The impact of COVID-19 on aflibercept treatment of neovascular AMD in Sweden - data from the Swedish Macula Register.

BACKGROUND: The purpose of the study was to compare the real-world aflibercept treatment and visual outcomes, and to examine the adherence to pandemic guidelines in two groups of patients with treatment-naïve neovascular age-related macular degeneration (nAMD) before and during the first year of the COVID-19 pandemic in Sweden up to the 1-year follow-up. METHODS: This is a retrospective observational study including 2915 treatment naïve eyes with nAMD. Using data from the Swedish Macula Register (SMR), 1597 eyes initiating treatment between 1 July 2018 and 31 January 2019 (pre-pandemic group) were compared with 1318 eyes starting treatment between 1 February and 31 August 2020 (pandemic group). The eyes were then followed for 1 year ± 2 months, hence the first group was unaffected by the pandemic while the second group was affected. The focus was on baseline characteristics, visual acuity (VA) change from baseline, number of injections, treatment regimen, number of appointments and the frequency and length of appointment delays. The Wilcoxon Signed-Rank Test was used to compare baseline VA to follow-up VA within the respective groups. The Mann-Whitney U-test and Fisher's exact test were used to compare outcomes between the groups. RESULTS: Baseline characteristics were similar between the two groups. The percentage of eyes with an available follow-up VA after 1 year was 58% in the pre-pandemic group vs. 44% in the pandemic group. VA in the pre-pandemic group had increased significantly after 1 year, from 62.2 ± 14.1 letters to 64.8 ± 16.1 letters (n = 921); p < 0.0001. In the pandemic group, VA increased from 61.1 ± 15.8 to 64.9 ± 16.9 (n = 575); p < 0.0001. There was no significant difference in mean VA change between the groups; p = 0.1734. The pre-pandemic group had significantly more delays than the pandemic group, 45% vs. 36%; p < 0.0001. CONCLUSIONS: The pre-pandemic and pandemic groups had similar VA gains at 1-year follow-up, but with a reduced number of available VA in the pandemic group. Clinics were able to implement and prioritize injection visits excluding VA measurements, helping to reduce delays and maintain VA gains during the COVID-19 pandemic.

Targeting of Scavenger Receptors Stabilin-1 and Stabilin-2 Ameliorates Atherosclerosis by a Plasma Proteome Switch Mediating Monocyte/Macrophage Suppression.

BACKGROUND: Scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are preferentially expressed by liver sinusoidal endothelial cells. They mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. Studies suggest that Stab1 and Stab2 may affect atherosclerosis. Although subsets of tissue macrophages also express Stab1, hematopoietic Stab1 deficiency does not modulate atherogenesis. Here, we comprehensively studied how targeting Stab1 and Stab2 affects atherosclerosis. METHODS: ApoE-KO mice were interbred with Stab1-KO and Stab2-KO mice and fed a Western diet. For antibody targeting, Ldlr-KO mice were also used. Unbiased plasma proteomics were performed and independently confirmed. Ligand binding studies comprised glutathione-S-transferase-pulldown and endocytosis assays. Plasma proteome effects on monocytes were studied by single-cell RNA sequencing in vivo, and by gene expression analyses of Stabilin ligand-stimulated and plasma-stimulated bone marrow-derived monocytes/macrophages in vitro. RESULTS: Spontaneous and Western diet-associated atherogenesis was significantly reduced in ApoE-Stab1-KO and ApoE-Stab2-KO mice. Similarly, inhibition of Stab1 or Stab2 by monoclonal antibodies significantly reduced Western diet-associated atherosclerosis in ApoE-KO and Ldlr-KO mice. Although neither plasma lipid levels nor circulating immune cell numbers were decisively altered, plasma proteomics revealed a switch in the plasma proteome, consisting of 231 dysregulated proteins comparing wildtype with Stab1/2-single and Stab1/2-double KO, and of 41 proteins comparing ApoE-, ApoE-Stab1-, and ApoE-Stab2-KO. Among this broad spectrum of common, but also disparate scavenger receptor ligand candidates, periostin, reelin, and TGFBi (transforming growth factor, ß-induced), known to modulate atherosclerosis, were independently confirmed as novel circulating ligands of Stab1/2. Single-cell RNA sequencing of circulating myeloid cells of ApoE-, ApoE-Stab1-, and ApoE-Stab2-KO mice showed transcriptomic alterations in patrolling (Ccr2-/Cx3cr1++/Ly6Clo) and inflammatory (Ccr2+/Cx3cr1+/Ly6Chi) monocytes, including downregulation of proatherogenic transcription factor Egr1. In wildtype bone marrow-derived monocytes/macrophages, ligand exposure alone did not alter Egr1 expression in vitro. However, exposure to plasma from ApoE-Stab1-KO and ApoE-Stab2-KO mice showed a reverted proatherogenic macrophage activation compared with ApoE-KO plasma, including downregulation of Egr1 in vitro. CONCLUSIONS: Inhibition of Stab1/Stab2 mediates an anti-inflammatory switch in the plasma proteome, including direct Stabilin ligands. The altered plasma proteome suppresses both patrolling and inflammatory monocytes and, thus, systemically protects against atherogenesis. Altogether, anti-Stab1- and anti-Stab2-targeted therapies provide a novel approach for the future treatment of atherosclerosis.

