Twenty-four hours intraocular pressure in keratoconic eyes assessed by applanation tonometry and Tono-Pen AVlA

INTRODUCTION

It is established that elevated intraocular pressure (IOP)is the main risk factor for the onset and progression of primary open angle glaucoma (POAG). Advanced Glaucoma Intervention Study (AGIS) demonstrated that longterm IOP changes are related to the progressive visual field deterioration in patients with low mean IOP measurements, but not in patients with high mean IOP measurements.

It is broadly accepted that IOP varies according to a 24-hour cycle. For some authors, the daily curve of intraocular pressure(DCPo) based on IOP measurements acquired by applanation tonometry at 6:00, in the dark, with the patient lying down in bed, is very important in establishing the diagnosis of glaucoma suspect and assessing IOP in glaucoma.Keratoconus is an ectatic corneal disease, with noninflammatory progressive thinning and anterior projection that results in an irregular conical shape. It is an asymmetrical bilateral condition that appears at youth. Topographic (inferior steepening, inferior-superior asymmetry, and irregular astigmatism) and clinical (conical protrusion, corneal stromal thinning, Fleischer ring and Vogt striae) signals are commonly considered together for staging and diagnosing the disorderEmerging ocular imaging technologies, such as Pentacam(Oculus Inc, Wetzlar, Hesse, Germany), have yielded precious information with regards to corneal and anterior ocular segment assessment.Diagnosing keratoconus has been refined by corneal pachymetric arrangement, curvature (elevation)maps, corneal volume and anterior segment information, all of which have been generated using a variety of currently available equipment.Proper IOP measurement is essential to the follow-up treatment and diagnosis of glaucoma. Goldmann applanation tonometer (GAT) is the gold standard method for IOP measurement. But, it might be interfered by variations in corneal thickness, structure, and curvature. Corneal alterations due to keratoconus may probably lead to inaccurate determining IOP in this status. Prior researchers have demonstrated that GAT tends to under evaluate IOP in keratoconic patients primarily because of differences in the cornea’s biomechanical properties and characteristically reduced corneal thickness. And also, some studies showed evidence that the IOP values of the dynamic contour tonometry(DCT) and a corneal-compensated IOP value (IOPcc) obtained by the ocular response analyzer (ORA) are less influenced by central corneal thickness (CCT) than GAT measurement,and should be considered more suitable to evaluate IOP in keratoconus.

Multiple linear regression models were built using TPA IOP as the dependent variable and covariates (cGAT, nGAT,Pentacam parameters: corneal astigmatism, maximum Ambrosio relational thickness (ART-Max), Belin/Ambrosio enhanced ectasia total deviation value (BAD-D), anterior chamber depth (ACD) as independent variables; since all of them expressed a-value<0.05 in univariate analysis. In order to account for multicollinearity stepwise regression was used,which is a combination of forward and backward selection techniques. In stepwise regression, all variables are checked at each step to see if their significance has been reduced below a certain point. Variables with a-value less than 0.05 are included in the model whereas if-value goes above 0.1 the variable is removed. Seeking to find the model with the greatest generalization capacity, five-fold cross-validation was used. Using the K-fold averaging cross-validation model selection procedure yielded the following equation:TPA IOP=5.49+0.775×cGAT-0.015×ACD-0.299×corneal astigmatism with an average2 of 0.708 (95%CI 0.686 to 0.730), which means that these 3 covariates account for an average of 70.8% of the variance in TPA IOP.

享有川南明珠、候鳥樂園、川南最大內(nèi)陸湖、內(nèi)江第一個國家級水利風(fēng)景區(qū)，國家4A級旅游景區(qū)等多個稱號的古宇廟水庫，位于四川省隆昌市，是一個中型水庫。水庫庫區(qū)周邊分水嶺以內(nèi)主要有如下污染來源：鎮(zhèn)生活污染源、農(nóng)業(yè)生活污染源、農(nóng)田徑流污染源及牲畜養(yǎng)殖污染源。水庫內(nèi)禁止飼養(yǎng)畜禽，沒有大規(guī)模的養(yǎng)殖戶，養(yǎng)殖廢水部分通過溝渠匯入水庫庫區(qū)。通過收集水庫(2006～2016年)水質(zhì)資料，利用改進的內(nèi)梅羅污染指數(shù)法、綜合營養(yǎng)狀態(tài)指數(shù)法、季節(jié)性肯德爾檢驗方法分別對古宇廟水庫及隆昌河(補水水源)進行水質(zhì)評價、富營養(yǎng)化評價及近10年來的水質(zhì)變化趨勢評價，為水庫的環(huán)境保護和水庫保護的發(fā)展提供數(shù)據(jù)基礎(chǔ)。

