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    Research update: Issue 500

    The latest research highlights for 7 June 2021.

    7 June 2021


    Defining Nonadherence and Nonpersistence to Anti-Vascular Endothelial Growth Factor Therapies in Neovascular Age-Related Macular Degeneration

    JAMA Ophthalmol. 2021 Jun 3.

    Mali Okada, Tien Yin Wong, Paul Mitchell, Bora Eldem, S James Talks, Tariq Aslam, Vincent Daien, Francisco J Rodriguez, Richard Gale, Jane Barratt, Robert P Finger, Anat Loewenstein  

    PMID: 34081099 DOI: 10.1001/jamaophthalmol.2021.1660

    Importance: Poor adherence or persistence to treatment can be a barrier to optimizing clinical practice (real-world) outcomes to intravitreal injection therapy in patients with neovascular age-related macular degeneration (nAMD). Currently, there is a lack of consensus on the definition and classification of adherence specific to this context.

    Objective: To describe the development and validation of terminology on patient nonadherence and nonpersistence to anti-vascular endothelial growth factor therapy.

    Design, setting, and participants: Following a systematic review of currently used terminology in the literature, a subcommittee panel of retinal experts developed a set of definitions and classification for validation. Definitions were restricted to use in patients with nAMD requiring intravitreal anti-vascular endothelial growth factor therapy. Validation by the full nAMD Barometer Leadership Coalition was established using a modified Delphi approach, with predetermined mean scores of 7.5 or more signifying consensus. Subsequent endorsement of the definitions was provided from a second set of retinal experts, with more than 50% members agreeing or strongly agreeing with all definitions.

    Main outcomes and measures: Development of consensus definitions for the terms adherence and persistence and a classification system for the factors associated with treatment nonadherence or nonpersistence in patients with nAMD.

    Results: Nonadherence was defined as missing 2 or more treatment or monitoring visits over a period of 12 months, with a visit considered missed if it exceeded more than 2 weeks from the recommended date. Nonpersistence was defined by nonattendance or an appointment not scheduled within the last 6 months. The additional terms planned discontinuation and transfer of care were also established. Reasons for treatment nonadherence and nonpersistence were classified into 6 dimensions: (1) patient associated, (2) condition associated, (3) therapy associated, (4) health system and health care team associated, (5) social/economic, and (6) other, with subcategories specific to treatment for nAMD.

    Conclusions and relevance: This classification system provides a framework for assessing treatment nonadherence and nonpersistence over time and across different health settings in the treatment of nAMD with current intravitreal anti-vascular endothelial growth factor treatments. This may have additional importance, given the potential association of the coronavirus pandemic on adherence to treatment in patients with nAMD.

    Questionnaire for the assessment of adherence barriers of intravitreal therapy: the ABQ-IVT

    Int J Retina Vitreous. 2021 Jun 2;7(1):43.

    Sabrina Müller, Sophia Junker, Thomas Wilke, Albrecht Lommatzsch, Alexander K Schuster, Hakan Kaymak, Christoph Ehlken, Focke Ziemssen  

    PMID: 34078475 PMCID: PMC8170736 DOI: 10.1186/s40942-021-00311-x

    Objective: To develop and validate a questionnaire for the investigation of non-adherence (NA) barriers in patients receiving intravitreal injection (IVT).

    Design: Questionnaire development and cross-sectional patient survey combined with a retrospective medical chart review.

    Participants: German patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) receiving anti-vascular endothelial growth factor (anti-VEGF) treatment via IVT.

    Methods: The previously validated (indications: atrial fibrillation, human immunodeficiency virus, chronic inflammatory lung disease) Adherence Barriers Questionnaire (ABQ) was revised according to specifications of IVT, within the framework of an expert panel. The ABQ-IVT, which initially consisted of 24 items formulated as statements (4-point-Likert-scale ranging from “strongly agree” to “strongly disagree”), was applied in a cross-sectional survey. Evaluation of the questionnaire included an assessment of internal consistency and factor analysis. The occurrence of potential barriers in the patient sample was evaluated using descriptive statistics. To identify patient subpopulations, hierarchical cluster analysis was performed using ABQ-IVT answers as predictors. Due to difficulties in capturing NA as an external criterion, the evaluation of the questionnaire was limited to its internal validity and reliability.

    Main outcome measures: Patients’ answers to the ABQ-IVT questionnaire and interviews.

    Results: Of 253 patients, 234 (92%) were able to complete the ABQ-IVT questionnaire. Within the reliability analysis, the ABQ-IVT was reduced to 17 items. The condensed questionnaire demonstrated good internal consistency (Cronbach’s alpha = 0.78), and factor analysis showed no evidence for subscales of the questionnaire. Nearly half of the patients (49%) reported being affected by at least three different barriers. On average, a patient was affected by 3.1 barriers. The most frequently reported barriers were “Challenge due to time commitment of physician visits” (45% of the patients), “Depression” (29%) and “Travel and opportunity costs” (27%). Cluster analysis identified six patient subpopulations, each affected by different sets of barriers and differed regarding their patient characteristics.

    Conclusions: The ABQ-IVT is a practical and reliable instrument for identifying patient-specific barriers to IVT treatment adherence. In practice, the questionnaire may be useful in assessing whether individual patients are at higher risk of NA due to specific adherence barriers. Aside from better awareness, this allows earlier interventions, though these still need to be validated. Patient subpopulations face different barriers and may, therefore, need distinct preventative care.

    Results of Intravitreal Anti-Vascular Endothelial Growth Factor Therapy in Inflammatory Choroidal Neovascularization

    J Curr Ophthalmol. 2021 Mar 26;33(1):68-74.

    Sourour Zina, Sana Khochtali, Alessandro Invernizzi, Imen Ksiaa, Ben Amor Hager, Francesco Viola, Nesrine Abroug, Moncef Khairallah  

    PMID: 34084960 PMCID: PMC8102949 DOI: 10.4103/JOCO.JOCO_128_20

    Purpose: To report the visual outcomes of intravitreal (IVT) anti-vascular endothelial growth factor (anti-VEGF) in inflammatory choroidal neovascularization (iCNV).

    Methods: A retrospective study of 43 eyes of 38 patients with active choroidal neovascularization (CNV) related to ocular inflammatory disease, treated with IVT injections of anti-VEGF (bevacizumab, ranibizumab, or aflibercept), with or without associated systemic anti-inflammatory therapy, at Fattouma Bourguiba University Hospital, Monastir, Tunisia (24 eyes of 23 patients) and at Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy (19 eyes of 15 patients) from January 1, 2013, to December 31, 2018.

    Results: The mean age was 35.5 ± 16.4 years. The sex ratio male:female was 0.27. Seventeen eyes (39.5%) of 17 patients (44.7%) had only anti-VEGF injections, and 26 eyes (60.5%) of 21 patients (45.3%) had anti-VEGF injections and associated systemic anti-inflammatory therapy. Bevacizumab was injected in 36 eyes (83.7%), ranibizumab in six eyes (14%), and aflibercept in one eye (2.3%). Mean follow-up was 20.3 ± 19.2 months (range, 6-106 months). Mean visual acuity improved from 0.8 ± 0.37 logMAR (approximate Snellen equivalent 20/125) to 0.51 ± 0.42 logMAR (approximate Snellen equivalent 20/63) (P < 0.001). Mean central macular thickness on optical coherence tomography decreased from 403.7 ± 121.9 to 293.7 ± 82.8 μm (P < 0.001). Mean gain of vision was 2.9 ± 3.1 lines. The mean number of injections was 2.5. Twenty eyes (46.5%) received a single injection. There were no side effects related to the IVT injections of anti-VEGF.