Additional measures of macular function beyond visual acuity.

PURPOSE: Visual function is a complex process in which external visual stimuli are interpreted. Patients with retinal diseases and prolonged follow-up times may experience changes in their visual function that are not detected by the standard visual acuity measure, as they are a result of other alterations in visual function. With the advancement of different methods to evaluate visual function, additional measurements have become available, and further standardization suggests that some methods may be promising for use in clinical trials or routine clinical practice. The objectives of this article are to review these additional measurements and to provide guidance on their application. METHODS: The Vision Academy's membership of international retinal disease experts reviewed the literature and developed consensus recommendations for the application of additional measures of visual function in routine clinical practice or clinical trials. RESULTS: Measures such as low-luminance visual acuity, contrast sensitivity, retinal fixation and microperimetry, and reading performance are measures which can complement visual acuity measurements to provide an assessment of overall visual function, including impact on patients' quality of life. Measures such as dark adaptation, color vision testing, binocular vision testing, visual recognition testing, and shape discrimination require further optimization and validation before they can be implemented in everyday clinical practice. CONCLUSION: Additional measurements of visual function may help identify patients who could benefit from earlier diagnosis, detection of disease progression, and therapeutic intervention. New and additional functional clinical trial endpoints are required to fully understand the early stages of macular disease, its progression, and the response to treatment.

Electrophysiological evaluation and 18-month follow-up of two regimens with aflibercept for neovascular age-related macular degeneration.

PURPOSE: To compare two aflibercept treatment regimens and the electrophysiological outcome concerning cone and rod function in age-related macular degeneration (nAMD) over 18 months. METHODS: 41 patients with treatment-naïve nAMD were randomized 1:1 to either arm 1 or 2. Arm 1 received three consecutive monthly aflibercept injections, followed by bimonthly treatment until week 52. Thereafter, a treat-and-extend (TAE) regimen was applied. Arm 2 was treated according to a TAE protocol throughout the 18-month follow-up. We assessed visual acuity (VA), central retinal thickness (CRT), injection rate and interval, and evaluated cone and rod function with full-field and multifocal electroretinography (ffERG, mERG). RESULTS: There were no statistically significant differences in mean baseline VA, lesion type, age, gender, or symptom duration between the two arms. During the 18-month follow-up, mean VA improved in arm 1 (n = 19) from 63.5 ± 10.5 to 69.1 ± 9.2 letters; p = 0.098; and in arm 2 (n = 20) from 66.8 ± 13.6 to 73.9 ± 9.0 letters; p = .002. In both arms, mean CRT was significantly reduced; p < 0.000. At month 18, we found no significant difference in the number of injections or injection intervals between groups. Arm 1 had received 11.3 ± 1.7 injections vs. 10.9 ± 2.0 in arm 2. The mean injection interval was 9.2 ± 3.4 weeks vs. 9.5 ± 3.1, with 52% (n = 10) on the maximum 12-week interval in arm 1, and 50% (n = 10) in arm 2. The combined rod-cone a-wave amplitude significantly decreased over time; p = 0.043. The isolated rod b-wave amplitude showed a statistically significant decline; p = 0.026. The overall mERG amplitude and implicit time remained unchanged over time; p = 0.878 vs. p = 0.922. The central ring 1 mERG amplitude improved; p = 0.041, with an unaffected implicit time. CONCLUSIONS: After 18 months, both treatments arms have received a similar number of injections at comparable intervals. Electrophysiological evaluation shows no signs of toxicity concerning cone function. But ffERGs for the combined and isolated rod response have declined, possibly reflecting either toxic effects of the drug to rods or the natural course of the disease itself.

