Structural and quantum chemical basis for OCP-mediated quenching of phycobilisomes.

Cyanobacteria use large antenna complexes called phycobilisomes (PBSs) for light harvesting. However, intense light triggers non-photochemical quenching, where the orange carotenoid protein (OCP) binds to PBS, dissipating excess energy as heat. The mechanism of efficiently transferring energy from phycocyanobilins in PBS to canthaxanthin in OCP remains insufficiently understood. Using cryo-electron microscopy, we unveiled the OCP-PBS complex structure at 1.6- to 2.1-angstrom resolution, showcasing its inherent flexibility. Using multiscale quantum chemistry, we disclosed the quenching mechanism. Identifying key protein residues, we clarified how canthaxanthin's transition dipole moment in its lowest-energy dark state becomes large enough for efficient energy transfer from phycocyanobilins. Our energy transfer model offers a detailed understanding of the atomic determinants of light harvesting regulation and antenna architecture in cyanobacteria.

Functional and structural insights into activation of TRPV2 by weak acids.

Transient receptor potential (TRP) ion channels are involved in the surveillance or regulation of the acid-base balance. Here, we demonstrate that weak carbonic acids, including acetic acid, lactic acid, and CO2 activate and sensitize TRPV2 through a mechanism requiring permeation through the cell membrane. TRPV2 channels in cell-free inside-out patches maintain weak acid-sensitivity, but protons applied on either side of the membrane do not induce channel activation or sensitization. The involvement of proton modulation sites for weak acid-sensitivity was supported by the identification of titratable extracellular (Glu495, Glu561) and intracellular (His521) residues on a cryo-EM structure of rat TRPV2 (rTRPV2) treated with acetic acid. Molecular dynamics simulations as well as patch clamp experiments on mutant rTRPV2 constructs confirmed that these residues are critical for weak acid-sensitivity. We also demonstrate that the pore residue Glu609 dictates an inhibition of weak acid-induced currents by extracellular calcium. Finally, TRPV2-expression in HEK293 cells is associated with an increased weak acid-induced cytotoxicity. Together, our data provide new insights into weak acids as endogenous modulators of TRPV2.

High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design.

Rational design of next-generation therapeutics can be facilitated by high-resolution structures of drug targets bound to small-molecule inhibitors. However, application of structure-based methods to macromolecules refractory to crystallization has been hampered by the often-limiting resolution and throughput of cryogenic electron microscopy (cryo-EM). Here, we use high-resolution cryo-EM to determine structures of the CDK-activating kinase, a master regulator of cell growth and division, in its free and nucleotide-bound states and in complex with 15 inhibitors at up to 1.8 Å resolution. Our structures provide detailed insight into inhibitor interactions and networks of water molecules in the active site of cyclin-dependent kinase 7 and provide insights into the mechanisms contributing to inhibitor selectivity, thereby providing the basis for rational design of next-generation therapeutics. These results establish a methodological framework for the use of high-resolution cryo-EM in structure-based drug design.

Cryo-EM structure of SRP68/72 reveals an extended dimerization domain with RNA-binding activity.

The signal recognition particle (SRP) is a critical component in protein sorting pathways in all domains of life. Human SRP contains six proteins bound to the 7S RNA and their structures and functions have been mostly elucidated. The SRP68/72 dimer is the largest SRP component and is essential for SRP function. Although the structures of the SRP68/72 RNA binding and dimerization domains have been previously reported, the structure and function of large portions of the SRP68/72 dimer remain unknown. Here, we analyse full-length SRP68/72 using cryo-EM and report that SRP68/72 depend on each other for stability and form an extended dimerization domain. This newly observed dimerization domain is both a protein- and RNA-binding domain. Comparative analysis with current structural models suggests that this dimerization domain undergoes dramatic translocation upon SRP docking onto SRP receptor and eventually comes close to the Alu domain. We propose that the SRP68/72 dimerization domain functions by binding and detaching the Alu domain and SRP9/14 from the ribosomal surface, thus releasing elongation arrest upon docking onto the ER membrane.

Rationale and protocol paper for the Asia Pacific Network for inherited eye diseases.

