Retinal nerve fiber layer thickness and retinal vascular caliber alterations in coal miners in northern China: a community-based observational study

INTRODUCTION

Nowadays, coal is still one of the most important energy sources providing energy and electricity worldwide.Work-place exposure to coal mine dust during coal mining remains a significant hazard worldwide. The occupational exposure to crystalline silica may cause progressive lung inflammation culminating in forming of pneumoconiosis.Coal mine dust may lead to systemic silica-associated inflammatory response triggered by cytokines released from macrophages, lymphocytes and epithelial cells. Such cytotoxic effect of inhaled silica dusts may cause alterations of various organs throughout the body, including inner structures of the eye such as choroid and retinal tissue. Previous investigations revealed that active inflammation led to a significantly thickened retinal nerve fiber layer (RNFL), which can be clearly detected by optical coherence tomography(OCT), a high-resolution imaging technique suitable for evaluating the RNFL at and around the optic nerve head(ONH).

The metabolism in the outer retina and retinal blood flow had been demonstrated to be increased in darkness, such alterations may affect the progression of retinal disease during coal mining. However, studies on the retinal thickness changes in long-term effects of working underground by means of OCT have been scarce so far. Besides, our group also would like to explore the retinal vessel caliber alterations in the dark working environment, since the retinal hemodynamics and oxygen saturation can be different in the dark.

We applied a non-mydriatic approach in a dimly lit room by using a digital fundus camera (Type CR6‐45NM; Canon, Ōta,Tokyo, Japan) to obtain retinal photographs. Two 45° color fundus photographs of each participant were obtained, centered on optic disc and fovea. The retinal vessel diameters were measured using a semiautomated algorithm interactive vessel analysis software (IVAN; Vasculomatic ala Nicola, University of Wisconsin-Madison, WI, USA), as described in our previous studies. Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) diameters were measured through an area of 0.5 to 1 disc diameter surrounding the optic disc margin, estimated by means of the Big-6 formula on the infrared fundus photographs. The arteriovenous ratio (AVR)was calculated as CRAE divided by CRVE.

SUBJECTS AND METHODS

This research conducted in accordance with the ethical standards of the Helsinki Declaration and the study protocol was approved by the Institutional Ethics Committee of the Beijing Tongren Hospital. All participants in our study gave their written informed consent before enrolment.

The community-based observational study was a subgroup of the longitudinal Kailuan Study which included 101 510 employees and retirees of a coal mining company (Kailuan Group Company), as described in our previous studies. From 2012 to 2013, randomly selected participants completed baseline data collection, out of whom 4004 individuals eventually met the inclusion criteria and underwent fundus photography and OCT from 2013 to 2014.Exclusion criteria were history of any ocular diseases and ocular surgeries, or any use of medications that affect the eyes.Cataract and pseudophakia not affecting the quality of OCT and fundus photography images were not exclusion criteria.Among them, individuals that worked underground were included as study group, and participants working above the ground were defined as control group.

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（98）齿萼羽苔 Plagiochila hakkodensis Steph.熊源新等（2006）；杨志平（2006）

The aim of this study was to explore the potential alterations of retinal thickness and retinal vessel calibers in coal mine workers. In attempt to reduce the risk of a referral bias, we chose the design of a relatively community-based study population.

目前我国公共图书馆系统未成年人服务很大程度上落后于成人服务，少儿图书馆事业发展很不平衡，农村地区无此项服务[33](P18)，而学校图书馆面临着专业化、规范化的建设任务，其发展同样有较严重的区域、年级和管理部门等的差距[34]（P254-285）。没有有效、强有力的图书馆未成年人服务的理论与实践支撑，可以说语文教育的概念就会成为绝大多数师生的空中楼阁与极少数人的游乐园。另外这两类主要的未成年人服务机构分属我国文化和教育系统，容易出现力量分散、资源浪费、各行其是等问题，两者间的合作与协调也有赖于行政部门的积极作为。

All the study participants underwent a spectral-domain OCT(iVue SD-OCT; Optovue Inc, Fremont, California, USA)examination obtaining images of the ONH, macula and adjacent retina. A 6×6 mmraster scan was centered on the optic disc and macula. The mean temporal, nasal, inferior,superior quadrant peripapillary RNFL thicknesses and central macular thickness (CMT) were assessed from high resolution images. RNFL segmentation was checked for every OCT image. Images not centered, or a signal strength index less than 40, any algorithm failures, motion artifacts, poor focusing were excluded from the assessment. As described in our previous study, two experienced ophthalmologists scanned all subjects.

