Screen failures in clinical trials in retina.

PURPOSE: Disparities in clinical trials are a major problem due to significant underrepresentation of certain gender, racial and ethnic groups. Several factors including stringent eligibility criteria and recruitment strategies hinder our understanding of retinal disease. Thus, we aimed to study the various reasons of screen failures and specific patient and study characteristics among screen failures. DESIGN: This is a cross-sectional retrospective study METHODS: Screening data of 87 trials from 6 centers were analyzed. Study characteristics (disease studied, phase of trial, route of drug administration) and patient demographics (age, gender, race, ethnicity, and employment status) were compared among different causes of screen failures. Screen failures were broadly classified into six categories: exclusion due to vision-based criteria, exclusion due to imaging findings, exclusion due to other factors, patient-related criteria, physician related criteria and miscellaneous. Descriptive statistics, Pearson Chi-square test and ANOVA were used for statistical analysis. MAIN OUTCOME MEASURES: Determine the prevalence of various reasons for screen failures in multiple trials and its trend among different study and patient characteristics. RESULTS: Among 87 trials and 962 patients, 465(48.2%) patients were successfully randomized and 497(51.8%) patients were classified as screen failures. The trials were conducted for various retinal diseases. Mean age was 76.50 ±10.45 years and 59.4% were females. Predominantly whites(93.4%) and unemployed/retired patients(66.6%) were screened. Of the 497 screen failures, most were due to patients not meeting inclusion criteria of imaging findings (n=221[44.5%]) followed by inclusion of vision-based criteria (n=73 [14.7%]), exclusion due to other factors (n=75[15.1%]), patient-related (n=34[6.8%]), physician-related (n=28[5.6%]) and miscellaneous reasons (n= 39[17.8%]). Reason for screen failure was not available for 27(5.4%) patients. A higher proportion of patients screened for surgical trials (15%) declined to participate in the study compared to non-invasive trials involving topical drugs and photobiomodulation (0%).(p=0.02) CONCLUSION: Patients not meeting the imaging and vision-cased criteria were the most common reasons for screen failures. Whites and unemployed patients predominantly participated in clinical trials. Patients are more inclined to continue participation in non-invasive clinical trials compared to surgical trials. Better recruitment strategies and careful consideration of study criteria can aid in decreasing the rate of screen failures.

ChatGPT enters the room: what it means for patient counseling, physician education, academics, and disease management.

PURPOSE OF REVIEW: This review seeks to provide a summary of the most recent research findings regarding the utilization of ChatGPT, an artificial intelligence (AI)-powered chatbot, in the field of ophthalmology in addition to exploring the limitations and ethical considerations associated with its application. RECENT FINDINGS: ChatGPT has gained widespread recognition and demonstrated potential in enhancing patient and physician education, boosting research productivity, and streamlining administrative tasks. In various studies examining its utility in ophthalmology, ChatGPT has exhibited fair to good accuracy, with its most recent iteration showcasing superior performance in providing ophthalmic recommendations across various ophthalmic disorders such as corneal diseases, orbital disorders, vitreoretinal diseases, uveitis, neuro-ophthalmology, and glaucoma. This proves beneficial for patients in accessing information and aids physicians in triaging as well as formulating differential diagnoses. Despite such benefits, ChatGPT has limitations that require acknowledgment including the potential risk of offering inaccurate or harmful information, dependence on outdated data, the necessity for a high level of education for data comprehension, and concerns regarding patient privacy and ethical considerations within the research domain. SUMMARY: ChatGPT is a promising new tool that could contribute to ophthalmic healthcare education and research, potentially reducing work burdens. However, its current limitations necessitate a complementary role with human expert oversight.

Conversion to faricimab after prior anti-vascular endothelial growth factor therapy for persistent diabetic macular oedema.