2016年后的網(wǎng)絡(luò)電影呈現(xiàn)出精致發(fā)展，如愛奇藝平臺播放的《山炮進城》，本片由本山傳媒、華誼兄弟共同出品，小沈陽主演，該劇以院線為目標，最后在互聯(lián)網(wǎng)平臺發(fā)行，整體水平并不比院線差，明星小沈陽的加入使專業(yè)從業(yè)者關(guān)注網(wǎng)絡(luò)電影的發(fā)展。如優(yōu)酷播放的《不一樣的煙火》從海報上顯露這是一部青春片，影片的角色都透露高中生的青澀。

SUBJECTS AND METHODS Ethical Approval Keratoconi

c patients attended at S?o Geraldo Eye Hospital were included. Written informed consent was acquired from all patients, and investigation that acceded to the tenets of the Declaration of Helsinki started after the approval of the protocol by Ethics Committee of Federal University of Minas Gerais. All participants underwent a detailed ophthalmologic examination.

As far as we are aware, this is the first study to investigate changes in IOP during DCPo in keratoconic eyes, obtaining cGAT, nGAT and TPA IOP profiles, and also to assess correlations among these IOP measurements. Even though irregular corneas could interfere in IOP applanation measurements, we decided to use GAT, Perkins and TPA due to the fact that with them we were able to perform IOP 6:00measurement with the patient lying down in bed and in the dark. Although the IOP values of DCT and IOPcc values obtained by ORA are less influenced by CCT than GAT measurement, and should be considered more suitable to evaluate IOP in keratoconus, is technically impracticable to perform all measurements of the DCPo with these instruments.Iwaszkiewiczassessed IOP diurnal fluctuations of 73 keratoconic eyes, however, he used a pneumotonometer, and IOP at 6:00was not evaluated. In fact, the author took IOP measurements only from 7:00to 10:00He found the mean upper value of 19.24±2.84 mm Hg for right eye and 18.06±2.80 mm Hg for left eye. These values are higher than our mean IOP values, and means oscillation of IOP in a day equalized 7.00±2.41 mm Hg in the right eye and 6.00±2.38 mm Hg in the left eye, also higher than our findings. However, there are few reports using pneumotonometer, mainly in keratoconus, so it is difficult to know how accurate it would be in DCPo.

DCPo are described in Table 2. IOP mean at 6:00was higher than the other 4 DCPo measurements in all methods used of IOP assessment (cGAT, nGAT and TPA). Comparisons of mean DCPo values between cGAT-nGAT, cGAT-TPA,and nGAT-TPA are shown in Figures 1 and 2, and Table 3. We found that cGAT IOP DCPo mean was higher than nGAT (difference of 1.32±1.31;<0.01) and lower than TPA (difference of -1.02±2.08;=0.004), so DCPo was underestimated by nGAT and overestimated by TPA with a difference statistically significant. Moreover, nGAT was overestimated by TPA (-2.35±2.23;<0.01) with statistically significant difference (Table 3).

Each subject underwent a DCPo which was comprised of 5 IOP measurements; 4 performed with GAT (Haag-Streit,Harlow, Essex, United Kingdom) and TPA at 9:00 and 11:00, 6:00 and 10:00and in the morning of the next day at 6:00with patient lying down in bed and in the dark and before they had become erected when applanation tonometry measurement was done with Perkins applanation tonometer (Haag-Streit, Harlow, Essex, United Kingdom)followed by TPA. Considering irregular corneal astigmatism in keratoconic eyes, the prism red line of the applanation tonometer (GAT or Perkins tonometer) was placed at prism degree mark corresponding to the flattest meridian (minus cylinder) to correct intraocular pressure measurement (cGAT)of each patient; also, measurement without that astigmatism correction was done (nGAT). All IOP measurements were performed by one glaucoma specialist (Cronemberger S)and registered by another (Veloso AW). The IOP was taken sequentially with nGAT, followed by cGAT and TPA with an interval of three minutes among them. GAT was performed after a drop of 0.5% proxymetacaine hydrochloride followed by a drop of 0.25% fluorescein sodium instillation. Using TPA,10 IOP measurements were obtained with accuracy of at least 95%.