Estimates of cumulative silica dust exposure (CDE), presented in milligrams/cubic meter-years, was calculated as follow:the duration of exposure in years multiplied by the dust concentration during the same time of employment period for each coal worker. Given by the department of dust detection and monitoring of the Kailuan Colliery Company,dust concentration and free silica content were measured using national standard methods in order to calculate the geometric means yearly. These numerical data were collected by gravimetric method, and then used to calculate the CDE for each subject.

This community based study found that the retinal vessels diameters was significantly thicker in coal workers than in the control group. In addition, the RNFL thickness was significantly higher in the study group while the CMT was lower in the underground coal workers as compared to the controls. As a corollary, thicker RNFL was significantly associated with higher CDE, and wider retinal veins were also significantly correlated to higher CDE after adjustment for age. A higher CDE was significantly associated with a thicker RNFL in multivariable analysis.

Structured interviews with standardized questions included information on the working areas, history of occupational exposure, level of education, history of systemic medical disorders such as diabetes and hyperlipidemia,alcohol consumption and smoking, were performed by trained investigators, as described in our previous study. The working areas in the Kailuan Colliery Group were defined as above the ground and underground. We also measured height and weight and calculated body mass index (BMI). Systolic blood pressure and diastolic blood pressure were measured twice with the participant sitting for at least 5min using a mercury sphygmomanometer. For all study participants,we collected blood samples under fasting conditions and transfused into vacuum tubes containing ethylene diamine tetraacetic acid (EDTA). All blood samples were analyzed using an auto-analyzer and underwent a biochemical analysis of the serum concentration of glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride,total cholesterol and uric acid.

RESULTS

A total of 4004 participants [1720 women (43.0%)] with a mean age of 59.7±11.0y were included into the present investigation. After matched with age (±1y), spherical equivalent and gender, we included 659 coal workers (working underground) as study group, and 477 participants (working above the ground) as control group. There is no significant difference between study and control group in gender(=0.41), age (51.0±7.8y51.8±7.5y;=0.077), diabetes status (=0.105), alcohol consumption (=0.242) or smoking history (=0.714; Table 1).

As compared to the control group, the study group showed a significantly thicker retinal artery (154.52±19151.56±19.8 μm;=0.012) and vein diameters (236.27±27.3230.35±27.75 μm;<0.001), while the AVR did not differ significantly (0.66±0.120.67±0.11;=0.687) between both groups (Table 2). Additionally, the RNFL thickness was significantly higher in the study group than the control in superior and temporal quadrants (124.15±14.93121.66±16.76 μm,=0.012; 81.59±14.1479.02±12.21 μm,=0.002, respectively), while the CMT was lower in the downhole workers as compared to the control (246.17±22.1249.06±19.61 μm;=0.032; Table 2).

The retinal vein diameter was correlated with the CDE in both univariate and multivariable analysis. Nemmarmeasured the distribution of radioactivity after the inhalation of pollutant particles and found that inhaled pollutant particles can cross the pulmonary epithelium into the cardiovascular system and thus exert direct effects on the cardiovascular system or the indirect effects mediated by the inflammatory response on the heart and vessels. With the central retinal artery as branch of the ophthalmic artery and internal carotid artery, the microvascular system of the retina can be assumed as part of the cardiovascular system. In addition, Nagaoka and Yoshidadetected that the stage of chronic kidney disease was a significant variable for the serum concentration of low‐density lipoprotein and retinal blood flow. Both retina and kidney are low-resistance end organs that are supplied by small blood vessels, which are vulnerable to fluctuations in blood flow. The anatomical similarities in the vascularization of the retina and kidney may lead to similar aspects in the pathogenesis of cellular apoptosis and upregulation of pro-inflammatory markers in both organs. Therefore, it is reasonable to assume that long-term silica dust exposure can initiate the inflammation response on vascular endothelial cells which may influence ocular structures.

