Neighborhood-Level Social Determinants of Health and Presenting Characteristics for Rhegmatogenous Retinal Detachments.

Importance: Functional outcomes after repair of rhegmatogenous retinal detachments (RRDs) are highly dependent on baseline visual acuity and foveal status. Adverse social determinants of health (SDOH) can present barriers to timely presentation for repair and limit vision outcomes. Objective: To evaluate the association between neighborhood-level SDOH with baseline severity (visual acuity and fovea status) of RRD. Design, Setting, and Participants: This was a retrospective cohort study that included adult patients 18 years and older who underwent primary repair of uncomplicated RRD at the Wilmer Eye Institute from January 2008 to December 2018. Study data were analyzed from December 2023 to April 2024. Exposures: The census block group of patient home addresses were matched to multiple neighborhood-level SDOH including the Area Deprivation Index (ADI), per capita income, percentage of renters, percentage of rent burden, percentage of people using a food assistance program, percentage of uninsured individuals, mode of transportation to work, distance to the nearest transit stop, total road density, National Walkability Index, Index of Medical Underservice score, and aggregate cost of medical care. Main Outcomes and Measures: Odds of presenting with vision worse than 20/40 or fovea-involving RRD using multivariable logistic regression adjusting for age, sex, race and ethnicity, and insurance. Results: A total of 700 patients (mean [SD] age, 57.9 [12.4] years; 432 male [61.7%]) were included. Every decile increase in ADI, indicating more socioeconomic disadvantage, was associated with an increased odds of presenting with worse visual acuity and fovea-involving RRD (odds ratio [OR], 1.14; 95% CI, 1.04-1.24; P = .004 and OR, 1.13; 95% CI, 1.04-1.22; P = .005, respectively). Each $1000 increase in per capita income was associated with lower odds of presenting with worse vision (OR, 0.99; 95% CI, 0.98-0.99; P = .001). Every 1% increase in percentage of workers who drove to work was associated with an increased odds of presenting with worse vision and fovea-involving RRD (OR, 1.02; 95% CI, 1.01-1.03; P = .005 and OR, 1.01; 95% CI, 1.00-1.03; P = .04, respectively). Conclusions and Relevance: Results of this cohort study suggest that patients with a residence in neighborhoods with more socioeconomic deprivation or a higher percentage of workers who drove to work were more likely to present with more severe RRD even after accounting for multiple individual-level characteristics. These findings support consideration of public policy changes to address the barriers faced by patients residing in certain neighborhoods who seek prompt surgical intervention for RRD to reduce health disparities in RRD outcomes.

SURGICAL OUTCOMES OF RETINAL DETACHMENT ASSOCIATED WITH PROLIFERATIVE SICKLE CELL RETINOPATHY.

PURPOSE: To evaluate the long-term anatomic and visual outcomes in eyes with sickle cell retinopathy-related retinal detachments (RDs). METHODS: Patients who underwent surgery for sickle cell retinopathy-related RDs at the Wilmer Eye Institute or Wills Eye Hospital between 2008 and 2020 and followed for at least 6 months postoperatively were retrospectively reviewed. The primary outcome was the rate of single-surgery anatomic success and final reattachment. RESULTS: This study included 30 eyes from 28 patients (16 women and 12 men) with tractional RD (n = 13), rhegmatogenous RD (n = 1), and combined tractional RD/rhegmatogenous RD (n = 16). Mean age was 42.1 ± 15.1 years. The mean follow-up duration was 47.8 ± 34.1 months. Twenty-five (83.3%) eyes underwent pars plana vitrectomy and five (16.7%) eyes underwent pars plana vitrectomy with scleral buckling. Single-surgery anatomic success was achieved in 21 (70.0%) eyes at 6 months. Final reattachment was achieved in 28 (93.3%) eyes (22 eyes [73.3%] without tamponade). Recurrence of RDs was significantly associated with male gender (P = 0.041), absence of previous laser (P = 0.032), iatrogenic breaks (P = 0.035), retinectomy (P = 0.034), and silicone oil tamponade (P = 0.024). Overall, the logarithm of the minimum angle of resolution visual acuity improved from 1.53 ± 0.57 (Snellen equivalent, 20/678) to 1.15 ± 1.01 (20/283) at the final visit (P = 0.03); however, eyes with recurrent RD did not achieve significant visual improvement. CONCLUSION: Pars plana vitrectomy to repair sickle cell retinopathy-related RDs was effective in achieving anatomic success and improving vision in most eyes. Single-surgery anatomic success is critical for optimizing visual outcomes.

