Clinical and Experimental Ophthalmology最新文献_第5页

Elevated aqueous TNF-α levels are associated with more severe functional and anatomic findings in eyes with diabetic macular oedema. 在患有糖尿病性黄斑水肿的眼睛中，水样 TNF-α 水平升高与更严重的功能和解剖结果有关。

IF 4.9 2区医学 Q1 OPHTHALMOLOGY

Clinical and Experimental Ophthalmology

Pub Date : 2024-07-28 DOI: 10.1111/ceo.14425

Sky Chew, Tuan Tran, Paul Sanfilippo, Lyndell L Lim, Sukhpal S Sandhu, Sanjeewa Wickremasinghe

Background: Intravitreal ranibizumab for diabetic macular oedema (DMO) has been recently shown to modulate levels of aqueous cytokines. This study investigates the associations between changes in aqueous cytokine levels following intravitreal ranibizumab therapy and the corresponding anatomical and functional changes in the eye.

Methods: Twenty-five patients comprising 30 eyes diagnosed with DMO were prospectively recruited. All eyes received three loading dose ranibizumab injections at baseline, week 4 and week 8, followed by pro re nata treatment based on best-corrected visual acuity (BCVA) and central macular thickness (CMT) up to week 48. Prior to ranibizumab administration, aqueous samples were collected from all eyes, and subsequent sampling was performed at week 8. Levels of 32 cytokines were assessed at baseline and at week 8.

Results: At baseline, higher aqueous TNF-α levels were associated with poorer BCVA (p = 0.033), greater macular volume (p = 0.017) and worse diabetic retinopathy (p = 0.047). Higher levels of IL-7 were associated with poorer BCVA and greater macular volume (MV). Following treatment with ranibizumab there was a significant correlation with reduction of aqueous TNF-α and improvements in BCVA and MV, both at 6 months (BCVA [r = -0.558, p = 0.001], MV [r = 0.410, p = 0.024]) and 12-months (BCVA [r = -0.413, p = 0.023], MV [r = 0.482, p = 0.008]). The change in VEGF concentration following ranibizumab treatment did not correlate with either BCVA or MV improvements (p > 0.05).

Conclusions: Higher levels of aqueous TNF-α and IL-7 correlated with worse DMO, both anatomically and functionally. Reductions in levels of aqueous TNF-α, but not VEGF, post ranibizumab treatment were associated with improvement in BCVA and MV.

背景：最近的研究表明，玻璃体内雷尼单抗治疗糖尿病性黄斑水肿（DMO）可调节水细胞因子的水平。本研究探讨了玻璃体内雷尼珠单抗治疗后水样细胞因子水平的变化与眼部相应的解剖和功能变化之间的关联：前瞻性招募了25名患者，包括30只被诊断为DMO的眼睛。所有眼球分别在基线、第4周和第8周接受了三次负荷剂量的雷尼珠单抗注射，随后根据最佳矫正视力（BCVA）和黄斑中心厚度（CMT）进行顺应性治疗，直至第48周。在使用雷尼珠单抗前，采集了所有眼球的水样，并在第8周进行了后续采样。在基线和第 8 周时评估了 32 种细胞因子的水平：结果：基线时，较高的 TNF-α 水样水平与较差的 BCVA（p = 0.033）、较大的黄斑体积（p = 0.017）和较差的糖尿病视网膜病变（p = 0.047）相关。IL-7 水平越高，BCVA 越差，黄斑体积（MV）越大。使用雷尼珠单抗治疗后，水体 TNF-α 的减少与 BCVA 和 MV 的改善有显著相关性，6 个月时（BCVA [r = -0.558，p = 0.001]，MV [r = 0.410，p = 0.024]）和 12 个月时（BCVA [r = -0.413，p = 0.023]，MV [r = 0.482，p = 0.008]）均是如此。雷尼珠单抗治疗后血管内皮生长因子浓度的变化与BCVA或MV的改善均无相关性（p > 0.05）：结论：较高水平的眼TNF-α和IL-7与DMO在解剖和功能上的恶化相关。雷尼珠单抗治疗后，眼部TNF-α（而非血管内皮生长因子）水平的降低与BCVA和MV的改善相关。