    Conclusions: CNV is a sight-threatening complication of uveitis. IVT anti-VEGF seems to be an effective and safe treatment for iCNV when inflammation is controlled.

    2-Year Real-World Outcomes with Intravitreal Aflibercept in Neovascular Age-Related Macular Degeneration: Literature Review and Meta-analysis of Patient-Relevant Outcomes

    Ophthalmol Ther. 2021 Jun 1.

    Joao Carrasco, Vincent Daien, Bora M Eldem, Jelle A Spoorendonk, Jisu Yoon  

    PMID: 34075564 DOI: 10.1007/s40123-021-00350-5

    Background: The 96 weeks’ assessment from the VIEW studies provided insights into the long-term efficacy of intravitreal aflibercept (IVT-AFL) in neovascular age-related macular degeneration (nAMD) and demonstrated that it was possible to maintain long-term outcomes while moving from a fixed bimonthly regimen in Year 1 to a variable dosing regimen in Year 2. The aim of this analysis was to perform a literature review and meta-analysis assessing the use of IVT-AFL and real-world outcomes in treatment-naïve patients with nAMD treated with IVT-AFL for 2 years, as per label.

    Methods: A literature review and meta-analysis were performed to provide an overview of the baseline characteristics of the population, the 2-year outcomes, the associated treatment burden, and safety.

    Results: Eleven publications providing data from patients with nAMD who had treatment initiated with IVT-AFL between 2012 and 2016 were identified. The mean baseline age of patients was 78.62 years, with a baseline best-corrected visual acuity (BCVA) of 57.73 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Patients reported a mean BCVA at 2 years of 62.55 ETDRS letters, with 47.39% of patients having a BCVA ≥ 70 ETDRS letters. Mean gain in BCVA versus baseline was + 4.49 ETDRS letters for the combined population (+ 5.91 letters for patients treated with a treat-and-extend regimen). Over the 2 years of the study, patients received an average of 12.34 injections, with a reduction in injections in Year 2 versus Year 1. The qualitative assessment of the safety data suggested that no new safety signals were identified.

    Conclusion: Patients treated with IVT-AFL reported significant gains in visual acuity versus baseline after 2 years. The evidence identified indicates that the visual gains achieved during the first year of treatment are maintained through the second year and that these were achieved with a reduction in the mean number of IVT-AFL injections administered in Year 2 of treatment.

    Brolucizumab for Choroidal Neovascular Membrane with Pigment Epithelial Tear and Subretinal Fluid

    J Clin Med. 2021 May 30;10(11):2425.

    Alper Bilgic, Laurent Kodjikian, Shail Vasavada, Shyamal Jha, Samaresh Srivastava, Aditya Sudhalkar, Thibaud Mathis  

    PMID: 34070774 DOI: 10.3390/jcm10112425

    The aim of this study was to determine the utility of brolucizumab in the management of choroidal neovessels (CNV) with a retinal pigment epithelial (RPE) tear and subretinal fluid. We used a case series of patients with CNV who developed an RPE tear either spontaneously or following an intravitreal injection. All patients received intravitreal brolucizumab as primary or switch therapy. Appropriate data were collected. Follow-up was one year. The paired t-test was used to determine the significance of the results. The primary outcome measure was the change in best corrected visual acuity (BCVA). Secondary outcome measures were the change in subretinal fluid and complications, if any. A total of five patients were included in the analysis. The age range was 67-74 years and baseline BCVA was from 20/80 to 20/100. On average, all patients showed improvement in BCVA (p = 0.012) and also showed a significant anatomical improvement (p = 0.03). None of the patients had any complications, and all patients responded to additional anti-VEGF injections. In conclusion, all patients showed significant visual and anatomical improvement with brolucizumab; no complications were noted. All patients, including those who received switch, demonstrated a favorable anatomical and visual response to intravitreal brolucizumab without safety concerns.

    Evaluation of Blood Coagulation Parameters and ADMA, NO, IL-6, and IL-18 Serum Levels in Patients with Neovascular AMD before, during, and after the Initial Loading Phase of Intravitreal Aflibercept

    Life (Basel). 2021 May 14;11(5):441.

    Michał Wiciński, Małgorzata Seredyka-Burduk, Sławomir Liberski, Daria Marczak, Magdalena Pol, Bartosz Malinowski, Katarzyna Pawlak-Osińska, Bartlomiej J Kaluzny  

    PMID: 34069173 PMCID: PMC8156295 DOI: 10.3390/life11050441

    We evaluated the effect of intravitreal injections of aflibercept (IVA) on blood coagulation parameters including prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT), as well as asymmetric dimethylarginine (ADMA), nitric oxide (NO), interleukin 6 (IL-6), and interleukin 18 (IL-18) serum levels in patients with neovascular AMD (nAMD). Twenty-two eyes of 22 patients with nAMD were included. Parameters were evaluated before and 2-3 days after the first IVA injection, and then immediately before and 2-3 days after the third IVA injection. We revealed prolongation of the TT after the initial loading phase of IVA (p = 0.041) and a significant increase in IL-18 serum concentration immediately before the third IVA administration compared to baseline (p = 0.037). There were no statistically significant differences of other parameters and PT, APTT, ADMA, NO, and IL-6 values remained within the normal range at each of the time points of the study. Our results suggest that repeated IVA administration may affect the common blood coagulation pathway, which manifests as a prolongation of the TT value. Furthermore, we showed a significant increase in serum concentration of the pro-inflammatory cytokineIL-18during the initial loading phase of IVA.

    Impurities in Drug Vials Intended for Intravitreal Medication

    Case Rep Ophthalmol Med. 2020 Dec 2;2020:8824585.

    Lisa Pohl, Lisa Strudel, Spyridon Dimopoulos, Focke Ziemssen  

    PMID: 34055435 PMCID: PMC8142807 DOI: 10.1155/2020/8824585

    Sterility is an important prerequisite for minimizing the risk of severe vision loss due to endophthalmitis after intravitreal injections. We describe three cases series of incidents where an unclear contamination of the drug solution or syringe caused the injection process to stop and continue with a new preparation. During a period of 12 months with 30,502 intravitreal injections at a tertiary center, wherein 7,076 were of the drug Aflibercept drawn up from a glass vial, three cases of the critical incident reporting system relating to intravitreal injections were identified: (1) After a typical contact with the filter cannula, the glass of an Aflibercept vial was no longer intact. (2) In the course of another injection, there was a clear deposition of debris on the outer edge of the syringe when removing the attached filter cannula. (3) After inserting the syringe into the rubber top of the vial, a whitish particle of unclear origin was identified within the drug solution. Later, this contamination/particle was identified as part of the greyish rubber that was punched out with the cannula, according to the analyses of the material sent in and the manufacturer’s investigations. Thus, even in busy clinics, visual inspection of the injection solution and materials used for impurities, preferably before and after pulling them out of a vial, must be an essential part of the injection process. Even when using ready-to-use prefilled syringes (PFS), vigilance must be kept high, knowing the risk of potential contamination.