The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.

Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.

Significance of Social Determinants of Health in Tumor Presentation, Hospital Readmission, and Overall Survival in Ocular Oncology.

PURPOSE: To evaluate the association between social determinants of health (SDH) with presentation and outcomes in patients with ocular cancer. METHODS: The National Cancer Database was queried for primary clinical tumor (cT) classifications of T1 to T4 N0M0 uveal melanoma, conjunctival melanoma, or retinoblastoma diagnosed between January 2006 and December 2017. Pearson χ2 analysis assessed differences in SDH-related characteristics between cancer cohorts. Binary logistic regression with adjusted odds ratios (aORs) and multivariate Cox proportional hazards ratios (HRs) with 95% confidence intervals (CIs) were performed. DESIGN: Cross-sectional with a nationally representative sample. RESULTS: Three thousand nine hundred sixty-eight uveal melanoma cases, 352 conjunctival melanoma cases, and 480 retinoblastoma cases were included. Differences in race, primary payer status, income quartile, population density, facility location, Charlson-Deyo comorbidity score, history of malignancy, cT classification at presentation, surgical treatment, radiotherapy, chemotherapy, 30-day readmission, and overall survival (OS) were observed among the cancers. Female sex (aOR 0.819 [95% CI 0.689-0.973]) and top income quartile (aOR 0.691 [95% CI 0.525-0.908]) had decreased likelihood of advanced cT classification at presentation. No insurance (aOR 1.736 [95% CI 1.159-2.601]) and Medicaid primary payer status (aOR 1.875 [95% CI 1.323-2.656]) had increased likelihood of advanced cT classification. Patients in rural areas (aOR 7.157 [95% CI 1.875-27.320]) were more likely to be readmitted within 30 days after initial treatment. Increased age was associated with decreased 5-year OS (HR 1.040 [95% CI 1.033-1.047]). CONCLUSIONS: SDH may influence advanced cT classification at presentation and 30-day readmission compared with OS in patients with ocular cancer, highlighting the need for ophthalmologists and public health efforts to address disparities in SDH.

In-Depth Analysis of Preoperative OCT Markers as Prognostic Factors for Lamellar Macular Holes and Epiretinal Membrane Foveoschisis.

OBJECTIVE: To identify preoperative OCT markers that correlate with postoperative visual acuity (VA) changes in eyes with lamellar macular hole (LMH) and epiretinal membrane foveoschisis (ERMF) after pars plana vitrectomy (PPV). DESIGN: Cross-sectional retrospective study. SUBJECTS: Patients seen at the Wilmer Eye Institute between 2011 and 2021 with an International Classification of Diseases, Ninth Revision, or International Classification of Diseases, 10th Revision, code for "macular hole" that underwent PPV, and demonstrated all OCT criteria present for either LMH or ERMF based on the Hubschman et al (2020) classification. METHODS: Optical coherence tomography markers including hole dimensions, retinal layer continuity, and ellipsoid zone (EZ) convexity and pixelated intensity were quantified. Visual acuity immediately before PPV and at the last follow-up date available were both recorded. MAIN OUTCOME MEASURES: Preoperative OCT variables that are correlated with postoperative changes in VA. RESULTS: Forty-two eyes from 42 patients with LMH (n = 11) and ERMF (n = 31) that underwent PPV were identified. Visual acuity in the ERMF cohort significantly improved at last follow-up compared with preoperative VA (P < 0.001), whereas VA in the LMH cohort did not (P = 0.14). In the LMH cohort, retinal layer continuity at the hole edge was positively correlated with change in VA at final follow-up, whereas hole height was negatively correlated with VA. In the ERMF cohort, preoperative VA was negatively correlated with change in VA at final follow-up. CONCLUSIONS: Retinal layer continuity at the hole and hole height are novel preoperative markers that predict postoperative VA change in LMH. After identifying the type of macular lesion, surgeons should consider using these preoperative OCT markers when counseling patients on potential postoperative VA outcomes and when managing patient expectations. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Risk Factors Associated with Cystoid Macular Edema among Patients Undergoing Primary Repair of Rhegmatogenous Retinal Detachment.

