Serum 25-Hydroxyvitamin D Levels and Dry Eye Syndrome: Differential Effects of Vitamin D on Ocular Diseases
Serum 25-Hydroxyvitamin D Levels and Dry Eye Syndrome: Differential Effects of Vitamin D on Ocular Diseases
Donghyun Jee 0 1
Seungbum Kang 0 1
Changzheng Yuan 0 1
Eunyoung Cho 0 1
Jorge G. Arroyo 0 1
The Epidemiologic Survey Committee of the Korean Ophthalmologic Society 0 1
0 1 Department of Ophthalmology and Visual Science, College of Medicine, Catholic University of Korea , Suwon , Korea , 2 Department of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America, 3 Department of Ophthalmology and Visual Science , Daejeon St. Mary's Hospital, College of Medicine, Catholic University of Korea , Daejeon , Korea , 4 Department of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America, 5 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston , Massachusetts, United States of America, 6 Department of Dermatology, The Warren Alpert Medical School of Brown University , Providence , Rhode Island, United States of America, 7 Department of Ophthalmology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, Massachusetts , United States of America
1 Editor: Andrew W Taylor, Boston University School of Medicine, UNITED STATES
To investigate associations between serum 25-hydroxyvitamin D levels and dry eye
syndrome (DES), and to evaluate the differential effect of vitamin D on ocular diseases
including age-related macular disease (AMD), diabetic retinopathy (DR), cataract, and DES.
A total of 16,396 participants aged >19 years were randomly selected from the Korean
National Health and Nutrition Examination Survey. All participants participated in
standardized interviews, blood 25-hydroxyvitamin D level evaluations, and comprehensive
ophthalmic examinations. DES was defined by a history of clinical diagnosis of dry eyes by a
physician. The association between vitamin D and DES was compared to the associations
between vitamin D and AMD, DR, cataract, and DES from our previous studies.
The odds of DES non-significantly decreased as the quintiles of serum 25-hydroxyvitamin D
levels increased (quintile 5 versus 1, OR = 0.85, 95%CI: 0.55–1.30, P for trend = 0.076)
after adjusting for potential confounders including age, sex, hypertension, diabetes,
smoking status, and sunlight exposure times. The relative odds of DES (OR = 0.70, 95% CI:
0.30–1.64) and cataract (OR = 0.76, 95% CI: 0.59–0.99) were relatively high, while those of
Funding: The authors wish to acknowledge the
financial support of the St. Vincent’s hospital,
research institute of medical science
(SVHR-201312). The funder had no role in study design, data
collection and analysis, decision to publish, or
preparation of the manuscript.
Competing Interests: The authors have declared
that no competing interests exist.
The present study does not support an association between serum 25-hydroxyvitamin D
levels and DES. The preventive effect of serum 25-hydroxyvitamin D may be more effective
for DR and late AMD than it is for cataract and DES.
Dry eye syndrome (DES) is one of the most common ocular diseases and has been recognized
as an important public health problem. Dry eye is associated with chronic eye pain and an
increased risk of ocular surface diseases, such as corneal ulcers and corneal abrasions. DES is a
multifactorial disorder of the tear film and ocular surface. During the past decades, many
studies have demonstrated that inflammation is the core mechanism that plays a key role in the
pathogenesis of DES [
]. Oxidative stress-induced inflammation may be involved in the
functional decline of tear production [
]. In addition, ocular surface inflammation was associated
with excessive tear evaporation, which leads to tear film instability. We previously
demonstrated that decreasing inflammatory cytokines and increasing anti-oxidant cytokines in tears
can improve the symptoms and signs of DES [
Vitamin D is a multifunctional hormone which plays a significant role in various biological
functions in addition to its traditional role in regulating calcium homeostasis. Vitamin D can
reduce inflammatory mediators and shows anti-oxidative functions [
]. Many human
studies have shown an inverse relationship between vitamin D and chronic diseases associated with
chronic inflammation including diabetes mellitus, hypertension, heart disease, multiple
sclerosis, schizophrenia, and rheumatoid arthritis [
]. In the eye, vitamin D levels influence the
development of a wide range of pathologies such as myopia [
], age-related macular
degeneration (AMD) [
], diabetic retinopathy (DR) [
], and uveitis. We previously reported an
inverse association between vitamin D and AMD , DR [
], and age-related cataracts [
in the Korean general population. However, to the best of our knowledge, no population-based
epidemiologic studies have evaluated the associations between vitamin D levels and DES. The
cornea, a main component of the ocular surface, contains vitamin D receptors and significant
vitamin D concentrations, which suggests that vitamin D in the cornea may play a role in the
anterior segment of the eye [
]. Therefore, we hypothesized that serum vitamin D levels play
a role in DES development. To test our hypothesis, we examined the relationship between
serum 25-hydroxyvitamin D levels and DES in a representative Korean population. In
addition, we compared the association between vitamin D and DES to the associations between
vitamin D and other ocular diseases including AMD, DR, and cataract from our previous
reports to evaluate the differential effect of vitamin D on ocular diseases.