引理1.3[8] 设τ1,τ2为集合X上的两个拓扑且τ1⊆τ2,则CIrrτ2(X)⊆CIrrτ1(X)。

DISCUSSION

The statistical analysis of this study was applied using a commercially available statistical package(SPSS for Mac, version 25.0; IBM/SPSS, Chicago, Illinois,USA). For the first analysis, we described the mean values(presented as mean standard deviation) of the participants’characteristics. Then the Studenttest for un-paired sampleswas to evaluate the statistical significance of differences between the coal workers and the controls. Multiple linear regression analysis was applied to evaluate the potential associations between ocular and systematic risk factors. The 95% confidence intervals of each risk factor were presented.Two-tailed-values were considered to be statistically significant if lower than 0.05.

一个洁净的外部环境，能够让患者更好的配合治疗。现代医院中生殖医学中心的外部环境要保持干净、整洁，室内安装空气调节过滤器，保证诊室内部的空气质量较好，温度适宜，为患者提供一个温馨、舒适的就医环境。在选址的过程当中，尽量避免化学放射源，减小化学放射源对胚胎的影响。

The results of our study indicated that long-term working underground may lead to vessel dilation, which supported by Kappelgaardthat dark adaptation was associated with wider retinal vessel. Previous study has demonstrated that increased flow velocity in the central retinal artery in dark may relate to the square of the vascular caliber. In addition, increased metabolic activity of the retina induced by dark adaptation may also lead to retinal vasodilation.However, there had apparently contradictory findings. Barcsayreported results with a venular constriction of 1.5% in 11 healthy young adults during dark and light adaptation by near-infrared laser light of 785 nm wavelength. Similarly, von Hannoobserved a slightly venular constriction (2.8%)after dark exposure, while no difference was observed in retinal artery diameter. Reasons for this discrepancy may have been the differences in study population and methodology.Our results may help explain how long-term changing of light conditions affect retinal vessels.

In multivariable linear regression analysis (regression coefficient=0.42), a thicker RNFL was associated with a higher CDE (=0.005,=0.002, 95%CI: 0.001, 0.003) after adjusting for younger age (<0.001,=-0.339, 95%CI: -0.437,-0.241), smaller cup-to-disc ratio (<0.001,=-6.315, 95%CI:-9.75, -2.879) and larger spherical equivalent (<0.001,=1.863, 95%CI: 1.324, 2.403). In a reverse pattern (regression coefficient=0.19), a higher CDE was significantly associated with a thicker RNFL (=0.004,=5.194, 95%CI: 1.624, 8.763)after adjusting for age (=0.003,=0.094, 95%CI: 2.389,11.955), high-density lipoproteins (=0.009,=0.082, 95%CI:18.897, 134.474) and uric acid (<0.001,=-0.118, 95%CI:-1.026, -0.322). Wider retinal vein diameters were associated with higher CDE (=0.036,=0.004, 95%CI: 0, 0.009) after adjusting for younger age (<0.001,=-1.056, 95%CI: -1.367,-0.744) and larger spherical equivalent (=0.027,=1.876,95%CI: 0.211, 3.541).

网络初中数学原创精品资源基地的建立，旨在构建符合素质教育要求、变革教与学行为方式、融合数学文化的课程体系，提升学生学习快乐感和教师的职业幸福感.同时体现先行先为与分析共享结合，围绕解决做什么、怎么做的问题，先行试验、总结提升，通过各种形式建立便于向其他中小学和社区开放的资源共享平台.