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引用次数: 0

Epidemiology of Field of Vision Disorders (eFOVID) study, Western Australia, 1988–2022. Report 1: Data collection and aggregation protocol 视力障碍流行病学 (eFOVID) 研究，西澳大利亚州，1988-2022 年。报告 1：数据收集和汇总协议。

IF 4.9 2区医学 Q1 OPHTHALMOLOGY

Clinical and Experimental Ophthalmology

Pub Date : 2024-07-28 DOI: 10.1111/ceo.14422

Siobhan Manners MD, William Morgan FRANZCO, Nigel Morlet FRANZCO, Lynn Meuleners PhD, Wei Liu PhD, Hector Morlet, Jonathon Q. Ng FRANZCO

Background

Computerised static visual field testing using dedicated machines such as the Humphrey Field Analyzer (HFA) can assess and track changes in visual field sensitivity. The use of retrospective visual field databases is a novel undertaking, with no studies published utilising large scale population-level data. This study phase developed a method to extract HFA data into a large standardised population-based database including point sensitivity data with additional derived variables.

Methods

Retrospective, longitudinal, population study of visual field data from people who attended an ophthalmology service and had a HFA field test, in Western Australia, between 1988 and 2022. Raw test data included patient demographic fields, sensitivity readings and test parameters. Calculated fields included reliability scores, and a novel combined reliability score.

Results

There were 606 230 tests for 92 215 study individuals, from 22 ophthalmology practices in metropolitan Perth and three public hospital eye clinics, representing around 85% of the field tests performed by ophthalmologists each year. Raw sensitivity values were available for all tests, and additional descriptors were available for most tests (97.5%–100% of tests) with the exception of data variables retired by the manufacturer.

Conclusions

Visual field data from 606 230 tests were collated into a single dataset, which is highly representative over a long period of time, for a defined population. This dataset has been linked to other administrative datasets to allow for epidemiological investigation of field of vision disorders.

背景：使用汉弗莱视野分析仪（HFA）等专用机器进行计算机化静态视野测试，可以评估和跟踪视野敏感度的变化。使用回顾性视野数据库是一项新颖的工作，目前尚未有利用大规模人群数据的研究发表。本研究阶段开发了一种方法，可将 HFA 数据提取到大型标准化人群数据库中，包括点敏感度数据和其他衍生变量：方法：对1988年至2022年期间在西澳大利亚州接受眼科服务和HFA视野测试的人群的视野数据进行回顾性、纵向和人口研究。原始测试数据包括患者人口统计学领域、灵敏度读数和测试参数。计算字段包括可靠性评分和新的综合可靠性评分：共对 92 215 名研究对象进行了 606 230 次测试，这些研究对象来自珀斯大都会的 22 家眼科诊所和 3 家公立医院眼科诊所，约占眼科医生每年进行的现场测试的 85%。所有测试都有原始灵敏度值，大多数测试（97.5%-100% 的测试）都有附加描述符，只有制造商放弃的数据变量除外：来自 606 项 230 次测试的视野数据被整理成一个数据集，该数据集在很长一段时间内对特定人群具有很强的代表性。该数据集已与其他行政数据集链接，以便对视野障碍进行流行病学调查。

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引用次数: 0

Endophthalmitis following intravitreal injections administered by junior medical officers in rural Western Australia 西澳大利亚农村地区初级医务人员进行玻璃体内注射后引发眼内炎。

IF 4.9 2区医学 Q1 OPHTHALMOLOGY

Clinical and Experimental Ophthalmology

Pub Date : 2024-07-25 DOI: 10.1111/ceo.14421

Jackson Chee Chea Lee BMed, Hessom Razavi FRANZCO, Marcel Maziyar Nejatian MD, Jocelyn Drinkwater PhD, Angus Warwick Turner FRANZCO

Background

Patients in rural Australia have limited access to intravitreal treatments due to a maldistribution of the ophthalmology workforce. To improve access, a novel outreach service model was implemented whereby junior medical staff administered intravitreal injections under a supervising ophthalmology consultant. This model involves outreach visits in hospitals, mobile clinics and a remote hub with intravitreal injections administered by junior doctors overseen by an ophthalmologist. The article explores the safety of this approach with respect to the rate of post-injection endophthalmitis.

Methods

A retrospective audit was conducted by the Lions Outback Vision outreach ophthalmology service from 2017 to mid-2023. The number of injections, locations, diagnoses, intravitreal agents used, designation of administering doctor and cases of endophthalmitis were reviewed.