Materials and Methods
This study used data acquired for the Korean National Health and Nutrition Examination
Survey (KNHANES), which is a nationwide and population-based cross-sectional study conducted by the Korean Ministry of Health and Welfare and the Division of Chronic Disease
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Fig 1. Flow diagram showing the selection of study participants.
Surveillance at the Korean Centers for Disease Control and Prevention. The study design and
the methods on KNHANES are reported in detail elsewhere [
]. KNHANES adopted a
rolling sampling design, which was used to perform a stratified, complex, multistage
probability cluster survey, with proportional allocations based on the National Census Registry for the
non-institutional Korean civilian population. Data for the present study were obtained from
the fifth (2010–2012) KNHANES to estimate the association between serum
25-hydroxyvitamin D levels and DES. 25,534 individuals who participated in KNHANES were enrolled. Of
these, we excluded 6,755 subjects who were aged <19 years, 1,593 subjects who did not have
their serum 25-hydroxyvitamin D levels measured, and 790 subjects who skipped the question
on the diagnosis of DES. Finally, 16,396 participants aged 19 years were included (Fig 1). The
study design followed the tenets of the Declaration of Helsinki for biomedical research. The
institutional review board at the Catholic University of Korea in Seoul approved protocols for
this study. All participants provided signed, written informed consent.
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Assessment of Serum 25-Hydroxyvitamin D Levels
The analysis of serum 25-hydroxyvitamin D levels is described previously [14–16]. Serum sam
ples were collected after an 8-h fast, and serum 25-hydroxyvitamin D levels were measured by
a radioimmunoassay kit (DiaSorin Inc., Stillwater, MN, USA) using a gamma counter (1470
Wizard, Perkin-Elmer, Waltham, MA, USA), which is often used in mass surveys such as
KNHANES. KNHANES participates in the Vitamin D Standardization Program; hence, the
measurement of 25-hydroxyvitamin D was standardized in accordance with the National
Institute of Standards and Technology-Ghent University reference procedure [
]. All serum
samples were appropriately processed, promptly refrigerated, and transported cold to a laboratory
that is certified by the Korean Ministry of Health and Welfare at the Neodin Medical Institute
in Seoul. Blood samples were analyzed within 24 hours after transportation. The detection
limit for 25-hydroxyvitamin D by radioimmunoassay is 1.2 ng/ml, and the interassay
coefficients of variation were 1.9–6.1% for samples taken between 2010 and 2012. In addition to
analyzing serum 25-hydroxyvitamin D levels, fasting glucose, hemoglobin A1c (HbA1c), total
cholesterol, and triglyceride levels were measured using a Hitachi 7600 clinical analyzer
(Hitachi High-Technologies Corporation, Tokyo, Japan).