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.

Guidance for anti-VEGF intravitreal injections during the COVID-19 pandemic.

PURPOSE: There is an urgent need to address how to best provide ophthalmic care for patients with retinal disease receiving intravitreal injections with anti-vascular endothelial growth factor agents during the ongoing global COVID-19 pandemic. This article provides guidance for ophthalmologists on how to deliver the best possible care for patients while minimizing the risk of infection. METHODS: The Vision Academy's Steering Committee of international retinal disease experts convened to discuss key considerations for managing patients with retinal disease during the COVID-19 pandemic. After reviewing the existing literature on the issue, members put forward recommendations that were systematically refined and voted on to develop this guidance. RESULTS: The considerations focus on the implementation of steps to minimize the exposure of patients and healthcare staff to COVID-19. These include the use of personal protective equipment, adherence to scrupulous hygiene and disinfection protocols, pre-screening to identify symptomatic patients, and reducing the number of people in waiting rooms. Other important measures include triaging of patients to identify those at the greatest risk of irreversible vision loss and prioritization of treatment visits over monitoring visits where possible. In order to limit patient exposure, ophthalmologists should refrain from using treatment regimens that require frequent monitoring. CONCLUSION: Management of patients with retinal disease receiving intravitreal injections during the COVID-19 pandemic will require adjustment to regular clinical practice to minimize the risk of exposure of patients and healthcare staff, and to prioritize those with the greatest medical need. The safety of patients and healthcare staff should be of paramount importance in all decision-making.

CURRENT CONCEPTS AND MODALITIES FOR MONITORING THE FELLOW EYE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: An Expert Panel Consensus.

PURPOSE: The presence of neovascular age-related macular degeneration (nAMD) in one eye is a major risk factor for the development of disease in the fellow eye. Several methods exist to help physicians monitor the fellow eye, with new technologies becoming increasingly available. METHODS: We provide an overview of modalities for nAMD monitoring, including advances in home-based options, and review their utility for fellow-eye monitoring, based on a review of the literature and a consensus of retinal experts. RESULTS: Studies demonstrate the importance of early detection of nAMD in the fellow eye so that interventions can be made before significant vision loss occurs. A series of techniques exist for the early detection of nAMD including chart-based methods and imaging devices. The increased availability of home-based methods has presented an opportunity for patients to monitor their vision at home. CONCLUSION: Frequent monitoring of the fellow eye in patients with unilateral nAMD is of critical importance to prevent vision loss and maintain quality of life. Patients should be examined every 3 to 4 months from the time of choroidal neovascularization diagnosis and encouraged to monitor their vision at home using home-based technologies where available, to provide the best opportunity for early detection.

Association between diabetic eye disease and other complications of diabetes: Implications for care. A systematic review.

The aim of this systematic review was to examine the associations between diabetic retinopathy (DR) and the common micro- and macrovascular complications of diabetes mellitus, and how these could potentially affect clinical practice. A structured search of the PubMed database identified studies of patients with diabetes that assessed the presence or development of DR in conjunction with other vascular complications of diabetes. From 70 included studies, we found that DR is consistently associated with other complications of diabetes, with the severity of DR linked to a higher risk of the presence of, or of developing, other micro- and macrovascular complications. In particular, DR increases the likelihood of having or developing nephropathy and is also a strong predictor of stroke and cardiovascular disease, and progression of DR significantly increases this risk. Proliferative DR is a strong risk factor for peripheral arterial disease, which carries a risk of lower extremity ulceration and amputation. Additionally, our findings suggest that a patient with DR has an overall worse prognosis than a patient without DR. In conclusion, this analysis highlights the need for a coordinated and collaborative approach to patient management. Given the widespread use of DR screening programmes that can be performed outside of an ophthalmology office, and the overall cost-effectiveness of DR screening, the presence and severity of DR can be a means of identifying patients at increased risk for micro- and macrovascular complications, enabling earlier detection, referral and intervention with the aim of reducing morbidity and mortality among patients with diabetes. Healthcare professionals involved in the management of diabetes should encourage regular DR screening.