PURPOSE: There are major gaps in our knowledge of hereditary ocular conditions in the Asia-Pacific population, which comprises approximately 60% of the world's population. Therefore, a concerted regional effort is urgently needed to close this critical knowledge gap and apply precision medicine technology to improve the quality of lives of these patients in the Asia-Pacific region. DESIGN: Multi-national, multi-center collaborative network. METHODS: The Research Standing Committee of the Asia-Pacific Academy of Ophthalmology and the Asia-Pacific Society of Eye Genetics fostered this research collaboration, which brings together renowned institutions and experts for inherited eye diseases in the Asia-Pacific region. The immediate priority of the network will be inherited retinal diseases (IRDs), where there is a lack of detailed characterization of these conditions and in the number of established registries. RESULTS: The network comprises 55 members from 35 centers, spanning 12 countries and regions, including Australia, China, India, Indonesia, Japan, South Korea, Malaysia, Nepal, Philippines, Singapore, Taiwan, and Thailand. The steering committee comprises ophthalmologists with experience in consortia for eye diseases in the Asia-Pacific region, leading ophthalmologists and vision scientists in the field of IRDs internationally, and ophthalmic geneticists. CONCLUSIONS: The Asia Pacific Inherited Eye Disease (APIED) network aims to (1) improve genotyping capabilities and expertise to increase early and accurate genetic diagnosis of IRDs, (2) harmonise deep phenotyping practices and utilization of ontological terms, and (3) establish high-quality, multi-user, federated disease registries that will facilitate patient care, genetic counseling, and research of IRDs regionally and internationally.

Guidelines from an expert panel for the management of diabetic macular edema in the Malaysian population.

AIM: To derive a Malaysia guideline and consensus as part of the Malaysia Retina Group's efforts for diagnosis, treatment, and best practices of diabetic macular edema (DME). The experts' panel suggests that the treatment algorithm to be divided into groups according to involvement the central macula. The purpose of DME therapy is to improve edema and achieve the best visual results with the least amount of treatment load. METHODS: On two different occasions, a panel of 14 retinal specialists from Malaysia, together with an external expert, responded to a questionnaire on management of DME. A consensus was sought by voting after compiling, analyzing and discussion on first-phase replies on the round table discussion. A recommendation was deemed to have attained consensus when 12 out of the 14 panellists (85%) agreed with it. RESULTS: The terms target response, adequate response, nonresponse, and inadequate response were developed when the DME patients' treatment responses were first characterized. The panelists reached agreement on a number of DME treatment-related issues, including the need to classify patients prior to treatment, first-line treatment options, the right time to switch between treatment modalities, and side effects associated with steroids. From this agreement, recommendations were derived and a treatment algorithm was created. CONCLUSION: A detail and comprehensive treatment algorithm by Malaysia Retina Group for the Malaysian population provides guidance for treatment allocation of patients with DME.

Polypoidal Choroidal Vasculopathy: Updates on Risk Factors, Diagnosis, and Treatments.

There have been recent advances in basic research and clinical studies in polypoidal choroidal vasculopathy (PCV). A recent, large-scale, population-based study found systemic factors, such as male gender and smoking, were associated with PCV, and a recent systematic review reported plasma C-reactive protein, a systemic biomarker, was associated with PCV. Growing evidence points to an association between pachydrusen, recently proposed extracellular deposits associated with the thick choroid, and the risk of development of PCV. Many recent studies on diagnosis of PCV have focused on applying criteria from noninvasive multimodal retinal imaging without requirement of indocyanine green angiography. There have been attempts to develop deep learning models, a recent subset of artificial intelligence, for detecting PCV from different types of retinal imaging modality. Some of these deep learning models were found to have high performance when they were trained and tested on color retinal images with corresponding images from optical coherence tomography. The treatment of PCV is either a combination therapy using verteporfin photodynamic therapy and anti-vascular endothelial growth factor (VEGF), or anti-VEGF monotherapy, often used with a treat-and-extend regimen. New anti-VEGF agents may provide more durable treatment with similar efficacy, compared with existing anti-VEGF agents. It is not known if they can induce greater closure of polypoidal lesions, in which case, combination therapy may still be a mainstay. Recent evidence supports long-term follow-up of patients with PCV after treatment for early detection of recurrence, particularly in patients with incomplete closure of polypoidal lesions.