Dry Eye Syndrome Assessments and Other Variables
DES examination and the diagnosis of KNHANES have been described in detail elsewhere [
]. DES was defined by a history of a clinical diagnosis of dry eye syndrome by a physician,
based on responses to a questionnaire. The questionnaire included the following yes/no
question: "Have you ever been diagnosed by an ophthalmologist as having DES?" Demographic
information was collected during health interviews. Height and weight measurements were
obtained while subjects wore light clothing and no shoes. Body mass indices were calculated as
follows: weight (kg)/height (m)2. Smoking status was self-reported, and subjects were classified
as current smokers, past smokers, or non-smokers. Data on sunlight exposure were obtained
by asking the participants whether they were exposed to the sun for < 2 h, 2–5 hrs, or 5 h
per day. Three blood pressure measurements were taken at 5-min intervals using a
sphygmomanometer with the subjects sitting down, and the average of the second and third
measurements was used for the analysis. The presence of diabetes mellitus was defined as a fasting
blood-glucose level 126 mg/dL or the use of anti-glycemic medication. The presence of
hypertension was defined as a systolic blood pressure 140 mmHg, a diastolic blood pressure
90 mmHg, or use of antihypertensive medication.
Statistical analyses were performed using the IBM1 SPSS1 software version 18.0 (IBM,
Armonk, NY, USA). Strata, sampling units, and sampling weights were used to obtain point
estimates and standard errors. Participant characteristics were described using means and
standard errors for continuous variables and percentages and standard errors for categorical
variables based on the presence of DES. Analysis of variance or chi-square tests were used to
compare the patients’ demographic characteristics. To evaluate the association between
25-hydroxyvitamin D and DES, serum 25-hydroxyvitamin D levels were categorized into
quintiles, and simple and multiple logistic regression analyses were used. After calculating the crude
odds ratios (OR) (Model 1), values were adjusted for age and sex (Model 2). They were then
further adjusted for other confounding factors including smoking, hypertension, diabetes, and
sunlight exposure times (Model 3). All variables considered for the logistic regression analyses
were examined for multicollinearity, and only variables with a variance inflation factor <5
were used. P values were two-tailed, and a P value < 0.05 indicated statistical significance.
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Of the 17,186 eligible subjects aged >19 years who had their serum 25-hydroxyvitamin D levels
measured, 16,396 (95.4%) subjects had their cataract statuses examined. The prevalence of DES
is 9.8% (Standard error [SE], 0.5%). The prevalence of DES is significantly higher in women
(mean: 15.0%, SE: 0.9%) than in men (mean: 4.5%, SE: 0.5%, P < 0.001). The demographic
characteristics of these subjects according to their DES statuses are summarized in Table 1,
while data standardized by age and sex are shown in S1 Table. Average serum
25-hydroxyvitamin D levels were 17.1 ng/mL, and the prevalence of DES was 9.8% (un-weighted
number = 1,679). Subjects with DES were more likely to be female (P < 0.001), older (P = 0.009),
and non-smokers (P < 0.001), and were more likely to have lower diastolic blood pressures
(P < 0.001), lower triglycerides (P = 0.006), and shorter sun-exposure times (P = 0.005).
The demographic and clinical characteristics of the patients according to blood 25-hydroxy
vitamin D quintiles showed that as serum 25-hydroxyvitamin D levels increased, participants
were more likely to be male (P trend < 0.001), older (P trend < 0.001), hypertensive (P
trend = 0.001), and smokers (P trend < 0.001), and were more likely to have higher total
cholesterol (P trend = 0.010) and have experienced longer sun exposures (P < 0.001, Table 2, and
S2 Table after standardization by age and sex). Average blood 25-hydroxyvitamin D levels
(n = 2383)
Data are expressed as weighted means or weighted frequency (%) with standard errors.
* p < 0.05
were 17.3 ng/mL (95% confidence interval [CI], 17.0–17.6). Men had significantly higher blood
25-hydroxyvitamin D levels (18.3 ng/mL, 95% CI, 17.9–18.6) than women (16.4 ng/mL, 95%
CI, 16.0–16.8, P < 0.001). Women, but not men, showed significant differences in their serum
25-hydroxyvitamin D levels in relation to the presence of hypertension (P < 0.001, Table 3).
The prevalence of vitamin D deficiency is 71.6 ± 1.1%, and the prevalence of vitamin D defi
ciency was higher in women (65.8 ± 1.4%) than in men (77.3 ± 1.3%, P < 0.001).