PURPOSE: To investigate predictors of the development and resolution of cystoid macular edema (CME) after rhegmatogenous retinal detachment (RRD) repair. DESIGN: Retrospective cross sectional study. SUBJECTS: Patients who underwent primary repair of uncomplicated RRD. METHODS: Demographics, ophthalmic history, visual acuity, RRD features, time to development/resolution of CME, OCT characteristics of CME/epiretinal membrane (ERM), type of surgery, and treatments were collected. Logistic regressions were used to identify predictors of CME development and resolution. MAIN OUTCOME MEASURES: Predictors of CME development and resolution. RESULTS: A total of 708 eyes were included, of which 55 (7.8%) developed CME. Factors associated with an increased risk of CME development included total number of retinal detachment surgeries (odds ratio [OR] 1.66 [1.24-2.23], P < 0.001), prior intraocular surgery (OR 4.43 [1.19-16.51], P = 0.03), and presence of ERM after surgery (OR 4.49 [2.30-8.74], P < 0.001). Patients undergoing pars plana vitrectomy (PPV) were more likely to develop CME compared with patients undergoing scleral buckling (SB; OR 3.09 [1.18-8.10], P = 0.02). A longer average time to CME detection was associated with lower CME resolution (OR 0.94 [0.89-0.998], P = 0.04). In patients who developed an ERM postsurgically, those who developed CME after ERM had a lower rate of resolution compared with those who developed CME before ERM (P = 0.03). CONCLUSIONS: Cystoid macular edema may be more likely to develop in patients undergoing PPV than SB, those who underwent more surgeries for RRD repair, those who had prior intraocular surgery, or those who developed an ERM after RRD repair. Resolution of CME may be affected by the time to detection of CME and ERM development. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Lysosomes in retinal health and disease.

Lysosomes play crucial roles in various cellular processes - including endocytosis, phagocytosis, and autophagy - which are vital for maintaining retinal health. Moreover, these organelles serve as environmental sensors and act as central hubs for multiple signaling pathways. Through communication with other cellular components, such as mitochondria, lysosomes orchestrate the cytoprotective response essential for preserving cellular homeostasis. This coordination is particularly critical in the retina, given its high metabolic rate and susceptibility to photo-oxidative stress. Consequently, impaired lysosomal function and dysregulated communication between lysosomes and other organelles contribute significantly to the pathobiology of major retinal degenerative diseases. This review explores the pivotal role of lysosomes in retinal cells and their involvement in retinal degenerative diseases.

The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in atrophic AMD.

Age-related macular degeneration (AMD), the leading cause of geriatric blindness, is a multi-factorial disease with retinal-pigmented epithelial (RPE) cell dysfunction as a central pathogenic driver. With RPE degeneration, lysosomal function is a core process that is disrupted. Transcription factors EB/E3 (TFEB/E3) tightly control lysosomal function; their disruption can cause aging disorders, such as AMD. Here, we show that induced pluripotent stem cells (iPSC)-derived RPE cells with the complement factor H variant [ CFH (Y402H)] have increased AKT2, which impairs TFEB/TFE3 nuclear translocation and lysosomal function. Increased AKT2 can inhibit PGC1α, which downregulates SIRT5, an AKT2 binding partner. SIRT5 and AKT2 co-regulate each other, thereby modulating TFEB-dependent lysosomal function in the RPE. Failure of the AKT2/SIRT5/TFEB pathway in the RPE induced abnormalities in the autophagy-lysosome cellular axis by upregulating secretory autophagy, thereby releasing a plethora of factors that likely contribute to drusen formation, a hallmark of AMD. Finally, overexpressing AKT2 in RPE cells in mice led to an AMD-like phenotype. Thus, targeting the AKT2/SIRT5/TFEB pathway could be a potential therapy for atrophic AMD.

Thermal Shift Assay in Ferroptosis.

