.72
24.82 ± 0.77
After 1 year(mm)
24.98 ± 0.70
25.20 ± 0.78
0.27 ± 0.17
0.38 ± 0.13
P < 0.01
P < 0.01
Axial length in different degrees of myopia inthe ortho-k and spectacle groups during the study period
Axial length (mm, initial)
Axial length (mm,1 year)
Axial elongation (mm)
N = 91
24.57 ± 0.72
24.85 ± 0.66
0.28 ± 0.18
N = 68
24.46 ± 0.61
24.85 ± 0.63
0.38 ± 0.15
N = 50
24.97 ± 0.66
25.22 ± 0.71
0.25 ± 0.16
N = 62
25.34 ± 0.68
25.72 ± 0.69
0.38 ± 0.12
In the current study, 18 of 141 subjects in the ortho-k group had previously had orthokeratology-associated infectious disease. Among them, most children experienced only slight discomfort, and only 3childrenhad a severe condition and received eye drop treatment before they restarted wearing the lenses.
Studies on myopia control using ortho-k lens
Swarbrick HAet al. (2015) 
Meng-Jun Zhu et al. (2014) 
Jaime Paunéet al. (2015) 
Hiraortho-k a T et al. (2012) 
Lin HJ et al. (2014) 
Duration of study
With control group
rigid gas-permeable (RGP)
spectacles refractive gradient (SRRG)
0.125 % atropine
Method of assignment
−2.43 ± 0.98
−4.29 ± 2.04
−0.75 ± 0.25
−1.89 ± 0.82
−4.25 ± 1.5
Initial SER (Control, D)
−2.39 ± 0.93
−4.24 ± 2.38
−0.76 ± 0.27
−1.83 ± 1.06
−4.0 ± 1.75
Increase in axial length in 1 y (Ortho-k, mm)
0.16 ± 0.17
0.15 ± 0.10
0.99 ± 0.47
0.28 ± 0.08
Increase in axial length in 1 y (Control, mm)
0.09 ± 0.09
0.39 ± 0.21
0.26 ± 0.15
1.41 ± 0.68
0.38 ± 0.09
Reduction in myopia progression in 1 year
Many studies have shown that the ortho-k lens is effective in myopia control, but the mechanism by which the ortho-k lens might control myopia is still under debate. It was believed that the imaging properties of the fovea were the main reason for emmetropia in the past, but animal studies have indicated that compared with the fovea, peripheral visual signals play a more important role in emmetropia . Peripheral hyperopia may act as a signal for eye growth . Norton et al. proposed that relative peripheral hyperopic defocus in myopes may trigger axial elongation . Thus, correction of peripheral hyperopia may be the mechanism by which the ortho-k lens suppresses myopic eye growth.
It was found that the axial length is related to the initial age at baseline , and studies have shown that myopic progression slows with age . In the current study, a negative correlation was found between axial elongation and initial age (Fig. 1a). The percentage of fast progressors in the ortho-k group was 38.0 % among younger subjects and 24.3 % among older subjects, while the percentage of fast progressors in the control group was 76.5 % among younger subjects and 12.3 % among older subjects. Among younger children, the percentage of fast progressors was 38.0 % in the ortho-k group and 76.5 % in the control group, and among older children, the percentage of fast progressors was 24.3 % in the ortho-k group and 12.3 % in the control group (Fig. 2); these findings showed that the ortho-k lens had a better effect on controlling myopia compared with single-vision spectacles and that the younger group had a faster progression of myopia than did the older group. Donovan et al.  showed a similar result. Comparing the percentage composition within different age groups, the ortho-k group included 32.4 % younger subjects with slow progression and 38 % with fast progression, whereas the control group included 7.3 % with slow progression and 76.5 % with fast progression. Similar to the younger population, the ortho-k group included 51.4 % older subjects with slow progression and 24.3 % with fast progression, whereas the control group included 16.1 % with slow progression and 12.9 % with fast progression (Fig. 2). This study demonstrates that younger myopic children will experience a greater benefit from ortho-k treatment than will older myopic children. Hiraoka et al.  suggested that the earlier ortho-k lens treatment is initiated, the greater its inhibitory effect will be on axial growth.