    Assessment of Patients’ Confidence Regarding a New Triage Concept in a Medical Retina Clinic during the First COVID-19 Outbreak

    Int J Environ Res Public Health. 2021 May 29;18(11):5846.

    Anahita Bajka, Maximilian Robert Justus Wiest, Timothy Hamann, Mario Damiano Toro, Sandrine Anne Zweifel 

    PMID: 34072435 DOI: 10.3390/ijerph18115846

    Background: During the first COVID-19 pandemic outbreak, a new triage concept had to be implemented for patients with retinal diseases having a scheduled appointment at the medical retina clinic. In this study, we aimed to assess patients’ confidence in this triage concept and patients’ satisfaction regarding the received treatment during the outbreak.

    Methods: This retrospective study included all patients with a diagnosed retinal disease, triaged into three priority groups based on their condition’s urgency during lockdown. After restrictions were eased, a subset of previously triaged patients was interviewed to assess their confidence in the triage and their satisfaction regarding the received treatment during the pandemic.

    Results: In total, 743 patients were triaged during the lockdown. Over 80% received an urgent appointment (priority 1). Among all priority 1 patients, over 84% attended their appointment and 77% received an intravitreal injection (IVI), while 7% cancelled their appointment due to COVID-19. In post-lockdown interviews of 254 patients, 90% trusted the emergency regimen and received treatment.

    Conclusions: Our triage seemed to be useful in optimizing access to treatment for patients with retinal diseases. An excellent rating of patients’ confidence in the triage and satisfaction regarding the received treatment during the first COVID-19 outbreak could be achieved.


    Outer retinal layer thickening predicts the onset of exudative neovascular age related macular degeneration: Outer retinal thickening predicts neovascular AMD

    Am J Ophthalmol. 2021 May 28;S0002-9394(21)00308-1.

    Alessandro Invernizzi, Salvatore Parrulli, Davide Monteduro, Matteo G Cereda, Vuong Nguyen, Giovanni Staurenghi, Chui Ming Gemmy Cheung, Mark Gillies, Kelvin Yi Chong Teo  

    PMID: 34058152 DOI: 10.1016/j.ajo.2021.05.015

    Objective: To assess changes in outer retinal layer (ORL) thickness before the development of exudative macular neovascularization (MNV) in eyes with age-related macular degeneration (AMD).

    Design: Retrospective observational case series Methods: Eyes with AMD that eventually developed exudative MNV followed with sequential optical coherence tomography (OCT) for at least two years before the exudation occurred were enrolled. The ORL thickness was automatically calculated by the OCT software for each sector of the early treatment diabetic retinopathy study map at each follow-up visit. The ORL thickness change from baseline to the day when the exudative MNV developed was compared between sectors that eventually developed exudative MNV and those that did not.

    Results: 47 eyes (47 patients) were included. At baseline (24±3 months before exudative MNV), mean[SD] ORL thickness of sectors which eventually developed exudative MNV was similar to that of sectors that did not (85.2[8.2]µm vs 86.8[5.7]µm, p=0.08). ORL thickness significantly increased in sectors that developed exudative MNV compared to those that did not (+5.8 [10.4]µm vs -2.8 [3.6]µm, p<0.01). The regression model based on these data predicted an increase in ORL thickness from baseline of +4.2% 55 days and +11.1% 30 days before exudative MNV was detected. The ORL thickness of areas that did not develop exudative MNV did not change.

    Conclusions: Thickening of the ORL begins in the area where exudative MNV will develop long before the exudation, accelerating significantly in the last 2 months. The occurrence of exudative MNV could be predicted by 2 months using this simple analysis.

    RetFluidNet: Retinal Fluid Segmentation for SD-OCT Images Using Convolutional Neural Network

    J Digit Imaging. 2021 Jun 2.

    Loza Bekalo Sappa, Idowu Paul Okuwobi, Mingchao Li, Yuhan Zhang, Sha Xie, Songtao Yuan, Qiang Chen  

    PMID: 34080105 DOI: 10.1007/s10278-021-00459-w

    Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness and is characterized by fluid-related accumulations such as intra-retinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED). Spectral-domain optical coherence tomography (SD-OCT) is the primary modality used to diagnose AMD, yet it does not have algorithms that directly detect and quantify the fluid. This work presents an improved convolutional neural network (CNN)-based architecture called RetFluidNet to segment three types of fluid abnormalities from SD-OCT images. The model assimilates different skip-connect operations and atrous spatial pyramid pooling (ASPP) to integrate multi-scale contextual information; thus, achieving the best performance. This work also investigates between consequential and comparatively inconsequential hyperparameters and skip-connect techniques for fluid segmentation from the SD-OCT image to indicate the starting choice for future related researches. RetFluidNet was trained and tested on SD-OCT images from 124 patients and achieved an accuracy of 80.05%, 92.74%, and 95.53% for IRF, PED, and SRF, respectively. RetFluidNet showed significant improvement over competitive works to be clinically applicable in reasonable accuracy and time efficiency. RetFluidNet is a fully automated method that can support early detection and follow-up of AMD.

    Correlation Between Choriocapillaris Density and Retinal Sensitivity in Age-Related Macular Degeneration

    Transl Vis Sci Technol. 2021 Jun 1;10(7):2.

    Luigi Di Perna, Paolo Melillo, Carlo Gesualdo, Filomena Palmieri, Francesco Testa, Mario Bifani, Settimio Rossi, Francesca Simonelli 

    PMID: 34061948 DOI: 10.1167/tvst.10.7.2

    Purpose: The purpose of this study was to investigate the relationship between perfusion of the choriocapillaris (CC) and retinal sensitivity in eyes with intermediate age-related macular degeneration (iAMD).

    Methods: This prospective study included patients with iAMD and healthy controls. All enrolled subjects underwent optical coherence tomography angiography (OCT-A) in order to compute the percent perfused choriocapillaris area (PPCA). In patients with iAMD, microperimetry (MP) testing was performed in order to quantify: mean retinal sensitivity (MRS), over an area of 10 degrees; mean macular sensitivity (MMS), over the macular area scanned with OCT-A; and retinal sensitivity (RS) in each macular point.

    Results: Eighteen eyes of 13 patients were included in the analysis. In addition, 18 eyes of 12 healthy subjects were enrolled as controls. No statistically significant difference (P value > 0.2) was observed in age between patients (73.9 ± 2.0 years) and controls (70.1 ± 2.8 years). We observed significantly lower values of PPCA between patients with iAMD and healthy controls (42.0% ± 3.8% vs. 66.4% ± 3.0%; -β = 23.8%; P value < 0.001). Among iAMD eyes, higher values of PPCA were significantly associated with higher values of MRS (P value = 0.002) and MMS (P value = 0.013). Finally, higher values of RS in each macular point analyzed with MP were significantly (P value < 0.001) associated with higher values of PPCA computed in circular regions of interest (ROIs) centered in each analyzed MP point with radii of 0.5 degrees and 1.0 degree.

    Conclusions: Using OCT-A, we demonstrated a significant association between CC impairment and macular dysfunction, quantified by MP, in iAMD eyes.