The odds of DES significantly decreased across the quintiles of the serum
25-hydroxyvitamin D levels (P for trend = 0.026, Model 1). However, this association was attenuated after
adjusting for potential confounders including age, sex, hypertension, diabetes, smoking, and
sun light exposure times (P for trend = 0.076, Model 3). Higher serum 25-hydroxyvitamin D
levels were significantly associated with the decreasing odds of DES (Model1, quintile 5 versus
1, OR = 0.73, 95%CI: 0.51–0.97). However, this association was also attenuated after adjusting
for potential confounders (Model 3, quintile 5 versus 1, OR = 0.85, 95%CI: 0.55–1.30, Fig 2). In
subgroup analysis by gender, the OR of DES in those with higher serum 25-hydroxyvitamin D
levels versus those with low levels was lower in men than women (Model 3, quintile 5 versus 1,
adjusted OR = 0.70 in men, OR = 0.92 in women), but this was not statistically significant
(Table 4). The prevalence of DES was not different between subjects with and without vitamin
D deficiency (Table 5). The relative odds of DR (OR = 0.37, 95% CI: 0.18–0.76)[
lateAMD (OR = 0.32, 95% CI: 0.12–0.81)[
] in subjects with the highest vitamin D quintile
versus the lowest one were relatively low, whereas the relative odds of cataract (OR = 0.76, 95%
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All subjects aged 19+ years
Dry eye syndrome
Dry eye syndrome
Data are expressed as weighted means or weighted frequency (%) with standard errors.
Fig 2. The odds ratios of dry eye syndrome according to quintiles of blood vitamin D levels (reference
group = <12.3 ng/ml)
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Prevalence was expressed as weighted estimates [%] (standard errors [%], 95% confidence intervals).
Model 1: Crude. Model 2: adjusted for sex and age. Model 3: adjusted for sex, age, diabetes, hypertension, sunlight exposure time, smoking, and body
CI: 0.59–0.99) and DES were relatively high in men (Table 6). In women, serum vitamin D
levels were not associated with ocular diseases.
The crude odds of DES significantly decreased across the quintiles of serum 25-hydroxyvita
min D levels, and higher serum 25-hydroxyvitamin D levels were significantly associated with
decreasing odds of DES. However, these associations were attenuated after adjusting for
confounders. In addition, the relative odds of DR and late AMD were relatively low, while those of
cataract and DES were high.
After adjusting for potentially confounding factors including sex, age, smoking, hypertension, diabetes, and sunlight exposure times, subjects in the highest serum 25-hydroxyvitamin
Data are expressed as weighted means or weighted frequency (%) with standard errors.
D quintile had a 15% lower risk of DES than subjects within the lowest quintile. However, the
95% CI of this association included the null point of 1.0 and did not show statistical
significance. Our study is consistent with a previous cross sectional study that serum 25 vitamin D
levels were not associated with the presence or severity of disease, although higher vitamin D
levels were associated with decreased subjective DES symptoms [
]. However, other
case-control studies reported that vitamin D deficiency was associated with the decreased tear break-up
time and Shirmer test scores, which imply that vitamin D deficiency may be associated with
dry eye symptoms [
]. The present study did not find a significant inverse association
between vitamin D and DES. We hypothesized that serum vitamin D has a limited effect
on DES. Serum vitamin D may have difficulty in reaching the cornea, due to its lack of
Several studies reported that vitamin D can be anti-inflammatory at the ocular surface. In a
mouse model, topical administration of vitamin D inhibits migration of Langerhans cells and
maturation, and delayed neovascularization of the central cornea [
]. In a rat keratoplasty
model, topical vitamin D protected against keratoplasty rejection, inhibiting the
pro-inflammatory cytokines interleukin-1 and tumor necrosis factor [
]. However, these studies used
topical vitamin D and not serum vitamin D. We hypothesized that the effect of serum vitamin D
on the cornea may be limited due to the decreased blood supply to the cornea.