Ferroptosis is a recently described process of cell death that is dependent on unregulated cellular iron accumulation with induction of oxidative stress. Ferroptosis has been linked to several human diseases; therefore, investigations aimed at better understanding the pathway and elucidating avenues for future drug development are warranted. Current assays that target ferroptosis/oxidative stress in cells is limited to western blotting and imaging techniques, and unfortunately provide only a broad understanding that is insufficient to effectively assess novel drugs (ligands). Specifically, these assays do not provide insights about ligand interactions with specific proteins associated with these processes. Herein, we discuss a cell-based thermal shift assay that enables screening of ligands under specific cellular conditions for targeting ferroptosis and/or oxidative stress pathways. These data would provide detailed preliminary evidence required for drug development that targets this pathway.

Using the language of surgery to enhance ophthalmology surgical education.

Background: Currently, surgical education utilizes a combination of the apprentice model, wet-lab training, and simulation, but due to reliance on subjective data, the quality of teaching and assessment can be variable. The "language of surgery," an established concept in engineering literature whose incorporation into surgical education has been limited, is defined as the description of each surgical maneuver using quantifiable metrics. This concept is different from the traditional notion of surgical language, generally thought of as the qualitative definitions and terminology used by surgeons. Methods: A literature search was conducted through April 2023 using MEDLINE/PubMed using search terms to investigate wet-lab, virtual simulators, and robotics in ophthalmology, along with the language of surgery and surgical education. Articles published before 2005 were mostly excluded, although a few were included on a case-by-case basis. Results: Surgical maneuvers can be quantified by leveraging technological advances in virtual simulators, video recordings, and surgical robots to create a language of surgery. By measuring and describing maneuver metrics, the learning surgeon can adjust surgical movements in an appropriately graded fashion that is based on objective and standardized data. The main contribution is outlining a structured education framework that details how surgical education could be improved by incorporating the language of surgery, using ophthalmology surgical education as an example. Conclusion: By describing each surgical maneuver in quantifiable, objective, and standardized terminology, a language of surgery can be created that can be used to learn, teach, and assess surgical technical skill with an approach that minimizes bias. Key message: The "language of surgery," defined as the quantification of each surgical movement's characteristics, is an established concept in the engineering literature. Using ophthalmology surgical education as an example, we describe a structured education framework based on the language of surgery to improve surgical education. Classifications: Surgical education, robotic surgery, ophthalmology, education standardization, computerized assessment, simulations in teaching. Competencies: Practice-Based Learning and Improvement.

Effects of fetal haemoglobin on systemic oxygenation in preterm infants and the development of retinopathy of prematurity PacIFiHER Report No. 2.

BACKGROUND/AIMS: Fetal haemoglobin (HbF) has an oxyhaemoglobin dissociation curve that may affect systemic oxygenation and the development of retinopathy of prematurity (ROP). The study aim is to characterise the effects of HbF levels on systemic oxygenation and ROP development. METHODS: Prospective study conducted from 1 September 2017 through 31 December 2018 at the Johns Hopkins NICU. Preterm infants with HbF measured at birth, 31, 34 and 37 weeks post-menstrual age (PMA), complete blood gas and SpO2 recorded up to 42 weeks PMA, and at least one ROP exam were included. RESULTS: Sixty-four preterm infants were enrolled. Higher HbF was associated with significantly higher SpO2, lower PCO2, lower FiO2 from birth to 31 weeks PMA and 31 to 34 weeks PMA (rs=0.51, rs=-0.62 and rs=-0.63; p<0.0001 and rs=0.71, rs=-0.58 and rs=-0.79; p<0.0001, respectively). To maintain oxygen saturation goals set by the neonatal intensive care unit, higher median FiO2 was required for HbF in the lowest tercile from birth compared with HbF in the highest tercile to 31 weeks and 31 to 34 weeks PMA; FiO2=35 (21-100) versus 21 (21-30) p<0.006 and FiO2=30 (28-100) versus 21 (21-30) p<0.001, respectively. Preterm infants with ROP had poorer indices of systemic oxygenation, as measured by median levels of SpO2 and PCO2, and lower levels of HbF (p<0.039 and p<0.0001, respectively) up to 34 weeks PMA. CONCLUSION: Low HbF levels correlated with poor oxygenation indices and increased risk for ROP. O2 saturation goals to prevent ROP may need to incorporate relative amount of HbF.