Results

A 12 632 intravitreal injections were administered across 32 locations throughout rural Western Australia in the 6.5-year period. Three cases of endophthalmitis occurred representing a rate of 0.0237%.

Conclusion

The rate of endophthalmitis in the outreach service is comparable to other centres. The outreach model with supervising ophthalmology consultant support in person or via telehealth and administration of injections by junior medical staff has improved access for underserved or marginalised populations.

背景：由于眼科医务人员分布不均，澳大利亚农村地区的患者接受玻璃体内治疗的机会有限。为了改善患者的就医条件，我们采用了一种新颖的外展服务模式，即由初级医务人员在眼科顾问的指导下进行玻璃体内注射。这种模式包括在医院、流动诊所和远程中心进行外展访问，由初级医生在眼科医生的监督下进行玻璃体内注射。文章从注射后眼内炎的发生率方面探讨了这种方法的安全性：从 2017 年到 2023 年中期，Lions Outback Vision 外展眼科服务进行了一次回顾性审计。对注射次数、地点、诊断、使用的玻璃体内药剂、指定的管理医生和眼底病病例进行了审查：在 6.5 年的时间里，西澳大利亚州农村地区的 32 个地点共进行了 12 632 次玻璃体内注射。发生了三例眼内炎，发生率为 0.0237%：结论：外联服务的眼底病发生率与其他中心相当。外展模式由眼科顾问亲自或通过远程医疗提供指导支持，并由初级医务人员进行注射，这改善了服务不足或边缘化人群的就医条件。

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引用次数: 0

Iris melanoma in an Australian cohort 澳大利亚队列中的虹膜黑色素瘤。

IF 4.9 2区医学 Q1 OPHTHALMOLOGY

Clinical and Experimental Ophthalmology

Pub Date : 2024-07-24 DOI: 10.1111/ceo.14424

Lindsay A. McGrath MPhil, FRANZCO, Sunil K. Warrier FRANZCO, William J. Glasson FRANZCO, Matthew G. D'Mellow BSc, Hayley R. Hamilton BNurs, Jane M. Palmer RN, Kelly M. Brooks PhD, Peter A. Johansson PhD, Nicholas K. Hayward PhD

Background

To report the clinicopathological features and epidemiology of iris melanoma in Queensland, Australia.

Methods

This was a retrospective study of 86 patients with iris melanoma treated between 2001 and 2022 at the Queensland Ocular Oncology Service, Brisbane, Australia. Main outcome measures included demographics, clinical and phenotypic features, age-adjusted incidence and relative survival.

Results

Eighty-six patients (63% female) were included. Mean age was 54 years (range 17–82 years). The majority of patients (97%) were Caucasian, with blue eyes, fair skin and Fitzpatrick Skin Type I or II. Demographic features and clinical history showed a tendency for high ultraviolet radiation (UVR) exposure in the cohort. Histopathology was available in 69 cases (82%), and of these, 77% tumours were of spindle cell origin, with low-risk genetic profiles. Patients were followed for a mean of 8 years (median 7, range 1–21 years) after diagnosis, and only one case of metastasis was documented.

Conclusions

The association of iris freckles, history of UVR exposure and dermatologic findings supports the role of UVR in iris melanoma. Occupation and avocation history, as well as evaluation of iris freckles may offer an easily accessible way of stratifying the risk of an individual for development of UVR-related uveal melanoma.

背景：报告澳大利亚昆士兰州虹膜黑色素瘤的临床病理特征和流行病学：报告澳大利亚昆士兰州虹膜黑色素瘤的临床病理特征和流行病学：这是一项回顾性研究，研究对象是2001年至2022年期间在澳大利亚布里斯班昆士兰眼肿瘤学服务机构接受治疗的86名虹膜黑色素瘤患者。主要结果指标包括人口统计学、临床和表型特征、年龄调整后发病率和相对生存率：共纳入 86 名患者（63% 为女性）。平均年龄为 54 岁（17-82 岁不等）。大多数患者（97%）为白种人，蓝眼睛，皮肤白皙，菲茨帕特里克皮肤类型 I 型或 II 型。人口统计学特征和临床病史显示，该组患者有紫外线辐射（UVR）暴露较高的倾向。69例患者（82%）获得了组织病理学检查结果，其中77%的肿瘤为纺锤形细胞来源，遗传特征风险较低。患者在确诊后平均随访了8年（中位数为7年，范围为1-21年），仅有一例转移病例记录在案：结论：虹膜雀斑、紫外线照射史和皮肤病学检查结果都支持紫外线照射在虹膜黑色素瘤中的作用。职业和职业史以及对虹膜雀斑的评估可提供一种简便易行的方法，用于对个人罹患紫外线相关葡萄膜黑色素瘤的风险进行分层。