Posttranslational proteolytic processing of Leda-1/Pianp involves cleavage by MMPs, ADAM10/17 and gamma-secretase.

Leda-1/Pianp is a type I transmembrane protein expressed by CNS cells, murine melanoma cell line B16F10 and rat liver sinusoidal endothelial cells. The early steps of posttranslational modifications of Leda-1/Pianp have been described to include glycosylation and processing by proprotein convertases. Here, we comprehensively characterized the subsequent steps of proteolytic processing of Leda-1/Pianp. For this purpose specific protease inhibitors and cell lines deficient in PS1, PS2, PS1/PS2 and ADAM10/17 were deployed. Leda-1/Pianp was cleaved at numerous cleavage sites within the N-terminal extracellular domain. The sheddases involved included MMPs and ADAM10/17. Ectodomain shedding yielded C-terminal fragments (CTF) of ∼15 kDa. The CTF was further processed by the γ (gamma)-secretase complex to generate the intracellular domain (ICD) of ∼10 kDa. Although PS1 was the dominant intramembrane protease, PS2 was also able to cleave Leda-1/Pianp in the absence of PS1. Thus, Leda-1/Pianp is constitutively processed by proprotein convertases, sheddases including MMPs and ADAM10/17 and intramembrane protease γ-secretase.

Counter-regulation of the ligand-receptor pair Leda-1/Pianp and Pilrα during the LPS-mediated immune response of murine macrophages.

Liver endothelial differentiation-associated protein-1 (Leda-1/Pianp) is a type-I-transmembrane protein that is able to bind and activate immune inhibitory receptor Pilrα. Here we show that Leda-1/Pianp is strain-specifically expressed in lymphoid organs and macrophages of Th2-prone BALB/c mice but not of Th1-prone C57BL/6J mice. LPS stimulation of BALB/c bone marrow-derived macrophages (BMM) and macrophage-like Raw 264.7 cells conversely regulated Leda-1/Pianp and Pilrα expression. Pilrα induction was caused by LPS-mediated transcriptional modulation and increased mRNA expression. On the other hand, the LPS-mediated decline of Leda-1/Pianp expression was the result of proteolytic degradation by matrix metalloproteinases. In summary, these findings demonstrate that counter-regulation of the ligand-receptor pair Leda-1/Pianp and Pilrα is part of the complex innate immune response of macrophages and its genetically determined strain-specific modulation.

Peripheral retinal function assessed with 30-Hz flicker seems to improve after treatment with Lucentis in patients with diabetic macular oedema.

PURPOSE: To evaluate the influence of ranibizumab on the multifocal electroretinogram (Mf-ERG), full-field electroretinogram (Ff-ERG) and optical coherence tomography (OCT) in diabetic eyes (n = 20) with macular oedema. METHODS: In 20 eyes (20 diabetic subjects) with no or background diabetic retinopathy and macular oedema (age 65.7 ± 9.8 years, duration 16.5 ± 10.0 years), the change in ETDRS letters, Mf-ERG, Ff-ERG and OCT was analysed, at baseline, 4 weeks after the first injection, (just before the second injection), and 4 weeks after the last injection with ranibizumab. RESULTS: From baseline, mean BCVA improved from 64.0 ± 10.0 ETDRS letters to 75.0 ± 7.3 ETDRS letters (p = 0.005) 1 month after the last injection. Mean OCT thickness reduced after the first injection from 418 ± 117 to 311 ± 126 µm; (p = 0.001) and to 302 ± 74 µm after the third injection. Mf-ERG demonstrated in the innermost three rings a shorter implicit time after the first injection with p values of 0.002, 0.005 and 0.017, respectively. After the third injection, implicit time was prolonged to almost the original levels. Cone implicit time with 30-Hz flicker improved significantly between baseline (35.5 ± 3.6 ms) and final follow-up (34.6 ± 3.1 ms) (p = 0.04). DISCUSSION: Though the central retinal thickness was reduced after three injections of ranibizumab and the subjects gained a mean of 11 ETDRS letters, there was no significant change in amplitude or implicit time in Mf-ERG. The shortened 30-Hz flicker implicit time might imply that ranibizumab has no negative impact on the entire peripheral cone function, but can improve it instead.

The prognosis of diabetic retinopathy in patients with type 2 diabetes since 1996-1998: the Skaraborg Diabetes Register.