To further support our hypothesis, we compared the relative odds of DES in subjects in the
highest vitamin D quintile versus those in the lowest quintile with their relative odds of other
ocular diseases including DR, AMD, and cataract, from our previous studies using the same
KNHANE population (Fig 3) [
]. In men, the relative odds of DR (OR = 0.37, 95% CI:
0.18–0.76) or late AMD (OR = 0.32, 95% CI: 0.12–0.81) are lower than cataract (OR = 0.76,
95% CI: 0.59–0.99) or DES (OR = 0.70, 95% CI: 0.30–1.64). The distribution of OR is consistent
with the location of the lesion in ocular anatomy. The retina and macula, where relative lower
ORs were observed, are located in the posterior part of the eye, whereas the lens and cornea,
where relatively higher ORs were observed, are in the anterior part of the eye. The retina and
macula have more blood supply than the lens and cornea do. The effect of serum vitamin D
may be attenuated in case of decreased blood supply, because serum vitamin D reaches the eye
through the blood supply. In addition, the lens may be more affected by sunlight (UVB), which
is a risk factor for cataracts, than it is by vitamin D. On the contrary, the macula would be less
influenced by the harmful effect of UVB, because only a small portion of UVB reaches to the
retina. This suggests that different locations of ocular lesions may be the cause of the
differential effects of vitamin D.
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Fig 3. The comparison of odds ratios of dry eye syndrome (DES), cataract, age-related macular degeneration (AMD), any diabetic retinopathy (DR),
and vision-threatening DR (VTDR) according to blood vitamin D levels (reference group = lowest vitamin D quintile group).
Another interesting finding is that the inverse association between vitamin D and ocular
disease is significant in men, but not in women. Although the adjusted ORs of DR, AMD, and
cataract in the highest quintile versus the lowest one were significantly decreased in men, such
an association was not shown in women (Fig 3). Moreover, the ORs of DR and AMD in
women have the opposite direction to those in men. One possible reason is that men are
usually involved in more activities outside, which leads to greater exposure to sunlight than
women. Sunlight exposure is the main driver for vitamin D production in the skin. Another
possible reason is that women have reduced sensitivities to vitamin D, or they may more
frequently use sunlight protective instruments such as clothes, sun block cream, hats, or
sunglasses. However, this is purely speculative. Further studies are required to identify the factors
responsible for this gender difference and to elucidate the exact sex-specific biological
The average vitamin D concentrations were low (17.1 ng/mL), which is lower than the
vitamin D deficiency criteria (20.0 ng/mL). Moreover, vitamin D levels increased with age. These
findings are supported by previous studies in which the prevalence of vitamin D insufficiency
was about 70% or higher, and elderly people had higher vitamin D levels compared with young
people in countries such as Korea and Thailand [
]. One possible explanation is that aged
persons have more opportunity to spend time to do outdoor activities. The rapid economic
development in Korea often means that young people have indoor jobs, whereas old persons
have outdoor jobs .
Alternative explanation for result of the present study is that DES may be associated with
vitamin D receptor dysfunction, not serum 25-hydroxyvitamin D levels [
we could not confirm it, because KNHANES did not have information on the vitamin D
receptor dysfunction. In addition, it is possible that vitamin D may get direct access to the cornea.
Vitamin D is a fat-soluble steroid that should be taken up by the lacrimal gland and possibly secreted in tears onto the ocular surface.
The results from this study warrant further investigation. Vitamin D levels differ according to the latitude, ethnicity, and culture of the study population. Vitamin D production in the skin varies with UVB exposure, which is affected by many factors including sun bathing, time spent
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outside, clothing traditions, the use of sun protection agents, and skin color [
]. In addition,
exposure to UVB declines from the equator to the polar regions, creating a gradient of vitamin
D production in the skin. Thus, the effect of vitamin D on ocular diseases may differ in different parts of the world, which needs further study in the future.
In the present study only serum 25-hydroxyvitamin D levels were examined to assess the
vitamin D status. However, recent advancements in technology make the measurement of
metabolites of vitamin D possible [
]. Given that measuring only 25-hydroxyvitamin D
cannot give the complete explanation about association between vitamin D and disease, further
study is needed to include the measuring vitamin D metabolites.
