AI-driven discovery of blood xenobiotic biomarkers in neovascular age-related macular degeneration using iterative random forests.

PURPOSE: To investigate the xenobiotic profiles of patients with neovascular age-related macular degeneration (nAMD) undergoing anti-vascular endothelial growth factor (anti-VEGF) intravitreal therapy (IVT) to identify biomarkers indicative of clinical phenotypes through advanced AI methodologies. METHODS: In this cross-sectional observational study, we analyzed 156 peripheral blood xenobiotic features in a cohort of 46 nAMD patients stratified by choroidal neovascularization (CNV) control under anti-VEGF IVT. We employed Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) for measurement and leveraged an AI-driven iterative Random Forests (iRF) approach for robust pattern recognition and feature selection, aligning molecular profiles with clinical phenotypes. RESULTS: AI-augmented iRF models effectively refined the metabolite spectrum by discarding non-predictive elements. Perfluorooctanesulfonate (PFOS) and Ethyl ß-glucopyranoside were identified as significant biomarkers through this process, associated with various clinically relevant phenotypes. Unlike single metabolite classes, drug metabolites were distinctly correlated with subretinal fluid presence. CONCLUSIONS: This study underscores the enhanced capability of AI, particularly iRF, in dissecting complex metabolomic data to elucidate the xenobiotic landscape of nAMD and environmental impact on the disease. The preliminary biomarkers discovered offer promising directions for personalized treatment strategies, although further validation in broader cohorts is essential for clinical application.

Treatment of neovascular age-related macular degeneration: insights into drug-switch real-world from the Berlin Macular Registry.

PURPOSE: Bevacizumab, ranibizumab, and aflibercept are commonly used to treat neovascular age-related macular degeneration (nAMD). The results of various interventional, mostly randomized head-to-head studies, indicate statistical non-inferiority of these three drugs. The results of these studies are often interpreted as the three drugs being freely interchangeable, resulting in some health systems to pressure ophthalmologists to preferentially use the less expensive bevacizumab. This study analyzes switching from aflibercept or ranibizumab to bevacizumab and back under real-world conditions in order to investigate the assumption of interchangeability of the drugs. METHODS: Treatment data of IVT patients with diagnosed nAMD were extracted from the clinical Berlin Macular Registry database. Patients who underwent a drug switch from aflibercept or ranibizumab to bevacizumab were subject of this study. Statistical comparisons were pre-planned for best corrected visual acuity, central retinal thickness, macular volume, and length of injection interval. Additional endpoints were analyzed descriptively. RESULTS: Mean visual acuity decreased from 0.57 ± 0.05 under aflibercept/ranibizumab to 0.68 ± 0.06 logMAR after the switch (P = 0.001; N = 63). CRT increased from 308 ± 11 µm to 336 ± 16 µm (P = 0.011; N = 63). About half of the subjects were switched back: visual acuity increased from 0.69 ± 0.08 logMAR to 0.58 ± 0.09 logMAR (N = 26). CRT decreased from 396 ± 28 to 337 ± 20 µm (N = 28). CONCLUSION: The data provides real-world evidence that there is loss of visual acuity and an increase in retinal edema after switching to bevacizumab. Thus, the assumption of free interchangeability cannot be confirmed in this cohort.

Systemic Blood Proteome Patterns Reflect Disease Phenotypes in Neovascular Age-Related Macular Degeneration.

There is early evidence of extraocular systemic signals effecting function and morphology in neovascular age-related macular degeneration (nAMD). The prospective, cross-sectional BIOMAC study is an explorative investigation of peripheral blood proteome profiles and matched clinical features to uncover systemic determinacy in nAMD under anti-vascular endothelial growth factor intravitreal therapy (anti-VEGF IVT). It includes 46 nAMD patients stratified by the level of disease control under ongoing anti-VEGF treatment. Proteomic profiles in peripheral blood samples of every patient were detected with LC-MS/MS mass spectrometry. The patients underwent extensive clinical examination with a focus on macular function and morphology. In silico analysis includes unbiased dimensionality reduction and clustering, a subsequent annotation of clinical features, and non-linear models for recognition of underlying patterns. The model assessment was performed using leave-one-out cross validation. The findings provide an exploratory demonstration of the link between systemic proteomic signals and macular disease pattern using and validating non-linear classification models. Three main results were obtained: (1) Proteome-based clustering identifies two distinct patient subclusters with the smaller one (n = 10) exhibiting a strong signature for oxidative stress response. Matching the relevant meta-features on the individual patient's level identifies pulmonary dysfunction as an underlying health condition in these patients. (2) We identify biomarkers for nAMD disease features with Aldolase C as a putative factor associated with superior disease control under ongoing anti-VEGF treatment. (3) Apart from this, isolated protein markers are only weakly correlated with nAMD disease expression. In contrast, applying a non-linear classification model identifies complex molecular patterns hidden in a high number of proteomic dimensions determining macular disease expression. In conclusion, so far unconsidered systemic signals in the peripheral blood proteome contribute to the clinically observed phenotype of nAMD, which should be examined in future translational research on AMD.