Diabetes mellitus is the main reason for visual impairment among patients of working ages. The aim of this paper was to investigate the prognosis of eye complications in patients with diabetes during 10 years of follow-up and contributing risk factors. Data from ophthalmological records (occurrence of retinopathy and laser treatment and visual acuity), and clinical data (blood pressure, glycosylated hemoglobin (HbA1c), body mass index (BMI), and antihypertensive treatment) from the Skaraborg Diabetes Register were retrieved in the Skaraborg Screening Program of 1,258 patients diagnosed during 1996-1998. Kaplan Meyer survival analysis and Log Rank test were used to analyze eye complications in 773 patients with type 2 diabetes and ≤70 years at diagnosis. Visual acuity was above the limit for driving license in 96 % of 548 patients and only nineteen patients were treated by laser. At diagnosis of diabetes, mean HbA1c was 6.7 ± 1.7 % (59 ± 7.1 mmol/mol), and systolic blood pressure was 142.9 ± 0.7 mmHg; neither changed significantly during follow-up. Retinopathy appeared about 1 year, and maculopathy 2 years earlier, if HbA1c ≥ 7 % (63 mmol/mol) at diagnosis (p < 0.001 and p < 0.006). Antihypertensive treatment, higher BMI, and higher age at diagnosis were associated with less retinopathy during follow-up. Most patients with diabetes develop little retinopathy for the first 10 years after diagnosis. High HbA1c at baseline was associated with retinopathy and maculopathy during follow-up. Antihypertensive treatment, probably a proxy for regular controls and early detection of diabetes, was associated with less retinopathy.

Rationale and Design of VOYAGER: Long-term Outcomes of Faricimab and Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema in Clinical Practice.

Purpose: To describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision. Design: Primary data collection, noninterventional, prospective, multinational, multicenter clinical practice study. Participants: At least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries). Methods: Management will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions. Main Outcome Measures: Primary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety. Results: Recruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually. Conclusions: VOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Proteolytic cleavage of LEDA-1/PIANP by furin-like proprotein convertases precedes its plasma membrane localization.

Liver endothelial differentiation-associated protein-1 (LEDA-1/PIANP) is a type-I-transmembrane protein first identified by us as a putative junctional protein in liver sinusoidal endothelial cells. Others have shown that LEDA-1/PIANP binds and activates immune inhibitory receptor PILRα in trans, a process that requires sialidation of LEDA-1/PIANP. Here we show that LEDA-1/PIANP is subject to O-glycosylation and sialidation as demonstrated in brain tissue as well as in LEDA-1 expressing cell lines by using anti-LEDA-1/PIANP C-terminal antibodies. In addition, analysis of LEDA-1/PIANP processing with His-tags inserted at different positions in the extracellular domain revealed that multiple steps of proteolytic cleavage occur during maturation of the protein. Proteolytic cleavage between aa59 and aa83 preceded sorting of the protein to the plasma membrane. Deletion of aa75-79 and inhibition with Furin inhibitor I confirmed that LEDA-1/PIANP is processed by a Furin-like proprotein convertase. In summary, these findings show that Furin-like proprotein convertase-dependent processing precedes plasma membrane localization of LEDA-1/PIANP that is a pre-requisite of functional receptor-ligand interactions in vitro and in vivo.

Deficiency for scavenger receptors Stabilin-1 and Stabilin-2 leads to age-dependent renal and hepatic depositions of fasciclin domain proteins TGFBI and Periostin in mice.

Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are two major scavenger receptors of liver sinusoidal endothelial cells that mediate removal of diverse molecules from the plasma. Double-knockout mice (Stab-DKO) develop impaired kidney function and a decreased lifespan, while single Stabilin deficiency or therapeutic inhibition ameliorates atherosclerosis and Stab1-inhibition is subject of clinical trials in immuno-oncology. Although POSTN and TFGBI have recently been described as novel Stabilin ligands, the dynamics and functional implications of these ligands have not been comprehensively studied. Immunofluorescence, Western Blotting and Simple Western™ as well as in situ hybridization (RNAScope™) and qRT-PCR were used to analyze transcription levels and tissue distribution of POSTN and TGFBI in Stab-KO mice. Stab-POSTN-Triple deficient mice were generated to assess kidney and liver fibrosis and function in young and aged mice. TGFBI and POSTN protein accumulated in liver tissue in Stab-DKO mice and age-dependent in glomeruli of Stabilin-deficient mice despite unchanged transcriptional levels. Stab-POSTN-Triple KO mice showed glomerulofibrosis and a reduced lifespan comparable to Stab-DKO mice. However, alterations of the glomerular diameter and vascular density were partially normalized in Stab-POSTN-Triple KO. TGFBI and POSTN are Stabilin-ligands that are deposited in an age-dependent manner in the kidneys and liver due to insufficient scavenging in the liver. Functionally, POSTN might partially contribute to the observed renal phenotype in Stab-DKO mice. This study provides details on downstream effects how Stabilin dysfunction affects organ function on a molecular and functional level.

