Decrease of tear break-up time at Japanese eye clinics during five consecutive years

The aim of this retrospective chart review study was to evaluate the 5-year trend of ocular surface examination results in participants who visited the eye clinic from 2015 to 2019, underwent corneal and lacrimal examinations, refraction, and intra-ocular pressure measurements, and reported six dry eye-related symptoms. A total of 1468 patients were analyzed. Tear break-up time (BUT) decreased continuously for five consecutive years: 4.76 ± 1.84 s in 2015, 4.57 ± 1.70 s in 2016 (p = 0.999, vs 2015), 4.35 ± 2.06 s in 2017 (p = 0.662), 3.83 ± 2.18 s in 2018 (p < 0.001), and 3.63 ± 2.10 s in 2019 (p < 0.001). The decrease of BUT was more prominent in women than men (p < 0.001) and the correlation coefficient between calendar year and BUT was greater in women than men (p = 0.002). Schirmer test value, strip tear meniscometry value, and corneal staining score did not exhibit significant changes. Prevalence of blurring, photophobia, and pain increased toward 2019 among symptoms surveyed (eye fatigue, blurring, photophobia, dryness, irritation, and pain) and regression analysis indicated blurring (p < 0.001), photophobia (p < 0.001), and pain (p < 0.001) were correlated with BUT. In conclusion, BUT decreased continuously for five consecutive years from 2015 to 2019 and was associated with dry-eye related symptoms.

Inclusion and exclusion criteria. The study consecutively recruited patients from the participating clinics between January 2015 and December 2019. We included outpatients only at first visit with best-corrected visual acuity above 20/30 in both eyes. The exclusion criteria were use of eyedrops, ocular surgery within the previous month, and acute eye disease within the previous week.
Ophthalmological examinations. The ophthalmological examination was carried out according to Yokoi et al. 21,22 . Briefly, BUT was defined as the time interval between blink and the appearance of the first dark spot in the cornea. From 2016, break-up pattern was classified as 'line' , 'spot' , 'area' , 'dimple' , and 'random' according to Yokoi's classification 21 . A corneal staining score was determined to grade corneal epitheliopathy, graded at 0-2 for severity and area. Schirmer test was performed without topical anesthesia. Strips of filter paper (Whatman No. 41; Showa Yakuhin Kako, Tokyo, Japan) were placed at the temporal lower conjunctival fornix for 5 min. The length of the wetted filter paper was recorded. Schirmer test was performed at least 5 min after tear strip meniscometry. To measure aqueous availability at the lower tear meniscus, the wetted length for tear strip meniscometry was obtained. The strips (SMTube, Echo Electricity Co., Ltd., Fukushima, Japan) were inserted into the lateral side of the tear meniscus of the lower lid for 5 s without touching the ocular surface. Intra-ocular pressure and refraction were determined by three successive readings with a noncontact tonometer and refractometer (Tonoref™ II, Nidek Co., Ltd., Aichi, Japan). During examination, temperature and humidity of the examination room were adjusted to 21-25 °C and 40-60%, respectively. According to the Japan Meteorological Agency 23

Patient interviews for dry-eye related symptoms.
Patients were asked about the presence or absence of six common DE-related symptoms: dryness, irritation, pain, eye fatigue, blurring and photophobia. These symptoms were selected from validated questionnaire DEQS 25 as the six most prevalent symptoms reported by outpatients visiting the dry eye clinic of Keio University Hospital in 2012.
Statistical analysis. The sample size was calculated with a 0.05 margin of error and 95% confidence interval using G*power 3.1 (American Statistical Association). Effect size was derived from a measured value in the current study. An effect size of 0.272 was identified in BUT with an appropriate total sample size of 137 for the comparison of 2015 and 2019. Where appropriate, data are given as the mean ± SD. The data from the right eye for BUT, corneal staining score, Schirmer test value, and tear strip meniscometry value were analyzed. One-way ANOVA and Mann-Whitney U test were performed as appropriate to assess the 5-year variance of parameters. The Bonferroni test was applied to avoid type I errors from multiple comparisons. The regression line was computed for BUT and year by the least-square method and the difference in slopes and correlation coefficient was compared by t-test after stratification for sex. Correlations between signs and symptoms were evaluated using a standardized partial regression coefficient. The number of participants in 2017 and 2018 was low due to a transfer of the investigator (MA). Nevertheless, sample size is still sufficient for statistical analysis and multiple comparison was performed to minimize errors. All analyses were performed using StatFlex (Atech, Osaka, Japan) with p < 0.05 being considered statistically significant.  www.nature.com/scientificreports/ 3.83 ± 2.18 s in 2018 (p < 0.001), and 3.63 ± 2.10 s in 2019 (p < 0.001). This trend was stable across the three participating clinics (Fig. 1). The decrease of BUT was more prominent in women than men (p < 0.001) (Fig. 2) and correlation coefficient between year and BUT was greater in women (− 0.291) than men (− 0.137) (p = 0.002). The line break pattern was most prevalent among five tear break-up patterns and its proportion increased toward 2019 with statistical significance (p = 0.026, 2016 vs 2019, chi square test) (Fig. 3). Tear break-up patterns from 2016 to 2019 could be categorized as line (45.1%), dimple (20.2%), random (2.1%), spot (15.4%), and area (17.2%). Schirmer test value, tear strip meniscometry value, and corneal staining score did not change ( Table 1).

