Ophthalmology science最新文献_第4页

Comparison of Machine Learning Models to a Novel Score in the Identification of Patients at Low Risk for Diabetic Retinopathy 在识别糖尿病视网膜病变低风险患者时将机器学习模型与新型评分进行比较

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science

Pub Date : 2024-08-03 DOI: 10.1016/j.xops.2024.100592

Amanda Luong BS , Jesse Cheung BS , Shyla McMurtry MD , Christina Nelson BS , Tyler Najac MD , Philippe Ortiz MD , Stephen Aronoff MD, MBA , Jeffrey Henderer MD , Yi Zhang MD, PhD

Purpose

To develop an easily applicable predictor of patients at low risk for diabetic retinopathy (DR).

Design

An experimental study on the development and validation of machine learning models (MLMs) and a novel retinopathy risk score (RRS) to detect patients at low risk for DR.

Subjects

All individuals aged ≥18 years of age who participated in the telemedicine retinal screening initiative through Temple University Health Systems from October 1, 2016 through December 31, 2020. The subjects must have documented evidence of their diabetes mellitus (DM) diagnosis as well as a documented glycosylated hemoglobin (HbA1c) recorded in their chart within 6 months of the retinal screening photograph.

Methods

The charts of 1930 subjects (1590 evaluable) undergoing telemedicine screening for DR were reviewed, and 30 demographic and clinical parameters were collected. Diabetic retinopathy is a dichotomous variable where low risk is defined as no or mild retinopathy using the International Clinical Diabetic Retinopathy severity score. Five MLMs were trained to predict patients at low risk for DR using 1050 subjects and further underwent 10-fold cross validation to maximize its performance indicated by the area under the receiver operator characteristic curve (AUC). Additionally, a novel RRS is defined as the product of HbA1c closest to screening and years with DM. Retinopathy risk score was also applied to generate a predictive model.

Main Outcome Measures

The performance of the trained MLMs and the RRS model was compared using DeLong’s test. The models were further validated using a separate unseen test set of 540 subjects. The performance of the validation models were compared using DeLong’s test and chi-square tests.

Results

Using the test set, the AUC for the RRS was not statistically different from 4 out of 5 MLM. The error rate for predicting low-risk patients using the RRS was significantly lower than the naive rate (0.097 vs. 0.19; P < 0.0001), and it was comparable to the error rates of the MLMs.

Conclusions

This novel RRS is a potentially useful and easily deployable predictor of patients at low risk for DR.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

目的开发一种易于应用的糖尿病视网膜病变（DR）低风险患者预测指标.设计一项关于机器学习模型（MLM）和新型视网膜病变风险评分（RRS）的开发和验证的实验研究，以检测DR低风险患者.受试者2016年10月1日至2020年12月31日期间通过坦普尔大学医疗系统参加远程医疗视网膜筛查计划的所有年龄≥18岁的人。受试者必须在视网膜筛查照片拍摄后 6 个月内的病历中记录有糖尿病 (DM) 诊断证据以及糖化血红蛋白 (HbA1c) 记录。方法对接受远程医疗 DR 筛查的 1930 名受试者（1590 名可评估）的病历进行审查，并收集 30 项人口统计学和临床参数。糖尿病视网膜病变是一个二分变量，使用国际临床糖尿病视网膜病变严重程度评分将低风险定义为无视网膜病变或轻度视网膜病变。利用 1050 名受试者训练了五种 MLM 来预测 DR 低风险患者，并进一步进行了 10 倍交叉验证，以最大限度地提高其性能，具体表现为接收器运算特征曲线下面积（AUC）。此外，新的 RRS 被定义为最接近筛查的 HbA1c 与 DM 年数的乘积。主要结果测量使用 DeLong 检验比较了训练有素的 MLM 和 RRS 模型的性能。使用由 540 名受试者组成的单独未见测试集对这些模型进行了进一步验证。结果使用测试集，RRS 的 AUC 与 5 个 MLM 中的 4 个无统计学差异。使用 RRS 预测低风险患者的错误率明显低于天真率（0.097 vs. 0.19; P < 0.0001），与 MLM 的错误率相当。

{"title":"Comparison of Machine Learning Models to a Novel Score in the Identification of Patients at Low Risk for Diabetic Retinopathy","authors":"Amanda Luong BS , Jesse Cheung BS , Shyla McMurtry MD , Christina Nelson BS , Tyler Najac MD , Philippe Ortiz MD , Stephen Aronoff MD, MBA , Jeffrey Henderer MD , Yi Zhang MD, PhD","doi":"10.1016/j.xops.2024.100592","DOIUrl":"10.1016/j.xops.2024.100592","url":null,"abstract":"<div><h3>Purpose</h3><div>To develop an easily applicable predictor of patients at low risk for diabetic retinopathy (DR).</div></div><div><h3>Design</h3><div>An experimental study on the development and validation of machine learning models (MLMs) and a novel retinopathy risk score (RRS) to detect patients at low risk for DR.</div></div><div><h3>Subjects</h3><div>All individuals aged ≥18 years of age who participated in the telemedicine retinal screening initiative through Temple University Health Systems from October 1, 2016 through December 31, 2020. The subjects must have documented evidence of their diabetes mellitus (DM) diagnosis as well as a documented glycosylated hemoglobin (HbA1c) recorded in their chart within 6 months of the retinal screening photograph.</div></div><div><h3>Methods</h3><div>The charts of 1930 subjects (1590 evaluable) undergoing telemedicine screening for DR were reviewed, and 30 demographic and clinical parameters were collected. Diabetic retinopathy is a dichotomous variable where low risk is defined as no or mild retinopathy using the International Clinical Diabetic Retinopathy severity score. Five MLMs were trained to predict patients at low risk for DR using 1050 subjects and further underwent 10-fold cross validation to maximize its performance indicated by the area under the receiver operator characteristic curve (AUC). Additionally, a novel RRS is defined as the product of HbA1c closest to screening and years with DM. Retinopathy risk score was also applied to generate a predictive model.</div></div><div><h3>Main Outcome Measures</h3><div>The performance of the trained MLMs and the RRS model was compared using DeLong’s test. The models were further validated using a separate unseen test set of 540 subjects. The performance of the validation models were compared using DeLong’s test and chi-square tests.</div></div><div><h3>Results</h3><div>Using the test set, the AUC for the RRS was not statistically different from 4 out of 5 MLM. The error rate for predicting low-risk patients using the RRS was significantly lower than the naive rate (0.097 vs. 0.19; <em>P</em> < 0.0001), and it was comparable to the error rates of the MLMs.</div></div><div><h3>Conclusions</h3><div>This novel RRS is a potentially useful and easily deployable predictor of patients at low risk for DR.</div></div><div><h3>Financial Disclosure(s)</h3><div>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</div></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"5 1","pages":"Article 100592"},"PeriodicalIF":3.2,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142322310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical Evidence of a Photoreceptor Origin in Diabetic Retinal Disease 糖尿病视网膜病变源于光感受器的临床证据

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science

Pub Date : 2024-08-02 DOI: 10.1016/j.xops.2024.100591

Rithwick Rajagopal MD, PhD , Timothy Kern PhD

Clinical Relevance

Although diabetes is associated with a classic microvascular disease of the retina, it is also increasingly being recognized as a cause of retinal neuropathy. Preclinical evidence suggests that retinal neuropathy in diabetes manifests in part as photoreceptor dysfunction, preceding the development of vascular features in experimental models. It remains unknown whether such findings are relevant to patients with diabetes.

Methods

Here, we review 4 lines of clinical evidence suggesting that diabetes-associated photoreceptor pathology is linked to the development of retinal microvascular disease.

Results

First, a major population-based investigation of susceptibility loci for diabetic retinopathy (DR) implicated a photoreceptor protein product as a protective factor. Next, electroretinography and other studies of visual function collectively show that rod and/or cone-derived abnormalities occur decades before the development of vascular features of DR. Third, protection from DR seemingly develops in patients with coincident retinitis pigmentosa, as suggested by several case series. Finally, based on anatomic features, we propose that the beneficial effect of macular laser in DR occurs via ablation of diseased photoreceptors.

Conclusions

The evidence we present is limited due to the small patient populations used in the studies we cite and due to the lack of methodologies that allow causative relationships to be inferred. Collectively, however, these clinical observations suggest that photoreceptors are involved in early diabetic retinal disease and may in fact give rise to the classic features of DR.