Increased LCN2 (lipocalin 2) in the RPE decreases autophagy and activates inflammasome-ferroptosis processes in a mouse model of dry AMD.

In dry age-related macular degeneration (AMD), LCN2 (lipocalin 2) is upregulated. Whereas LCN2 has been implicated in AMD pathogenesis, the mechanism remains unknown. Here, we report that in retinal pigmented epithelial (RPE) cells, LCN2 regulates macroautophagy/autophagy, in addition to maintaining iron homeostasis. LCN2 binds to ATG4B to form an LCN2-ATG4B-LC3-II complex, thereby regulating ATG4B activity and LC3-II lipidation. Thus, increased LCN2 reduced autophagy flux. Moreover, RPE cells from cryba1 KO, as well as sting1 KO and Sting1Gt mutant mice (models with abnormal iron chelation), showed decreased autophagy flux and increased LCN2, indicative of CGAS- and STING1-mediated inflammasome activation. Live cell imaging of RPE cells with elevated LCN2 also showed a correlation between inflammasome activation and increased fluorescence intensity of the Liperfluo dye, indicative of oxidative stress-induced ferroptosis. Interestingly, both in human AMD patients and in mouse models with a dry AMD-like phenotype (cryba1 cKO and KO), the LCN2 homodimer variant is increased significantly compared to the monomer. Sub-retinal injection of the LCN2 homodimer secreted by RPE cells into NOD-SCID mice leads to retinal degeneration. In addition, we generated an LCN2 monoclonal antibody that neutralizes both the monomer and homodimer variants and rescued autophagy and ferroptosis activities in cryba1 cKO mice. Furthermore, the antibody rescued retinal function in cryba1 cKO mice as assessed by electroretinography. Here, we identify a molecular pathway whereby increased LCN2 elicits pathophysiology in the RPE, cells known to drive dry AMD pathology, thus providing a possible therapeutic strategy for a disease with no current treatment options.Abbreviations: ACTB: actin, beta; Ad-GFP: adenovirus-green fluorescent protein; Ad-LCN2: adenovirus-lipocalin 2; Ad-LCN2-GFP: adenovirus-LCN2-green fluorescent protein; LCN2AKT2: AKT serine/threonine kinase 2; AMBRA1: autophagy and beclin 1 regulator 1; AMD: age-related macular degeneration; ARPE19: adult retinal pigment epithelial cell line-19; Asp278: aspartate 278; ATG4B: autophagy related 4B cysteine peptidase; ATG4C: autophagy related 4C cysteine peptidase; ATG7: autophagy related 7; ATG9B: autophagy related 9B; BLOC-1: biogenesis of lysosomal organelles complex 1; BLOC1S1: biogenesis of lysosomal organelles complex 1 subunit 1; C57BL/6J: C57 black 6J; CGAS: cyclic GMP-AMP synthase; ChQ: chloroquine; cKO: conditional knockout; Cys74: cysteine 74; Dab2: DAB adaptor protein 2; Def: deferoxamine; DHE: dihydroethidium; DMSO: dimethyl sulfoxide; ERG: electroretinography; FAC: ferric ammonium citrate; Fe2+: ferrous; FTH1: ferritin heavy chain 1; GPX: glutathione peroxidase; GST: glutathione S-transferase; H2O2: hydrogen peroxide; His280: histidine 280; IFNL/IFNλ: interferon lambda; IL1B/IL-1ß: interleukin 1 beta; IS: Inner segment; ITGB1/integrin ß1: integrin subunit beta 1; KO: knockout; LC3-GST: microtubule associated protein 1 light chain 3-GST; C-terminal fusion; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LCN2: lipocalin 2; mAb: monoclonal antibody; MDA: malondialdehyde; MMP9: matrix metallopeptidase 9; NLRP3: NLR family pyrin domain containing 3; NOD-SCID: nonobese diabetic-severe combined immunodeficiency; OS: outer segment; PBS: phosphate-buffered saline; PMEL/PMEL17: premelanosome protein; RFP: red fluorescent protein; rLCN2: recombinant LCN2; ROS: reactive oxygen species; RPE SM: retinal pigmented epithelium spent medium; RPE: retinal pigment epithelium; RSL3: RAS-selective lethal; scRNAseq: single-cell ribonucleic acid sequencing; SD-OCT: spectral domain optical coherence tomography; shRNA: small hairpin ribonucleic acid; SM: spent medium; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; STAT1: signal transducer and activator of transcription 1; STING1: stimulator of interferon response cGAMP interactor 1; TYR: tyrosinase; VCL: vinculin; WT: wild type.