In diabetic eyes, multifocal ERG reflects differences in function between the nasal part and the temporal part of the macula.

PURPOSE: The purpose of the present study was to compare retinal function between the perifoveal nasal and perifoveal temporal areas of diabetic eyes using multifocalERG (mfERG). METHODS: We included 36 eyes from 27 patients with diabetes (age 58 ± 14 years; duration of diabetes 13 ± 9 years; HbA(1c) 7.1 ± 1.8%) and a control group with 18 eyes from 18 healthy subjects (age 57 ± 11 years). Retinal thickness was assessed with optical coherence tomography (OCT) in the perifoveal areas corresponding to the summed nasal and temporal inner and outer areas. MfERG amplitude and implicit time were recorded from corresponding areas. RESULTS: Diabetic eyes showed lower mfERG amplitude in the nasal area than in the temporal area (14 ± 6 vs 17 ± 7 nV/deg(2); p < 0.0001) and longer implicit time (31 ± 3 vs 30 ± 3 ms; p = 0.005). In the control group, there were no significant differences between the two areas. CONCLUSION: Diabetic eyes showed lower amplitude and longer implicit time in the nasal area than in the temporal, which might indicate that the nasal area is more vulnerable. These findings may be of importance for evaluation of diabetic maculopathy and outcome after laser treatment.

What about the fellow eye in treatment of neovascular age-related macular degeneration? Analysis of data from the Swedish macula register.

PURPOSE: To analyse the development of neovascular age-related macular degeneration (nAMD) in the fellow eye in patients initially presenting with unilateral nAMD, using data from the Swedish Macula Register. METHODS: This observational study included data on treatment-naïve patients who initially underwent unilateral treatment for nAMD, and then required bilateral treatment, between 2010 and 2018, according to the Swedish Macula Register (SMR). The data were also stratified according into three time periods (2010-2013; 2014-2016; 2017-2018). Treatment duration, best-corrected visual acuity (BCVA) in the first and second eye, number of injections in the first eye before falling ill in the second, and the time between the last injection in the first eye and the start of treatment of the fellow eye were analysed. RESULTS: 5216 out of 28 670 (18%) patients treated for nAMD subsequently required bilateral treatment. The mean age was 77.7 ± 7.3 years, and 69% were female. The mean duration of treatment of the first eye before nAMD was diagnosed in the fellow eye was 1.58 years, and the mean number of injections in the first eye was 8.9 ± 8.6. Best-corrected visual acuity, according to the ETDRS chart, was higher in the second eye at the time when treatment started in that eye compared to treatment start in the first eye: 62.8 (14.7) versus 57.6 (15.5); p < 0.001, and was higher in the 66% whose first eye was still undergoing treatment: 63.6 ± 14.5 versus 61.0 ± 14.8; p = 0.001. CONCLUSIONS: The mean duration of treatment of the first eye before treatment started in the fellow eye was 19 months, and treatment of the second eye had started within 2 years in 61% of the patients. Best-corrected visual acuity was higher in the second eye than in the first eye at the start of treatment of that eye and was higher in the second eye at the start of treatment of that eye when the first eye was still being treated.

Exploration of real-world outcomes and treatment patterns in patients treated with anti-vascular endothelial growth factors for neovascular age-related macular degeneration in Sweden.