LOW VULNERABILITY OF THE POSTERIOR EYE SEGMENT TO SARS-COV-2 INFECTION: Chorioretinal SARS-CoV-2 Vulnerability.

PURPOSE: Retinal manifestations have been described in COVID-19 patients, but it is unknown whether SARS-CoV-2, the causal agent in COVID-19, can directly infect posterior ocular tissues. Here, we investigate SARS-CoV-2 host factor gene expression levels and their distribution across retinal and choroidal cell types. METHODS: Query of single-cell RNA sequencing data from human retina and choroid. RESULTS: We find no relevant expression of two key genes involved in SARS-CoV-2 entry, ACE2 and TMPRSS2, in retinal cell types. By contrast, scarce expression levels could be detected in choroidal vascular cells. CONCLUSION: Given the current understanding of viral host cell entry, these findings suggest a low vulnerability of the posterior eye segment to SARS-CoV-2 with a potential weak spot in the vasculature, which could play a putative causative role in ocular lesions in COVID-19 patients. This may qualify the vasculature of the human posterior eye segment as an in vivo biomarker for life-threatening vascular occlusions in COVID-19 patients.

INTRAVITREAL NESVACUMAB (ANTIANGIOPOIETIN 2) PLUS AFLIBERCEPT IN DIABETIC MACULAR EDEMA: Phase 2 RUBY Randomized Trial.

PURPOSE: The purpose of this study was to compare intravitreal nesvacumab (anti-angiopoietin 2) plus aflibercept with intravitreal aflibercept injection (IAI) in diabetic macular edema. METHODS: The eyes (n = 302) were randomized (1:2:3) to nesvacumab 3 mg + aflibercept 2 mg (LD combo), nesvacumab 6 mg + aflibercept 2 mg (HD combo), or IAI 2 mg at baseline, Weeks 4 and 8. LD combo continued every 8 weeks (q8w). HD combo was rerandomized at Week 12 to q8w or every 12 weeks (q12w); IAI to q8w, q12w, or HD combo q8w through Week 32. RESULTS: Week 12 best-corrected visual acuity gains for LD and HD combo versus IAI were 6.8, 8.5, and 8.8 letters; Week 36 changes were similar. Central subfield retinal thickness reductions at Week 12 were -169.4, -184.0, and -174.6 µm (nominal P = 0.0183, HD combo vs. IAI); Week 36 reductions for LD combo and HD combo q8w and q12w versus IAI were -210.4, -223.4, and -193.7 versus -61.9 µm (nominal P < 0.05). At Week 12, 13.3% and 21.3% versus 15.2% had ≥2-step Diabetic Retinopathy Severity Scale improvement (LD and HD combos vs. IAI) and 59.6% and 66.3% versus 53.7% had complete foveal center fluid resolution. Safety was comparable across groups. CONCLUSION: Nesvacumab + aflibercept demonstrated no additional visual benefit over IAI. Anatomic improvements with HD combo may warrant further investigation.

Influence of Ranibizumab versus laser photocoagulation on radiation retinopathy (RadiRet) - a prospective randomized controlled trial.