Management of uncomplicated rhegmatogenous retinal detachments: a comparison of practice patterns and clinical outcomes in a real-world setting.

OBJECTIVE: To investigate practice patterns and clinical outcomes in the repair of uncomplicated rhegmatogenous retinal detachments (RRD) in a real-world setting over a 10-year period. METHODS: We compared preferences for scleral buckling (SB), pars plana vitrectomy (PPV), PPV/SB, or pneumatic retinopexy (PR) over time, and examined the 1-year single surgery anatomic success (SSAS) and best-corrected visual acuity (BCVA) at a tertiary academic institution from 2008-2018. RESULTS: Eight hundred eight eyes had RRD repair between 2008-2011 (n = 240), 2012-2014 (n = 271), and 2015-2017 (n = 297). Compared to 2008-2011, PPV was preferred over SB in 2012-2014 (OR: 2.93; 95% CI: 1.86-4.63) and 2015-2017 (OR: 5.94; 95% CI: 3.76-9.38), and over PPV/SB in 2012-2014 (OR: 2.74; 95% CI: 1.65-4.56) and 2015-2017 (OR: 3.16; 95% CI: 31.96-5.12). PR was uncommonly utilized (<10%). Younger surgeons (graduating 2010-2017) favored PPV over SB when compared to older surgeons [graduating 1984-2000 (OR: 1.77; 95% CI: 1.18-2.65) and 2001-2009 (OR 1.73; 95% CI: 1.14-2.65)], but similarly selected PPV vs. PPV/SB as their older counterparts (p > 0.05). Compared to PPV, SSAS was higher with SB (OR: 1.53; 95% CI: 1.03-2.26) and PPV/SB (OR: 2.55; 95% CI: 1.56-4.17). One-year BCVA was markedly improved compared to baseline only for eyes that achieved SSAS (p < 0.001). CONCLUSIONS: Over the past 10 years, PPV has become the favored approach to repair uncomplicated RRD and this appears to be driven by younger surgeons' preferences. Given the superior long-term SSAS in SB and PPV/SB as compared to PPV, SB and PPV/SB should be more frequently considered when determining the appropriate repair strategy for uncomplicated RRD.

URINARY METABOLOMICS OF CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To analyze the urinary metabolomic profile of central serous chorioretinopathy cases. METHODS: In a cross-sectional study, 80 participants with central serous chorioretinopathy were compared with 80 age-matched and sex-matched controls. Urinary metabolites were measured using Metabolon's Discovery HD4 platform. RESULTS: Of 1,031 metabolites total that were measured in urine samples, 53 were upregulated and 27 downregulated in central serous chorioretinopathy participants compared with controls. After exclusion of potentially confounding xenobiotics and bile compounds that could represent digestive processes, 14 metabolites were significantly higher and 12 metabolites were significantly lower in cases compared with controls. One upregulated metabolite (tetrahydrocortisol sulfate) is involved in the corticosteroid subpathway. The downregulated metabolites are unrelated to the identified corticosteroid subpathway. CONCLUSION: The upregulation of urinary tetrahydrocortisol sulfate in central serous chorioretinopathy cases provides a precise molecular basis to further study the role of corticosteroids in producing choroidal venous congestion.

Mitophagy initiates retrograde mitochondrial-nuclear signaling to guide retinal pigment cell heterogeneity.