Financial Disclosure(s)

Proprietary or commercial disclosures may be found in the Footnotes and Disclosures at the end of this article.

临床意义虽然糖尿病与典型的视网膜微血管病变有关，但人们也越来越认识到糖尿病也是视网膜神经病变的原因之一。临床前证据表明，糖尿病视网膜神经病变部分表现为光感受器功能障碍，比实验模型中血管特征的出现更早。结果首先，一项基于人群的糖尿病视网膜病变（DR）易感性位点调查显示，光感受器蛋白产品是一种保护性因素。其次，视网膜电图和其他视觉功能研究共同表明，视杆细胞和/或视锥细胞的异常在出现 DR 的血管特征之前几十年就已出现。第三，正如几个病例系列所表明的那样，DR 的保护作用似乎发生在同时患有视网膜色素变性的患者身上。最后，根据解剖学特征，我们认为黄斑激光对 DR 的有益作用是通过消融病变的光感受器实现的。结论由于我们引用的研究中使用的患者群体较小，而且缺乏推断因果关系的方法，因此我们提供的证据是有限的。但总的来说，这些临床观察结果表明，光感受器参与了早期糖尿病视网膜病变，并可能在事实上导致了DR的典型特征。

{"title":"Clinical Evidence of a Photoreceptor Origin in Diabetic Retinal Disease","authors":"Rithwick Rajagopal MD, PhD , Timothy Kern PhD","doi":"10.1016/j.xops.2024.100591","DOIUrl":"10.1016/j.xops.2024.100591","url":null,"abstract":"<div><h3>Clinical Relevance</h3><p>Although diabetes is associated with a classic microvascular disease of the retina, it is also increasingly being recognized as a cause of retinal neuropathy. Preclinical evidence suggests that retinal neuropathy in diabetes manifests in part as photoreceptor dysfunction, preceding the development of vascular features in experimental models. It remains unknown whether such findings are relevant to patients with diabetes.</p></div><div><h3>Methods</h3><p>Here, we review 4 lines of clinical evidence suggesting that diabetes-associated photoreceptor pathology is linked to the development of retinal microvascular disease.</p></div><div><h3>Results</h3><p>First, a major population-based investigation of susceptibility loci for diabetic retinopathy (DR) implicated a photoreceptor protein product as a protective factor. Next, electroretinography and other studies of visual function collectively show that rod and/or cone-derived abnormalities occur decades before the development of vascular features of DR. Third, protection from DR seemingly develops in patients with coincident retinitis pigmentosa, as suggested by several case series. Finally, based on anatomic features, we propose that the beneficial effect of macular laser in DR occurs via ablation of diseased photoreceptors.</p></div><div><h3>Conclusions</h3><p>The evidence we present is limited due to the small patient populations used in the studies we cite and due to the lack of methodologies that allow causative relationships to be inferred. Collectively, however, these clinical observations suggest that photoreceptors are involved in early diabetic retinal disease and may in fact give rise to the classic features of DR.</p></div><div><h3>Financial Disclosure(s)</h3><p>Proprietary or commercial disclosures may be found in the Footnotes and Disclosures at the end of this article.</p></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"5 1","pages":"Article 100591"},"PeriodicalIF":3.2,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666914524001271/pdfft?md5=03b8c3f460842b579f490019dd45ab72&pid=1-s2.0-S2666914524001271-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phase I Study of Intravitreal Injection of Autologous CD34+ Stem Cells from Bone Marrow in Eyes with Vision Loss from Retinitis Pigmentosa 在视网膜色素变性视力丧失患者眼中静脉注射骨髓自体 CD34+ 干细胞的 I 期研究

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science

Pub Date : 2024-07-31 DOI: 10.1016/j.xops.2024.100589

Susanna S. Park MD, PhD , Gerhard Bauer , Brian Fury MS , Mehrdad Abedi MD , Nicholas Perotti MD , Dane Colead-Bergum MA , Jan A. Nolta PhD

Purpose

To evaluate the feasibility and safety of intravitreal injection of autologous CD34+ stem cells from bone marrow (BMSCs) in eyes with vision loss from retinitis pigmentosa (RP).

Design

Phase I prospective, open-label, single-center study.

Participants

Seven eyes (7 patients) with RP with best-corrected visual acuity (BCVA) of 20/60 to 20/400 or visual field constriction to within 10°.

Methods

A comprehensive examination with ETDRS BCVA, macular OCT, perimetry, and fluorescein angiography was performed at baseline, 1 to 3 months, and 6 months after study treatment. Bone marrow aspiration, isolation of CD34+ BMSCs under good manufacturing practice conditions, and intravitreal cell injection were performed on the same day. The CD34+ cells were isolated from bone marrow using a Ficoll gradient and the Miltenyi CliniMACS system. Isolated CD34+ cells were released for clinical use if viability, sterility, and purity met the release criteria accepted by the United States Food and Drug Administration for this clinical study.

Main Outcome Measures

Number of CD34+ cells isolated for injection and adverse events associated with study treatment during follow-up. Secondary outcome measures are changes in BCVA and perimetry.

Results

All isolated CD34+ cells passed the release criteria. A mean of 3.26 ± 0.66 million viable CD34+ cells (range 1.6 to 7.05 million) were injected intravitreally per eye. No adverse event was noted during the study follow-up except for 1 participant who was noted with transient cells in the anterior chamber with mild elevation in intraocular pressure at 18 hours after study injection which normalized by 24 hours. Best-corrected visual acuity remained within 2 lines of baseline or improved in all participants at 6 months follow-up. Perimetry was stable or improved in all eyes during study follow-up except 1 eye with transient improvement at 1 month and worsening of both eyes at 6 months.

Conclusions

Intravitreal injection of autologous CD34+ BMSCs is feasible and appears to be well tolerated in eyes with vision loss from RP. A larger randomized prospective study would be needed to evaluate further the safety and potential efficacy of this cell therapy for vision loss associated with RP.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

目的评估在因视网膜色素变性（RP）导致视力下降的眼睛中进行自体骨髓CD34+干细胞（BMSCs）玻璃体内注射的可行性和安全性。方法在基线期、研究治疗后 1-3 个月和 6 个月进行全面检查，包括 ETDRS BCVA、黄斑 OCT、周视力测定和荧光素血管造影。骨髓抽取、在良好生产规范条件下分离 CD34+ BMSCs 和玻璃体内细胞注射均在同一天进行。采用 Ficoll 梯度和 Miltenyi CliniMACS 系统从骨髓中分离出 CD34+ 细胞。如果分离的 CD34+ 细胞的存活率、无菌性和纯度符合美国食品和药物管理局为这项临床研究制定的释放标准，则可释放供临床使用。次要结果指标为BCVA和周边视力的变化。结果所有分离出的CD34+细胞都通过了释放标准。平均每只眼玻璃体内注射了 326 ± 0.66 万个存活的 CD34+ 细胞（160 万到 705 万个不等）。研究随访期间未发现任何不良事件，只有一名参与者在注射后18小时发现前房有一过性细胞，眼压轻度升高，24小时后恢复正常。随访 6 个月时，所有参与者的最佳矫正视力均保持在基线 2 线以内或有所提高。结论玻璃体内注射自体 CD34+ BMSCs 是可行的，而且对于因 RP 导致视力下降的患者来说似乎耐受性良好。需要进行更大规模的随机前瞻性研究，以进一步评估这种细胞疗法治疗RP相关视力丧失的安全性和潜在疗效。