PURPOSE: To demonstrate superiority of intravitreal ranibizumab 0.5 mg compared to focal and peripheral laser treatment in patients with radiation retinopathy for choroidal melanoma. METHODS: Inclusion criteria were as follows: patients with radiation retinopathy and visual acuity impairment due to radiation maculopathy accessible for laser therapy, age ≥ 18 years, and BCVA less than 20/32. The main objective was to study the change in best-corrected visual acuity (BCVA) over 6 months from ranibizumab 0.5 mg (experimental) compared to focal laser of the macula and panretinal laser treatment of the ischemic retina (control) in patients with radiation retinopathy in choroidal melanoma. The secondary objectives of the radiation retinopathy study were to compare functional and anatomical results between ranibizumab and laser group over 12 months and to measure the frequency of vitreous hemorrhage and rubeosis iridis. RESULTS: The intention-to-treat analysis included 31 patients assigned to ranibizumab (n = 15) or laser treatment (n = 16). In terms of BCVA at month 6, ranibizumab was superior to laser treatment, with an advantage of 0.14 logMAR, 95% CI 0.01 to 0.25, p = 0.030. The positive effect of ranibizumab disappeared after treatment was discontinued. Similar results without statistically significant difference were found with respect to macular thickness. In both groups, no change was observed at month 6 in the size of ischemia in the macula or periphery compared to baseline. There was 1 case of vitreous hemorrhage in the laser group and no case of rubeosis iridis over time. CONCLUSIONS: This study showed a statistically significant improvement in visual acuity and clear superiority of ranibizumab compared to laser treatment up to 26 weeks, but this effect disappeared at week 52 after completion of intravitreal treatment. Ranibizumab and PRP are considered equivalent in terms of the non-appearance of proliferative radiation retinopathy during the study. TRIAL REGISTRATION: EudraCT Number: 2011-004463-69.

Side effects of proton beam therapy of choroidal melanoma in dependence of the dose to the optic disc and the irradiated length of the optic nerve.

PURPOSE: To analyze the impact of the dose to the optic disc and the irradiated length of the optic nerve on radiation-induced optic neuropathy, radiation-induced retinopathy, iris neovascularization, secondary glaucoma, enucleation, and local tumor control after proton beam therapy (PBT) of choroidal melanoma. METHOD: Retrospective analysis of 1129 patients, who received primary PBT for the treatment of choroidal melanoma with a dose of 60 cobalt gray equivalents (CGE) between 1998 and 2013 at the Helmholtz-Zentrum Berlin, Germany. Kaplan-Meier curves and logrank test have been used for time-to-event analyses. Adjustment for potential confounders was done using multiple Cox regression models with forward and backward selection. RESULTS: We found a significant correlation between the irradiated length of the optic nerve and the dose to the optic disc (correlation coefficient, 0.93). Multivariate Cox regression revealed the dose to the optic disc as an independent predictive risk factor for the development of radiation-induced optic neuropathy (p < 0.001, HR 1.023, 95 CI 1.016-1.029), iris neovascularization (p < 0.001, HR 1.013, 95% CI 1.008-1.019), secondary glaucoma (p < 0.001, HR 1.017, 95% CI: 1.011-1.023) and enucleation (p < 0.001, HR 1.037, 95% CI 1.020-1.053). The irradiated length of the optic nerve was not a statistically independent predictive risk factor in multivariate analysis. CONCLUSION: Our data implicate the predominance of the dose to the optic disc over the irradiated length of the optic nerve regarding radiation-induced optic neuropathy, iris neovascularization, secondary glaucoma, and enucleation.

Rupture of the Globe: What to Do, What not to Do. / Bulbusberstung: Vorgehen und Ergebnisse.

Due to their complexity, globe ruptures are highly compromising traumas for the patient. This is due on the one hand to the eye injury itself with the accompanying loss of vision and on the other hand due to the need for extended treatment with uncertain prognosis and the resulting psychological stress. Globe ruptures are among the prognostically most unfavorable injuries due to the force and peak pressure impacting the eye. Furthermore, contusional retinal necrosis may be of significance prognostically. In the present review, we discuss treatment of globe ruptures involving retinal surgery. We discuss the primary sugery, its chronological planning and extent as well as the necessity for follow-up interventions. We also discuss the origin of traumatic retinal detachment with differential diagnosis of giant retinal tear versus oradialysis as well as secondary sequelae of traumas such as formation of macular holes and their treatment. On this basis, the use of buckling surgery versus pars-plana vitrectomy is discussed. Further focus is set on the role of the iris lens diaphragm in surgery of globe ruptures.

The Developing Regorafenib Eye drops for neovascular Age-related Macular degeneration (DREAM) study: an open-label phase II trial.

AIMS: This programme investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age-related macular degeneration (nAMD). METHODS: Topical regorafenib was investigated in an open-label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 µl, 30 mg ml-1 ) three times a day for 12 weeks. The primary endpoint of the phase II/a/b study was mean change in best-corrected visual acuity (BCVA) from baseline to weeks 4 and 12. RESULTS: In nAMD patients (N = 51), mean changes in BCVA were +1.2 [90% confidence interval (CI) -0.61, 2.97] and -2.4 (90% CI -4.18, -0.54) letters at weeks 4 and 12, respectively. Ocular treatment-emergent adverse events (TEAEs) (study eye) were reported in 21 patients by week 12. There was one serious ocular TEAE (visual acuity reduced) that was not drug related. Twenty patients required rescue (intravitreal ranibizumab). CONCLUSIONS: The programme was terminated after phase IIa ended because efficacy was lower than with current nAMD treatments. According to elaborate post hoc analyses, the most likely reason was insufficient exposure in the target compartment (back of the eye).