BACKGROUND: To assess the anatomical and functional outcomes in eyes with persistent diabetic macular oedema (pDME) on chronic anti-vascular endothelial growth factor therapy switched to intravitreal faricimab. METHODS: Patients with pDME on chronic anti-vascular endothelial growth factor therapy that were switched to faricimab and received at least three injections at our institution between April 2022 and May 2023 were included in this study. Patients were excluded if they had complete response to previous treatment but were switched to extend treatment intervals if they had steroid or laser treatment for DME within 6 months prior to switch. Clinical and imaging data were extracted from the electronic medical record. Central foveal thickness (CFT) and Snellen visual acuity (VA) were obtained before and after three intravitreal faricimab injections. Generalised estimating equations were used to analyse the change in CFT and VA. RESULT: During the study period, 69 eyes of 53 patients met inclusion criteria. The mean age was 68.6±9.0 years. The mean number of injections prior to switch was 18.1±16.0. Pre-switch mean logarithm of the minimal angle of resolution VA was 0.40±0.30 (Snellen equivalent 20/50) and 0.38±0.27 (Snellen equivalent 20/48) after three faricimab injections (p=0.397). Mean CFT improved from 380±155 microns to 323±147 microns (p<0.001). No ophthalmic or systemic adverse events occurred during the study period. CONCLUSIONS: Intravitreal faricimab can improve anatomic outcomes while maintaining visual acuity in eyes with pDME previously treated with anti-VEGF therapy.

Clinical Outcomes of Faricimab in Patients with Previously Treated Neovascular Age-Related Macular Degeneration.

PURPOSE: To assess the anatomic and functional outcomes in eyes with neovascular age-related macular degeneration (nAMD) previously treated with anti-VEGF therapy in response to intravitreal faricimab. DESIGN: Retrospective, interventional, consecutive case series. SUBJECTS: Patients with previously treated nAMD who received ≥ 4 consecutive injections of faricimab were included. The study period was from March through November 2022. METHODS: Clinical and imaging data were extracted from the electronic medical record. Central foveal thickness (CFT), maximum fibrovascular pigment epithelial detachment (fvPED) height, and Snellen visual acuity (VA) were obtained. Generalized estimating equations were used to analyze the change in CFT, maximum fvPED height, and logarithm of the minimum angle of resolution VA. MAIN OUTCOME MEASURES: Change in CFT, maximum fvPED height, and Snellen VA before faricimab and after ≥ 4 faricimab intravitreal injections. RESULTS: During the study period, 218 eyes of 191 patients met inclusion criteria. Mean age was 79.9 (range, 70.6-89.2) years. The mean number of intravitreal anti-VEGF injections received before faricimab was 34.2 (range, 6.4-62). The following results were found after ≥ 4 faricimab injections. Mean logarithm of the minimum angle of resolution VA before switching to faricimab was 0.58 (Snellen VA ∼20/76; range, 20/22-20/264) and was 0.55 (Snellen VA ∼20/71; range, 20/21-20/235; P = 0.20) after switching. Mean maximum fvPED height was 195.0 (range, 50.2-339.8) µm before switching to faricimab and improved to 165.0 (range, 33.6-296.4; P < 0.001) µm after switching. Mean CFT was 354.8 (range, 184.7-524.9) µm before switching to faricimab and improved to 306.6 (range, 144.4-468.8; P < 0.001) after switching. The proportion of eyes with intraretinal fluid was 36.7% (80/218 eyes) before switching, and decreased to 24.8% (54/218 eyes, P < 0.001) after switching. The proportion of eyes with subretinal fluid was 53.2% (116/218 eyes) before switching and decreased to 26.6% (58/218 eyes, P < 0.001) after switching. CONCLUSIONS: Intravitreal faricimab may improve anatomic outcomes in patients with previously treated nAMD, while maintaining VA in the short-term. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Incidence and Outcomes of Recurrent Retinal Detachment after Cataract Surgery in Eyes with Prior Retinal Detachment Repair.