{"title":"Phase I Study of Intravitreal Injection of Autologous CD34+ Stem Cells from Bone Marrow in Eyes with Vision Loss from Retinitis Pigmentosa","authors":"Susanna S. Park MD, PhD , Gerhard Bauer , Brian Fury MS , Mehrdad Abedi MD , Nicholas Perotti MD , Dane Colead-Bergum MA , Jan A. Nolta PhD","doi":"10.1016/j.xops.2024.100589","DOIUrl":"10.1016/j.xops.2024.100589","url":null,"abstract":"<div><h3>Purpose</h3><p>To evaluate the feasibility and safety of intravitreal injection of autologous CD34+ stem cells from bone marrow (BMSCs) in eyes with vision loss from retinitis pigmentosa (RP).</p></div><div><h3>Design</h3><p>Phase I prospective, open-label, single-center study.</p></div><div><h3>Participants</h3><p>Seven eyes (7 patients) with RP with best-corrected visual acuity (BCVA) of 20/60 to 20/400 or visual field constriction to within 10°.</p></div><div><h3>Methods</h3><p>A comprehensive examination with ETDRS BCVA, macular OCT, perimetry, and fluorescein angiography was performed at baseline, 1 to 3 months, and 6 months after study treatment. Bone marrow aspiration, isolation of CD34+ BMSCs under good manufacturing practice conditions, and intravitreal cell injection were performed on the same day. The CD34+ cells were isolated from bone marrow using a Ficoll gradient and the Miltenyi CliniMACS system. Isolated CD34+ cells were released for clinical use if viability, sterility, and purity met the release criteria accepted by the United States Food and Drug Administration for this clinical study.</p></div><div><h3>Main Outcome Measures</h3><p>Number of CD34+ cells isolated for injection and adverse events associated with study treatment during follow-up. Secondary outcome measures are changes in BCVA and perimetry.</p></div><div><h3>Results</h3><p>All isolated CD34+ cells passed the release criteria. A mean of 3.26 ± 0.66 million viable CD34+ cells (range 1.6 to 7.05 million) were injected intravitreally per eye. No adverse event was noted during the study follow-up except for 1 participant who was noted with transient cells in the anterior chamber with mild elevation in intraocular pressure at 18 hours after study injection which normalized by 24 hours. Best-corrected visual acuity remained within 2 lines of baseline or improved in all participants at 6 months follow-up. Perimetry was stable or improved in all eyes during study follow-up except 1 eye with transient improvement at 1 month and worsening of both eyes at 6 months.</p></div><div><h3>Conclusions</h3><p>Intravitreal injection of autologous CD34+ BMSCs is feasible and appears to be well tolerated in eyes with vision loss from RP. A larger randomized prospective study would be needed to evaluate further the safety and potential efficacy of this cell therapy for vision loss associated with RP.</p></div><div><h3>Financial Disclosure(s)</h3><p>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"5 1","pages":"Article 100589"},"PeriodicalIF":3.2,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666914524001258/pdfft?md5=26ee261925521bae1e4cb8e10d7ee52b&pid=1-s2.0-S2666914524001258-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Subconjunctival Administration of an Adeno-Associated Virus Expressing Stanniocalcin-1 Provides Sustained Intraocular Pressure Reduction in Mice 结膜下注射表达 Stanniocalcin-1 的腺相关病毒可持续降低小鼠眼压

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science

Pub Date : 2024-07-31 DOI: 10.1016/j.xops.2024.100590

Gavin W. Roddy MD, PhD, Darrell Kohli MD, Parvin Niknam PhD, Mohammed E. Omer MBBS, Uttio Roy Chowdhury PhD, Kjersten J. Anderson, Johann M. Pacheco Marrero MD, Tommy A. Rinkoski MS, Michael P. Fautsch PhD

<div><h3>Purpose</h3><p>To investigate subconjunctival administration of a single-stranded, adeno-associated virus, serotype 2, engineered to express stanniocalcin-1 with a FLAG tag (ssAAV2-STC-1-FLAG) as a novel sustained (IOP) lowering agent with a reduced ocular surface side effect profile.</p></div><div><h3>Design</h3><p>In vivo preclinical investigation in mice.</p></div><div><h3>Subjects</h3><p>C57BL/6J, DBA/2J, prostaglandin F (FP) receptor knockout mice.</p></div><div><h3>Methods</h3><p>Normotensive C57BL/6J mice were treated with a subconjunctival injection of ssAAV2-STC-1-FLAG (2 μL; 6 × 10<sup>9</sup> viral genomes [VGs]) in 1 eye and the same volume and concentration of ssAAV2-green fluorescent protein (GFP) or the same volume of phosphate-buffered saline in the fellow eye. Ocular hypertensive DBA/2J mice were subconjunctivally injected with 6 × 10<sup>9</sup> VGs of ssAAV2-STC-1-FLAG or ssAAV2-GFP. Steroid-mediated ocular hypertension was induced in C57BL/6J mice with weekly injections of dexamethasone into the conjunctival fornix, and mice were then injected subconjunctivally with 6 × 10<sup>9</sup> VGs of ssAAV2-STC-1-FLAG or ssAAV2-GFP. Prostaglandin F receptor knockout mice were injected subconjunctivally with 6 × 10<sup>9</sup> VGs of ssAAV2-STC-1-FLAG or phosphate-buffered saline. An identical vector was constructed without the FLAG tag (ssAAV2-STC-1) and evaluated in normotensive C57BL/6J mice. Intraocular pressure was assessed using the Tonolab tonometer for all experiments. Tumor necrosis factor alpha (TNFα), a marker of ocular surface inflammation, was compared between subconjunctivally delivered ssAAV2-STC-1-FLAG and other treatments including daily topical latanoprost.</p></div><div><h3>Main Outcome Measures</h3><p>Intraocular pressure assessment.</p></div><div><h3>Results</h3><p>Subconjunctival delivery of ssAAV2-STC-1-FLAG significantly reduced IOP for 10 weeks post injection in normotensive mice. Maximal IOP reduction was seen at week 3 postinjection (17.4%; 17.1 ± 0.8 vs. 14.1 ± 0.8 mmHg, <em>P</em> < 0.001). After the IOP-lowering effect had waned, a second injection restored the ocular hypotensive effect. Subconjunctivally delivered ssAAV2-STC-1-FLAG lowered IOP in DBA/2J mice (16.9%; 17.8 ± 2.0 vs. 14.8 ± 0.9 mmHg, <em>P</em> < 0.001) and steroid-mediated ocular hypertensive mice (20.0%; 19.0 ± 0.6 vs. 15.2 ± 0.7 mmHg, <em>P</em> < 0.001) over the experimental period. This construct also reduced IOP to a similar extent in wild-type (15.9%) and FP receptor knockout (15.7%) mice compared with the fellow eye. A related construct also lowered IOP without the FLAG tag in a similar manner. Reduction in conjunctival TNFα was seen when comparing subconjunctivally delivered ssAAV2-STC-1-FLAG to daily topical latanoprost.</p></div><div><h3>Conclusions</h3><p>Subconjunctival delivery of the STC-1 transgene with a vector system may represent a novel treatment strategy for sustained IOP reduction and improved ocular to

目的研究结膜下给药单链腺相关病毒 2 号血清型（ssAAV2-STC-1-FLAG）以表达带有 FLAG 标记的斯坦尼钙素-1（stanniocalcin-1），作为一种新型的持续性（眼压）降低药物，同时减少眼表副作用。方法正常血压的 C57BL/6J 小鼠的一只眼球结膜下注射 ssAAV2-STC-1-FLAG（2 μL；6 × 109 病毒基因组 [VGs]），另一只眼球注射相同体积和浓度的 ssAAV2-绿色荧光蛋白（GFP）或相同体积的磷酸盐缓冲盐水。给眼压过高的 DBA/2J 小鼠结膜下注射 6 × 109 VGs 的 ssAAV2-STC-1-FLAG 或 ssAAV2-GFP。每周向 C57BL/6J 小鼠结膜穹窿注射地塞米松诱导类固醇介导的眼压过高，然后向小鼠结膜下注射 6 × 109 VGs 的 ssAAV2-STC-1-FLAG 或 ssAAV2-GFP。前列腺素 F 受体基因敲除小鼠结膜下注射 6 × 109 VGs ssAAV2-STC-1-FLAG 或磷酸盐缓冲盐水。还构建了不含 FLAG 标记的相同载体（ssAAV2-STC-1），并在血压正常的 C57BL/6J 小鼠中进行了评估。所有实验均使用 Tonolab 眼压计评估眼压。主要结果测量眼压评估结果结膜下注射 ssAAV2-STC-1-FLAG 能显著降低正常血压小鼠注射后 10 周的眼压。最大眼压降幅出现在注射后第 3 周（17.4%；17.1 ± 0.8 vs. 14.1 ± 0.8 mmHg，P < 0.001）。在降低眼压的作用减弱后，第二次注射可恢复降眼压作用。在实验期间，结膜下注射 ssAAV2-STC-1-FLAG 可降低 DBA/2J 小鼠（16.9%；17.8 ± 2.0 vs. 14.8 ± 0.9 mmHg，P <；0.001）和类固醇介导的眼压升高小鼠（20.0%；19.0 ± 0.6 vs. 15.2 ± 0.7 mmHg，P <；0.001）的眼压。野生型小鼠（15.9%）和FP受体基因敲除小鼠（15.7%）的眼压降低程度与同侧眼相似。一种相关的构建物也以类似的方式降低了没有FLAG标记的小鼠的眼压。结论用载体系统结膜下递送STC-1转基因可能是一种持续降低眼压和改善眼部耐受性的新型治疗策略，同时也避免了现有药物的每日用药要求。