Characterisation of macular neovascularisation subtypes in age-related macular degeneration to optimise treatment outcomes.

The aim of this review is to identify the common characteristics and prognoses of different subtypes of neovascular age-related macular degeneration (nAMD). We also propose recommendations on how to tailor treatments to the subtype of neovessels to optimise patient outcomes. The authors, selected members of the Vision Academy, met to discuss treatment outcomes in nAMD according to macular neovascularisation (MNV) subtypes, using evidence from a literature search conducted on the PubMed database (cut-off date: March 2019). This review article summarises the recommendations of the Vision Academy on how the characterisation of MNV subtypes can optimise treatment outcomes in nAMD. The identification of MNV subtypes has been facilitated by the advent of multimodal imaging. Findings from fluorescein angiography, indocyanine green angiography and spectral-domain optical coherence tomography collectively help refine and standardise the determination of the MNV subtype. To date, three subtypes have been described in the literature and have specific characteristics, as identified by imaging. Type 1 MNV is associated with better long-term outcomes but usually requires more intense anti-vascular endothelial growth factor dosing. Type 2 MNV typically responds quickly to treatment but is more prone to the development of fibrotic scars, which may be associated with poorer outcomes. Type 3 MNV tends to be highly sensitive to anti-vascular endothelial growth factor treatment but may be associated with a higher incidence of outer retinal atrophy, compared with other subtypes. Accurately assessing the MNV subtype provides information on prognosis and helps to optimise the management of patients with nAMD.

A Review of Intraocular Biomolecules in Retinal Vein Occlusion: Toward Potential Biomarkers for Companion Diagnostics.

Retinal vein occlusion (RVO) is one of the most common retinal vascular diseases. The pathogenesis of RVO is multifactorial and involves a complex interplay among a variety of vascular and inflammatory mediators. Many cytokines, chemokines, growth factors, and cell adhesion molecules have been reported to be implicated. Treatments for RVO are directed at the management of underlying risk factors and vision-threatening complications, including macula edema (ME) and neovascularization. Intravitreal anti-VEGF agents are currently considered as the first-line treatment for ME secondary to RVO (RVO-ME), but a substantial proportion of patients responded insufficiently to anti-VEGF agents. Since RVO-ME refractory to anti-VEGF agents generally responds to corticosteroids and its visual outcome is negatively correlated to disease duration, prediction of treatment response at baseline in RVO-ME may significantly improve both cost-effectiveness and visual prognosis. Several bioactive molecules in the aqueous humor were found to be associated with disease status in RVO. This review aims to present a comprehensive review of intraocular biomolecules reported in RVO, including VEGF, IL-6, IL-8, MCP-1, sICAM-1, IL-12, IL-13, sVEGFR-1, sVEGFR-2, PDGF-AA, etc., highlighting their association with disease severity and/or phenotype, and their potential roles in prognostic prediction and treatment selection. Some of these molecules may serve as biomarkers for aqueous humor-based companion diagnostics for the treatment of RVO in the future.