OBJECTIVE: To investigate the incidence and outcomes of recurrent retinal detachment (RD) after cataract extraction (CE). DESIGN: Retrospective case series. SUBJECTS: Phakic eyes with RD that were successfully repaired with pneumatic retinopexy (PR), scleral buckle (SB), pars plana vitrectomy (PPV), or combined PPV/SB and subsequently underwent cataract surgery. METHODS: A retrospective review of phakic eyes that underwent successful RD repair followed by subsequent cataract surgery between April 2012 and January 2023 was performed. Patients with multiple RD surgeries before CE and those with silicone oil tamponade before cataract surgery were excluded. Eyes that redetached were matched 1:2 with eyes that did not redetach after cataract surgery. MAIN OUTCOME MEASURES: Incidence of redetachment after cataract surgery as well as visual and anatomic outcomes at 6 months after first redetachment and at the final visit. RESULTS: Of 4833 phakic eyes at the time of initial RD, 1893 patients (39.2%) underwent cataract surgery. After applying exclusion criteria, 763 patients were included. The mean (standard deviation) duration of follow-up was 48.4 (29.1) months. The overall incidence of retinal redetachment after cataract surgery was 2.5% (19/763 eyes). The rate of redetachment based on the type of initial RD repair was 9.1% (1/11), 5.3% (2/38), 2.8% (9/317), and 1.8% (7/397) for PR, SB, PPV, and combined PPV/SB, respectively (P = 0.24). The median (interquartile range [IQR]; range) duration between the cataract surgery and first redetachment was 301 (104-1222; 8-2760) days. Single surgery anatomic success for the RD repair after cataract surgery was achieved in 17 eyes (89.5%) at 3 months and 14 eyes (73.7%) at 6 months and at the final visit. Final anatomic success rate for reattachment was 100% (19/19). The median (IQR) logarithm of the minimal angle of resolution visual acuity (VA) at the final visit was 1.00 (0.18-2.00, Snellen equivalent, 20/200) with significant worsening compared with vision after cataract surgery (0.18 [0.10-0.48], 20/30) (P = 0.001). CONCLUSION: Recurrent RD was not uncommon in patients with a prior history of RD repair after CE. Reoperation resulted in relatively favorable anatomic success but there were declines in VA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references in the Footnotes and Disclosures at the end of this article.

Intrastromal versus subconjunctival injection of mesenchymal stem/stromal cells for promoting corneal repair.

PURPOSE: Different approaches to delivery of mesenchymal stem/stromal cells (MSCs) for ameliorating corneal injuries have been investigated. This study was aimed to compare the efficacy of intrastromal and subconjunctival injection of human bone marrow-derived MSCs (hBM-MSCs) in a corneal epithelial injury model. METHODS: Twenty-four C57BL/6J mice underwent total corneal and limbal epithelial debridement. Then, the mice were divided into three different groups: (1) intrastromal hBM-MSCs injection, (2) subconjunctival hBM-MSCs injection, and (3) injection of frozen medium as a control. Mice were monitored by slit lamp and underwent anterior segment optical coherence tomography (ASOCT). Following euthanasia, the corneas were further evaluated by histology and immunostaining. RESULTS: hBM-MSC injection successfully healed epithelial defects regardless of the delivery route (P < 0.001). However, intrastromal injection was superior to subconjunctival injection in reducing defect area (P = 0.001). Intrastromal injection of hBM-MSCs also significantly reduced corneal opacity and neovascularization and improved ASOCT parameters compared to subconjunctival injection or no treatment (P < 0.001, P = 0.003, and P < 0.001, respectively). Although both of the treatment groups were positive for CK12 and had reduced levels of MUC5AC compared to the control, CK12 staining was stronger in the intrastromal group compared to the subconjunctival group. Also, persistency of MSCs was confirmed by in vivo (up to 2 weeks) and in vitro assessments (up to 4 weeks). CONCLUSIONS: Although the injection of hBM-MSC using both intrastromal and subconjunctival methods improve wound healing and reduce neovascularization and opacity, the intrastromal approach is superior in terms of corneal healing.

Cellular senescence implication in mustard keratopathy.

Mustard agents are vesicants that were used in warfare multiple times. They are potent alkylating agents that activate cellular pathways of apoptosis, increase oxidative stress, and induce inflammation. Eyes are particularly susceptible to mustard exposure with a wide range of ocular surface damage. Three main categories of mustard-related eye injuries are acute, chronic, and delayed-onset manifestations. Mustard keratopathy (MK) is a known complication characterized by corneal opacification, ulceration, thinning, and neovascularization that can lead to severe vision loss and discomfort. Recently, a few reports demonstrated the role of senescence induction as a new pathological mechanism in mustard-related injuries that could affect wound healing. We ran the first murine model of delayed-onset MK and nitrogen mustard-induced senescence, evaluating the pathological signs of senescence in the cornea using beta-galactosidase staining. Our results suggest that nitrogen mustard exposure causes senescence in the corneal cells, which could be the underlying mechanism for chronic and late-onset ocular surface damage. We also found a significant correlation between the percentage of positive beta-galactosidase staining and the degree of fibrosis in the cornea. This provides valuable insight into the possible role of anti-senescence drugs in the near future for accelerating corneal healing and restricting fibrosis in patients with mustard keratopathy.