{"title":"Subconjunctival Administration of an Adeno-Associated Virus Expressing Stanniocalcin-1 Provides Sustained Intraocular Pressure Reduction in Mice","authors":"Gavin W. Roddy MD, PhD, Darrell Kohli MD, Parvin Niknam PhD, Mohammed E. Omer MBBS, Uttio Roy Chowdhury PhD, Kjersten J. Anderson, Johann M. Pacheco Marrero MD, Tommy A. Rinkoski MS, Michael P. Fautsch PhD","doi":"10.1016/j.xops.2024.100590","DOIUrl":"10.1016/j.xops.2024.100590","url":null,"abstract":"<div><h3>Purpose</h3><p>To investigate subconjunctival administration of a single-stranded, adeno-associated virus, serotype 2, engineered to express stanniocalcin-1 with a FLAG tag (ssAAV2-STC-1-FLAG) as a novel sustained (IOP) lowering agent with a reduced ocular surface side effect profile.</p></div><div><h3>Design</h3><p>In vivo preclinical investigation in mice.</p></div><div><h3>Subjects</h3><p>C57BL/6J, DBA/2J, prostaglandin F (FP) receptor knockout mice.</p></div><div><h3>Methods</h3><p>Normotensive C57BL/6J mice were treated with a subconjunctival injection of ssAAV2-STC-1-FLAG (2 μL; 6 × 10<sup>9</sup> viral genomes [VGs]) in 1 eye and the same volume and concentration of ssAAV2-green fluorescent protein (GFP) or the same volume of phosphate-buffered saline in the fellow eye. Ocular hypertensive DBA/2J mice were subconjunctivally injected with 6 × 10<sup>9</sup> VGs of ssAAV2-STC-1-FLAG or ssAAV2-GFP. Steroid-mediated ocular hypertension was induced in C57BL/6J mice with weekly injections of dexamethasone into the conjunctival fornix, and mice were then injected subconjunctivally with 6 × 10<sup>9</sup> VGs of ssAAV2-STC-1-FLAG or ssAAV2-GFP. Prostaglandin F receptor knockout mice were injected subconjunctivally with 6 × 10<sup>9</sup> VGs of ssAAV2-STC-1-FLAG or phosphate-buffered saline. An identical vector was constructed without the FLAG tag (ssAAV2-STC-1) and evaluated in normotensive C57BL/6J mice. Intraocular pressure was assessed using the Tonolab tonometer for all experiments. Tumor necrosis factor alpha (TNFα), a marker of ocular surface inflammation, was compared between subconjunctivally delivered ssAAV2-STC-1-FLAG and other treatments including daily topical latanoprost.</p></div><div><h3>Main Outcome Measures</h3><p>Intraocular pressure assessment.</p></div><div><h3>Results</h3><p>Subconjunctival delivery of ssAAV2-STC-1-FLAG significantly reduced IOP for 10 weeks post injection in normotensive mice. Maximal IOP reduction was seen at week 3 postinjection (17.4%; 17.1 ± 0.8 vs. 14.1 ± 0.8 mmHg, <em>P</em> < 0.001). After the IOP-lowering effect had waned, a second injection restored the ocular hypotensive effect. Subconjunctivally delivered ssAAV2-STC-1-FLAG lowered IOP in DBA/2J mice (16.9%; 17.8 ± 2.0 vs. 14.8 ± 0.9 mmHg, <em>P</em> < 0.001) and steroid-mediated ocular hypertensive mice (20.0%; 19.0 ± 0.6 vs. 15.2 ± 0.7 mmHg, <em>P</em> < 0.001) over the experimental period. This construct also reduced IOP to a similar extent in wild-type (15.9%) and FP receptor knockout (15.7%) mice compared with the fellow eye. A related construct also lowered IOP without the FLAG tag in a similar manner. Reduction in conjunctival TNFα was seen when comparing subconjunctivally delivered ssAAV2-STC-1-FLAG to daily topical latanoprost.</p></div><div><h3>Conclusions</h3><p>Subconjunctival delivery of the STC-1 transgene with a vector system may represent a novel treatment strategy for sustained IOP reduction and improved ocular to","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"5 1","pages":"Article 100590"},"PeriodicalIF":3.2,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S266691452400126X/pdfft?md5=923846108f994b5e9af7245756c01095&pid=1-s2.0-S266691452400126X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142239012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Re: Angela S Li et al Gradeability and Reproducibility of Geographic Atrophy Measurement in GATHER-1, a Phase II/III Randomized Interventional Trial Re：Angela S Li 等人的 GATHER-1 地理萎缩测量的可分级性和可重复性，一项 II/III 期随机干预试验

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science

Pub Date : 2024-07-29 DOI: 10.1016/j.xops.2024.100567

Siamak Sabour MD, PhD, Fariba Ghassemi MD

引用次数: 0

Impact of Tumor Pigmentation in 6934 Patients with Uveal Melanoma at a Single Center 一个中心 6934 名葡萄膜黑色素瘤患者肿瘤色素沉着的影响

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science

Pub Date : 2024-07-26 DOI: 10.1016/j.xops.2024.100585

Samuel J. Goldstein BSPH, Ferris Bayasi MD, George Thomas MD, Matthew Barke MD, Michael K. Nguyen BA, Samantha Pastore BS, Carol L. Shields MD

<div><h3>Purpose</h3><p>To evaluate clinical features and outcomes associated with degree of tumor pigmentation in patients with uveal melanoma (UM) of the choroid and ciliary body.</p></div><div><h3>Design</h3><p>Retrospective observational study.</p></div><div><h3>Subjects</h3><p>Six thousand nine hundred thirty-four consecutive patients with choroidal or ciliary body melanoma between 1971 and 2007 from a single ocular oncology center.</p></div><div><h3>Methods</h3><p>Data on patient demographics, tumor characteristics, treatment approach, and clinical outcomes were collected. Comparisons between pigmented (>80% pigmentation by surface area), partially pigmented (20%–80%), and nonpigmented tumors (<20%) were performed using relevant hypothesis testing. Survival analyses for metastasis and melanoma-related death were conducted using the Kaplan–Meier method with log-rank tests for univariate comparisons. A multivariate Cox regression analysis was performed to assess the independent effects of multiple covariates on time-to-metastasis.</p></div><div><h3>Main Outcome Measures</h3><p>Extraocular extension, ocular melanocytosis, time to tumor recurrence, tumor location, and melanoma-related metastasis and death.</p></div><div><h3>Results</h3><p>There were 6934 eyes with UM and the degree of tumor pigmentation was classified as pigmented (n = 3762; 54%), partially pigmented (n = 2115; 31%), or nonpigmented (n = 1057; 15%). Pigmented UM was associated with extraocular extension (<em>P</em> < 0.001), ocular melanocytosis (<em>P</em> = 0.003), earlier tumor recurrence (<em>P</em> < 0.001), and more anterior tumor epicenter location (ciliary body, and equator to ora serrata) (<em>P</em> < 0.001). Pigmented UMs also exhibited the highest 10-year metastasis rate at 26%, compared with 19% for partially pigmented UMs and 16% for nonpigmented UMs (<em>P</em> < 0.001). Kaplan–Meier survival curves demonstrated differences among the tumor pigmentation groups for melanoma-related metastasis (<em>P</em> < 0.001) and melanoma-related death (<em>P</em> < 0.001). Multivariate Cox regression analysis for melanoma-related metastasis showed that pigmented UMs had a 29% higher relative risk of developing metastasis compared with partially pigmented UMs (<em>P</em> = 0.002) and a 54% higher relative risk of developing metastasis compared with nonpigmented UMs (<em>P</em> < 0.001).</p></div><div><h3>Conclusions</h3><p>Pigmented choroidal and ciliary body melanoma is more often associated with ocular melanocytosis, extraocular extension, anterior tumor epicenter, and earlier tumor recurrence. We also revealed that patients with pigmented UMs demonstrate a higher 10-year rate of metastatic disease and have decreased metastatic survival relative to partially pigmented and nonpigmented UMs.</p></div><div><h3>Financial Disclosures</h3><p>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p><