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引用次数: 0

Axial length adjustment in eyes with silicone oil endotamponade reduces overestimation by a swept-source optical coherence tomography-based biometer 硅油内腔填塞眼的轴向长度调整可减少基于扫源光学相干断层扫描的生物测量仪的过高估计。

IF 4.9 2区医学 Q1 OPHTHALMOLOGY

Clinical and Experimental Ophthalmology

Pub Date : 2024-07-21 DOI: 10.1111/ceo.14418

Klemens Paul Kaiser MD, Tyll Jandewerth MD, Julian Bucur MD, Thomas Kohnen MD, PhD, Christoph Lwowski MD

Background

To assess changes in ocular biometry of the phakic eye after pars-plana-vitrectomy (PPV) and silicone oil (SO) endotamponade in eyes with a retinal detachment.

Methods

This retrospective, consecutive case series included 72 eyes of 72 patients who underwent PPV with 5000-centistokes SO endotamponade between July 2018 and June 2023. Pseudophakic eyes and eyes with a combined phacovitrectomy were excluded. Primary endpoints were keratometry values, anterior chamber depth (ACD), lens thickness (LT), horizontal corneal diameter (HCD), and axial length (AL) measured by swept-source optical coherence tomography-based biometry (IOLMaster 700) preoperatively and six weeks postoperatively. A recently described formula was used to adjust the AL (aAL) in eyes with SO endotamponade and a theoretical intraocular lens (IOL) calculation was performed.

Results

The mean age was 62.1 ± 8.3 years (range: 37–85). After PPV with SO fill, there was an increase in K_mean (0.19 ± 0.51D), while ACD (0.05 ± 0.13 mm), LT (0.03 ± 0.14 mm), and HCD (0.02 ± 0.24 mm) decreased. Preoperatively, the mean AL was 25.22 ± 1.78 mm, while postoperatively the AL was overestimated by 0.12 ± 0.42 mm on average (p = 0.04). By adjusting the AL, the mean difference could be reduced to −0.002 ± 0.41 mm. The aAL resulted in a difference in the refractive outcome in eyes with an AL > 25 mm of 0.34 ± 0.10D in the IOL calculation.

Conclusions

While changes in biometry after PPV with SO endotamponade in the anterior segment are clinically less relevant, a considerable overestimation of AL with IOLMaster 700 was found. We recommend the use of a recently introduced formula for adjusting AL in eyes with SO, allowing overestimation to be minimised considerably.

背景：目的：评估视网膜脱离患者在接受视网膜旁切除术（PPV）和硅油（SO）眼内填塞术后，法眼眼部生物测量的变化：该回顾性连续病例系列包括2018年7月至2023年6月期间接受PPV和5000厘斯托克斯SO内填塞术的72名患者的72只眼睛。假性角膜病变眼和合并虹膜切除术的眼被排除在外。主要终点是角膜测量值、前房深度（ACD）、晶状体厚度（LT）、角膜水平直径（HCD）和轴向长度（AL），测量方法是基于扫源光学相干断层扫描的生物测量法（IOLMaster 700），测量时间为术前和术后六周。使用最近描述的公式调整了有 SO 内陷的眼睛的 AL（aAL），并进行了理论眼内晶状体（IOL）计算：平均年龄为 62.1 ± 8.3 岁（37-85 岁）。SO填充PPV后，Kmean增加（0.19 ± 0.51D），ACD（0.05 ± 0.13 mm）、LT（0.03 ± 0.14 mm）和HCD（0.02 ± 0.24 mm）下降。术前，平均 AL 为 25.22 ± 1.78 毫米，而术后 AL 平均被高估了 0.12 ± 0.42 毫米（p = 0.04）。通过调整 AL，平均差异可降至 -0.002 ± 0.41 毫米。在计算人工晶体时，AL>25毫米的眼睛的屈光结果与AL>25毫米的眼睛的屈光结果相差0.34±0.10D：虽然前段SO内膜填塞PPV后生物测量的变化与临床关系不大，但使用IOLMaster 700发现AL被高估了很多。我们建议使用最近推出的公式来调整有 SO 的眼睛的 AL 值，这样可以大大降低高估的程度。