EFFICACY AND SAFETY OUTCOMES OF INTRAVITREAL AFLIBERCEPT FOCUSING ON PATIENTS WITH DIABETIC MACULAR EDEMA FROM JAPAN.

PURPOSE: To evaluate the efficacy and safety of intravitreal aflibercept injection (IAI) in Japanese patients with diabetic macular edema (DME). METHODS: VIVID-DME was a Phase 3 study comprising patients with DME randomized 1:1:1 to IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 4 weeks until Week 16 then 8-week dosing (2q8), and laser. A total of 403 patients (76 Japanese) were included in this study. VIVID-Japan (72; all Japanese patients) was a nonrandomized, open-label study comprising Japanese patients with DME receiving IAI 2q4 until Week 16, then 2q8. Primary efficacy endpoint (Week 52) of VIVID-DME was mean change from baseline in best-corrected visual acuity; VIVID-Japan evaluated safety and tolerability. RESULTS: Mean change in best-corrected visual acuity (letters) for 2q4, 2q8, and laser groups was +10.6, +10.9, and +1.2 and +9.8, +9.5, and +1.1 in the non-Japanese and Japanese populations of VIVID-DME, respectively. In VIVID-Japan, it was +9.3 for IAI 2q8. Intravitreal aflibercept injection also provided consistently greater benefits for anatomical outcomes versus laser. Adverse events were consistent with the known safety profile of IAI. CONCLUSION: In Japanese patients with DME, IAI treatment was superior to laser for visual and anatomical outcomes and resulted in efficacy and safety outcomes similar to those in a non-Japanese patient population.

[Pharmacotherapy of Non-neovascular AMD]. / Medikamentöse Therapieansätze für die nicht neovaskuläre AMD.

BACKGROUND: Non-neovascular age-related macular degeneration (AMD) is not yet treatable. This article summarises current clinical research approaches. The reasons for the current lack of success are analysed. METHODS: Literature and databank search. RESULTS: The number of therapeutic approaches and mechanisms is limited. Only reduction in lipofuscin containing deposits is specific for AMD. Further approaches include modulation of inflammation and neuroprotection. Confirmatory studies have failed to demonstrate efficacy in AMD, i.e. slowing or stopping AMD progression. DISCUSSION: To increase the probability of success for future developments, the pharmacological target space needs to be broadened. This may be achieved by application of molecular network analyses. As visual acuity is commonly not primarily affected by non-neovascular AMD, research on patient perspective is required to define reasonable target profiles for future therapies.

[Peripheral Ischemia in Diabetic Retinopathy and Retinal Vein Occlusion: New Insights with Ultra-Wide-Angle Fundus Imaging and Wide-Angle Fluorescein Angiography]. / Periphere Ischämie bei diabetischer Retinopathie und retinalen Venenthrombosen: neue Einblicke durch die Ultraweitwinkelfundusfotografie und Weitwinkelangiografie.

BACKGROUND: In several diseases such as diabetic retinopathy and retinal vein occlusion, relevant pathophysiological changes take place in the retinal periphery. These changes may determine the prognosis and outcomes of therapy. Recent ultra-wide-angle camera systems promise improved and simplified visualisation of the outer periphery of the retina. This could potentially lead to novel clinical applications of these methods, with potential impact on therapy decisions. MATERIAL AND METHODS: Literature and database research on ultra-wide imaging for diabetic retinopathy and retinal vein occlusion. RESULTS: With ultra-wide-angle angiography, it is possible to visualise up to 3.2-fold more retinal surface than conventional 7SF images (7SF: 7 standard field). Initial studies imply that diabetic changes can be found outside of the boundaries of the 7SF images. Patients with central vein occlusion have more extended and severe macular oedema and poorer visual acuity if ischemia of the periphery is more pronounced (measured by the ischemic index [ISI]). The amount of ischemia influences the size of the macular oedema, its resolution under therapy and the number of anti-VEGF injections needed to treat it. DISCUSSION: Ultra-wide-angle camera systems allow visualisation of the peripheral retina outside the boundaries of standard methods. Initial studies have detected potentially relevant changes in the outer periphery, which would have been missed by 7SF. Nevertheless, there have been no systematic studies on the relevance of these changes with regards to prognosis and therapeutic decisions.