國有企業(yè)屬于股份制企業(yè)，企業(yè)的大部分控制權(quán)掌握在股東手中。由于溝通渠道廣泛，人力資源豐富，“法人”管理多家企業(yè)，這樣的管理模式導(dǎo)致管理不善，運行困難，無法保障少數(shù)股東的權(quán)力。同時，監(jiān)事會和董事會的職責(zé)也沒有明確界定。

All statistical analyses were performed with software R version 4.0.3 (The R foundation) and SPSS Version 21 (IBM Corp., Armonk, NY, USA). Pearson correlation coefficients were calculated to report the power of linear relationship among IOP values. Anvalue of >0.5 revealed moderate significance. An evaluation of Bland-Altman correspondence was used to compare GAT and TPA values.An extent of accordance was determined as mean±2 standard deviation.

As demonstrated by some studies, appropriate IOP assessment with its measurement taken with an applanation tonometer at 6:00in bed and in the dark before the patient became erected is essential to detect IOP peaks. As a matter of fact,our study is the first to investigate IOP keratoconus peak in this way, and we found the highest DCPo mean values at 6:00independently of the way used to measure IOP (cGAT 15.0±3.8 mm Hg, nGAT 12.5±3.1 mm Hg, TPA 14.3±3.3 mm Hg).Normal and abnormal DCPo values have already been established in previous study. The normal superior value for mean IOP and variability were 14.62 mm Hg and 2.28,respectively (age of patients from 15 to 25y), and 15.93 mm Hg and 2.28, respectively (age of patients from 26 to 35y), which implies that normal superior DCPo mean limits are 16.9 and 18.20 mm Hg for 15-25y and 26-35y respectively. In the present study, all mean IOP values were under normal limits.Highest mean IOP DCPo value was observed with TPA(12.3±3.1 mm Hg), and lowest with nGAT (9.9±2.6 mm Hg) in keratoconic eyes. However, at 6:00the highest IOP mean measurement was verified with cGAT (15.0±3.8 mm Hg).Therefore, in accordance with the normal superior DCPo IOP mean limits established, an IOP equal to or more than 17 mm Hg in keratoconic eyes would require glaucoma investigation with exams such as fundoscopy and optic coherence tomography.

式中，f spk為復(fù)合地基承載力特征值，kPa；λ為單樁承載力發(fā)揮系數(shù)；m為面積置換率；R a為單樁承載力特征值，kN；A p為樁的截面積，m2；β為樁間土承載力發(fā)揮系數(shù)；f sk為處理后樁間土承載力特征值，kPa，應(yīng)按靜載荷試驗確定，無試驗資料時可取天然地基承載力特征值。

Multiple linear regression assessments were done using TPA IOP as a result with cGAT IOP and corneal parameters.value of ≤0.01 was regarded statistically relevant. Five‐fold cross‐validation was used to find the model with the greatest generalization capacity. Linear mixed outcomes templates adjusting for nonindependence of right and left eye values were built and adjusted to the data.

RESULTS

A total of 24 patients (48 eyes) with keratoconus were included in the study. Nine eyes of these patients were excluded from analysis. Six had corneal transplantation and 3 had intrastromal corneal rings, leaving 39 eyes in final assessment. Table 1 summarizes clinical, ultrasound CCT and Oculus Pentacam features of patients.

當(dāng)下，我們面臨國內(nèi)外極為嚴峻的形勢，再一次走到歷史關(guān)口，因此新的思想解放又將會為新的改革開放創(chuàng)造基礎(chǔ)。梳理40年來的改革開放，我們每次思想解放都是與那些舊規(guī)則、“左”的思想決裂，每次都會更加融入國際社會，促進社會文明的進步，那么今天是否還會走這條路徑？

Bland-Altman scenarios are displayed in Figure 3, describing mean difference (estimated bias) between cGAT-TPA and nGAT-TPA as well as the quantity of variance (±2 SD) around means. Mean difference between cGAT‐TPA was 1.02 mm Hg and nGAT-TPA was 2.35 mm Hg, with most of values dropping within 2 SD of the mean.

A positive and statistically significant correlation was identified between cGAT-nGAT, cGAT-TPA and nGAT-TPA(Table 3).