Fluid Control in Neovascular Age-Related Macular Degeneration with Brolucizumab: An Analysis of the HAWK and HARRIER Phase 3 Trials.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD) is characterized by exudation of fluid from abnormally growing blood vessels in the macula. Anti-vascular endothelial growth factor (VEGF) therapy is standard treatment for nAMD. Fluid resolution is used both as an indicator of disease control and to guide the frequency of treatment because of anti-VEGF therapy effectiveness in reducing neovascularization-related exudation. Herein reports a post hoc assessment of the HAWK and HARRIER trials comparing the efficacy and safety of brolucizumab with aflibercept in patients with nAMD. MATERIALS AND METHODS: HAWK randomized 1,078 patients with untreated, active choroidal neovascularization due to AMD in the study eye to receive brolucizumab 3, 6 mg or aflibercept 2 mg. In HARRIER, 739 patients received brolucizumab 6 mg or aflibercept 2 mg. Brolucizumab was injected at weeks 0, 4, and 8, and thereafter q12w unless disease activity was identified (injection interval: q8w). Aflibercept was injected q8w after the loading phase, aligned with approved dosing at study initiation. The objective of this analysis was to assess effects of brolucizumab versus aflibercept on retinal fluid resolution during two phase 3 trials (HAWK and HARRIER) in patients with nAMD. Anatomical assessments for intraretinal fluid (IRF) and subretinal fluid (SRF) were performed every 4 weeks by spectral domain optical coherence tomography. Sustained dryness was defined as a patient being fluid-free (SRF and IRF) on ≥3 consecutive visits. Time to sustained dryness was determined by Kaplan-Meier estimates. RESULTS: At week 96, fluid resolution (absence of IRF and SRF) was achieved by more brolucizumab- (6 mg; 76.1%) versus aflibercept-treated patients (63.1%; p = 0.0002, HAWK); 75.4% versus 61.8% (p < 0.0001, HARRIER). More patients achieved sustained dryness with brolucizumab versus aflibercept: at 96 weeks, 87.9% (brolucizumab 3 mg) and 86.1% (brolucizumab 6 mg) versus 82.0% (aflibercept) in HAWK, and 91.2% (brolucizumab) versus 78.0% (aflibercept) in HARRIER. Sustained dryness was achieved faster and hence with fewer brolucizumab injections. DISCUSSION/CONCLUSION: Brolucizumab dried the macula in patients with nAMD faster and to a greater degree than aflibercept. Achieving sustained dryness faster, and therefore with fewer injections, provides an opportunity for earlier decisions relating to treatment interval extension potentially reducing treatment burden.

Routine Collection of High-Resolution cryo-EM Datasets Using 200 KV Transmission Electron Microscope.

Cryo-electron microscopy (cryo-EM) has been established as a routine method for protein structure determination during the past decade, taking an ever-increasing share of published structural data. Recent advances in TEM technology and automation have boosted both the speed of data collection and quality of acquired images while simultaneously decreasing the required level of expertise for obtaining cryo-EM maps at sub-3 Å resolutions. While most of such high-resolution structures have been obtained using state-of-the-art 300 kV cryo-TEM systems, high-resolution structures can be also obtained with 200 kV cryo-TEM systems, especially when equipped with an energy filter. Additionally, automation of microscope alignments and data collection with real-time image quality assessment reduces system complexity and assures optimal microscope settings, resulting in increased yield of high-quality images and overall throughput of data collection. This protocol demonstrates the implementation of recent technological advances and automation features on a 200 kV cryo-transmission electron microscope and shows how to collect data for the reconstruction of 3D maps that are sufficient for de novo atomic model building. We focus on best practices, critical variables, and common issues that must be considered to enable the routine collection of such high-resolution cryo-EM datasets. Particularly the following essential topics are reviewed in detail: i) automation of microscope alignments, ii) selection of suitable areas for data acquisition, iii) optimal optical parameters for high-quality, high-throughput data collection, iv) energy filter tuning for zero-loss imaging, and v) data management and quality assessment. Application of the best practices and improvement of achievable resolution using an energy filter will be demonstrated on the example of apo-ferritin that was reconstructed to 1.6 Å, and Thermoplasma acidophilum 20S proteasome reconstructed to 2.1-Å resolution using a 200 kV TEM equipped with an energy filter and a direct electron detector.

Recommendations for OCT Angiography Reporting in Retinal Vascular Disease: A Delphi Approach by International Experts.