The relatively large number of participants and the study’s design are the major strengths of
this study. Another strength is the rigorous quality control for the measurements of serum
25-hydroxyvitamin D levels. This study also has several limitations. First, DES was evaluated
by a self-reported method that was not based on the clinical examination, which may cause
bias in the diagnosis of DES. The questionnaire did not include the current status of DES and
that of potential patients. Even though DES is a complex disorder, with subtypes such as tear
deficiency DES and evaporative DES, the severity of DES was not assessed by measures such as
the keratoconjunctival epithelial damage score in the present study. Second, it was not possible
to adjust for seasonal variations in serum 25-hydroxyvitamin D levels because KNHANES
does not contain information about the dates on which the blood samples were taken. A recent
study showed that an Asian population did not display any significant seasonal variations in its
vitamin D status [
], whereas, another study reported significant seasonal variation, with
lower vitamin D levels in winter [
]. In addition, we could not control for potential
confounders DES-like symptoms such as recurrent corneal erosion, conjunctivochalasiasis, various
neuropathies, or epithelial basement membrane dystrophy, and DES-inducing conditions such as
depression, rheumatoid arthritis, or contact lens wear, which were not available in KNHANES.
Third, ocular vitamin D levels were not examined. Serum vitamin D levels may not reflect ocu
lar vitamin D levels. Finally, the current study is cross-sectional in its design, which makes
inferring causality difficult.
To the best of our knowledge, the study provides the first population-based epidemiologic
data on the associations between serum 25-hydroxyvitamin D levels and DES. We did not find
a significant inverse association between serum 25-hydroxyvitamin D levels and DES in a
representative Korean population. For prevention or treatment of DES, topical vitamin D is likely
to be better rather than systemic vitamin D. Furthermore, our study suggests a differential
effect of vitamin D on DR, AMD, cataract, and DES. The effect of vitamin D on these ocular
diseases may differ by the location of the lesion in the eye.
S1 Table. Age- and Sex- standardized demographic and clinical characteristics.
S2 Table. Demographic characteristics by quartile blood 25-Hydroxyvitamin D categories.
The authors would like to express their appreciation of the Epidemiologic Survey Committee of the Korean Ophthalmologic Society for conducting the KNHANES examinations and for supplying the data for this study. The authors wish to acknowledge the financial support of the
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St.Vincent’s hospital, research institute of medical science (SVHR-2013-12). The Epidemio
logic Survey Committee of the Korean Ophthalmologic Society, the members are:
Se Woong Kang; Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, Korea,
Seung-Hee Baek; Department of Ophthalmology, Kim’s Eye Hospital, Konyang University
College of Medicine,Seoul, Korea,
versity College of Medicine, Seoul, Korea,
Chan Yun Kim; Institute of Vision Research, Department of Ophthalmology, Yonsei Uni
Sang-Duck Kim; Department of Ophthalmology, Wonkwang University College of Medi
Seung-Hyun Kim; Department of Ophthalmology, Korea University College of Medicine,
Jong Soo Lee; Department of Ophthalmology, Pusan National University College of Medicine, Iksan, Korea,
cine, Busan, Korea,
cine, Seoul, Korea,
Key Hwan Lim; Department of Ophthalmology, Ewha Womans University School of Medi
Ki Ho Park; Department of Ophthalmology, Seoul,National University College of Medicine,
Young Jeung Park; Department of Ophthalmology, Cheil Eye Hospital, Daegu, Korea,
Jae Pil Shin; Department of Ophthalmology, Kyungpook National University School of
Medicine, Daegu, Korea, wan University School of Medicine, Seoul, Korea, of Medicine, Seoul, Korea,
Su Jeong Song; Department of Ophthalmology, Kangbuk Samsung Hospital, Sungkyunk
Suk-Woo Yang; Department of Ophthalmology, The Catholic University of Korea College
Kyung-Chul Yoon; Department of Ophthalmology, Chonnam National University Hospi
tal, Chonnam National University Medical School, Gwangju, Korea,
Seung-Young Yu; Department of Ophthalmology, Kyung Hee University School of Medicine, Seoul, Korea
Wrote the paper: DJ SK EC JA.
Conceived and designed the experiments: DJ SK EC JA. Performed the experiments: DJ EC JA. Analyzed the data: DJ SK EC JA. Contributed reagents/materials/analysis tools: DJ SK CY.
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with preexisting dry-eye syndrome. Journal of cataract and refractive surgery. 2014. Epub 2014/12/10.
doi: 10.1016/j.jcrs.2014.11.034 PMID: 25487027.
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