Sovereignty and Dharma: The Role of Justice in Classical Indian Political Thought

This thesis draws attention to the tension between the binding claims of dharma and the obligations of the king (qua state) to protect the material interests of his subjects. I argue that a significant part of the Mahābhārata can be understood as a response to this dilemma, and that a developed political philosophy and theory of justice is found therein. The picture of justice delineated within the Mahābharata emphasizes the ceteris paribus priority of dharma when the king or other functionaries of the state consider how they should act. When dharmas conflict or the demands of certain dharmas conflict with the king’s fundamental obligation to defend his subjects against violence and deprivation however, he reserves the right to decide how to act in such an instance. To prevent abuse in such situations, the king must be virtuous. In the context of the Mahābhārata, this means acting for the sake of the kingdom and his subjects, rather than for his own interest. The king demonstrates his virtue by his prior willingness to submit to the demands of dharma even when they are contrary to his material interests, while a king who shows himself to value his own flourishing over that of his subjects may find himself justly deposed by a more righteous king

Sovereignty and dharma : the role of justice in classical Indian political thought

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A Randomized Controlled Trial of OPT-302, a VEGF-C/D Inhibitor for Neovascular Age-Related Macular Degeneration

Funding Information: The trial was wholly funded by Opthea Ltd (Victoria, Australia). Opthea designed and interpreted the trial data, with input from consultant clinical advisors (T.L.J., J.S., P.U.D., C.C.W., D.S.B.). Opthea partnered with 2 contract research organizations during the conduct of the study, with Pharmaceutical Product Development LLC (Wilmington, DE) to execute the study, and with International Drug Development Institute (Louvain-la-Neuve, Belgium) to undertake the data management and biostatistical analysis. Opthea (and the coauthors) provided critical review of the first draft manuscript (prepared by T.L.J.). Publisher Copyright: © 2023 American Academy of OphthalmologyPurpose: Neovascular (wet) age-related macular degeneration (nAMD) is driven by VEGFs A, C, and D, which promote angiogenesis and vascular permeability. Intravitreal injections of anti–VEGF-A drugs are the standard of care, but these do not inhibit VEGF-C and D, which may explain why many patients fail to respond fully. This trial aimed to test the safety and efficacy of OPT-302, a biologic inhibitor of VEGF-C and D, in combination with the anti–VEGF-A inhibitor ranibizumab. Design: Dose-ranging, phase 2b, randomized, double-masked, sham-controlled trial. Participants: Participants with treatment-naive nAMD were enrolled from 109 sites across Europe, Israel, and the United States. Methods: Participants were randomized to 6, 4-weekly, intravitreal injections of 0.5 mg OPT-302, 2.0 mg OPT-302, or sham, plus intravitreal 0.5 mg ranibizumab. Main Outcome Measures: The primary outcome was mean change in ETDRS best-corrected visual acuity (BCVA) at 24 weeks. Secondary outcomes (comparing baseline with week 24) were the proportion of participants gaining or losing ≥ 15 ETDRS BCVA letters; area under the ETDRS BCVA over time curve; change in spectral-domain OCT (SD-OCT) central subfield thickness; and change in intraretinal fluid and subretinal fluid on SD-OCT. Results: Of 366 participants recruited from December 1, 2017, to November 30, 2018, 122, 123, and 121 were randomized to 0.5 mg OPT-302, 2.0 mg OPT-302, and sham, respectively. Mean (± standard deviation) visual acuity gain in the 2.0 mg OPT-302 group was significantly superior to sham (+14.2 ± 11.61 vs. +10.8 ± 11.52 letters; P = 0.01). The 0.5 mg OPT-302 group was not significantly different than the sham group (+9.44 ± 11.32 letters; P = 0.83). Compared with sham, the secondary BCVA outcomes favored the 2.0 mg OPT-302 group, with structural outcomes favoring both OPT-302 dosage groups. Adverse events (AEs) were similar across groups, with 16 (13.3%), 7 (5.6%), and 10 (8.3%) participants in the lower-dose, higher-dose, and sham groups, respectively, developing at least 1 serious AE. Two unrelated deaths both occurred in the sham arm. Conclusions: Significantly superior vision gain was observed with OPT-302 2.0 mg combination therapy, versus standard of care, with favorable safety (ClinicalTrials.gov identifier: NCT03345082). Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.Peer reviewe