Age-related macular degeneration (AMD), the leading cause of blindness among the elderly, is without treatment for early disease. Degenerative retinal pigment epithelial (RPE) cell heterogeneity is a well-recognized but understudied pathogenic factor. Due to the daily phagocytosis of photoreceptor outer segments, unique photo-oxidative stress, and high metabolism for maintaining vision, the RPE has robust macroautophagy/autophagy, and mitochondrial and antioxidant networks. However, the autophagy subtype, mitophagy, in the RPE and AMD is understudied. Here, we found decreased PINK1 (PTEN induced kinase 1) in perifoveal RPE of early AMD eyes. PINK1-deficient RPE have impaired mitophagy and mitochondrial function that triggers death-resistant epithelial-mesenchymal transition (EMT). This reprogramming is mediated by novel retrograde mitochondrial-nuclear signaling (RMNS) through superoxide, NFE2L2 (NFE2 like bZIP transcription factor 2), TXNRD1 (thioredoxin reductase 1), and phosphoinositide 3-kinase (PI3K)-AKT (AKT serine/threonine kinase) that induced canonical transcription factors ZEB1 (zinc finger E-box binding homeobox 1) and SNAI1 (Snail family transcriptional repressor 1) and an EMT transcriptome. NFE2L2 deficiency disrupted RMNS that paradoxically normalized morphology but decreased function and viability. Thus, RPE heterogeneity is defined by the interaction of two cytoprotective pathways that is triggered by mitophagy function. By neutralizing the consequences of impaired mitophagy, an antioxidant dendrimer tropic for the RPE and mitochondria, EMT (a recognized AMD alteration) was abrogated to offer potential therapy for early AMD, a stage without treatment.Abbreviations: ACTB: actin beta; AKT: AKT serine/threonine kinase; AMD: age-related macular degeneration; CCCP: cyanide m-chlorophenyl hydrazone; CDH1: cadherin 1; DAVID: Database for Annotation, Visualization and Integrated Discovery; DHE: dihydroethidium; D-NAC: N-acetyl-l-cysteine conjugated to a poly(amido amine) dendrimer; ECAR: extracellular acidification rate; EMT: epithelial-mesenchymal transition; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSEA: Gene Set Enrichment Analysis; HSPD1: heat shock protein family D (Hsp60) member 1; IVT: intravitreal; KD: knockdown; LMNA, lamin A/C; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MMP: mitochondrial membrane potential; NAC: N-acetyl-l-cysteine; NQO1: NAD(P)H quinone dehydrogenase 1; NFE2L2: NFE2 like bZIP transcription factor 2; O2-: superoxide anion; OCR: oxygen consumption rate; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; RMNS: retrograde mitochondrial-nuclear signaling; ROS: reactive oxygen species; RPE: retinal pigment epithelium; SNAI1: snail family transcriptional repressor 1; TJP1: tight junction protein 1; TPP-D-NAC: triphenyl phosphinium and N-acetyl-l-cysteine conjugated to a poly(amido amine) dendrimer; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; Trig: trigonelline; TXNRD1: thioredoxin reductase 1; VIM: vimentin; WT: wild-type; ZEB1: zinc finger E-box binding homeobox 1.

A Clinical and Preclinical Assessment of Clinical Trials for Dry Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness for the elderly in high-income countries. Although multivitamin antioxidant nutrients can slow the progression of intermediate "dry" or nonneovascular AMD, no treatment can halt or reverse any stage of dry disease. Multiple biologic pathways have been implicated in AMD pathobiology, including the complement pathway. These pathways have been targeted by various approaches in clinical trials. To date, no treatment has reached their prespecified primary end point in 2 phase III trials, a requirement by the US Food and Drug Administration for a new drug approval. Here, we describe perspectives on the failures and possible successes of various clinical trials that will guide further investigation. These perspectives will also discuss clinical trial design issues to consider in future investigations, and how recent insights into AMD pathobiology might both provide additional explanation for trials not reaching the prespecified primary end points and offer direction for identifying prioritized treatment targets.

Microglia-Neutrophil Interactions Drive Dry AMD-like Pathology in a Mouse Model.