[Optical Coherence Tomography in Disorders of the Central Nervous System]. / Optische Kohärenztomografie bei Erkrankungen des zentralen Nervensystems.

Retinal changes and visual symptoms are present in several inflammatory, degenerative and tumorous disorders of the central nervous system (CNS). Optical coherence tomography (OCT) is a method that can be used in clinical practice to detect and quantify the structural correlates of these visual symptoms in neurological disorders. OCT is a non-invasive imaging technique, based on interferometry, which can create high-resolution images of the retina and measure the thickness and volume of the different retinal layers. The combined ganglion cell- and inner plexiform layer (GCIPL) and the peripapillary retinal nerve fibre layer (pRNFL) are of particular interest in the field of neurological disorders, since they contain the neuronal bodies (ganglion cells) and their axons that form the optic nerve. In acute optic neuritis (ON), initial swelling of the pRNFL can be detected by OCT and this may contribute to the diagnosis and differential diagnosis of ON; moreover, the extent of the GCIPL-thinning within the first 4 weeks after an acute ON can contribute to the prediction of the long-term visual recovery. However, the role of OCT in the field of multiple sclerosis (MS) is not restricted in patients with ON, since even eyes without an ON-history show mild thinning of the pRNFL and GCIPL. This thinning seems to be associated with neurodegenerative processes in the entire CNS. Several studies showed correlations between these OCT-parameters and a higher risk of clinical deterioration (disability progression), cognitive deficits and disease activity in patients with MS. However, it is often still unclear how these correlations can be useful in the management of the individual patient. In recent years, OCT has been applied to a greater extent to neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS) and various forms of dementia. However, routine clinical use is still further away than for inflammatory CNS diseases, since the role of OCT in the diagnosis, differential diagnosis and prediction of the clinical course of neurodegenerative diseases is still unclear. This review article offers a summary of the available study results on OCT parameters and their role in inflammatory, degenerative and tumorous diseases of the central nervous system (CNS).

[Peripheral Exudative Haemorrhagic Chorioretinopathy: Course of Disease and Diagnosis - Including Wide-field Imaging of Associated Diseases Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy, Therapy]. / Peripher exsudative hämorrhagische Chorioretinopathie: Krankheitsverlauf, Diagnosestellung inklusive Weitwinkelbildgebung der assoziierten Erkrankungen altersabhängige Makuladegeneration und polypoidale Choriovaskulopathie, Therapie.

PEHCR (peripheral exudative haemorrhagic chorioretinopathy) is a disease manifested clinically, particularly by subretinal bleeding, retinal exudates, retinal pigment epithelium detachments (RPE detachments), exudative retinal detachment and sub-RPE bleeding. The PEHCR lesion is often characterized by its polypoidal pattern, which is very similar to PCV (polypoidal choroidal vasculopathy) polyps. Diagnosis is best made with a wide-field ICGA (indocyanine green angiography). In approximately half of patients, macular changes in the form of drusen, up to exudative AMD (age-related macular degeneration), are detected in the affected eye or partner eye. Since there is very little literature directly available on PEHCR, this work also discusses the peripheral changes described in the context of AMD that were investigated with wide-field imaging.

[Ultra-Wide Field Retinal Imaging and Angiography in the Differential Diagnosis and Therapeutic Decisions in Vascular Diseases of the Peripheral Retina]. / Ultraweitwinkel-Fundusfotografie und -angiografie in der Differenzialdiagnose und zur Therapieplanung bei peripheren vaskulären Netzhauterkrankungen.

Investigation of vascular diseases of the peripheral retina requires imaging procedures that allow a comprehensive view of the periphery, as well as reproducible pictures. In particular, ultra-wide field fluorescence angiography facilitates diagnosis, therapeutic decisions and follow-up examinations. While vasculopathies such as Coats disease and familiar exudative vitreoretinopathy are diagnosed within the first and second decade of life, patients' compliance during fundus imaging is typically reduced within this age range. Compared to the repeated imaging procedures for composite formation, ultra-wide field imaging has significantly reduced recording time. Nevertheless, current imaging systems are not able to map the entire retina in scaled proportions. Therefore, the imaging frame must be guided by patients' gaze onto the affected retinal area. Moreover, the medical photographer must be aware of the clinical setting and the region of interest. Hence, previous detailed funduscopy by trained ophthalmologists will remain indispensable.