    Translational relevance: OCT-A could be a useful tool for detecting CC alterations and to monitor disease progression.

    A Multimodal Imaging-Based Deep Learning Model for Detecting Treatment-Requiring Retinal Vascular Diseases: Model Development and Validation Study

    JMIR Med Inform. 2021 May 31;9(5):e28868.

    Eugene Yu-Chuan Kang, Ling Yeung, Yi-Lun Lee, Cheng-Hsiu Wu, Shu-Yen Peng, Yueh-Peng Chen, Quan-Ze Gao, Chihung Lin, Chang-Fu Kuo, Chi-Chun Lai  

    PMID: 34057419 DOI: 10.2196/28868

    Background: Retinal vascular diseases, including diabetic macular edema (DME), neovascular age-related macular degeneration (nAMD), myopic choroidal neovascularization (mCNV), and branch and central retinal vein occlusion (BRVO/CRVO), are considered vision-threatening eye diseases. However, accurate diagnosis depends on multimodal imaging and the expertise of retinal ophthalmologists.

    Objective: The aim of this study was to develop a deep learning model to detect treatment-requiring retinal vascular diseases using multimodal imaging.

    Methods: This retrospective study enrolled participants with multimodal ophthalmic imaging data from 3 hospitals in Taiwan from 2013 to 2019. Eye-related images were used, including those obtained through retinal fundus photography, optical coherence tomography (OCT), and fluorescein angiography with or without indocyanine green angiography (FA/ICGA). A deep learning model was constructed for detecting DME, nAMD, mCNV, BRVO, and CRVO and identifying treatment-requiring diseases. Model performance was evaluated and is presented as the area under the curve (AUC) for each receiver operating characteristic curve.

    Results: A total of 2992 eyes of 2185 patients were studied, with 239, 1209, 1008, 211, 189, and 136 eyes in the control, DME, nAMD, mCNV, BRVO, and CRVO groups, respectively. Among them, 1898 eyes required treatment. The eyes were divided into training, validation, and testing groups in a 5:1:1 ratio. In total, 5117 retinal fundus photos, 9316 OCT images, and 20,922 FA/ICGA images were used. The AUCs for detecting mCNV, DME, nAMD, BRVO, and CRVO were 0.996, 0.995, 0.990, 0.959, and 0.988, respectively. The AUC for detecting treatment-requiring diseases was 0.969. From the heat maps, we observed that the model could identify retinal vascular diseases.

    Conclusions: Our study developed a deep learning model to detect retinal diseases using multimodal ophthalmic imaging. Furthermore, the model demonstrated good performance in detecting treatment-requiring retinal diseases.


    The role of retinal fluid location in atrophy and fibrosis evolution of patients with neovascular age-related macular degeneration long-term treated in real world

    Acta Ophthalmol. 2021 Jun 4.

    Sara Llorente-González, Maria Hernandez, Jorge González-Zamora, Valentina Bilbao-Malavé, Patricia Fernández-Robredo, Manuel Saenz-de-Viteri, Jesús Barrio-Barrio, María José Rodríguez-Cid, Juan Donate, Francisco J Ascaso, Ana M Gómez-Ramírez, Javier Araiz, Félix Armadá, Óscar Ruiz-Moreno, Sergio Recalde, Alfredo García-Layana, Spanish AMD group

    PMID: 34085771 DOI: 10.1111/aos.14905

    Purpose: To assess the effect of clinical factors on the development and progression of atrophy and fibrosis in patients with neovascular age-related macular degeneration (nAMD) receiving long-term treatment in the real world.

    Methods: An ambispective 36-month multicentre study, involving 359 nAMD patients from 17 Spanish hospitals treated according to the Spanish Vitreoretinal Society guidelines, was designed. The influence of demographic and clinical factors, including the presence and location of retinal fluid, on best-corrected visual acuity (BCVA) and progression to atrophy and/or fibrosis were analysed.

    Results: After 36 months of follow-up and an average of 13.8 anti-VEGF intravitreal injections, the average BCVA gain was +1.5 letters, and atrophy and/or fibrosis were present in 54.8% of nAMD patients (OR = 8.54, 95% CI = 5.85-12.47, compared to baseline). Atrophy was associated with basal intraretinal fluid (IRF) (OR = 1.87, 95% CI = 1.09-3.20), whereas basal subretinal fluid (SRF) was associated with a lower rate of atrophy (OR = 0.40, 95% CI = 0.23-0.71) and its progression (OR = 0.44, 95% CI = 0.26-0.75), leading to a slow progression rate (OR = 0.34, 95% CI = 0.14-0.83). Fibrosis development and progression were related to IRF at any visit (p < 0.001). In contrast, 36-month SRF was related to a lower rate of fibrosis (OR = 0.49, 95% CI = 0.29-0.81) and its progression (OR = 0.50, 95% CI = 0.31-0.81).

    Conclusion: Atrophy and/or fibrosis were present in 1 of 2 nAMD patients treated for 3 years. Both, especially fibrosis, lead to vision loss. Subretinal fluid (SRF) was associated with good visual outcomes and lower rates of atrophy and fibrosis, whereas IRF yields worse visual results and a higher risk of atrophy and especially fibrosis in routine clinical practice.

    TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells

    Int J Mol Sci. 2021 May 5;22(9):4875.

    Sofia Ranta-Aho, Niina Piippo, Eveliina Korhonen, Kai Kaarniranta, Maria Hytti, Anu Kauppinen  

    PMID: 34062977 PMCID: PMC8125426 DOI: 10.3390/ijms22094875

    Chronic inflammation has been associated with several chronic diseases, such as age-related macular degeneration (AMD). The NLRP3 inflammasome is a central proinflammatory signaling complex that triggers caspase-1 activation leading to the maturation of IL-1β. We have previously shown that the inhibition of the chaperone protein, Hsp90, prevents NLRP3 activation in human retinal pigment epithelial (RPE) cells; these are cells which play a central role in the pathogenesis of AMD. In that study, we used a well-known Hsp90 inhibitor geldanamycin, but it cannot be used as a therapy due to its adverse effects, including ocular toxicity. Here, we have tested the effects of a novel Hsp90 inhibitor, TAS-116, on NLRP3 activation using geldanamycin as a reference compound. Using our existing protocol, inflammasome activation was induced in IL-1α-primed ARPE-19 cells with the proteasome and autophagy inhibitors MG-132 and bafilomycin A1, respectively. Intracellular caspase-1 activity was determined using a commercial caspase-1 activity kit and the FLICA assay. The levels of IL-1β were measured from cell culture medium samples by ELISA. Cell viability was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and lactate dehydrogenase (LDH) measurements. Our findings show that TAS-116 could prevent the activation of caspase-1, subsequently reducing the release of mature IL-1β. TAS-116 has a better in vitro therapeutic index than geldanamycin. In summary, TAS-116 appears to be a well-tolerated Hsp90 inhibitor, with the capability to prevent the activation of the NLRP3 inflammasome in human RPE cells.

    Serum levels of ARMS2, COL8A1, RAD51B, and VEGF and their correlations in Age-Related Macular Degeneration

    Curr Neurovasc Res. 2021 May 31.