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引用次数: 0

Repeatability and agreement of total corneal astigmatism measured in keratoconic eyes using four current devices 使用四种当前设备测量角膜病变眼全角膜散光的重复性和一致性。

IF 4.9 2区医学 Q1 OPHTHALMOLOGY

Clinical and Experimental Ophthalmology

Pub Date : 2024-07-21 DOI: 10.1111/ceo.14423

Yue Feng MD, MSc, Tore Nitter MD, PhD, Geir Bertelsen MD, PhD, Aleksandar Stojanovic MD, PhD

Background

To evaluate repeatability and agreement in measurements of total corneal astigmatism (TCA) in keratoconic eyes, using four optical coherence tomography (OCT)-based devices: Anterion, Casia SS-1000, IOLMaster 700, and MS-39.

Methods

Three consecutive measurements were taken with each device in 136 eyes. TCA values were converted into components J₀ and J₄₅. The Anterion and the IOLMaster 700 also provided axial length (AL) measurements. The repeatability was calculated using pooled within-subject standard deviation (S_w). The agreement among the four devices was assessed by pairwise comparisons and Bland–Altman plots.

Results

For all devices, the repeatability of TCA measurements showed S_w ≤0.23 D for TCA magnitude, ≤0.14 D for J₀, and ≤0.12 D for J₄₅. There were statistically significant differences in TCA magnitude for each pair, except for IOLMaster 700 with MS-39, and Anterion with MS-39. The repeatability (S_w) of axis measurements had a statistically significant negative correlation with the TCA magnitude (p < 0.001 for all devices). Both Anterion and IOLMaster 700 had high repeatability in AL measurements (S_w: 0.007 mm for Anterion and 0.009 mm for IOLMaster 700). The difference in AL between the two was 0.015 ± 0.033 mm (p < 0.001).

Conclusions

All four devices showed good repeatability in TCA measurements in keratoconic eyes, the agreement for TCA measurements between the tested devices was generally low. Anterion and IOLMaster 700 showed good repeatability and agreement in AL measurements.

背景：目的：评估使用四种光学相干断层扫描（OCT）设备测量角膜病变眼全角膜散光（TCA）的重复性和一致性：Anterion、Casia SS-1000、IOLMaster 700 和 MS-39：方法：使用每种设备对 136 只眼睛进行了三次连续测量。将 TCA 值转换成 J0 和 J45 组份。Anterion 和 IOLMaster 700 还提供了轴向长度 (AL) 测量值。重复性是通过汇总的受试者内标准偏差 (Sw) 计算得出的。通过配对比较和布兰德-阿尔特曼图评估了四种设备之间的一致性：所有设备的 TCA 测量重复性显示，TCA 幅值的 Sw ≤ 0.23 D，J0 ≤ 0.14 D，J45 ≤ 0.12 D。除 IOLMaster 700 与 MS-39 和 Anterion 与 MS-39 外，每对晶体的 TCA 量级在统计学上都有显著差异。轴测量的重复性（Sw）与 TCA 幅值呈统计学意义上的显著负相关（P w：Anterion 为 0.007 mm，IOLMaster 700 为 0.009 mm）。两者之间的 AL 差异为 0.015 ± 0.033 毫米（p 结论）：所有四种设备在角膜病变眼的 TCA 测量中都表现出良好的重复性，但测试设备之间的 TCA 测量一致性普遍较低。Anterion 和 IOLMaster 700 在 AL 测量中表现出良好的重复性和一致性。

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引用次数: 0

Real world impact: Towards holistic analysis of author-level publication metrics 真实世界的影响：对作者层面的出版指标进行整体分析。

IF 4.9 2区医学 Q1 OPHTHALMOLOGY

Clinical and Experimental Ophthalmology

Pub Date : 2024-07-15 DOI: 10.1111/ceo.14420

Thomas Muecke, Stephen Bacchi MBBS, PhD, Robert Casson DPhil, FRANZCO, Weng Onn Chan FRANZCO