Appropriateness and Readability of ChatGPT-4-Generated Responses for Surgical Treatment of Retinal Diseases.

OBJECTIVE: To evaluate the appropriateness and readability of the medical knowledge provided by ChatGPT-4, an artificial intelligence-powered conversational search engine, regarding common vitreoretinal surgeries for retinal detachments (RDs), macular holes (MHs), and epiretinal membranes (ERMs). DESIGN: Retrospective cross-sectional study. SUBJECTS: This study did not involve any human participants. METHODS: We created lists of common questions about the definition, prevalence, visual impact, diagnostic methods, surgical and nonsurgical treatment options, postoperative information, surgery-related complications, and visual prognosis of RD, MH, and ERM, and asked each question 3 times on the online ChatGPT-4 platform. The data for this cross-sectional study were recorded on April 25, 2023. Two independent retina specialists graded the appropriateness of the responses. Readability was assessed using Readable, an online readability tool. MAIN OUTCOME MEASURES: The "appropriateness" and "readability" of the answers generated by ChatGPT-4 bot. RESULTS: Responses were consistently appropriate in 84.6% (33/39), 92% (23/25), and 91.7% (22/24) of the questions related to RD, MH, and ERM, respectively. Answers were inappropriate at least once in 5.1% (2/39), 8% (2/25), and 8.3% (2/24) of the respective questions. The average Flesch Kincaid Grade Level and Flesch Reading Ease Score were 14.1 ± 2.6 and 32.3 ± 10.8 for RD, 14 ± 1.3 and 34.4 ± 7.7 for MH, and 14.8 ± 1.3 and 28.1 ± 7.5 for ERM. These scores indicate that the answers are difficult or very difficult to read for the average lay person and college graduation would be required to understand the material. CONCLUSIONS: Most of the answers provided by ChatGPT-4 were consistently appropriate. However, ChatGPT and other natural language models in their current form are not a source of factual information. Improving the credibility and readability of responses, especially in specialized fields, such as medicine, is a critical focus of research. Patients, physicians, and laypersons should be advised of the limitations of these tools for eye- and health-related counseling. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

VITRECTOMY FOR VITREOUS HEMORRHAGE ASSOCIATED WITH RETINAL VEIN OCCLUSION: Visual Outcomes, Prognostic Factors, and Sequelae.

PURPOSE: To report the outcomes of pars plana vitrectomy for vitreous hemorrhage (VH) associated with retinal vein occlusion and to identify prognostic indicators. METHODS: Interventional, retrospective consecutive case series between 2015 and 2021. RESULTS: The study included 138 eyes of 138 patients (64 female and 74 male); 81 patients had branch retinal vein occlusion and 57 had central retinal vein occlusion. The mean age was 69.8 years. The mean duration between the diagnosis of VH and surgery was 79.6 ± 115.3 (range, 1-572) days. The mean follow-up was 27.2 months. The logarithm of the minimum angle of resolution visual acuity significantly improved from 1.95 ± 0.72 (Snellen equivalent, 20/1782) to 0.99 ± 0.87 (20/195) at 6 months and to 1.06 ± 0.96 (20/230) at the final visit (both P < 0.001). The visual acuity at 6 months improved by three or more lines in 103 eyes (75%). Postoperative complications during follow-up included recurrent VH in 16 eyes (12%) (of which 8 eyes underwent reoperations), rhegmatogenous retinal detachment in six eyes (4%), and new neovascular glaucoma in three eyes (2%). Worse final visual acuity was significantly associated with older age ( P = 0.007), concurrent neovascular glaucoma ( P < 0.001), central retinal vein occlusion ( P < 0.001), worse preoperative visual acuity ( P < 0.001), postoperative new neovascular glaucoma ( P = 0.021), and postoperative retinal detachment ( P < 0.001). The duration of VH was not associated with visual outcomes ( P = 0.684). Preoperative antivascular endothelial growth factor injections and tamponade did not prevent postoperative recurrent VH. CONCLUSION: Pars plana vitrectomy is effective for VH associated with retinal vein occlusion, regardless of the duration of hemorrhage. However, pre-existing risk factors and postoperative sequelae may limit visual recovery.