    Priya Battu, Kaushal Sharma, Manjari Rain, Ramandeep Singh, Akshay Anand  

    PMID: 34060991 DOI: 10.2174/1567202618666210531130711

    Background: Many factors including genetic and environmental are responsible for the incidence of age-related macular degeneration (AMD). However, its pathogenesis has not been clearly elucidated yet.

    Objective: This study aimed to estimate the Age-Related Maculopathy Susceptibility 2 (ARMS2), Collagen type VIII Alpha 1 chain (COL8A1), Rad 51 paralog(RAD51B), and Vascular Endothelial Growth Factor (VEGF) protein levels in serum of AMD and control participants and to further investigate their correlation to understand AMD pathogenesis.

    Methods: For this cross-sectional study, 31 healthy control and 57 AMD patients were recruited from Advanced Eye Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India. A blood sample was taken and serum was isolated from it. ELISA(enzyme-linked immunosorbent assay)was used for the estimation of proteins in the serum of patients.

    Results: ARMS2 and COL8A1 levels were significantly elevated in the AMD group than in the control group. The highest levels of ARMS2, COL8A1, and VEGF proteins were recorded for the wet AMD sub-group. The study results endorsed significant positive correlation between these following molecules; ARMS2 and COL8A1 (r=0.933, p<0.0001), ARMS2 and RAD51B (r=0.704, p<0.0001), ARMS2 and VEGF (r=0.925, p<0.0001), COL8A1 and RAD51B (r=0.736, p<0.0001), COL8A1 and VEGF (r=0.879, p<0.0001),and RAD51B and VEGF (r=0.691, p<0.0001).

    Conclusion: The ARMS2 and COL8A1 levels were significantly higher and RAD51B was significantly lower in the AMD group than controls. Also, a significant statistical correlation was detected between these molecules, indicating that their interaction may be involved in the pathogenesis of AMD.

    The correlation between cytokine levels in the aqueous humor and the prognostic value of anti-vascular endothelial growth factor therapy for treating macular edema resulting from retinal vein occlusion

    Graefes Arch Clin Exp Ophthalmol. 2021 Jun 1.

    Hongfang Yong, Hui Qi, Hongtao Yan, Qianqian Wu, Ling Zuo  

    PMID: 34059950 DOI: 10.1007/s00417-021-05211-2

    Purpose: To determine the correlation between aqueous humor cytokine levels and the prognostic value of anti-vascular endothelial growth factor (VEGF) therapy for treating macular edema resulting from retinal vein occlusion (RVO-ME).

    Methods: This prospective study included 47 RVO-ME and 32 senile cataract cases. Aqueous humor collection was performed in patients with RVO-ME before intravitreal injection of ranibizumab and in patients before cataract surgery. VEGF, monocyte chemotactic protein 1 (MCP-1), interleukin (IL)-8, IL-6, basic fibroblast growth factor (b-FGF), and tumor necrosis factor-α (TNF-α) levels were measured in the aqueous humor. Central retinal thickness (CRT) was measured before ranibizumab treatment and during each follow-up visit. The recovery rate following ranibizumab treatment was calculated as (CRTBT-CRTAT1W)/CRTBT, in which CRTBT was the CRT measured before treatment and CRTAT1W was measured 1 week after treatment. The recurrence time of RVO-ME was recorded.

    Results: VEGF, MCP-1, IL-8, and IL-6 levels in the aqueous humor of patients with RVO-ME were significantly higher compared with control and were positively correlated with the CRTBT. Ranibizumab significantly reduced CRT, and VEGF levels positively correlated with the recovery rate. The mean recurrence time of RVO-ME was 43.5 days. IL-6 levels negatively correlated with the recurrence time of ME.

    Conclusion: VEGF, MCP-1, IL-8, and IL-6 levels were significantly increased in patients with RVO-ME and were positively correlated with ME. Higher VEGF levels were indicative of CRT recovery, and higher IL-6 levels were indicative of ME recurrence after ranibizumab treatment.

    The P300/XBP1s/Herpud1 axis promotes macrophage M2 polarization and the development of choroidal neovascularization

    J Cell Mol Med. 2021 May 31.

    Wendie Li, Ying Wang, Linling Zhu, Shu Du, Jinghai Mao, Yanyan Wang, Sangsang Wang, Qingyun Bo, Yuanyuan Tu, QuanYong Yi  

    PMID: 34057287 DOI: 10.1111/jcmm.16673

    Neovascular age-related macular degeneration (AMD), which is characterized by choroidal neovascularization (CNV), leads to vision loss. M2 macrophages produce vascular endothelial growth factor (VEGF), which aggravates CNV formation. The histone acetyltransferase p300 enhances the stability of spliced X-box binding protein 1 (XBP1s) and promotes the transcriptional activity of the XBP1s target gene homocysteine inducible endoplasmic reticulum protein with ubiquitin-like domain 1 (Herpud1). Herpud1 promotes the M2 polarization of macrophages. This study aimed to explore the roles of the p300/XBP1s/Herpud1 axis in the polarization of macrophages and the pathogenesis of CNV. Hypoxia-induced p300 interacted with XBP1s to acetylate XBP1s in RAW264.7 cells. Additionally, hypoxia-induced p300 enhanced the XBP-1s-mediated unfolded protein response (UPR), alleviated the proteasome-dependent degradation of XBP1s and enhanced the transcriptional activity of XBP1s for Herpud1. The hypoxia-induced p300/XBP1s/Herpud1 axis facilitated RAW264.7 cell M2 polarization. Knockdown of the p300/XBP1s/Herpud1 axis in RAW264.7 cells inhibited the proliferation, migration and tube formation of mouse choroidal endothelial cells (MCECs). The p300/XBP1s/Herpud1 axis increased in infiltrating M2-type macrophages in mouse laser-induced CNV lesions. Blockade of the p300/XBP1s/Herpud1 axis inhibited macrophage M2 polarization and alleviated CNV lesions. Our study demonstrated that the p300/XBP1s/Herpud1 axis in infiltrating macrophages increased the M2 polarization of macrophages and the development of CNV.


    Early and late stage gene therapy interventions for inherited retinal degenerations

    Prog Retin Eye Res. 2021 May 28;100975.

    Catherine Botto, Marco Rucli, Müge Defne Tekinsoy, Juliette Pulman, José-Alain Sahel, Deniz Dalkara 

    PMID: 34058340 DOI: 10.1016/j.preteyeres.2021.100975

    Inherited and age-related retinal degeneration is the hallmark of a large group of heterogeneous diseases and is the main cause of untreatable blindness today. Genetic factors play a major pathogenic role in retinal degenerations for both monogenic diseases (such as retinitis pigmentosa) and complex diseases with established genetic risk factors (such as age-related macular degeneration). Progress in genotyping techniques and back of the eye imaging are completing our understanding of these diseases and their manifestations in patient populations suffering from retinal degenerations. It is clear that whatever the genetic cause, the majority of vision loss in retinal diseases results from the loss of photoreceptor function. The timing and circumstances surrounding the loss of photoreceptor function determine the adequate therapeutic approach to use for each patient. Among such approaches, gene therapy is rapidly becoming a therapeutic reality applicable in the clinic. This massive move from laboratory work towards clinical application has been propelled by the advances in our understanding of disease genetics and mechanisms, gene delivery vectors, gene editing systems, and compensatory strategies for loss of photoreceptor function. Here, we provide an overview of existing modalities of retinal gene therapy and their relevance based on the needs of patient populations suffering from inherited retinal degenerations.