PURPOSE: To develop a consensus nomenclature for reporting OCT angiography (OCTA) findings in retinal vascular disease (e.g., diabetic retinopathy, retinal vein occlusion) by international experts. DESIGN: Delphi-based survey. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Twenty-five retinal vascular disease and OCTA imaging experts. METHODS, INTERVENTION, OR TESTING: A Delphi method of consensus development was used, comprising 2 rounds of online questionnaires, followed by a face-to-face meeting conducted virtually. Twenty-five experts in retinal vascular disease and retinal OCTA imaging were selected to constitute the OCTA Nomenclature in Delphi Study Group for retinal vascular disease. The 4 main areas of consensus were: definition of the parameters of "wide-field (WF)" OCTA, measurement of decreased vascular flow on conventional and WF-OCTA, nomenclature of OCTA findings, and OCTA in retinal vascular disease management and staging. The study end point was defined by the degree of consensus for each question: "strong consensus" was defined as ≥85% agreement, "consensus" as 80% to 84%, and "near consensus" as 70% to 79%. MAIN OUTCOME MEASURES: Consensus and near consensus on OCTA nomenclature in retinal vascular disease. RESULTS: A consensus was reached that a meaningful change in percentage of flow on WF-OCTA imaging should be an increase or decrease ≥30% of the absolute imaged area of flow signal and that a "large area" of WF-OCTA reduced flow signal should also be defined as ≥30% of the absolute imaged area. The presence of new vessels and intraretinal microvascular abnormalities, the foveal avascular zone parameters, the presence and amount of "no-flow areas," and the assessment of vessel density in various retinal layers should be added for the staging and classification of diabetic retinopathy. Decreased flow ≥30% of the absolute imaged area should define an ischemic central retinal vein occlusion. Several other items did not meet consensus requirements or were rejected in the final discussion round. CONCLUSIONS: This study provides international consensus recommendations for reporting OCTA findings in retinal vascular disease, which may help to improve the interpretability and description in clinic and clinical trials. Further validation in these settings is warranted and ongoing. Efforts are continuing to address unresolved questions.

Efficacy Outcomes of Brolucizumab Versus Aflibercept in Neovascular Age-Related Macular Degeneration Patients with Early Residual Fluid.

OBJECTIVE: To compare the outcomes of brolucizumab versus aflibercept in patients with neovascular age-related macular degeneration with early residual fluid in the HAWK and HARRIER studies. DESIGN: Post hoc analysis using pooled data from the phase 3 studies HAWK (NCT02307682) and HARRIER (NCT02434328). PARTICIPANTS: The early residual fluid cohort for this post hoc analysis consisted of patients treated with either brolucizumab 6 mg (n = 730 patients) or aflibercept 2 mg (n = 729 patients) and who had the presence of intraretinal fluid (IRF), subretinal fluid (SRF), or both verified by spectral-domain OCT at the week 12 clinic visit. METHODS: After 3 initial monthly doses, patients treated with brolucizumab received injections every 12 weeks (q12w) or every 8 weeks (q8w), depending on the neovascular age-related macular degeneration disease activity, whereas patients treated with aflibercept received fixed q8w dosing. MAIN OUTCOME MEASURES: The mean change in best-corrected visual acuity and central subfield thickness (CST) from the baseline to that at weeks 48 and 96, the proportion of patients treated with brolucizumab remaining on q12w dosing to week 96, and the change in fluid status at weeks 48 and 96. RESULTS: All analyses were based on 149 of 730 (20.4%) patients treated with brolucizumab and 217 of 729 (29.8%) patients treated with aflibercept with spectral-domain OCT-verified IRF, SRF, or both at their week 12 visit. The best-corrected visual acuity improvements from baseline at weeks 48 and 96 were numerically better for brolucizumab than for aflibercept (least square mean [standard error] 7.9 ± 1.1 vs. 4.6 ± 0.9 and 7.4 ± 1.3 vs. 2.9 ± 1.1 letters, respectively). The CST reductions from baseline at weeks 48 and 96 were consistently greater with brolucizumab than with aflibercept (least square mean [standard error], µm: -194.9 ± 13.7 vs. -123.9 ± 11.3; and -201.1 ± 14.5 vs. -134.2 ± 12.0, respectively). At weeks 48 and 96, patients treated with brolucizumab had a 40.4% and 31.3% probability of remaining on q12w dosing intervals, respectively. Fewer patients treated with brolucizumab had remaining IRF, SRF, or both at weeks 48 and 96 than patients treated with aflibercept (59.1% vs. 75.1% and 49.0% vs. 60.4%, respectively). CONCLUSIONS: In patients with early residual fluid, defined as spectral-domain OCT-verified IRF, SRF, or both at the week 12 clinic visit, brolucizumab resolved the early residual fluid and reduced CST more effectively than aflibercept, resulting in greater best-corrected visual acuity improvements through week 96 of anti-VEGF treatment.