Extracellular-Vesicle-Based Therapeutics in Neuro-Ophthalmic Disorders.

Extracellular vesicles (EVs) have been recognized as promising candidates for developing novel therapeutics for a wide range of pathologies, including ocular disorders, due to their ability to deliver a diverse array of bioactive molecules, including proteins, lipids, and nucleic acids, to recipient cells. Recent studies have shown that EVs derived from various cell types, including mesenchymal stromal cells (MSCs), retinal pigment epithelium cells, and endothelial cells, have therapeutic potential in ocular disorders, such as corneal injury and diabetic retinopathy. EVs exert their effects through various mechanisms, including promoting cell survival, reducing inflammation, and inducing tissue regeneration. Furthermore, EVs have shown promise in promoting nerve regeneration in ocular diseases. In particular, EVs derived from MSCs have been demonstrated to promote axonal regeneration and functional recovery in various animal models of optic nerve injury and glaucoma. EVs contain various neurotrophic factors and cytokines that can enhance neuronal survival and regeneration, promote angiogenesis, and modulate inflammation in the retina and optic nerve. Additionally, in experimental models, the application of EVs as a delivery platform for therapeutic molecules has revealed great promise in the treatment of ocular disorders. However, the clinical translation of EV-based therapies faces several challenges, and further preclinical and clinical studies are needed to fully explore the therapeutic potential of EVs in ocular disorders and to address the challenges for their successful clinical translation. In this review, we will provide an overview of different types of EVs and their cargo, as well as the techniques used for their isolation and characterization. We will then review the preclinical and clinical studies that have explored the role of EVs in the treatment of ocular disorders, highlighting their therapeutic potential and the challenges that need to be addressed for their clinical translation. Finally, we will discuss the future directions of EV-based therapeutics in ocular disorders. Overall, this review aims to provide a comprehensive overview of the current state of the art of EV-based therapeutics in ophthalmic disorders, with a focus on their potential for nerve regeneration in ocular diseases.

Mustard Gas-Induced Ocular Surface Disorders: An Update on the Pathogenesis, Clinical Manifestations, and Management.

PURPOSE: Mustard gas (MG) is a potent blistering and alkylating agent that has been used for military and terrorism purposes. Ocular surface injuries are common after exposure to MG. This review provides an update on the pathophysiology, ocular surface complications, and treatment options for MG-related ocular injuries. METHODS: Required information was obtained by reviewing various databases such as Cochrane Library, Google Scholar, and PubMed until March 2022. Data were collected by using keywords: "mustard gas" OR "sulfur mustard" AND "eye" OR "cornea" OR "ocular complication" OR "keratitis" OR "keratopathy" OR "limbal stem cell deficiency" OR "dry eye." RESULTS: Chronic intracellular toxicity, inflammation, and ischemia have been shown to play an essential role in the pathogenesis of MG injury. Ocular surface injuries can have acute, chronic, and most distinctly a delayed-onset presentation leading to various degrees of limbal stem cell deficiency. To date, no treatment has been agreed on as the standard treatment for chronic/delayed-onset MG keratopathy. Based on the authors' experience, we propose a management algorithm for MG-related ocular surface injuries involving optimization of ocular health, anti-inflammatory therapy, and if needed surgical interventions. The management of chronic and delayed-onset presentation remains challenging. CONCLUSIONS: MG keratopathy is a unique form of chemical injury which can lead to a range of ocular surface pathologies. Long-term anti-inflammatory therapy even in patients with seemingly mild disease may potentially reduce the likelihood of the development of more severe delayed-onset disease.

Applications of mesenchymal stem cells in ocular surface diseases: sources and routes of delivery.