目的评估脉络膜和睫状体葡萄膜黑色素瘤（UM）患者肿瘤色素沉着程度相关的临床特征和预后。方法收集患者人口统计学资料、肿瘤特征、治疗方法和临床预后。使用相关假设检验对色素性肿瘤（表面积色素沉着80%）、部分色素性肿瘤（20%-80%）和非色素性肿瘤（20%）进行比较。转移和黑色素瘤相关死亡的生存分析采用 Kaplan-Meier 法，单变量比较采用 log-rank 检验。主要结果指标眼外扩展、眼部黑色素细胞增多、肿瘤复发时间、肿瘤位置、黑色素瘤相关转移和死亡。结果6934只眼睛患有UM，肿瘤色素沉着程度分为色素沉着（n = 3762；54%）、部分色素沉着（n = 2115；31%）或非色素沉着（n = 1057；15%）。色素性 UM 与眼外扩展（P <；0.001）、眼部黑素细胞增多（P = 0.003）、肿瘤复发较早（P <；0.001）和肿瘤震中位置较前（睫状体、赤道部至血清轮）（P <；0.001）有关。色素性 UM 的 10 年转移率也最高，为 26%，而部分色素性 UM 为 19%，非色素性 UM 为 16%（P < 0.001）。卡普兰-梅耶生存曲线显示，不同色素沉着组的黑色素瘤相关转移率（P <0.001）和黑色素瘤相关死亡率（P <0.001）存在差异。黑色素瘤相关转移的多变量 Cox 回归分析显示，与部分色素沉着的 UMs 相比，色素沉着的 UMs 发生转移的相对风险高 29% （P = 0.结论色素性脉络膜和睫状体黑色素瘤通常与眼部黑素细胞增多、眼外扩展、肿瘤前部震中和肿瘤复发较早有关。我们还发现，与部分色素性和非色素性UMs相比，色素性UMs患者的10年转移率更高，转移生存率更低。

{"title":"Impact of Tumor Pigmentation in 6934 Patients with Uveal Melanoma at a Single Center","authors":"Samuel J. Goldstein BSPH, Ferris Bayasi MD, George Thomas MD, Matthew Barke MD, Michael K. Nguyen BA, Samantha Pastore BS, Carol L. Shields MD","doi":"10.1016/j.xops.2024.100585","DOIUrl":"10.1016/j.xops.2024.100585","url":null,"abstract":"<div><h3>Purpose</h3><p>To evaluate clinical features and outcomes associated with degree of tumor pigmentation in patients with uveal melanoma (UM) of the choroid and ciliary body.</p></div><div><h3>Design</h3><p>Retrospective observational study.</p></div><div><h3>Subjects</h3><p>Six thousand nine hundred thirty-four consecutive patients with choroidal or ciliary body melanoma between 1971 and 2007 from a single ocular oncology center.</p></div><div><h3>Methods</h3><p>Data on patient demographics, tumor characteristics, treatment approach, and clinical outcomes were collected. Comparisons between pigmented (>80% pigmentation by surface area), partially pigmented (20%–80%), and nonpigmented tumors (<20%) were performed using relevant hypothesis testing. Survival analyses for metastasis and melanoma-related death were conducted using the Kaplan–Meier method with log-rank tests for univariate comparisons. A multivariate Cox regression analysis was performed to assess the independent effects of multiple covariates on time-to-metastasis.</p></div><div><h3>Main Outcome Measures</h3><p>Extraocular extension, ocular melanocytosis, time to tumor recurrence, tumor location, and melanoma-related metastasis and death.</p></div><div><h3>Results</h3><p>There were 6934 eyes with UM and the degree of tumor pigmentation was classified as pigmented (n = 3762; 54%), partially pigmented (n = 2115; 31%), or nonpigmented (n = 1057; 15%). Pigmented UM was associated with extraocular extension (<em>P</em> < 0.001), ocular melanocytosis (<em>P</em> = 0.003), earlier tumor recurrence (<em>P</em> < 0.001), and more anterior tumor epicenter location (ciliary body, and equator to ora serrata) (<em>P</em> < 0.001). Pigmented UMs also exhibited the highest 10-year metastasis rate at 26%, compared with 19% for partially pigmented UMs and 16% for nonpigmented UMs (<em>P</em> < 0.001). Kaplan–Meier survival curves demonstrated differences among the tumor pigmentation groups for melanoma-related metastasis (<em>P</em> < 0.001) and melanoma-related death (<em>P</em> < 0.001). Multivariate Cox regression analysis for melanoma-related metastasis showed that pigmented UMs had a 29% higher relative risk of developing metastasis compared with partially pigmented UMs (<em>P</em> = 0.002) and a 54% higher relative risk of developing metastasis compared with nonpigmented UMs (<em>P</em> < 0.001).</p></div><div><h3>Conclusions</h3><p>Pigmented choroidal and ciliary body melanoma is more often associated with ocular melanocytosis, extraocular extension, anterior tumor epicenter, and earlier tumor recurrence. We also revealed that patients with pigmented UMs demonstrate a higher 10-year rate of metastatic disease and have decreased metastatic survival relative to partially pigmented and nonpigmented UMs.</p></div><div><h3>Financial Disclosures</h3><p>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p><","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"4 6","pages":"Article 100585"},"PeriodicalIF":3.2,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666914524001210/pdfft?md5=4d655f3e430b8f3aa54879df299e9a92&pid=1-s2.0-S2666914524001210-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141850483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lens Thickness in Infants and Children with Cataracts 婴幼儿白内障患者的晶状体厚度

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science

Pub Date : 2024-07-26 DOI: 10.1016/j.xops.2024.100588

Libby Wei MD , Taylor Kolosky , Sarah Byun , Alexandra S. Dolgetta MD , Moran R. Levin MD , Jana A. Friedman MD , Monica M. Manrique MD , Isabelle Dortonne MD , Camilo Martinez COA , Marlet Bazemore MD , Mohamad S. Jaafar MD , William P. Madigan MD , Laurence Magder PhD , Janet L. Alexander MD, MS

Purpose

The purpose of this study was to determine the association between lens thickness and cataract in participants aged 0 to 5 years.

Design

This was a prospective, multicenter, case–control study.

Participants

We enrolled 118 participants (171 eyes) aged 0 to 5 years, mean age 14.6 ± 17.0 months, range 0 to 60 months.

Methods

Lens thickness was measured on 342 ultrasound biomicroscopy (UBM) images.

Main Outcome Measures

Lens thickness; feasibility of lens thickness measurement from UBM images.

Results

The mean lens thickness among noncataracts was 3.60 ± 0.17 mm, compared with 3.16 ± 0.61 mm among cataracts (P < 0.0001). Lens thickness <3.5 mm was significantly associated with increased odds of cataract; adjusted odds ratio = 5.99 (95% confidence interval, 2.41–14.88; P < 0.0003) among participants age 0 to 7 months. Lens thickness was significantly associated with cataract laterality among participants age 0 to 7 months (P < 0.0001).

Conclusions

Quantitative UBM can be used to evaluate lens thickness in infants and children with congenital cataracts. The lens in congenital cataract eyes was thinner than that of controls among infants. Abnormal lens thickness was significantly associated with cataract. Future longitudinal studies will examine the association between lens thickness and postcataract surgery outcomes.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

目的本研究旨在确定0至5岁参与者的晶状体厚度与白内障之间的关系。结果非白内障患者的平均晶状体厚度为（3.60 ± 0.17）毫米，而白内障患者的平均晶状体厚度为（3.16 ± 0.61）毫米（P <0.0001）。在 0 到 7 个月的参与者中，晶状体厚度 <3.5 mm 与白内障发生几率的增加显著相关；调整后的几率比 = 5.99（95% 置信区间，2.41-14.88；P < 0.0003）。结论定量 UBM 可用于评估患有先天性白内障的婴幼儿的晶状体厚度。与对照组相比，先天性白内障婴儿眼中的晶状体更薄。晶状体厚度异常与白内障密切相关。未来的纵向研究将探讨晶状体厚度与白内障术后效果之间的关系。