Although in this study, there was no significant correlation between initial myopia and axial elongation (Fig. 1b), Fan et al.  noted that the higher the degree of myopia is, the faster the axial length will grow. As shown in our study, the percentage of fast progressors accounted for 56.4 % of moderate myopia in the control group (Fig. 3), which was comparable to Fan’s results. Previous studies have also reported that subjects with higher initial myopia benefitted the most from ortho-k treatment [12, 18]. Compared with the children with low myopia, children in this study who had an axial length indicating moderate myopia benefitted more from ortho-k treatment. Although there was no direct correlation between axial elongation and SER, this study generally showed that the treatment with the ortho-k lens led to slower axial elongation (Fig. 4). This study demonstrates that individuals with higher myopia would have better results with ortho-k lens treatment.
In addition, certain studies have reported that the ortho-k lens was a good treatment for myopia control, whereas other reports have demonstrated its adverse effects, such as variability in VA and sight-threatening infective keratitis and conjunctivitis [29–31]. Reviewing all reported cases of ortho-k-related keratitis between 2001 and 2007, the peak occurrence was in the early years of this 7-year period, followed by a decreasing trend afterward . It has been demonstrated that age, gender, ortho-k lens experience and contact lens care habits are the potential risk factors for ortho-k-related keratitis . Other treatments similar to the ortho-k lens also have side effects. Lin et al. reported that atropine-treated children may suffer photophobia and increasing IOP and that there is a risk of inducing crowding of the anterior chamber angle . There were no absolute conclusions about whether the ortho-k lens or another treatment was better. However, we suggest that in terms of controlling myopia, the ortho-k lens is a useful method.
Certain limitations existed in the present study. First, the sample size of this study was relatively small. To confirm the potential efficacy and limitations of long-term ortho-k treatment, a larger-scale study must be conducted. Second, factors that may affect myopic progression, such as pupil size, accommodative lag, retinal image quality, peripheral refractive status, and a history of parental myopia, were not considered in our study. Further studies should focus on these factors. Third, the study period was not long because the data were from the medical records of children who came to our clinic for vision correction using spectacles or ortho-k lenses from 2013 to 2014. However, subsequent follow-up will still be performed for further study.
In conclusion, the current study confirms that the ortho-k lens is a promising treatment method to control myopia in children with low to moderate myopia. In particular,this lens offers more benefits to younger children with fast progression and allows better control of higher degrees of myopia. Although the ortho-k lens cannot completely arrest axial elongation in myopic children, it can retard it to a certain extent, which suggests that this treatment is a good choice for myopic children for whom wearing the ortho-k lens is suitable.
BCVA, best-corrected visual acuity; IOL, intraocular lens; IOP, intraocular pressure; M/F ratio, male/female ratio; Non-RCTs, nonrandomized controlled trials; Ortho-k, orthokeratology; SER, spherical equivalent refractive error; VA, visual acuity
I would like to extend my sincere gratitude to Lucid Korea (Lucid Korea Co., Ltd., Korea) for providing complimentary contact lenses and solutions and to Jing Ma (Jing Ma Co., Ltd. Shanghai, China) and Hao Ya (Hao Ya Co., Ltd. Shanghai, China) for providing complimentary spectacle frames and lenses. I am also deeply indebted to my supervisor, Jing Yu, for her instructive advice and useful suggestions on my thesis. I am deeply grateful for her help in the completion of this thesis.
This work was financially supported by the National Natural Science Foundation of China in 2014 (81470648) and the project of Shanghai Health System Training Program for Outstanding Young Talents (XYQ2011067). The facilities used were supported by the Department of Ophthalmology, Shanghai Tenth People’s Hospital.
National Natural Science Foundation of China in 2014(81470648): design of the study and collection, analysis, and interpretation of data.
The project of Shanghai Health System Training Program for Outstanding Young Talents(XYQ2011067) : write the manuscript and pay for a professional language editing service.
Availability of data and material
We are very sorry about failing to share our data. For one thing, the data was from the patients’ medical records, they are not allowed to public. For another, the data we analyzed in this study are a part of the data we retrieved and rearranged from the medical records, and the data will be used in the following study, so we don’t wish to public the data before we finish our following study.