INTRODUCTION: Mesenchymal stem cells (MSCs) are novel, promising agents for treating ocular surface disorders. MSCs can be isolated from several tissues and delivered by local or systemic routes. They produce several trophic factors and cytokines, which affect immunomodulatory, transdifferentiating, angiogenic, and pro-survival pathways in their local microenvironment via paracrine secretion. Moreover, they exert their therapeutic effect through a contact-dependent manner. AREAS COVERED: In this review, we discuss the characteristics, sources, delivery methods, and applications of MSCs in ocular surface disorders. We also explore the potential application of MSCs to inhibit senescence at the ocular surface. EXPERT OPINION: Therapeutic application of MSCs in ocular surface disorders are currently under investigation. One major research area is corneal epitheliopathies, including chemical or thermal burns, limbal stem cell deficiency, neurotrophic keratopathy, and infectious keratitis. MSCs can promote corneal epithelial repair and prevent visually devastating sequelae of non-healing wounds. However, the optimal dosages and delivery routes have yet to be determined and further clinical trials are needed to address these fundamental questions.

Metallic intralenticular foreign body removal without crystalline lens extraction: a case report.

We describe a technique for metallic intralenticular foreign body (ILFB) removal in a patient in whom there was no or minimal cataract formation or other complications. This technique required creating two corneal small incisions around the ILFB for inserting iris retractors to expose the ILFB. At the foreign body position, a clear corneal incision was made, and then the ILFB was removed with minimal manipulation by an intraocular magnet without complications. Because most occupational traumas occur in young people, this technique avoids the adverse outcomes of lens extraction in this age group.

Etiology, pathogenesis, and management of acute intraocular lens opacification: a systematic review.

Millions of cataract surgeries with intraocular lens (IOL) implantation are performed worldwide. Although cataract surgery brings many benefits to the patients, the risk of various complications is still a concern. One of the infrequent adverse events but potentially affecting on patients' visual acuity and contrast sensitivity is losing the transparency of IOL. IOL opacification may lead to IOL removal or exchange, which is unpleasant to both the patient and the surgeon. Several reports of acute IOL clouding are available in the literature describing various etiologies of this phenomenon, however, the exact mechanism remained unclear in some cases. Herein, we aimed to review the causes and outcomes of intraoperative and early postoperative IOL opacification.

Infectious keratitis: trends in microbiological and antibiotic sensitivity patterns.

OBJECTIVES: To report the spectrum and trends of isolated microorganisms and their antibiotic susceptibility profile in patients with infectious keratitis in a 6-year period at a referral centre in Tehran. METHODS: The microbiology records of all corneal scrapings with a diagnosis of infectious keratitis were reviewed. RESULTS: A total of 6282 corneal scrapings were performed during the study period, of which 2479 (39.5%) samples were culture positive. Pseudomonas aeruginosa was found to be the most common causative agent in patients with keratitis, although Streptococcus pneumonia was the most prevalently isolated microorganism in patients older than 50 years. Fusarium sp. was the most common responsible pathogen in patients with fungal keratitis. The prevalence of bacterial keratitis due to gram positive microorganisms increased over time, however the number of Pseudomonas keratitis decreased in the second half of the study. Gram negative organisms showed a good sensitivity to levofloxacin, however, 34.1% of S. aureus isolates and 29.7% of coagulase negative staphylococci were resistant to this antibiotic. The odds of ciprofloxacin and levofloxacin resistance increased 1.25 and 1.15 for each 1-year increase in culture date, respectively (P < 0.001, P = 0.004). CONCLUSIONS: We documented an increasing trend in the percentage of gram positive bacteria. Levofloxacin monotherapy might still be a good option in patients with gram negative bacterial keratitis, however owing to increasing resistance of staphylococci to fluoroquinolones, a regimen consisting of a combination of fortified antibiotics may be more effective in staphylococcal keratitis.

Management of refractory Acanthamoeba keratitis, two cases.

Acanthamoeba keratitis is a serious infection of the eye that can result in permanent visual impairment or blindness, caused by free-living amoebae of the genus Acanthamoeba. Early diagnosis is necessary for effective treatment of Acanthamoeba keratitis. Acanthamoeba is abundant in nature and can be found in water, soil, and air. Acanthamoeba keratitis is usually diagnosed by culture from a scraping of the eye or by confocal microscopy. In this paper, two complicated Acanthamoeba keratitis cases are reported.