    EyeDiseases: an integrated resource for dedicating to genetic variants, gene expression and epigenetic factors of human eye diseases

    NAR Genom Bioinform. 2021 Jun 1;3(2):lqab050.

    Jian Yuan, Fukun Chen, Dandan Fan, Qi Jiang, Zhengbo Xue, Ji Zhang, Xiangyi Yu, Kai Li, Jia Qu, Jianzhong Su 

    PMID: 34085038 PMCID: PMC8168129 DOI: 10.1093/nargab/lqab050

    Eye diseases are remarkably common and encompass a large and diverse range of morbidities that affect different components of the visual system and visual function. With advances in omics technology of eye disorders, genome-scale datasets have been rapidly accumulated in genetics and epigenetics field. However, the efficient collection and comprehensive analysis of different kinds of omics data are lacking. Herein, we developed EyeDiseases (, the first database for multi-omics data integration and interpretation of human eyes diseases. It contains 1344 disease-associated genes with genetic variation, 1774 transcription files of bulk cell expression and single-cell RNA-seq, 105 epigenomics data across 185 kinds of human eye diseases. Using EyeDiseases, we investigated SARS-CoV-2 potential tropism in eye infection and found that the SARS-CoV-2 entry factors, ACE2 and TMPRSS2 are highly correlated with cornea and keratoconus, suggest that ocular surface cells are susceptible to infection by SARS-CoV-2. Additionally, integrating analysis of Age-related macular degeneration (AMD) GWAS loci and co-expression data revealed 9 associated genes involved in HIF-1 signaling pathway and voltage-gate potassium channel complex. The EyeDiseases provides a valuable resource for accelerating the discovery and validation of candidate loci and genes contributed to the molecular diagnosis and therapeutic vulnerabilities with various eyes diseases.

    Novel EDGE encoding method enhances ability to identify genetic interactions

    PLoS Genet. 2021 Jun 4;17(6):e1009534.

    Molly A Hall, John Wallace, Anastasia M Lucas, Yuki Bradford, Shefali S Verma, Bertram Müller-Myhsok, Kristin Passero, Jiayan Zhou, John McGuigan, Beibei Jiang, Sarah A Pendergrass, Yanfei Zhang, Peggy Peissig, Murray Brilliant, Patrick Sleiman, Hakon Hakonarson, John B Harley, Krzysztof Kiryluk, Kristel Van Steen, Jason H Moore, Marylyn D Ritchie  

    PMID: 34086673 DOI: 10.1371/journal.pgen.1009534

    Assumptions are made about the genetic model of single nucleotide polymorphisms (SNPs) when choosing a traditional genetic encoding: additive, dominant, and recessive. Furthermore, SNPs across the genome are unlikely to demonstrate identical genetic models. However, running SNP-SNP interaction analyses with every combination of encodings raises the multiple testing burden. Here, we present a novel and flexible encoding for genetic interactions, the elastic data-driven genetic encoding (EDGE), in which SNPs are assigned a heterozygous value based on the genetic model they demonstrate in a dataset prior to interaction testing. We assessed the power of EDGE to detect genetic interactions using 29 combinations of simulated genetic models and found it outperformed the traditional encoding methods across 10%, 30%, and 50% minor allele frequencies (MAFs). Further, EDGE maintained a low false-positive rate, while additive and dominant encodings demonstrated inflation. We evaluated EDGE and the traditional encodings with genetic data from the Electronic Medical Records and Genomics (eMERGE) Network for five phenotypes: age-related macular degeneration (AMD), age-related cataract, glaucoma, type 2 diabetes (T2D), and resistant hypertension. A multi-encoding genome-wide association study (GWAS) for each phenotype was performed using the traditional encodings, and the top results of the multi-encoding GWAS were considered for SNP-SNP interaction using the traditional encodings and EDGE. EDGE identified a novel SNP-SNP interaction for age-related cataract that no other method identified: rs7787286 (MAF: 0.041; intergenic region of chromosome 7)-rs4695885 (MAF: 0.34; intergenic region of chromosome 4) with a Bonferroni LRT p of 0.018. A SNP-SNP interaction was found in data from the UK Biobank within 25 kb of these SNPs using the recessive encoding: rs60374751 (MAF: 0.030) and rs6843594 (MAF: 0.34) (Bonferroni LRT p: 0.026). We recommend using EDGE to flexibly detect interactions between SNPs exhibiting diverse action.

    Long-term outcome of neovascular age-related macular degeneration: association between treatment outcome and major risk alleles

    Br J Ophthalmol. 2021 Jun 2;bjophthalmol-2021-319054.

    Brice Nguedia Vofo, Gala Beykin, Jaime Levy, Itay Chowers  

    PMID: 34083208 DOI: 10.1136/bjophthalmol-2021-319054

    Aims: To evaluate the long-term functional and anatomical outcomes of neovascular age-related macular degeneration (nvAMD) treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) for up to 10 years, and to identify associated risk factors.

    Methods: Clinical and optical coherence tomography findings were retrieved for nvAMD cases treated with intravitreal anti-VEGF compounds using a treat-and-extend protocol. In addition, the major risk alleles for AMD in the CFH (rs1061170), HTRA1 (rs1200638) and C3 (rs2230199) genes were genotyped.

    Results: From 276 eligible eyes in 206 patients, 80 eyes (29%) in 66 patients (32.0%) had a follow-up period of ≥8 years and were included in this study. Over a 10-year period, 73.3±28.0 (mean±SD) anti-VEGF injections were administered. Best-corrected visual acuity (BCVA; LogMAR) deteriorated from 0.55±0.53 at baseline to 1.00±0.73 at 10 years (p<0.0005). Central subfield thickness (CST) decreased from 415.8±162.1 µm at baseline to 323±113.6 µm (p<0.0005) after three monthly injections and remained lower than baseline throughout the follow-up period. Visual outcome was associated with BCVA and intraretinal fluid (IRF) at baseline, macular atrophy, and macular thinning at follow-up. The decrease in CST was inversely correlated with the number of CFH and/or C3 risk alleles carried by the patient (Pearson’s r: -0.608; p=0.003).

    Conclusions: Patients with nvAMD who received anti-VEGF therapy for 10 years developed substantial vision loss associated with the presence of IRF at baseline and macular atrophy. Major risk alleles for AMD in two complement genes were associated with a reduced long-term reduction in macular thickness.


    An electro-conductive hybrid scaffold as an artificial Bruch’s membrane

    Mater Sci Eng C Mater Biol Appl. 2021 Jul;126:112180.