[Multimodal Imaging of the Choroidal Melanoma, with Differential Diagnosis, Therapy (Radiation Planning) and Follow-up]. / Multimodale Bildgebung des Aderhautmelanoms mit seinen Differenzialdiagnosen, Therapie (Bestrahlungsplanung) und Verlaufskontrolle.

Imaging of intraocular tumors is multimodal, multi-purpose, and in continuous development. Therefore, imaging is indispensable for the detection, diagnosis, therapy and monitoring of intraocular tumours. A broad spectrum of imaging procedures is available for diagnostic testing and follow-up. This includes colour image acquisition, infrared imaging, autofluorescence imaging, fluorescence and indocyanine green angiography, optical coherence tomography (OCT) and sonography (US). In this article, the various investigations and their benefits are described using individual examples for the differential diagnosis of choroidal melanoma and retinal vascular tumours located in the fundus periphery.

[Eye Drops Instead of Intravitreal Injections? The Dream of Treating Macular Diseases by Topically Administered Drugs]. / Tropfen statt spritzen? Der Traum von einer Therapie von Makulaerkrankungen mit Augentropfen.

Background The introduction of VEGF inhibitors revolutionized treatment for age-related macular degeneration. However, it requires regular intravitreal (IVT) injections. Hence, replacement of IVT injections by topical, non-invasive eye drop treatment is subject to intensive research. Material and Methods Literature and database research on topical therapies for neovascular AMD. Results Several clinical projects with topical inhibitors of the VEGF pathway were initiated recently. Several candidate molecules were investigated and should have an efficacy potential in neovascular AMD given their ability to block the VEGF pathway. Preclinical experiments were quite promising. Still, translation into the clinical application has not been successful thus far. Differences in preclinical and clinical pharmacokinetics are assumed to be the major barrier to successful translation. In addition, specific algorithms for monitoring of disease activity are required for successful clinical implementation; otherwise, a topical therapy may reduce the IVT injection number, but patients would not gain independence through fewer office visits. Discussion It is required to refine the scientific basis including preclinical models and screening cascades. This will enable targeted selection of future candidates for clinical development.

Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies.

PURPOSE: To compare efficacy and safety of intravitreal aflibercept injection (IAI) with macular laser photocoagulation for diabetic macular edema (DME) over 3 years. DESIGN: Two similarly designed phase 3 trials: VISTADME and VIVIDDME. PARTICIPANTS: Patients (eyes; n = 872) with central-involved DME. METHODS: Eyes received IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 8 weeks after 5 monthly doses (2q8), or laser control. From week 24, if rescue treatment criteria were met, IAI patients received active laser, and laser control patients received IAI 2q8. From week 100, laser control patients who had not received IAI rescue treatment received IAI as needed per retreatment criteria. MAIN OUTCOME MEASURES: The primary end point was the change from baseline in best-corrected visual acuity (BCVA) at week 52. We report the 148-week results. RESULTS: Mean BCVA gain from baseline to week 148 with IAI 2q4, IAI 2q8, and laser control was 10.4, 10.5, and 1.4 letters (P < 0.0001) in VISTA and 10.3, 11.7, and 1.6 letters (P < 0.0001) in VIVID, respectively. The proportion of eyes that gained ≥15 letters from baseline at week 148 was 42.9%, 35.8%, and 13.6% (P < 0.0001) in VISTA and 41.2%, 42.2%, and 18.9% (P < 0.0001) in VIVID, respectively. Greater proportions of eyes treated with IAI 2q4 and IAI 2q8 versus those treated with laser control had an improvement of ≥2 steps in the Diabetic Retinopathy Severity Scale (DRSS) score in both VISTA (29.9% and 34.4% vs. 20.1% [P = 0.0350, IAI 2q4; P = 0.0052, IAI 2q8]) and VIVID (44.3% and 47.8% vs. 17.4% [P < 0.0001 for both]). In an integrated safety analysis, the most frequent ocular serious adverse event was cataract (3.1%, 2.1%, 0.3% for 2q4, 2q8, and control). CONCLUSIONS: Visual improvements observed with both IAI regimens (over laser control) at weeks 52 and 100 were maintained at week 148, with similar overall efficacy in the IAI 2q4 and IAI 2q8 groups. Treatment with IAI also had positive effects on the DRSS score. Over 148 weeks, the incidence of adverse events was consistent with the known safety profile of IAI.