{"title":"Lens Thickness in Infants and Children with Cataracts","authors":"Libby Wei MD , Taylor Kolosky , Sarah Byun , Alexandra S. Dolgetta MD , Moran R. Levin MD , Jana A. Friedman MD , Monica M. Manrique MD , Isabelle Dortonne MD , Camilo Martinez COA , Marlet Bazemore MD , Mohamad S. Jaafar MD , William P. Madigan MD , Laurence Magder PhD , Janet L. Alexander MD, MS","doi":"10.1016/j.xops.2024.100588","DOIUrl":"10.1016/j.xops.2024.100588","url":null,"abstract":"<div><h3>Purpose</h3><p>The purpose of this study was to determine the association between lens thickness and cataract in participants aged 0 to 5 years.</p></div><div><h3>Design</h3><p>This was a prospective, multicenter, case–control study.</p></div><div><h3>Participants</h3><p>We enrolled 118 participants (171 eyes) aged 0 to 5 years, mean age 14.6 ± 17.0 months, range 0 to 60 months.</p></div><div><h3>Methods</h3><p>Lens thickness was measured on 342 ultrasound biomicroscopy (UBM) images.</p></div><div><h3>Main Outcome Measures</h3><p>Lens thickness; feasibility of lens thickness measurement from UBM images.</p></div><div><h3>Results</h3><p>The mean lens thickness among noncataracts was 3.60 ± 0.17 mm, compared with 3.16 ± 0.61 mm among cataracts (<em>P</em> < 0.0001). Lens thickness <3.5 mm was significantly associated with increased odds of cataract; adjusted odds ratio = 5.99 (95% confidence interval, 2.41–14.88; <em>P</em> < 0.0003) among participants age 0 to 7 months. Lens thickness was significantly associated with cataract laterality among participants age 0 to 7 months (<em>P</em> < 0.0001).</p></div><div><h3>Conclusions</h3><p>Quantitative UBM can be used to evaluate lens thickness in infants and children with congenital cataracts. The lens in congenital cataract eyes was thinner than that of controls among infants. Abnormal lens thickness was significantly associated with cataract. Future longitudinal studies will examine the association between lens thickness and postcataract surgery outcomes.</p></div><div><h3>Financial Disclosure(s)</h3><p>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"5 1","pages":"Article 100588"},"PeriodicalIF":3.2,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666914524001246/pdfft?md5=d926594c5f4edb7fbd5f74572e84042f&pid=1-s2.0-S2666914524001246-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141847244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retinal Microstructural Changes Reflecting Treatment-Associated Cognitive Dysfunction in Patients with Lower-Grade Gliomas 反映低级别胶质瘤患者治疗相关认知功能障碍的视网膜微结构变化

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science

Pub Date : 2024-07-25 DOI: 10.1016/j.xops.2024.100577

Arina Nisanova BA , Ashutosh Parajuli BS , Bhavna Antony PhD , Orwa Aboud MD, PhD , Jinger Sun MD, PhD , Megan E. Daly MD , Ruben C. Fragoso MD, PhD , Glenn Yiu MD, PhD , Yin Allison Liu MD, PhD

Purpose

To determine whether microstructural retinal changes, tumor features, and apolipoprotein E (APOE) ε4 polymorphism are correlated with clinically detectable treatment-associated cognitive dysfunction (TACD) in patients with lower-grade gliomas.

Design

Cohort study.

Participants and Controls

Sixteen patients with lower-grade glioma at a United States academic ophthalmology department between January 2021 and November 2023. Normal controls were recruited from convenient sampling.

Methods

Montreal Cognitive Assessment (MoCA) scores and retinal changes were assessed in 6-month intervals. Apolipoprotein E genotyping was performed, and tumor details were recorded. Partial least-squares discriminant (PLSD) model was established to evaluate the association between TACD with APOE genotype, ophthalmic, and tumor features.

Main Outcome Measures

The main outcome measure was cognitive status as measured by the MoCA score and analyzed in relation to ophthalmic measurements, tumor features, and APOE genotype.

Results

Median time to first eye examination was 34 months (2–266) from tumor diagnosis and 23 months (0–246) from radiation. Nine patients (56%) had abnormal cognition (MoCA <26/30). Montreal Cognitive Assessment scores were significantly worse in patients with temporal (22 ± 7.2) than frontal lobe tumors (26 ± 3.1, P = 0.02) and those with oligodendrogliomas (22 ± 4.1) than astrocytomas (26 ± 3.6, = 0.02). Patients with TACD had significant radial peripapillary capillary density loss (45% ± 4.6) compared with those with normal cognition (49% ± 2.6, P = 0.02). A PLSD model correlated MoCA scores with retinal nerve fiber thickness, intraocular pressure, foveal avascular zone, best-corrected visual acuity, months since first diagnosis, and tumor pathology (oligodendroglioma or not). Using these features, the model identified patients with TACD with 77% accuracy. Apolipoprotein E genotyping showed: 2 ε2/ε3 (13%), 10 ε3/ε3 (63%), and 1 ε3/ε4 (6%).

Conclusions

Retinal microstructural changes may serve as biomarkers for TACD in patients with lower-grade gliomas. Temporal lobe tumors and oligodendrogliomas may increase susceptibility to TACD. Utilization of retinal markers may enhance TACD diagnosis, progression monitoring, and inform management of lower-grade patients with glioma. A larger study with serial eye examinations is warranted to evaluate the role of APOE ε4 and develop a predictive model.

Financial Disclosures

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

目的确定视网膜微结构变化、肿瘤特征和载脂蛋白E（APOE）ε4多态性是否与低级别胶质瘤患者临床上可检测到的治疗相关认知功能障碍（TACD）相关。方法每隔 6 个月评估蒙特利尔认知评估（MoCA）评分和视网膜变化。进行载脂蛋白 E 基因分型，并记录肿瘤细节。建立部分最小二乘判别（PLSD）模型，评估TACD与APOE基因型、眼科和肿瘤特征之间的关联。结果首次眼科检查的平均时间为肿瘤诊断后34个月（2-266），放射治疗后23个月（0-246）。九名患者（56%）认知异常（MoCA 26/30）。颞叶肿瘤患者的蒙特利尔认知评估评分（22 ± 7.2）明显低于额叶肿瘤患者（26 ± 3.1，P = 0.02），少突胶质细胞瘤患者的蒙特利尔认知评估评分（22 ± 4.1）明显低于星形细胞瘤患者（26 ± 3.6，= 0.02）。与认知功能正常的患者（49% ± 2.6，P = 0.02）相比，TACD 患者的径向毛细血管周围密度明显下降（45% ± 4.6）。PLSD模型将MoCA评分与视网膜神经纤维厚度、眼压、眼窝血管区、最佳矫正视力、首次诊断后的月数、肿瘤病理（是否少突胶质细胞瘤）相关联。利用这些特征，该模型识别TACD患者的准确率为77%。载脂蛋白 E 基因分型显示结论视网膜微结构变化可作为低级别胶质瘤患者 TACD 的生物标志物。颞叶肿瘤和少突胶质细胞瘤可能会增加TACD的易感性。利用视网膜标记物可加强TACD诊断和病情进展监测，并为低级别胶质瘤患者的管理提供信息。有必要进行更大规模的连续眼部检查研究，以评估APOE ε4的作用并建立预测模型。