Efficacy and Safety of Intravitreal Aflibercept Treat and Extend for Polypoidal Choroidal Vasculopathy in the ATLANTIC Study: A Randomized Clinical Trial.

IMPORTANCE: Polypoidal choroidal vasculopathy (PCV) is far less common and studied in a Caucasian population than in an Asian population, and the optimal treatment approach remains to be confirmed. METHODS: A 52-week, double-masked, sham-controlled, phase 4, investigator-initiated randomized clinical trial (RCT) in naive symptomatic Caucasian patients with PCV treated with aflibercept in a treat-and-extend regimen (T&E) (intravitreal aflibercept injection [IVAI] T&E). Patients were randomized at week 16 to receive IVAI T&E plus either sham photodynamic therapy (PDT) or standard fluence PDT with verteporfin. The main outcome measures were changes in best-corrected visual acuity (BCVA) from baseline to 52 weeks and polyp occlusion at week 52. Data are presented as median (interquartile range [IQR]) for BCVA, number of IVAI, and change in central retinal thickness (CRT). RESULTS: Of the 50 patients included in the study, 48 patients completed the 52 weeks of follow-up. During this period, a significant median (IQR) BCVA gain of 6 [2-12] Early Treatment Diabetic Retinopathy Study letters was observed for all patients (p < 0.001), after 8 (7-9) injections, with a significant reduction of -93.0 [-154.0, -44.0] µm in central macular thickness (p < 0.001). Using indocyanine green angiography, a complete occlusion of polypoidal lesions was documented in 72% of the cases. Still, no significant difference was detected between the sham PDT and the aflibercept PDT arms, at week 52, for BCVA change (6.5 [2-11] vs. 5 [2-13] letters (p = 0.98)), number of IVAIs (8.5 [7-9] vs. 8 [7-9] (p = 0.21)), change in CRT (-143 [-184; -47] vs. -89 [-123; -41.5] µm [p = 0.23]), and rates of complete polyp occlusion: 77 versus 68% (p = 0.53) or presence of fluid: 68 versus 57% (p = 0.56). No serious ocular adverse events were registered in the 2 arms. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first RCT to compare aflibercept T&E monotherapy with aflibercept T&E plus verteporfin PDT in a Caucasian population with PCV. Aflibercept monotherapy in a T&E showed to be effective and safe with a significant median BCVA improvement of 6 letters and a complete occlusion of polypoidal lesions in near 3 quarters of the eyes, at 1 year. As only 22% of the eyes underwent PDT treatment, the benefit of combined treatment for PCV in Caucasian patients could not be definitively elucidated from this study. TRIAL REGISTRATION: The clinical trial was registered in ClinicalTrials.gov Identifier NCT02495181 and the European Union Drug Regulating Authorities Clinical Trials Database EudraCT No. 2015-001368-20.

Efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy in Japanese participants of HAWK.

PURPOSE: To compare the efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy (PCV) over 96 weeks in the HAWK study. DESIGN: HAWK was a global, 2-year, randomised, double-masked, multicentre phase III trial in participants with neovascular age-related macular degeneration. METHODS: Of the Japanese participants with PCV, 39 received brolucizumab 6 mg and 30 received aflibercept 2 mg. After 3 monthly loading doses, brolucizumab-treated eyes received an injection every 12 weeks (q12w) but were adjusted to q8w if disease activity was detected. Aflibercept-treated eyes received fixed q8w dosing. Mean change in best-corrected visual acuity (BCVA), the proportion of participants on q12w, retinal thickness, retinal fluid changes and safety were assessed to Week 96. RESULTS: Mean change in BCVA (early treatment diabetic retinopathy study (ETDRS) letters) from baseline to week 48/week 96 was+10.4/+11.4 for brolucizumab and +11.6/+11.1 for aflibercept. For brolucizumab-treated eyes, the probability of only q12w dosing after loading through week 48 was 76%, and 68% through week 96. Fluid resolution was greater with brolucizumab than aflibercept: respective proportions of eyes with intraretinal fluid and/or subretinal fluid were 7.7% and 30% at week 48% and 12.8% and 16.7% at week 96. Brolucizumab exhibited an overall well-tolerated safety profile despite a higher rate of intraocular inflammation compared with aflibercept. CONCLUSION: In Japanese eyes with PCV, brolucizumab q12w/q8w monotherapy resulted in robust and consistent BCVA gains that were comparable to q8w aflibercept dosing. Anatomical outcomes favoured brolucizumab over aflibercept, with 76% of brolucizumab participants maintained on q12w dosing after loading to week 48.