Microvascular abnormalities secondary to radiation therapy in neovascular age-related macular degeneration:Findings from the INTREPID clinical trial

PURPOSE: To report the incidence and features of retinal microvascular abnormalities (MVAs) occurring secondary to stereotactic radiotherapy (SRT) in a randomised double-masked sham-controlled clinical trial at 21 European sites.METHODS: Two hundred and thirty participants with neovascular age-related macular degeneration (AMD) treated with at least three intravitreal antivascular endothelial growth factor (anti-VEGF) injections prior to enrolment, and demonstrating a continuing need for re-treatment.INTERVENTIONS: 16 Gy, 24 Gy or sham SRT. All three groups received pro re nata anti-VEGF injections if the lesion was judged to be active at review visits. Colour fundus images from baseline and 6 months and fluorescein angiograms from baseline and annual visits were graded for measures of morphological outcome and safety using a prespecified protocol with accompanying definitions to distinguish RT-related MVA from non-specific retinal vessel abnormalities that are known to occur in neovascular AMD. The main outcome measure was MVA detected by months 12, 24 and 36 after enrolment.RESULTS: The frequency of MVAs in the combined SRT arms was 0% in year 1, 13.1% in year 2 and 30.3% in year 3. The area of MVA was small and the mean change in visual acuity in year 2 was similar in a subset of SRT eyes with MVAs, versus those without MVAs. MVA was considered to have possibly contributed to vision loss in 2 of 18 cases with MVA in year 2, and 5 of 37 cases in year 3.CONCLUSION: Treatment with SRT is associated with development of subtle MVAs that have little or no impact on visual outcome. These findings can help clinicians recognise the retinal MVAs that occur in response to SRT.</p

Characterizing New-Onset Exudation in the Randomized Phase 2 FILLY Trial of Complement Inhibitor Pegcetacoplan for Geographic Atrophy.

To evaluate clinical characteristics of eyes in which investigator-determined new-onset exudative age-related macular degeneration (eAMD) developed during the FILLY trial.Post hoc analysis of the phase 2 study of intravitreal pegcetacoplan in geographic atrophy (GA).Patients with GA secondary to age-related macular degeneration (AMD), n = 246.Either 15 mg intravitreal pegcetacoplan or sham given monthly or every other month for 12 months followed by a 6-month off-treatment period.Time of new eAMD onset in the study eye, history of eAMD in the fellow eye, presence of double-layer sign (DLS) on structural OCT in the study eye, changes in retinal anatomic features by structural OCT and fluorescein angiography (FA), and changes in visual acuity.Exudation was reported in 26 study eyes across treatment groups over 18 months. Mean time to eAMD diagnosis was 256 days (range, 31-555 days). Overall, a higher proportion of patients with a baseline history of eAMD in the fellow eye (P = 0.016) and a DLS in the study eye (P = 0.0001) demonstrated eAMD. Among study eyes in which eAMD developed, 18 of 26 (69%) had history of fellow-eye eAMD and 19 of 26 (73.1%) had DLS at baseline, compared with 76 of 217 study eyes (35%; P = 0.0007) and 70 of 215 study eyes (32.5%; P0.0001), respectively, in which eAMD did not develop. All 21 patients with structural OCT imaging at the time of eAMD diagnosis demonstrated subretinal fluid, intraretinal cysts, or both consistent with exudation. Among 17 patients who underwent FA at eAMD diagnosis, 10 showed detectable macular neovascularization (MNV), all occult lesions. Development of eAMD did not have an appreciable impact on visual acuity, and all patients responded to anti-vascular endothelial growth factor (VEGF) therapy.Intravitreal pegcetacoplan slowed the rate of GA growth and was associated with an unexpected dose-dependent increased incidence of eAMD with no temporal clustering of onset. Exudative AMD seemed to be associated with baseline eAMD in the contralateral eye and a DLS, suggestive of nonexudative MNV, in the study eye. The safety profile of pegcetacoplan was acceptable to proceed to phase 3 studies without adjustments to enrollment criteria