PURPOSE: To analyse and compare the number and interval of anti-vascular endothelial growth factor (anti-VEGF) injections in neovascular age-related macular degeneration (nAMD), as well as the visual development in patients followed up for one to three years in clinical practice and during different index periods. METHODS: This observational study included treatment-naïve eyes with nAMD from the Swedish Macula Register that started treatment between 2007 and 2017, stratified by different index periods (2007-2010, 2011-2013, 2014-2015 and 2016-2017) and by follow-up cohorts for each index period of one, two or three years (cohorts 1-3). Their intravitreal anti-VEGF treatment was assessed by number of injections, injection intervals, visual acuity (VA) and near VA change. RESULTS: From the earliest index period 2007-2010 to the latest 2016-2017, the number of injections increased for the comparable follow-up time; 6.2 ± 1.4 versus 8.3 ± 2.0 injections after 1 year of treatment, 4.8 ± 1.6 versus 6.7 ± 2.4 during year 2. The last injection interval was 73 ± 34 days after 1, 71 ± 33 after 2 and 67 ± 32 after 3 years of follow-up for the index period 2014-2015. For the same period, the percentage of eyes with at least two consecutive 12-16 weeks of injection interval over 1-, 2- and 3-year follow-up increased from 5.2%, 15.0%, to 17.5% respectively. Baseline VA for eyes indexed 2016-2017 increased and presented with 62.1 ± 13.4 letters compared with 57.7 ± 13.5 letters in 2007-2010; p < 0.0001. CONCLUSIONS: From the earliest to the latest index periods, the number of injections increased for the comparable follow-up time. Accordingly, baseline VA and near VA and their outcomes improved continuously.

A novel tool to assess the quality of RWE to guide the management of retinal disease.

Despite the growing importance of real-world evidence (RWE) for guiding clinical decisions in retinal disease, there is currently no widely used guidance available for assessing the quality and relevance of RWE studies in ophthalmology. This paper summarizes the development of a user-friendly tool that facilitates assessment of the quality of available RWE for neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME) and retinal vein occlusion (RVO). A literature search was conducted to identify tools developed to assess the quality of RWE, in order to identify the most appropriate framework on which to base this tool. The Good Research for Comparative Effectiveness (GRACE) guidelines was chosen for this purpose as it is designed to assess the quality of observational studies and has been extensively validated, including demonstration of strong sensitivity and specificity. The GRACE guidelines were adapted to develop a straightforward tabular tool that allows simple assessment and comparison of the quality of published evidence in retinal disease for researchers and physicians alike, and includes guidance on treatment details, outcome measures, study population, and controlling for bias. The newly developed tool provides a simple method to support assessment of the strength of evidence and certainty of conclusions drawn from RWE in retinal disease, to ensure clinical decision-making is influenced by the highest quality evidence.

Using multifocal electroretinography hard exudates affect macular function in eyes with diabetic retinopathy.

UNLABELLED: To evaluate the influence of hard exudates on macular function in patients with diabetic retinopathy. METHODS: Thirty seven eyes from 27 diabetic patients, aged 57 +/- 14 years, diabetes duration 12.5 +/- 9 years, not previously treated with photocoagulation, underwent fundus photography, multifocal electroretinography (mfERG) and optical coherence tomography (OCT). Hard exudates were graded from fundus photography with superimposed OCT and a superimposed hexagonal pattern (mfERG) by one retinal specialist, unaware of mfERG and OCT results. We defined three groups; A = eyes with exudates in the analyzed zone, B = eyes with no exudates in the analyzed zone but elsewhere, and C = eyes with no exudates. The mfERG responses and OCT values from five defined areas in the macula were compared. RESULTS: MfERG showed that the implicit time was significantly prolonged in group A compared to group C in the central, middle and outer areas and in the nasal and temporal area (p = 0.045, 0.019, 0.017 and 0.035 and 0.016 respectively), in group B compared to group C in the central area (p = 0.016), and in group A compared to group B in the outer area (p = 0.035). Amplitude differed between group A and C in the middle area and outer area (14.2 +/- 5.2 nV/deg(2) vs 21.1 +/- 8.7 nV/deg(2), p = 0.037 and 14.1 +/- 3.9 nV/deg(2) vs 17.7 +/- 7.1 nV/deg(2) , p = 0.02 respectively), and between group B and C in the temporal area 14.5 +/- 2.2 nV/deg(2) vs 20.0 +/- 8.7 nV/deg(2), p = 0.017). Macular thickness assessed with OCT was similar between the groups. CONCLUSIONS: In eyes with diabetic retinopathy, hard exudates prolong the implicit time assessed with mfERG, compared to eyes without hard exudates, and independently of macular thickness. These results indicate that the hard exudates in the macular region, even at a distance from the fovea centre, have a deleterious effect on macular function.