    Maedeh Khodamoradi, Mahnaz Eskandari, Hamid Keshvari, Reza Zarei  

    PMID: 34082980 DOI: 10.1016/j.msec.2021.112180

    Many research groups have investigated the various kinds of scaffolds to mimic the natural Bruch’s membrane (BM) and support the retinal pigmented epithelial cells to form an organized cellular monolayer. While using prosthetic BM is identified as a promising treatment of age-related macular degeneration (AMD), a degenerative and progressive retinal disease, the effects of different signals such as electrical and morphological cues on the retinal pigmented epithelial (RPE) cells are still unknown. In this study, a laminated and conductive hydrogel/fiber composite scaffold by adding conductive polyaniline (PANi) to the scaffold’s nanofibrous phase was prepared. This hybrid scaffold offers the closest morphology to the native structure of the human Bruch’s membrane by imitating the inner and outer collagenous layer and induces the electrical signal to the scaffold to assess the electrical cue on behaviors of polarized retinal pigmented epithelial cells in the retina. The electrospun nanofibrous phase consisted of gelatin-Polyaniline in different ratios incorporated into the hydrogel precursor, a blend of gelatin and 4-armed PEG. We used a novel dual crosslinking process by incorporating the exposure of gamma irradiation and glutaraldehyde vapor treatment to construct the scaffold’s hydrogel phase. The results showed the best composition was the sample which included the 40/60, Polyaniline/gelatin nanofiber sheets ratio because this scaffold revealed a 2.66 ± 0.33 MPa, Young’s modulus and 1.84 ± 0.21 S/cm, electrochemical conductivity, which are close to the main features of native Bruch’s membrane. In addition, this scaffold showed good biocompatibility by reaching 83.47% cell viability.

    An Electro-spun Tri-component Polymer Biomaterial with Optoelectronic Properties for Neuronal Differentiation

    Acta Biomater. 2021 May 31;S1742-7061(21)00346-9.

    Bowei Yuan, Monir Riasad Fadle Aziz, Shuhong Li, Jun Wu, Dongmei Li, Ren-Ke Li  

    PMID: 34082104 DOI: 10.1016/j.actbio.2021.05.036

    Optoelectronic biomaterials have recently emerged as a potential treatment option for neurodegenerative diseases, such as optic macular degeneration. Though initial works in the field have involved bulk heterojunctions mimicking solar panels with photovoltaics (PVs) and conductive polymers (CPs), recent developments have considered abandoning CPs in such systems. Here, we developed a simple antioxidant, biocompatible, and fibrous membrane heterojunction composed of photoactive polymer poly(3-hexylthiophene) (P3HT), polycaprolactone (PCL) and polypyrrole (PPY), to facilitate neurogenesis of PC-12 cells when photo-stimulated in vitro. The photoactive prototype, referred to as PCL-P3HT/PPY, was fabricated via polymerization of pyrrole on electro-spun PCL-P3HT nanofibers to form a membrane. Four experimental groups, namely PCL alone, PCL/PPY, PCL-P3HT and PCL-P3HT/PPY, were tested. In the absence of the CP, PCL-P3HT demonstrated lower cell survival due to increased intracellular reactive oxygen/nitrogen species production. PCL-P3HT/PPY rescued these cells by virtue of scavenging radicals, where the CP, PPY, acted as an antioxidant. Apart from having lower impedance, the material also enhanced neurogenesis of PC-12 cells when photo-stimulated, compared to the traditional PCL-P3HT. Lastly, the in vitro system with PC-12 was used to demonstrate the practicality of the material for potential use as a cellular patch in optic and nerve regeneration. This work demonstrated the importance of maintaining PV-CP heterojunctions while simultaneously providing an optoelectrical platform for neural and optical tissue engineering. STATEMENT OF SIGNIFICANCE: : Regeneration and repair of injured nervous systems have always been a major clinical challenge. Stem cell therapy is a promising approach for nerve regeneration, and opto-electrical stimulation, which converts light into an electrical signal, has been shown to efficiently regulate stem cell behaviors with enhanced neurogenesis. We developed a micro-fibrous membrane, composed of photoactive polymer, P3HT, scaffold material PCL and conductive polymer PPY. Our heterojunction system improved cell survival via PPY quenching PCL-P3HT-generated cell-damaging reactive oxygen species. PPY also conducted electrons produced from light-stimulated P3HT to promote neurogenesis. This photoactive microfiber biomaterial has great potential as a highly biocompatible and efficient platform to wirelessly promote neurogenesis and survival. Our approach thus showed possibilities with respect to optical tissue engineering.


    Searching for the Antioxidant, Anti-Inflammatory, and Neuroprotective Potential of Natural Food and Nutritional Supplements for Ocular Health in the Mediterranean Population

    Foods. 2021 May 28;10(6):1231.

    Mar Valero-Vello, Cristina Peris-Martínez, José J García-Medina, Silvia M Sanz-González, Ana I Ramírez, José A Fernández-Albarral, David Galarreta-Mira, Vicente Zanón-Moreno, Ricardo P Casaroli-Marano, María D Pinazo-Duran 

    PMID: 34071459 DOI: 10.3390/foods10061231

     Adherence to a healthy diet offers a valuable intervention to compete against the increasing cases of ocular diseases worldwide, such as dry eye disorders, myopia progression, cataracts, glaucoma, diabetic retinopathy, or age macular degeneration. Certain amounts of micronutrients must be daily provided for proper functioning of the visual system, such as vitamins, carotenoids, trace metals and omega-3 fatty acids. Among natural foods, the following have to be considered for boosting eye/vision health: fish, meat, eggs, nuts, legumes, citrus fruits, nuts, leafy green vegetables, orange-colored fruits/vegetables, olives-olive oil, and dairy products. Nutritional supplements have received much attention as potential tools for managing chronic-degenerative ocular diseases. A systematic search of PubMed, Web of Science, hand-searched publications and historical archives were performed by the professionals involved in this study, to include peer-reviewed articles in which natural food, nutrient content, and its potential relationship with ocular health. Five ophthalmologists and two researchers collected the characteristics, quality and suitability of the above studies. Finally, 177 publications from 1983 to 2021 were enclosed, mainly related to natural food, Mediterranean diet (MedDiet) and nutraceutic supplementation. For the first time, original studies with broccoli and tigernut (chufa de Valencia) regarding the ocular surface dysfunction, macular degeneration, diabetic retinopathy and glaucoma were enclosed. These can add value to the diet, counteract nutritional defects, and help in the early stages, as well as in the course of ophthalmic pathologies. The main purpose of this review, enclosed in the Special Issue “Health Benefits and Nutritional Quality of Fruits, Nuts and Vegetables,” is to identify directions for further research on the role of diet and nutrition in the eyes and vision, and the potential antioxidant, anti-inflammatory and neuroprotective effects of natural food (broccoli, saffron, tigernuts and walnuts), the Mediterranean Diet, and nutraceutic supplements that may supply a promising and highly affordable scenario for patients at risk of vision loss. This review work was designed and carried out by a multidisciplinary group involved in ophthalmology and ophthalmic research and especially in nutritional ophthalmology.

    Sleeping pattern and activities of daily living modulate protein expression in AMD

    PLoS One. 2021 Jun 1;16(6):e0248523.