It is important to investigate how changes in IOP occur during DCPo in keratoconic patients, and when IOP peaks occur, based on 24-hour IOP measurements, including IOP measurements acquired by applanation tonometry at 6:00, in the dark, with the patient lying down in bed. And, it is possible to assess IOP in bed with GAT, that’s why this gold standard method was chosen to perform DCPo. Finally, it is also critical to compare DCPo GAT values with those acquired using Tono-Pen AVIA (TPA; Reichert Inc, Depew, New York,USA) in order to derive the profiles of both tonometers in keratoconic eyes. To the best of our knowledge, this is the first study that DCPo was performed in keratoconic patients using GAT and TPA.

With the generalized linear mixed model, TPA IOP was significantly related to ACD (=0.027) and corneal astigmatism(=0.007). Also, TPA ⅠOP was significantly related to cGAT IOP (<0.001) as for each increase in 1 mm Hg of cGAT IOP would mean an increase of 0.64 mm Hg in TPA IOP, with the other factors being fixed.

DISCUSSION

Diagnosis of keratoconus was firmed up using the subsequent criteria (one sign or a conjunction of signs): biomicroscopic signs: stromal thinning, conical protrusion, Fleischer ring, Vogt striae, and enlarged corneal nerves; an abnormal retinoscopy reflex;and Munson’s sign (V-shaped configuration of lower lid on down gaze). Diagnosis was recognized topographically with Oculus Pentacam (Oculus Inc, Wetzlar, Hesse, Germany)system (‘‘Topographical Keratoconus Classification’’; TKC).We excluded keratoconic eyes with acute corneal hydrops,corneal scarring, penetrating or lamellar keratoplasty, keratitis,intrastromal corneal rings, or corneal cross-linking procedure.Ultrasound CCT was measured by DGH 5100e A-Scan/Pachymeter (DGH Technology, Exton, Pennsylvania, USA).

We also compared average IOP and standard deviation of cGAT with normal upper limits (mean + two standard deviation of the DCPo and mean + two standard deviation of IOP) from normal subjects of the similar age range accessible in our Service.

It is well established that, in corneas with an astigmatism greater than three diopter (3 D), GAT measurement is misleading. The applanated area will not be circular, but elliptical. This mistake can be precluded by applanation at 43°to the axis of minus cylinder. To eliminate this error, we have performed IOP measurement by aligning the angle of minus cylinder with the prism with red mark on the prism holder. As far as we know, the present study is the first to compare ⅠOP GAT measurements respectively with and without astigmatism correction (cGAT and nGAT) in keratoconus. We found cGAT higher than nGAT IOP DCPo mean values with a difference statistically significant, and also higher at 6:00mean IOP measurement.

Many studies have compared different tonometers for measuring IOP, such as GAT, tonopen, dynamic contour tonometer, ORA,and rebound tonometry, in keratoconic eyes. However,our study is the first to compare GAT and TPA during the DCPo in keratoconic eyes. We have found a statistically significant difference between the mean ⅠOP of cGAT‐nGAT,cGAT-TPA, and nGAT-TPA. TPA presented the highest IOP mean DCPo values. Hypothetically, the highest IOP mean DCPo values found with TPA are due to the lower diameter of area and strength of applanation than those with cGAT.Therefore, GAT continues to be the gold-standard, even in keratoconic eyes, being more accurate to measure IOP with the cGAT than with TPA, especially in DCPo.

Ⅰn the present study, it was verified a mean ⅠOP DCPo value of 12.3±3.1 (TPA), 11.3±2.6 (cGAT) and 9.9±2.6 (nGAT) mm Hg.On the contrary, some authors reported higher cGAT values(varying from 11.12 to 13.76 mm Hg, in different stages of the keratoconus) than those of tonopen IOP measurements(varying from 9.24 to 11.51 mm Hg) in keratoconic eyes,however, DCPo was not done. These authors have measured IOP 3 times between 9:00and 11:00, but they used Tono-Pen XL (Medtronic Solan, Jacksonville, FL, USA)which is different from our study, and also, they found that only DCT IOP and ORA IOPcc didn’t have association with CCT in keratoconus eyes. In another study, Tono-Pen XL IOP measurements were 3.6±10 mm Hg higher than GAT in keratoconic eyes, similarly to our research, and DCT IOP was 2.7±6 mm Hg higher than GAT, nevertheless, DCPo was not executed as well. DCT and IOPcc were again found to be independent of CCT together with corneal hysteresis.In the same way, in keratoconus patients after intrastromal corneal ring segments implantation, Tono-Pen XL IOP values were 0.8±3.07 mm Hg higher than GAT, and DCT IOP was 1.0±3.26 mm Hg higher than GAT, and DCP IOP measurement wasn’t affected by CCT. In our study, TPA IOP mean DCPo values were 2.35±2.23 mm Hg higher than nGAT,and 1.02±2.08 mm Hg higher than cGAT values. The fact that DCT IOP measured is higher than GAT IOP in keratoconus was described in other study (DCT 14.8±3.07 mm Hg, GAT‐13.1±2.9 mm Hg) that also verified CCT independence of the DCT IOP measurement. ORA IOPcc value was found to be higher than GAT in keratoconus (ORA IOPcc 13.3±2.5 mm Hg,GAT 10.9±2 mm Hg), nevertheless, ORA reading seemed to be affected by corneal curvature.