HMM designed the study, analyzed and interpreted the patient data, and was the major contributor in writing the manuscript. DYR conducted the study, and help to collect the data. LQY, RCD, LJL and WQY help to collect the data. YJ and LL did the critical review and final approval of the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethical approval and consent to participate
The current study followed the Declaration of Helsinki and was approved by the Ethical Committee of the Shanghai Eye Disease Prevention and Treatment Center. All of the subjects, together with their guardians, were fully informed of the risks and benefits of the treatment and signed informed consent forms prior to treatment.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Wu LJ, You QS, Duan JL, Luo YX, Liu LJ, Li X, et al. Prevalence and associated factors of myopia in high-school students in Beijing. PLoS One. 2015;10:e120764.Google Scholar
- Saxena R, Vashist P, Tandon R, Pandey RM, Bhardawaj A, Menon V, et al. Prevalence of myopia and its risk factors in urban school children in Delhi: the North India myopia study (nim study). PLoS One. 2015;10:e117349.Google Scholar
- Cho P, Cheung SW, Edwards MH. Practice of orthokeratology by a group of contact lens practitioners in Hong Kong--part 1. general overview. Clin Exp Optom. 2002;85:365–71.View ArticlePubMedGoogle Scholar
- Williams KM, Verhoeven VJ, Cumberland P, Bertelsen G, Wolfram C, Buitendijk GH, et al. Prevalence of refractive error in Europe: the european eye epidemiology (e(3)) consortium. Eur J Epidemiol. 2015;30:305–15.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhao J, Mao J, Luo R, Li F, Munoz SR, Ellwein LB. The progression of refractive error in school-age children: Shunyi district, china. Am J Ophthalmol. 2002;134:735–43.View ArticlePubMedGoogle Scholar
- Lee JY, Sung KR, Han S, Na JH. Effect of myopia on the progression of primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2015;56:1775–81.View ArticlePubMedGoogle Scholar
- Kamal SR, Morillo-Sanchez MJ, Garcia-Ben A, Rius-Diaz F, Cilveti-Puche A, Figueroa-Ortiz L, et al. The effect of peripapillary detachment on retinal nerve fiber layer measurement by spectral domain optical coherence tomography in high myopia. Ophthalmologica. 2015;233(3-4):209–15.View ArticleGoogle Scholar
- Coppe AM, Ripandelli G, Parisi V, Varano M, Stirpe M. Prevalence of asymptomatic macular holes in highly myopic eyes. Ophthalmology. 2005;112:2103–9.View ArticlePubMedGoogle Scholar
- Zhu MJ, Feng HY, He XG, Zou HD, Zhu JF. The control effect of orthokeratology on axial length elongation in Chinese children with myopia. BMC Ophthalmol. 2014;14:141.View ArticlePubMedPubMed CentralGoogle Scholar
- Lum E, Swarbrick HA. Lens dk/t influences the clinical response in overnight orthokeratology. Optom Vis Sci. 2011;88:469–75.View ArticlePubMedGoogle Scholar
- Si JK, Tang K, Bi HS, Guo DD, Guo JG, Wang XR. Orthokeratology for myopia control: a meta-analysis. Optom Vis Sci. 2015;92(3):252–7.View ArticlePubMedGoogle Scholar
- Kakita T, Hiraoka T, Oshika T. Influence of overnight orthokeratology on axial elongation in childhood myopia. Invest Ophthalmol Vis Sci. 2011;52:2170–4.View ArticlePubMedGoogle Scholar
- Sun Y, Xu F, Zhang T, Liu M, Wang D, Chen Y, et al. Orthokeratology to control myopia progression: a meta-analysis. PLoS One. 2015;10(4):e0 124535.View ArticleGoogle Scholar
- Rabbetts RB, Mallen EAH. Distribution and ocular dioptrics ofametropia. In: Bennett and Rabbetts’ clinical visual optics. 4th ed. Edinburg: Elsevier/Butterworth–Heinemann; 2007. p. 425.Google Scholar