In our study, the RNFL thickness was significantly higher in the study group than the control in superior and temporal quadrants and the RNFL thickness was significantly associated with a higher CDE in multivariable analysis. The result of our study was in agreement with previous ophthalmological studies that active inflammation may lead to a significantly thickened RNFL. The finding may be explained by the theory that the breakdown in the blood-retinal barriers and increased production of prostaglandins, inflammatory cytokines, and vascular permeability factor may be related to increased RNFL thickness. Since exposure to silica dust may induce the accumulation of inflammatory cells, our result could go along with the similar mechanism. With the increased RNFL thickness as a sign of optic disc edema, the correlation between glaucoma severity and CDE is worth investigating further.

Interestingly, CMT was slightly thinner in study group compared with the control in our results. Former studies have indicated that cytokines (such as ⅠL‐1β, TNF‐α, MMPs and TGF‐β) induced by the inflammatory reactions occurred within the uveal tissue or the retinal pigment epithelium might give rise to retinal pathophysiologic changes.Hanreported that the CMT in the eyes of the Vogt-Koyanagi-Harada (VKH) patients was significantly lower at 12 and 24mo, while the RNFL thickness was significantly higher in VKH eyes at the initial visit and at the 6- and 12-mo follow-up visits. They suggested that the degeneration of choriocapillaris layer might have a correlation with the disruption of photoreceptor or external limiting membrane.Such results indicate that long-term accumulation of trace elements and chronic inflammation might result in decrease of retinal thickness in macular area, however, assessing the thickness of the RNFL. Ayarevaluated ocular findings in 46 coal mine workers who diagnosed with pneumoconiosis.Their results showed that CMT values were slightly thinner in coal miners than the controls. However, the difference did not reach a significant level. Reasons for the discrepancy between the results of Ayar’sstudy and ours may have been differences in the recruitment of study population(pneumoconiosis patientspopulation-based investigation).In additon, various systemic medical disorders (neurologic,cardiovascular, endocrinological, metabolic, inflammatory and rheumatologic) may affect the measurement of CMT. In our study, there was no significantly association between CDE and CMT after adjusted systemic parameters in multivariable analysis. To determine this more clearly, future studies may explore the pathology and longitudinal changes in retinal thickness affected by the respirable silica particles in coal miners.The main strengths of this study include a population-based cohort, quantitative measurements of retinal alterations and detailed information on systemic parameters. Nevertheless,potential limitations of our study should be considered. First,the recruitment of the study population was a randomly selected sub-group of the large Kailuan Study which was not representative for the Chinese population. The large sample size of our study however allows forming subgroups of coal miners. The study design may therefore enable to compare the study parameters within the influence of different working conditions. Second, we did not investigate the HbA1c level,which may better present the average level of glucose. Third,the changes of CMT and retinal vessel diameter were not analyzed in different layers or areas, which may better help us understand the pathological changes in the retina affected by the respirable silica particles. In addition, our study was a community-based observational cross-sectional investigation,the design of which did not allow drawing longitudinal conclusions.

In conclusion, the retinal vessels diameters and RNFL were significantly thicker in underground coal worker than the controls. The results of our study indicated that long-term coal mining may lead to retinal vessel dilation and inflammation.We therefore recommend that OCT and fundus photography examination might be needed within coal workers in order to monitor the occupational eye health as well as the incidence and progression of eye diseases.

Supported by Science and Technology Project of Beijing Municipal Science and Technology Commission(No.Z181100001818003); The Capital Health Research and Development of Special (No.2020-1-2052).

式中，RI—沉积物中重金属的潜在生态风险指数；重金属的潜在生态风险系数；沉积物中重金属i相对参比值的污染系数；Ci—重金属i的实测含量；重金属i的评价参比值，本研究以洞庭湖元素的背景值[4,19]作为参比值，Ba、V、Cr、Mn、Co、Ni、Cu、Zn、Pb的评价参比值依次为污染物i的毒性响应系数，反映重金属的毒性、污染水平和环境对重金属污染的敏感程度[22-23]．参考林丽钦[22]和徐争启等[23]的研究结果，9种重金属的毒性响应系数取值分别为Co = Ni= Cu =Pb = 5 > Ba = V = Cr = 2> Mn = Zn = 1．沉积物中重金属的潜在生态风险等级划分如表1．

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