Treat-and-Extend Regimens for the Management of Neovascular Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy: Consensus and Recommendations From the Asia-Pacific Vitreo-retina Society.

PURPOSE: Review and provide consensus recommendations on use of treat-and-extend (T&E) regimens for neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) management with relevance for clinicians in the Asia-Pacific region. METHODS: A systematic search of MEDLINE, EMBASE, and Cochrane databases, and abstract databases of the Asia-Pacific Vitreo-retina Society, European Society of Retina Specialists, American Academy of Ophthalmology, and Controversies in Ophthalmology: Asia-Australia congresses, was conducted to assess evidence for T&E regimens in nAMD. Only studies with ≥100 study eyes were included. An expert panel reviewed the results and key factors potentially influencing the use of T&E regimens in nAMD and PCV, and subsequently formed consensus recommendations for their application in the Asia-Pacific region. RESULTS: Twenty-seven studies were included. Studies demonstrated that T&E regimens with aflibercept, ranibizumab, or bevacizumab in nAMD, and with aflibercept in PCV, were efficacious and safe. The recommendation for T&E is, after ≥3 consecutive monthly loading doses, treatment intervals can be extended by 2 to 4 weeks up to 12 to 16 weeks. When disease activity recurs, the recommendation is to reinject and shorten intervals by 2 to 4 weeks until fluid resolution, after which treatment intervals can again be extended. Intraretinal fluid should be treated until resolved; however, persistent minimal subretinal fluid after consecutive treatments may be tolerated with treatment intervals maintained or extended if the clinical condition is stable. CONCLUSIONS: T&E regimens are efficacious and safe for nAMD and PCV, can reduce the number of visits, and minimize the overall burden for clinicians and patients.

The influence of delayed treatment due to COVID-19 on patients with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

PURPOSE: To explore the impact of coronavirus disease 2019 (COVID-19) on the prognosis of patients with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV), and share the experience in managing them during pandemics. METHOD: This is a retrospective study of nAMD and PCV patients treated at Peking Union Medical College Hospital from 31 December 2019 to 1 August 2020. Baseline demographic and clinical characteristics, best corrected visual acuity (BCVA), optical coherence tomography (OCT) features, duration of delayed treatment and number of anti-vascular endothelial growth factor (VEGF) injections were analyzed. RESULTS: A total of 130 nAMD patients (155 eyes) and 76 PCV patients (89 eyes) were identified. Compared to the conditions before COVID-19, the BCVA of delayed cases decreased significantly, and the proportion of patients presenting with sub-macular scar was significantly greater in the delayed treatment group (p < 0.05). The BCVA of non-delayed cases remained stable, with the percentage of patients with disease activity sub-retinal fluid and hemorrhage at the fovea decreasing significantly (p < 0.05). The stable cases who did not require anti-VEGF treatment had significantly worse baseline and final BCVA, these patients were likely to be chronic and 'burnt out' cases with significantly worse anatomical structures (p < 0.05). CONCLUSIONS: The delayed cases due to the pandemic suffered compromised visual function and a higher rate of sub-macular scar formation, while the visual function of non-delayed cases remained stable with favorable anatomical outcomes, suggesting the importance of regular follow-up for nAMD and PCV patients. Besides, effective measures of hospitals during pandemics are crucial to provide timely treatment for chronic disease.