引用次数: 0

Seventeen years of bird-related eye injuries at the Royal Victorian Eye and Ear Hospital, Melbourne, 2006–2022 2006-2022 年墨尔本维多利亚皇家眼耳医院十七年来与鸟类有关的眼部伤害。

IF 4.9 2区医学 Q1 OPHTHALMOLOGY

Clinical and Experimental Ophthalmology

Pub Date : 2024-07-09 DOI: 10.1111/ceo.14416

Jeremy P. M. Flanagan MD, Melissa Moyes MBChB, Todd Goodwin MBBS, Carmel Crock MBBS, Thomas G. Campbell PhD

引用次数: 0

In-vivo high-frequency quantitative ultrasound-derived parameters of the anterior sclera correlated with level of myopia and presence of staphyloma 体内高频定量超声波得出的前巩膜参数与近视程度和葡萄肿的存在相关。

IF 4.9 2区医学 Q1 OPHTHALMOLOGY

Clinical and Experimental Ophthalmology

Pub Date : 2024-07-04 DOI: 10.1111/ceo.14415

Cameron Hoerig PhD, Quan V. Hoang MD, PhD, Jonathan Mamou PhD

Background

A high-frequency point-of-care (POC) ultrasound instrument was used to evaluate the microstructural and biomechanical properties of the anterior sclera in vivo using parameters computed from quantitative ultrasound (QUS) methods.

Methods

In this cross-sectional study, both eyes of 85 enrolled patients were scanned with the POC instrument and ultrasound data were processed to obtain QUS parameters. Pearson correlation and multi-linear regression were used to identify relationships between QUS parameters and refractive error (RE) or axial length. After categorising eyes based on RE, binary support vector machine (SVM) classifiers were trained using the QUS or ophthalmic parameters (anterior chamber depth, central corneal thickness, corneal power, and intraocular pressure) to classify each eye. Classifier performance was evaluated by computing the area under the receiver-operating characteristic curve (AUC).

Results

Individual QUS parameters correlated with RE and axial length (p < 0.05). Multi-linear regression revealed significant correlation between the set of QUS parameters and both RE (R = 0.49, p < 0.001) and axial length (R = 0.46, p = 0.001). Classifiers trained with QUS parameters achieved higher AUC (𝑝 = 0.06) for identifying myopic eyes (AUC = 0.71) compared to classifiers trained with ophthalmic parameters (AUC = 0.63). QUS-based classifiers attained the highest AUC when identifying highly myopic eyes (AUC = 0.77).

Conclusions

QUS parameters correlate with progressing myopia and may be indicative of myopia-induced microstructural and biomechanical changes in the anterior sclera. These methods may provide critical clinical information complementary to standard ophthalmic measurements for predicting myopia progression and risk assessment for posterior staphyloma formation.

背景：方法：使用高频护理点（POC）超声仪器，利用定量超声（QUS）方法计算的参数，评估体内前巩膜的微观结构和生物力学特性：在这项横断面研究中，使用 POC 仪器扫描了 85 名入选患者的双眼，并对超声波数据进行了处理，以获得 QUS 参数。采用皮尔逊相关和多线性回归来确定 QUS 参数与屈光不正（RE）或轴向长度之间的关系。根据 RE 对眼睛进行分类后，使用 QUS 或眼科参数（前房深度、角膜中央厚度、角膜力和眼压）训练二元支持向量机 (SVM) 分类器，对每只眼睛进行分类。通过计算接收者工作特征曲线下面积（AUC）来评估分类器的性能：结果：单个 QUS 参数与 RE 和轴长相关（p 结论：QUS 参数与眼压和眼压的进展相关：QUS 参数与近视度数的进展相关，并可指示近视引起的前巩膜微结构和生物力学变化。这些方法可提供重要的临床信息，补充标准眼科测量方法，用于预测近视进展和评估后葡萄膜瘤形成的风险。

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引用次数: 0

Ageing and retinal thickness: An important association 老化与视网膜厚度：重要关联

IF 4.9 2区医学 Q1 OPHTHALMOLOGY

Clinical and Experimental Ophthalmology

Pub Date : 2024-07-01 DOI: 10.1111/ceo.14389

Robyn H. Guymer FRANZCO, PhD

引用次数: 0