{"title":"Retinal Microstructural Changes Reflecting Treatment-Associated Cognitive Dysfunction in Patients with Lower-Grade Gliomas","authors":"Arina Nisanova BA , Ashutosh Parajuli BS , Bhavna Antony PhD , Orwa Aboud MD, PhD , Jinger Sun MD, PhD , Megan E. Daly MD , Ruben C. Fragoso MD, PhD , Glenn Yiu MD, PhD , Yin Allison Liu MD, PhD","doi":"10.1016/j.xops.2024.100577","DOIUrl":"10.1016/j.xops.2024.100577","url":null,"abstract":"<div><h3>Purpose</h3><p>To determine whether microstructural retinal changes, tumor features, and <em>apolipoprotein E (APOE) ε4</em> polymorphism are correlated with clinically detectable treatment-associated cognitive dysfunction (TACD) in patients with lower-grade gliomas.</p></div><div><h3>Design</h3><p>Cohort study.</p></div><div><h3>Participants and Controls</h3><p>Sixteen patients with lower-grade glioma at a United States academic ophthalmology department between January 2021 and November 2023. Normal controls were recruited from convenient sampling.</p></div><div><h3>Methods</h3><p>Montreal Cognitive Assessment (MoCA) scores and retinal changes were assessed in 6-month intervals. <em>Apolipoprotein E</em> genotyping was performed, and tumor details were recorded. Partial least-squares discriminant (PLSD) model was established to evaluate the association between TACD with <em>APOE</em> genotype, ophthalmic, and tumor features.</p></div><div><h3>Main Outcome Measures</h3><p>The main outcome measure was cognitive status as measured by the MoCA score and analyzed in relation to ophthalmic measurements, tumor features, and <em>APOE</em> genotype.</p></div><div><h3>Results</h3><p>Median time to first eye examination was 34 months (2–266) from tumor diagnosis and 23 months (0–246) from radiation. Nine patients (56%) had abnormal cognition (MoCA <26/30). Montreal Cognitive Assessment scores were significantly worse in patients with temporal (22 ± 7.2) than frontal lobe tumors (26 ± 3.1, <em>P</em> = 0.02) and those with oligodendrogliomas (22 ± 4.1) than astrocytomas (26 ± 3.6, = 0.02). Patients with TACD had significant radial peripapillary capillary density loss (45% ± 4.6) compared with those with normal cognition (49% ± 2.6, <em>P</em> = 0.02). A PLSD model correlated MoCA scores with retinal nerve fiber thickness, intraocular pressure, foveal avascular zone, best-corrected visual acuity, months since first diagnosis, and tumor pathology (oligodendroglioma or not). Using these features, the model identified patients with TACD with 77% accuracy. <em>Apolipoprotein E</em> genotyping showed: 2 <em>ε2/ε3</em> (13%), 10 <em>ε3/ε3</em> (63%)<em>,</em> and 1 <em>ε3/ε4</em> (6%).</p></div><div><h3>Conclusions</h3><p>Retinal microstructural changes may serve as biomarkers for TACD in patients with lower-grade gliomas. Temporal lobe tumors and oligodendrogliomas may increase susceptibility to TACD. Utilization of retinal markers may enhance TACD diagnosis, progression monitoring, and inform management of lower-grade patients with glioma. A larger study with serial eye examinations is warranted to evaluate the role of <em>APOE ε</em>4 and develop a predictive model.</p></div><div><h3>Financial Disclosures</h3><p>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"4 6","pages":"Article 100577"},"PeriodicalIF":3.2,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666914524001131/pdfft?md5=25ad236fa7ec07fef6003a7e446c9ab3&pid=1-s2.0-S2666914524001131-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141845125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Safety and Tolerability of Suprachoroidal Axitinib Injectable Suspension, for Neovascular Age-related Macular Degeneration; Phase I/IIa Open-Label, Dose-Escalation Trial 脉络膜上腔阿昔替尼（CLS-AX）治疗新生血管性黄斑变性症的安全性和耐受性；1/2a期开放标签、剂量递增试验

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science

Pub Date : 2024-07-25 DOI: 10.1016/j.xops.2024.100586

Mark R. Barakat MD , David Brown MD , Allen Hu MD , Rahul N. Khurana MD , Dennis Marcus MD , Joel Pearlman MD, PhD , Charles C. Wykoff MD, PhD , Barry Kapik MS , Thomas Ciulla MD, MBA

Purpose

To evaluate the safety and tolerability of a single dose of axitinib injectable suspension (CLS-AX), a pan-anti-VEGF tyrosine kinase inhibitor (TKI), administered via suprachoroidal injection in patients with neovascular age-related macular degeneration (nAMD).

Design

Phase I/IIa, open-label, sequential dose escalation.

Participants

Anti-VEGF treatment-experienced patients with active subfoveal choroidal neovascularization secondary to nAMD.

Methods

The study included 4 cohorts (0.03, 0.10, 0.50, and 1.0 mg) of approximately 5 patients each enrolled in a dose-escalating fashion. Enrolled patients received intravitreal aflibercept (2 mg) followed by a single unilateral dose of CLS-AX 1 month later. All patients were followed monthly for 3 months with the option of an additional 3 months of extended follow-up for cohorts 2 to 4. End points included systemic and ocular safety and tolerability, visual acuity, retinal thickness, and need for aflibercept therapy.

Main Outcome Measures

The number of patients reporting treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), changes in ophthalmic examinations, and the number of patients qualifying for additional therapy for nAMD based on protocol-defined criteria.

Results

OASIS enrolled 27 patients with nAMD with mean age of 81 years, mean duration of nAMD diagnosis of 54 months, and between 5 and 90 prior anti-VEGF treatments. Twenty-six patients completed through 3 months, with 14 entering and completing the 3-month extension. No SAEs, drug-related TEAEs, or TEAEs leading to discontinuation were observed after CLS-AX administration; there were no adverse events related to ocular inflammation, vasculitis, intraocular pressure, or dispersion of drug into the vitreous or anterior chamber. Through 6 months, stable mean best-corrected visual acuity and stable mean central subfield thickness (CST) were observed, suggestive of TKI biologic effect. No aflibercept therapy was administered up to 3 months in 58% (15/26) of patients who completed 3 months of follow-up in OASIS. In the Extension, 57% (8/14) of patients went up to 6 months without receiving aflibercept therapy.

Conclusions

Up to 1.0 mg CLS-AX, a highly potent TKI targeted to the suprachoroidal space (SCS) via the SCS Microinjector, was well tolerated, with stable mean visual acuity and mean CST. A majority of patients followed for 6 months did not require aflibercept therapy.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

目的评估新生血管性年龄相关性黄斑变性（nAMD）患者通过脉络膜上腔注射单剂量阿昔替尼注射用混悬液（CLS-AX）这种泛抗 VEGF 酪氨酸激酶抑制剂（TKI）的安全性和耐受性。方法该研究包括 4 个组群（0.03、0.10、0.50 和 1.0 毫克），每个组群约有 5 名患者，以剂量递增的方式入组。入组患者接受玻璃体内阿弗利贝赛普（2 毫克）治疗，1 个月后单侧注射 CLS-AX。所有患者每月随访3个月，第2至第4组患者可选择延长3个月的随访时间。终点包括全身和眼部安全性与耐受性、视力、视网膜厚度和阿弗利百普治疗需求。主要结果指标报告治疗突发不良事件（TEAEs）和严重不良事件（SAEs）的患者人数、眼科检查的变化以及根据方案定义的标准有资格接受nAMD额外治疗的患者人数。结果OASIS共招募了27名nAMD患者，他们的平均年龄为81岁，nAMD诊断的平均持续时间为54个月，之前接受过5到90次抗VEGF治疗。26名患者完成了为期3个月的治疗，14名患者进入并完成了为期3个月的延长治疗。服用 CLS-AX 后，未观察到 SAE、与药物相关的 TEAE 或导致停药的 TEAE；也未发生与眼部炎症、血管炎、眼压或药物散入玻璃体或前房相关的不良事件。6个月后，观察到平均最佳矫正视力和平均中央子场厚度（CST）保持稳定，这表明TKI具有生物效应。在OASIS完成3个月随访的患者中，有58%（15/26）的患者在3个月内未接受过aflibercept治疗。结论通过 SCS 微型注射器注射 1.0 毫克 CLS-AX（一种靶向于脉络膜上腔 (SCS) 的高效 TKI）后，患者耐受性良好，平均视力和平均 CST 保持稳定。大多数随访6个月的患者不需要阿弗利贝赛普治疗。