Baseline Characteristics of the Fellow Eye in Patients with Neovascular Age-Related Macular Degeneration: Post Hoc Analysis of the VIEW Studies

PURPOSE The aim was to describe baseline characteristics of the fellow eye of patients with neovascular age-related macular degeneration (nAMD). METHODS A pooled, post hoc analysis of patients with nAMD enrolled in the VIEW studies was carried out. The VIEW studies compared intravitreal aflibercept (monthly or every 2 months after 3 monthly injections) with monthly ranibizumab. Baseline choroidal neovascularization (CNV) status of fellow eyes and baseline best-corrected visual acuity (BCVA) and lens status of all eyes were evaluated. Additional analyses evaluated the presence of drusen and pigment in fellow eyes. RESULTS When comparing both eyes, baseline BCVA was worse in 23.8% of fellow eyes and in 75.2% of study eyes. Lens status of fellow eyes and study eyes was similar. Baseline visual acuity of the study eye and that of the fellow eye were not correlated. Most fellow eyes had signs of early AMD, with 34.6% (n = 843) of fellow eyes having evidence of scarring. CONCLUSIONS In patients in the VIEW studies, most fellow eyes had evidence of AMD, highlighting the importance of examining both eyes, with close follow-up thereafter, in order to detect and treat CNV earlier as needed

Evaluation of very high- and very low-dose intravitreal aflibercept in patients with neovascular age-related macular degeneration.

PURPOSE: To determine bioactivity and duration of effect of intravitreal aflibercept injection (also known as vascular endothelial growth factor Trap-Eye) for neovascular age-related macular degeneration (AMD). METHODS: In this double-masked, phase 1 study, 28 patients with lesions ≤12 disc areas, ≥50% active choroidal neovascularization (CNV), and best corrected visual acuity (BCVA) ≤20/40 were randomized 1:1 to a single intravitreal injection of aflibercept 0.15 or 4 mg. The primary end point was the change from baseline in central retinal/lesion thickness (CR/LT) at week-8. Secondary outcomes were the change from baseline BCVA, the change in CNV lesion size and area of leakage, and proportion of patients requiring repeat injection at 8 weeks. RESULTS: Mean percent decrease in CR/LT for the 4-mg and 0.15-mg groups was, respectively, 34.2 versus 13.3 at week 4 (P=0.0065), 23.8 versus 5.9 at week 6 (P=0.0380), and 25.2% versus 11.3% at week 8 (P=0.150). The 4-mg group gained a mean of 4.5 letters in BCVA (6/14 patients gaining ≥10 letters) versus 1.1 letters in 0.15-mg group (1/14 gaining ≥10 letters) at week 8. Fewer patients needed retreatment in the 4-mg group at week 8. No serious adverse event or ocular inflammation was reported in either group. CONCLUSIONS: Intravitreal aflibercept 4 mg had a safety profile similar to that of the very low dose 0.15 mg, and was well-tolerated. The 4-mg dose significantly reduced foveal thickening at weeks 4 and 6, significantly improved BCVA at weeks 6, and reduced the need for repeat injection after 8 weeks compared with intravitreal aflibercept 0.15 mg in neovascular AMD patients

Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration : A Randomized Phase 2 Trial

Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.Peer reviewedPublisher PD