Cronembergerhave reported isolated IOP measurements taken by GAT (10.50±2.22 mm Hg for right eye and 10.80±1.89 mm Hg for left eye) at 720 postoperative days in eyes who underwent laser-assistedkeratomileusis(LASIK). These values were a little higher than those mean IOP DCPo value (9.9±2.6 mm Hg) were found in keratoconic eyes, but, without a statistically significant difference (the two-tailed=0.4741). These findings may be explained by differences in cornea’s biomechanical properties and the mean lower CCT in keratoconic eyes (469.0±75.8 μm) than in the eyes that underwent LASIK (492.7±20.4 μm). Based on our findings, the upper normal limit of GAT ⅠOP (mean+2 SD) in keratoconus would be 16.5 mm Hg which is below the superior limit we found for normal eyes (18 mm Hg). Therefore,when using GAT for evaluating keratoconus, it is necessary to use correction of astigmatism (cGAT). Besides this, it is important to emphasize that an ⅠOP≥17 mm Hg in one patient with keratoconus should be considered at least suspected of glaucoma depending on the findings of cup-to-disc ratio and retinal nerve fiber layer.

Our study has some limitations. IOP applanation measurement at 6:00with the patient lying down in bed and in the dark was done using Perkins tonometer (in which it is possible to do astigmatism correction), however, both GAT and Perkins handheld are applanation tonometers and their results are equivalent. Also, our results may be limited due to a relatively small number of cases. Further, as we were performing DCPo, and an IOP measurement in a supine position in bed should be performed, it was not technically possible to use DCT or ORA both considered more accurate in keratoconic eyes. In this study, all the tonometers were aimed at the same location, central cornea, for each IOP reading, to generate useful and meaningful results, however,regional differences in pachymetry are likely to be relevant to IOP. Although GAT is the gold standard method for IOP measurement, it might be interfered by variations in corneal biomechanics. Corneal alterations due to keratoconus may probably lead to inaccurate determining IOP, which could have interfered in our IOP measurements.

全球現(xiàn)有兒童特發(fā)性血小板減少性紫癜指南的循證評價…………………………………………………… 歸 舸等（4）：541

配合力是指利用自交系組配雜交組合各方面性狀相對大小的度量，是自交系的一種內(nèi)在特性,它不能通過自交系自身的農(nóng)藝、經(jīng)濟性狀表現(xiàn)來確定[10]。

WJ-III地圖工作站雖然提供了制圖綜合的知識庫模板，但是針對湖北省103個縣市區(qū)不同的地形，不同的縮編比例尺，需要進行相應(yīng)知識庫的調(diào)整。經(jīng)過不同參數(shù)的嘗試，最終形成山區(qū)、丘陵、平原三種地貌類型的知識庫，另外針對城市市區(qū)的道路綜合，形成城市地區(qū)的綜合知識庫，以滿足湖北省縣市區(qū)地理國情普查圖的編制要求。

In conclusion, we demonstrated that, in keratoconic eyes,highest DCPo values are obtained at 6:00measurement.So, our results suggest that an IOP peak in a keratoconic patient should be assessed at 6:00in a supine position in bed and darkness independent of the tonometer used. Furthermore,we found that TPA had higher mean DCPo values than GAT,and cGAT higher than nGAT with statistically significant difference. Also, a positive and statistically significant correlation was verified among TPA, cGAT, and nGAT mean ⅠOP DCPo measurements. Besides, linear regression assessment yielded an equation that, when corneal astigmatism and anterior chamber depth are considered, may enable transformation of cGAT IOP into TPA IOP measurements. Forthcoming studies should target to authenticate this equation and establish other corneal elements, such as CCT.

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