{"title":"Safety and Tolerability of Suprachoroidal Axitinib Injectable Suspension, for Neovascular Age-related Macular Degeneration; Phase I/IIa Open-Label, Dose-Escalation Trial","authors":"Mark R. Barakat MD , David Brown MD , Allen Hu MD , Rahul N. Khurana MD , Dennis Marcus MD , Joel Pearlman MD, PhD , Charles C. Wykoff MD, PhD , Barry Kapik MS , Thomas Ciulla MD, MBA","doi":"10.1016/j.xops.2024.100586","DOIUrl":"10.1016/j.xops.2024.100586","url":null,"abstract":"<div><h3>Purpose</h3><p>To evaluate the safety and tolerability of a single dose of axitinib injectable suspension (CLS-AX), a pan-anti-VEGF tyrosine kinase inhibitor (TKI), administered via suprachoroidal injection in patients with neovascular age-related macular degeneration (nAMD).</p></div><div><h3>Design</h3><p>Phase I/IIa, open-label, sequential dose escalation.</p></div><div><h3>Participants</h3><p>Anti-VEGF treatment-experienced patients with active subfoveal choroidal neovascularization secondary to nAMD.</p></div><div><h3>Methods</h3><p>The study included 4 cohorts (0.03, 0.10, 0.50, and 1.0 mg) of approximately 5 patients each enrolled in a dose-escalating fashion. Enrolled patients received intravitreal aflibercept (2 mg) followed by a single unilateral dose of CLS-AX 1 month later. All patients were followed monthly for 3 months with the option of an additional 3 months of extended follow-up for cohorts 2 to 4. End points included systemic and ocular safety and tolerability, visual acuity, retinal thickness, and need for aflibercept therapy.</p></div><div><h3>Main Outcome Measures</h3><p>The number of patients reporting treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), changes in ophthalmic examinations, and the number of patients qualifying for additional therapy for nAMD based on protocol-defined criteria.</p></div><div><h3>Results</h3><p>OASIS enrolled 27 patients with nAMD with mean age of 81 years, mean duration of nAMD diagnosis of 54 months, and between 5 and 90 prior anti-VEGF treatments. Twenty-six patients completed through 3 months, with 14 entering and completing the 3-month extension. No SAEs, drug-related TEAEs, or TEAEs leading to discontinuation were observed after CLS-AX administration; there were no adverse events related to ocular inflammation, vasculitis, intraocular pressure, or dispersion of drug into the vitreous or anterior chamber. Through 6 months, stable mean best-corrected visual acuity and stable mean central subfield thickness (CST) were observed, suggestive of TKI biologic effect. No aflibercept therapy was administered up to 3 months in 58% (15/26) of patients who completed 3 months of follow-up in OASIS. In the Extension, 57% (8/14) of patients went up to 6 months without receiving aflibercept therapy.</p></div><div><h3>Conclusions</h3><p>Up to 1.0 mg CLS-AX, a highly potent TKI targeted to the suprachoroidal space (SCS) via the SCS Microinjector, was well tolerated, with stable mean visual acuity and mean CST. A majority of patients followed for 6 months did not require aflibercept therapy.</p></div><div><h3>Financial Disclosure(s)</h3><p>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"5 1","pages":"Article 100586"},"PeriodicalIF":3.2,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666914524001222/pdfft?md5=7f4193eb9e1e0cf90b1d2460ea4427ec&pid=1-s2.0-S2666914524001222-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141846467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Estimating Uncertainty of Geographic Atrophy Segmentations with Bayesian Deep Learning 利用贝叶斯深度学习估计地理萎缩分割的不确定性

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science

Pub Date : 2024-07-24 DOI: 10.1016/j.xops.2024.100587

Theodore Spaide PhD , Anand E. Rajesh MD , Nayoon Gim , Marian Blazes MD , Cecilia S. Lee MD, MS , Niranchana Macivannan PhD , Gary Lee PhD, MEng , Warren Lewis MS , Ali Salehi PhD , Luis de Sisternes PhD , Gissel Herrera MD , Mengxi Shen MD, PhD , Giovanni Gregori PhD , Philip J. Rosenfeld MD, PhD , Varsha Pramil MD, MS , Nadia Waheed MD, MPH , Yue Wu PhD , Qinqin Zhang PhD , Aaron Y. Lee MD, MSCI

Purpose

To apply methods for quantifying uncertainty of deep learning segmentation of geographic atrophy (GA).

Design

Retrospective analysis of OCT images and model comparison.

Participants

One hundred twenty-six eyes from 87 participants with GA in the SWAGGER cohort of the Nonexudative Age-Related Macular Degeneration Imaged with Swept-Source OCT (SS-OCT) study.

Methods

The manual segmentations of GA lesions were conducted on structural subretinal pigment epithelium en face images from the SS-OCT images. Models were developed for 2 approximate Bayesian deep learning techniques, Monte Carlo dropout and ensemble, to assess the uncertainty of GA semantic segmentation and compared to a traditional deep learning model.

Main Outcome Measures

Model performance (Dice score) was compared. Uncertainty was calculated using the formula for Shannon Entropy.

Results

The output of both Bayesian technique models showed a greater number of pixels with high entropy than the standard model. Dice scores for the Monte Carlo dropout method (0.90, 95% confidence interval 0.87–0.93) and the ensemble method (0.88, 95% confidence interval 0.85–0.91) were significantly higher (P < 0.001) than for the traditional model (0.82, 95% confidence interval 0.78–0.86).

Conclusions

Quantifying the uncertainty in a prediction of GA may improve trustworthiness of the models and aid clinicians in decision-making. The Bayesian deep learning techniques generated pixel-wise estimates of model uncertainty for segmentation, while also improving model performance compared with traditionally trained deep learning models.

Financial Disclosures

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

目的应用各种方法量化深度学习分割地理萎缩（GA）的不确定性.设计对OCT图像进行回顾性分析并进行模型比较.参与者SWAGGER队列中87名患有GA的参与者的126只眼睛.方法在SS-OCT图像的结构性视网膜下色素上皮表面图像上对GA病变进行人工分割.为评估GA语义分割的不确定性，开发了2种近似贝叶斯深度学习技术（蒙特卡洛剔除和集合）模型，并与传统深度学习模型进行了比较。结果两种贝叶斯技术模型的输出都比标准模型显示出更多的高熵像素。蒙特卡洛剔除法（0.90，95% 置信区间 0.87-0.93）和集合法（0.88，95% 置信区间 0.85-0.91）的骰子得分显著高于传统模型（0.82，95% 置信区间 0.78-0.86）（P <0.001）。结论量化 GA 预测中的不确定性可提高模型的可信度，帮助临床医生做出决策。与传统训练的深度学习模型相比，贝叶斯深度学习技术能对模型的不确定性进行像素级估计，同时还能提高模型的性能。

{"title":"Estimating Uncertainty of Geographic Atrophy Segmentations with Bayesian Deep Learning","authors":"Theodore Spaide PhD , Anand E. Rajesh MD , Nayoon Gim , Marian Blazes MD , Cecilia S. Lee MD, MS , Niranchana Macivannan PhD , Gary Lee PhD, MEng , Warren Lewis MS , Ali Salehi PhD , Luis de Sisternes PhD , Gissel Herrera MD , Mengxi Shen MD, PhD , Giovanni Gregori PhD , Philip J. Rosenfeld MD, PhD , Varsha Pramil MD, MS , Nadia Waheed MD, MPH , Yue Wu PhD , Qinqin Zhang PhD , Aaron Y. Lee MD, MSCI","doi":"10.1016/j.xops.2024.100587","DOIUrl":"10.1016/j.xops.2024.100587","url":null,"abstract":"<div><h3>Purpose</h3><p>To apply methods for quantifying uncertainty of deep learning segmentation of geographic atrophy (GA).</p></div><div><h3>Design</h3><p>Retrospective analysis of OCT images and model comparison.</p></div><div><h3>Participants</h3><p>One hundred twenty-six eyes from 87 participants with GA in the SWAGGER cohort of the Nonexudative Age-Related Macular Degeneration Imaged with Swept-Source OCT (SS-OCT) study.</p></div><div><h3>Methods</h3><p>The manual segmentations of GA lesions were conducted on structural subretinal pigment epithelium en face images from the SS-OCT images. Models were developed for 2 approximate Bayesian deep learning techniques, Monte Carlo dropout and ensemble, to assess the uncertainty of GA semantic segmentation and compared to a traditional deep learning model.</p></div><div><h3>Main Outcome Measures</h3><p>Model performance (Dice score) was compared. Uncertainty was calculated using the formula for Shannon Entropy.</p></div><div><h3>Results</h3><p>The output of both Bayesian technique models showed a greater number of pixels with high entropy than the standard model. Dice scores for the Monte Carlo dropout method (0.90, 95% confidence interval 0.87–0.93) and the ensemble method (0.88, 95% confidence interval 0.85–0.91) were significantly higher (<em>P</em> < 0.001) than for the traditional model (0.82, 95% confidence interval 0.78–0.86).</p></div><div><h3>Conclusions</h3><p>Quantifying the uncertainty in a prediction of GA may improve trustworthiness of the models and aid clinicians in decision-making. The Bayesian deep learning techniques generated pixel-wise estimates of model uncertainty for segmentation, while also improving model performance compared with traditionally trained deep learning models.</p></div><div><h3>Financial Disclosures</h3><p>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"5 1","pages":"Article 100587"},"PeriodicalIF":3.2,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666914524001234/pdfft?md5=678a9a10974ce3ddf09356f4abea5102&pid=1-s2.0-S2666914524001234-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141846967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0