In dry age-related macular degeneration (AMD), inflammation plays a key role in disease pathogenesis. Innate immune cells such as microglia and neutrophils infiltrate the sub-retinal space (SRS) to induce chronic inflammation and AMD progression. But a major gap in our understanding is how these cells interact with each other in AMD. Here, we report a novel concept of how dynamic interactions between microglia and neutrophils contribute to AMD pathology. Using well-characterized genetically engineered mouse models as tools, we show that in the diseased state, retinal pigmented epithelial (RPE) cells trigger pro-inflammatory (M1) transition in microglia with diminished expression of the homeostatic marker, CX3CR1. Activated microglia localize to the SRS and regulate local neutrophil function, triggering their activation and thereby inducing early RPE changes. Ligand receptor (LR)-loop analysis and cell culture studies revealed that M1 microglia also induce the expression of neutrophil adhesion mediators (integrin ß1/α4) through their interaction with CD14 on microglia. Furthermore, microglia-induced neutrophil activation and subsequent neutrophil-mediated RPE alterations were mitigated by inhibiting Akt2 in microglia. These results suggest that the Akt2 pathway in microglia drives M1 microglia-mediated neutrophil activation, thereby triggering early RPE degeneration and is a novel therapeutic target for early AMD, a stage without treatment options.

Symptom-Based Risk Factors for Retinal Tears and Detachments in Suspected Posterior Vitreous Detachment.

INTRODUCTION: The aim of this study was to determine symptom-level risk factors for retinal tear/retinal detachment (RT/RD) in our patients presenting with symptoms of posterior vitreous detachment (PVD). METHODS: We conducted a prospective cohort study of patients presenting to outpatient ophthalmology clinics at a single academic institution with complaint(s) of flashes, floaters, and/or subjective field loss (SFL). Patients received a standardized questionnaire regarding past ocular history and symptom characteristics including number, duration, and timing of flashes and floaters, prior to dilated ocular examination. Final diagnosis was categorized as RT/RD, PVD, ocular migraine, vitreous syneresis, or "other." Simple and multivariate logistic regressions were used to identify symptoms predictive of various pathologies. RESULTS: We recruited 237 patients (age 20-93 years) from March 2018 to March 2019. The most common diagnosis was PVD (141, 59.5%), followed by vitreous syneresis (38, 16.0%) and RT/RD (34, 14.3%). Of those with RT/RD, 16 (47.1%) had retinal tear and 15 (44.1%) had RD. Significant differences in demographic and examination-based factors were observed between these groups. Symptom-based predictive factors for RT/RD were the presence of subjective visual reduction (SVR; OR 2.77, p = 0.03) or SFL (OR 2.47, p = 0.04), and the absence of either floaters (OR 4.26, p = 0.04) or flashes (OR 2.95, p = 0.009). The number, duration, and timing of flashes and floaters did not predict the presence of RT/RD in our cohort. Within the RT/RD group, patients with RT were more likely to report floaters (100% vs. 66.7%, p = 0.018) and less likely to report SFL (0% vs. 86.7%, p < 0.001) compared to those with RD. CONCLUSION: While well-known demographic and exam-based risk factors for RT/RD exist in patients with PVD symptoms, the relative importance of symptom characteristics is less clear. We found that the presence of SVR and SFL, as well as the absence of either flashes or floaters, predicts RT/RD in patients with PVD symptoms. However, the number, duration, and timing of flashes and floaters may be less relevant in the triage of these patients.

Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy.

The retinal pigment epithelium (RPE) plays an important role in the development of diabetic retinopathy (DR), a leading cause of blindness worldwide. Here we set out to explore the role of Akt2 signaling-integral to both RPE homeostasis and glucose metabolism-to DR. Using human tissue and genetically manipulated mice (including RPE-specific conditional knockout (cKO) and knock-in (KI) mice), we investigate whether Akts in the RPE influences DR in models of diabetic eye disease. We found that Akt1 and Akt2 activities were reciprocally regulated in the RPE of DR donor tissue and diabetic mice. Akt2 cKO attenuated diabetes-induced retinal abnormalities through a compensatory upregulation of phospho-Akt1 leading to an inhibition of vascular injury, inflammatory cytokine release, and infiltration of immune cells mediated by the GSK3ß/NF-κB signaling pathway; overexpression of Akt2 has no effect. We propose that targeting Akt1 activity in the RPE may be a novel therapy for treating DR.