Discussion
The results revealed a continuous decrease of the BUT, which could imply an increasing prevalence of DE throughout the five calendar years. This trend was not limited to specific local clinics and could be generalized nationwide in Japan. Increasing prescription of mucin secretagogue eyedrops (diquafosol sodium) reported by Japan's largest pharmaceutical company 9 reasonably supported the current results.
The association of DE and weather and air quality is an emerging issue. As indicated in the "Methods" section, temperature/humidity did not exhibit specific trends during the study period and were not obviously associated with the decrease of BUT. Although rough trends could be inferred from the data on air quality (NO 2 , SPM, SO 2 ,    Digital eye strain is a serious health problem in the modern computerized society with a growing habitual screen time. According to a cohort study involving 672 Japanese office workers who used visual display terminals, the prevalence of short BUT (≦ 5 s) was as high as 78.6% (mean age: 43.2 years) 26 . A systematic review and meta-analysis of DE in visual display workers estimated the prevalence at 9.5-87.5% depending on criteria of DE 27 . Digital tasks at near distance pose a risk for the development and worsening of DE due to exposure to blue light emitted from the display 28 and decreased blinking 29 . Another potential hazard is stress. A national survey reported that stress continuously increased in Japanese people from 2013 to 2018 30 , and is a considerable risk factor for DE 31 . In addition, sleep quality is deteriorating with Japanese reporting a mean sleep duration of 7 h 27 m in 1995 that continuously decreased to 7 h 15 m in 2015 32 . Sleep habits could be associated with DE since poor sleep and a disturbed circadian rhythm may worsen DE 33 . It is noteworthy that BUT decreased more rapidly in women than men. The prevalence of DE is much higher in women than men and our results could be a manifestation of women being at higher risk of changes in BUT during this period.
Blurring was strongly associated with BUT and this finding is consistent with numerous previous investigations describing decreased visual function with DE 34 . Pain and photophobia were also correlated with BUT and calendar year. These symptoms are associated with trigeminal neuralgia and could be exacerbated by local or systemic disorders since the prevalence of women's trigeminal neuralgia is twice that of men 35 , and can be evoked by various triggers including digital eye strain and DE 36 . Synergic effects of DE, digital eye strain, and stress could be responsible for increased blurring, pain, and photophobia during 2015-2019. The present results of the proportion of break-up patterns are comparable to previous results of a multicenter study by Shigeyasu et al. 22 reporting line (51.6%), dimple (16.3%), random (13.5%), spot (10.5%), and area (4.6%). The line break pattern is observed in the lower cornea of eyes with a mild-to-moderate aqueous tear deficiency. This may be related to a temporary decrease of the aqueous tear thickness in that region as the lower meniscus takes up moisture and an upward drag caused by the tear film spreading 21 . In the present study, Schirmer test values and strip meniscometry values did not change for 5 years and their trend did not correspond to the trend of line break patterns, hence, we speculate that an impaired moisturizing function of corneal epithelial cells and mucin www.nature.com/scientificreports/ or oil layer dysfunction rather than aqueous tear deficiency may be responsible for an increased proportion of line break patterns. Strengths of the current study include being a multicenter study, having sufficient sample size, and accumulating 5 years of data from physician examinations. This study measured the prevalence and severity of ocular status as well as DE-related symptoms in a clinic-based cohort. Participating clinics were distributed across the center and east of Japan's Honshu Island and the results could be generalized.
The current study has several limitations. Although a detailed evaluation of the symptoms was conducted in the present study, dry eye questionnaires including OSDI and DEQ-5 that can quantitatively evaluate symptoms were not applied. This lack may be an insufficiency in this study and should be ameliorated in follow-up research. An analysis of the role of psychological status, lifestyle, other systemic comorbidities, and medications in addition to local environmental factors would enhance the results of the current study although we consecutively recruited first-visit patients only and the participants may be representative of the general population including individuals with adequate systemic health. It is also recommended that these factors (or their proxies VDT use time, anxiety index and average sleeping time) should be recorded and evaluated in a subsequent study.
In conclusion, BUT continuously decreased as the prevalence of blurring, pain and photophobia increased at Japanese eye clinics from 2015 to 2019. Decrease of BUT was more prominent in women than men. We hypothesize that DE and digital eye strain due to rapid digitalization and a decreasing sleep duration and increasing stress may synergistically contribute to the findings.