Non-ICGA treatment criteria for Suboptimal Anti-VEGF Response for Polypoidal Choroidal Vasculopathy: APOIS PCV Workgroup Report 2.

PURPOSE: To develop and validate OCT and color fundus photography (CFP) criteria in differentiating polypoidal choroidal vasculopathy (PCV) from typical neovascular age-related macular degeneration (nAMD) in eyes with suboptimal response to anti-vascular endothelial growth factor (VEGF) monotherapy and to determine whether OCT alone can be used to guide photodynamic therapy (PDT) treatment. DESIGN: Clinical study evaluating diagnostic accuracy. PARTICIPANTS: Patients with nAMD who received 3-month anti-VEGF monotherapy but had persistent activity defined as subretinal fluid or intraretinal fluid at month 3 assessments. METHODS: In phase 1, international retina experts evaluated OCT and CFP of eyes with nAMD to identify the presence or absence of features due to PCV. The performance of individual and combinations of these features were compared with ICGA. In phase 2, these criteria were applied to an independent image set to assess generalizability. In a separate exercise, retinal experts drew proposed PDT treatment spots using only OCT and near-infrared (NIR) images in eyes with PCV and persistent activity. The location and size of proposed spot were compared with ICGA to determine the extent of coverage of polypoidal lesions (PLs) and branching neovascular network (BNN). MAIN OUTCOME MEASURES: Sensitivity and specificity of CFP and OCT criteria to differentiate PCV from nAMD and accuracy of coverage of OCT-guided PDT compared with ICGA. RESULTS: In eyes with persistent activity, the combination of 3 non-ICGA-based criteria (sharp-peaked pigment epithelial detachment [PED], subretinal pigment epithelium [RPE] ring-like lesion, and orange nodule) to detect PCV showed good agreement compared with ICGA, with an area under the receiver operating characteristic curve of 0.85. Validation using both an independent image set and assessors achieved an accuracy of 0.77. Compared with ICGA, the OCT-guided PDT treatment spot covered 100% of PL and 90% of the BNN. CONCLUSIONS: In nAMD eyes with persistent activity, OCT and CFP can differentiate PCV from typical nAMD, which may allow the option of adjunct PDT treatment. Furthermore, OCT alone can be used to plan adjunct PDT treatment without the need for ICGA, with consistent and complete coverage of PL.

Anti-VEGF intravitreal injections in the era of COVID-19: responding to different levels of epidemic pressure.

PURPOSE: Following the first wave of the COVID-19 pandemic in early 2020, the easing of strict measures to reduce its spread has led to a resurgence of cases in many countries at both the national and local level. This article addresses how guidance for ophthalmologists on managing patients with retinal disease receiving intravitreal injections of anti-vascular endothelial growth factor (VEGF) during the pandemic should be adapted to the local epidemic pressure, with more or less stringent measures implemented according to the ebb and flow of the pandemic. METHODS: The Vision Academy's membership of international retinal disease experts analyzed guidance for anti-VEGF intravitreal injections during the COVID-19 pandemic and graded the recommendations according to three levels of increasing epidemic pressure. The revised recommendations were discussed, refined, and voted on by the 14-member Vision Academy Steering Committee for consensus. RESULTS: Protocols to minimize the exposure of patients and healthcare staff to COVID-19, including use of personal protective equipment, physical distancing, and hygiene measures, should be routinely implemented and intensified according to local infection rates and pressure on the hospital/clinic or healthcare system. In areas with many COVID-19-positive clusters, additional measures including pre-screening of patients, postponement of non-urgent appointments, and simplification of complex intravitreal anti-VEGF regimens should be considered. Treatment prioritization for those at greatest risk of irreversible vision loss should be implemented in areas where COVID-19 cases are increasing exponentially and healthcare resources are strained. CONCLUSION: Consistency in monitoring of local infection rates and adjustment of clinical practice accordingly will be required as we move forward through the COVID-19 era. Ophthalmologists must continue to carefully weigh the risk-benefits to minimize the exposure of patients and healthcare staff to COVID-19, ensure that patients receive sight-saving treatment, and avoid the potential long-term impact of prolonged treatment postponement.