- Reinstein DZ, Gobbe M, Archer TJ, Couch D, Bloom B, et al. Epithelial, stromal, and corneal pachymetry changes during orthokeratology. Optom Vis Sci. 2009;86:e1006–14.View ArticlePubMedGoogle Scholar
- Zhong X, Chen X, Xie RZ, Yang J, Li S, Yang X, et al. Differences between overnight and long-term wear of orthokeratology contact lenses in corneal contour, thickness, and cell density. Cornea. 2009;28:271–9.View ArticlePubMedGoogle Scholar
- Kang P, Swarbrick H. Peripheral refraction in myopic children wearing orthokeratology and gas-permeable lenses. Optom Vis Sci. 2011;88:476–82.View ArticlePubMedGoogle Scholar
- Chen C, Cheung SW, Cho P. Myopia control using toric orthokeratology (to-see study). Invest Ophthalmol Vis Sci. 2013;54:6510–7.View ArticlePubMedGoogle Scholar
- Swarbrick HA, Alharbi A, Watt K, Lum E, Kang P. Myopia control during orthokeratology lens wear in children using a novel study design. Ophthalmology. 2015;122:620–30.View ArticlePubMedGoogle Scholar
- Pauné J, Morales H, Armengol J, Quevedo L, Faria-Ribeiro M, González-Méijome JM. Myopia control with a novel peripheral gradient soft lens and orthokeratology: a 2-year clinical trial. Biomed Res Int. 2015;2015:507572.View ArticlePubMedPubMed CentralGoogle Scholar
- Hiraoka T, Kakita T, Okamoto F, Takahashi H, Oshika T. Long-term effect of overnight orthokeratology on axial length elongation in childhood myopia: a 5-year follow-up study. Invest Ophthalmol Vis Sci. 2012;53:3913–9.View ArticlePubMedGoogle Scholar
- Lin HJ, Wan L, Tsai FJ, Tsai YY, Chen LA, Tsai AL, et al. Overnight orthokeratology is comparable with atropine in controlling myopia. BMC Ophthalmol. 2014;14:40.View ArticlePubMedPubMed CentralGoogle Scholar
- Smith ER, Hung LF, Huang J. Relative peripheral hyperopic defocus alters central refractive development in infant monkeys. Vision Res. 2009;49:2386–92.View ArticlePubMedPubMed CentralGoogle Scholar
- Mutti DO, Sholtz RI, Friedman NE, Zadnik K. Peripheral refraction and ocular shape in children. Invest Ophthalmol Vis Sci. 2000;41:1022–30.PubMedGoogle Scholar
- Norton TT, Jr Siegwart JT. Animal models of emmetropization: matching axial length to the focal plane. J Am Optom Assoc. 1995;66:405–14.PubMedGoogle Scholar
- Fan DS, Lam DS, Lam RF, Lau JT, Chong KS, Cheung EY, et al. Prevalence, incidence, and progression of myopia of school children in hong kong. Invest Ophthalmol Vis Sci. 2004;45:1071–5.View ArticlePubMedGoogle Scholar
- Edwards MH. The development of myopia in Hong Kong children between the ages of 7 and 12 years: a five-year longitudinal study. Ophthalmic Physiol Opt. 1999;19:286–94.View ArticlePubMedGoogle Scholar
- Donovan L, Sankaridurg P, Ho A, Naduvilath T, Smith ER, Holden BA. Myopia progression rates in urban children wearing single-vision spectacles. Optom Vis Sci. 2012;89:27–32.View ArticlePubMedPubMed CentralGoogle Scholar
- Walline JJ, Rah MJ, Jones LA. The children’s overnight orthokeratology investigation (cooki) pilot study. Optom Vis Sci. 2004;81:407–13.View ArticlePubMedGoogle Scholar
- Chan TC, Li EY, Wong VW, Jhanji V. Orthokeratology-associated infectious keratitis in a tertiary care eye hospital in Hong Kong. Am J Ophthalmol. 2014;158(6):1130–5.View ArticlePubMedGoogle Scholar
- Lo J, Kuo MT, Chien CC, Tseng SL, Lai YH, Fang PC. Microbial bioburden of orthokeratology contact lens care system. Eye Contact Lens. 2016;42:61–7.Google Scholar
- Watt KG, Swarbrick HA. Trends in microbial keratitis associated with orthokeratology. Eye Contact Lens. 2007;33:373–7. 382.View ArticlePubMedGoogle Scholar