    Kaushal Sharma, Ramandeep Singh, Suresh Kumar Sharma, Akshay Anand 

    PMID: 34061866 DOI: 10.1371/journal.pone.0248523

    Degeneration of macular photoreceptors is a prominent characteristic of age-related macular degeneration (AMD) which leads to devastating and irreversible vision loss in the elderly population. In this exploratory study, the contribution of environmental factors on the progression of AMD pathology by probing the expression of candidate proteins was analyzed. Four hundred and sixty four participants were recruited in the study comprising of AMD (n = 277) and controls (n = 187). Genetics related data was analyzed to demonstrate the activities of daily living (ADL) by using regression analysis and statistical modeling, including contrast estimate, multinomial regression analysis in AMD progression. Regression analysis revealed contribution of smoking, alcohol, and sleeping hours on AMD by altered expression of IER-3, HTRA1, B3GALTL, LIPC and TIMP3 as compared to normal levels. Contrast estimate supports the gender polarization phenomenon in AMD by significant decreased expression of SLC16A8 and LIPC in control population which was found to be unaltered in AMD patients. The smoking, food habits and duration of night sleeping hours also contributed in AMD progression as evident from multinomial regression analysis. Predicted model (prediction estimate = 86.7%) also indicated the crucial role of night sleeping hours along with the decreased expression of TIMP-3, IER3 and SLC16A8. Results revealed an unambiguous role of environmental factors in AMD progression mediated by various regulatory proteins which might result in intermittent AMD phenotypes and possibly influence the outcome of anti-VEGF treatment.

    Comparison of Antioxidant Properties of Dehydrolutein with Lutein and Zeaxanthin, and their Effects on Cultured Retinal Pigment Epithelial Cells

    Antioxidants (Basel). 2021 May 10;10(5):753.

    Małgorzata B Różanowska, Barbara Czuba-Pelech, John T Landrum, Bartosz Różanowski  

    PMID: 34068492 PMCID: PMC8151661 DOI: 10.3390/antiox10050753

    Dehydrolutein accumulates in substantial concentrations in the retina. The aim of this study was to compare antioxidant properties of dehydrolutein with other retinal carotenoids, lutein, and zeaxanthin, and their effects on ARPE-19 cells. The time-resolved detection of characteristic singlet oxygen phosphorescence was used to compare the singlet oxygen quenching rate constants of dehydrolutein, lutein, and zeaxanthin. The effects of these carotenoids on photosensitized oxidation were tested in liposomes, where photo-oxidation was induced by light in the presence of photosensitizers, and monitored by oximetry. To compare the uptake of dehydrolutein, lutein, and zeaxanthin, ARPE-19 cells were incubated with carotenoids for up to 19 days, and carotenoid contents were determined by spectrophotometry in cell extracts. To investigate the effects of carotenoids on photocytotoxicity, cells were exposed to light in the presence of rose bengal or all-trans-retinal. The results demonstrate that the rate constants for singlet oxygen quenching are 0.77 × 1010, 0.55 × 1010, and 1.23 × 1010 M-1s-1 for dehydrolutein, lutein, and zeaxanthin, respectively. Overall, dehydrolutein is similar to lutein or zeaxanthin in the protection of lipids against photosensitized oxidation. ARPE-19 cells accumulate substantial amounts of both zeaxanthin and lutein, but no detectable amounts of dehydrolutein. Cells pre-incubated with carotenoids are equally susceptible to photosensitized damage as cells without carotenoids. Carotenoids provided to cells together with the extracellular photosensitizers offer partial protection against photodamage. In conclusion, the antioxidant properties of dehydrolutein are similar to lutein and zeaxanthin. The mechanism responsible for its lack of accumulation in ARPE-19 cells deserves further investigation.

    Anti-inflammatory role of curcumin in retinal disorders (Review)

    Exp Ther Med. 2021 Jul;22(1):790.

    Federica Franzone, Marcella Nebbioso, Tiziano Pergolizzi, Giuseppe Attanasio, Angela Musacchio, Antonio Greco, Paolo Giuseppe Limoli, Marco Artico, Demetrios A Spandidos, Samanta Taurone, Enzo Agostinelli 

    PMID: 34055089 PMCID: PMC8145690 DOI: 10.3892/etm.2021.10222

    Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-hepta-1,6-diene-3,5-dione], the main component of turmeric (Curcuma longa, a flowering plant of the ginger family, Zingiberaceae), is known to possess different pharmacological activities, particularly anti-inflammatory and antioxidant properties. Since an underlying inflammatory process exists in several ocular conditions, such as anterior uveitis, glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR), the aim of the present review was to summarize the pleiotropic effects exerted by this molecule, focusing in particular on its beneficial role in retinal diseases. The anti-inflammatory activity of curcumin has also been described in numerous systemic inflammatory pathologies and tumors. Specifically, the biological, pharmaceutical and nutraceutical properties of curcumin are associated with its ability to downregulate the expression of the following genes: IκBα, cyclooxygenase 2, prostaglandin E2, interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor-α. According to this finding, curcumin may be useful in the treatment of some retinal disorders. In DR, proliferative vitreoretinopathy and AMD, beneficial effects have been observed following treatment with curcumin, including slowing down of the inflammatory process. Despite the aforementioned evidence, the main disadvantage of this substance is that it possesses a low solubility, as well as poor oral bioavailability due to its reduced absorption, rapid metabolism and rapid elimination. Therefore, several curcumin analogues have been synthesized and tested over the years, in order to improve the possible obtainable therapeutic effects. The purpose of the present review was to identify new aspects that could guide future research on this important traditional medicine, which is a well-tolerated natural product, and is widely considered safe and economical.

    Patients’ perceptions of visual impairment associated with smoking: A cross-sectional study of a United Kingdom tertiary eye centre

    Eur J Ophthalmol. 2021 May 31;11206721211020647.

    Diya Baker, Onyinye Akpenyi, Haris Shahzad, Faye Mellington  

    PMID: 34053334 DOI: 10.1177/11206721211020647

    Smoking is a well-established risk factor for several eye disorders including cataracts and age-related macular degeneration. While many individuals are informed of the various adverse health effects, there is limited research into patients’ awareness of the relationship between smoking and eye disease and the potential impact this might have on reducing smoking behaviour. Our findings document the low level of awareness of the risk of blindness from smoking at a tertiary eye unit in the United Kingdom and highlight the need for increased involvement from eye care professionals, alongside health campaigns to educate the public of this consequence of smoking.


    An Innovatory Surgical Technique for Submacular Hemorrhage Displacement by Means of a Bioengineering Perspective

    Vision (Basel). 2021 May 18;5(2):23.

    George Pappas, Nectarios Vidakis, Markos Petousis, Vasiliki Kounali, Apostolos Korlos 

    PMID: 34069949 PMCID: PMC8163192 DOI: 10.3390/vision5020023

    The purpose of this case report is to present a new surgical technique for the treatment of large Subretinal Hemorrhage (SRH) secondary to Age-related Macular Degeneration (AMD). Considering the biomechanics of foam evolution theory, bubble coarsening effect, and gas-liquid biphasic absorption, an SRH due to an AMD case was treated with vitrectomy. The treatment was implemented by subretinal injection of air bubbles combined with rtPA followed by air fluid exchange. The air bubbles helped mess up and remove the blood from the macula area, and no complications occurred. Two weeks postoperatively, there was no sign of hemorrhage and the Central Macular Thickness (CMT) was sharply decreased from 443 μm to 317 μm. At the five-month follow-up, the CMT remained at 267 μm and the patient’s visual acuity improved from light perception to 20/70 according to the Snellen chart. The combination of injecting multiple air bubbles and submacular rtPA, followed by air fluid exchange, was able to displace more than (90%) of the subretinal blood just two weeks postoperatively. Our technique is a promising alternative surgical approach for the displacement of SMH due to AMD, with a clear visual and anatomical benefit seen in the early follow-up period.