Investigating the Relationship Between Lipid-Lowering Agents and the Complications of Diabetic Retinopathy.

BACKGROUND AND OBJECTIVE: As the therapeutic efficacy of lipid-lowering agents (LLA) against diabetic retinopathy (DR) remains controversial, this study aimed to evaluate whether various LLA therapies are associated with a reduced risk of DR progression. PATIENTS AND METHODS: This retrospective study of the medical records of adults with type 2 diabetes mellitus and DR compared the risk of adverse progression of DR between patients who received statins, fibrates, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and no LLA (control). RESULTS: Patients in the statin cohort had a reduced rate of progression to proliferative DR compared to controls (HR = 0.30, CI = 0.11 to 0.83). The PCSK9 inhibitor cohort had a reduced risk of progressing to other secondary complications of DR compared to the control (RR = 0.52, CI = 0.43 to 0.64), statin (RR = 0.69, CI = 0.61 to 0.79), and fibrate (RR = 0.67, CI = 0.59 to 0.77) cohorts. CONCLUSIONS: These findings suggest use of statins and PCSK9 inhibitors are associated with a reduced risk of adverse progression of DR. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Development of a Consensus Guideline for the Diagnosis and Management of Chronic Noninfectious Uveitis Affecting the Posterior Segment.

BACKGROUND AND OBJECTIVE: A consensus exercise was carried out to address unmet needs in the classification, diagnosis, and management of patients with chronic noninfectious uveitis affecting the posterior segment (NIU-PS), with a focus on chronic postoperative inflammation/cystoid macular edema. METHODS: Eight experts participated in roundtable discussions and consensus-building exercises to develop clear guidelines for the diagnosis and management of chronic NIU-PS. The group addressed questions surrounding clinical features, diagnostic tests, and treatment considerations. RESULTS: Clinicians agreed that chronic uveitis/intraocular inflammation should be defined as having persistence or recurrence for 3 or more months. Diagnosis is informed by evaluation of signs and symptoms, use of imaging, and exclusion of infectious etiologies. Management should be initiated with the least invasive therapies, proceeding to intraocular injections, and/or long-term intravitreal or systemic therapies, as necessary. CONCLUSION: This manuscript offers an up-to-date consensus guideline based on clinical experience. Future clinical trials may help to test and reevaluate these recommendations. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Long-term Visual Outcomes in Patients With Idiopathic Macular Hole Surgery.

BACKGROUND AND OBJECTIVE: This study assesses long-term outcomes following surgical repair of idiopathic full-thickness macular holes (FTMHs) in patients with at least 5 years of postoperative follow-up. PATIENTS AND METHODS: A retrospective study evaluated patients diagnosed with idiopathic FTMH who received surgical repair at a single tertiary center with at least 5 years of postoperative follow-up. Data collection included demographic and preoperative characteristics along with macular hole structural integrity as determined by spectral-domain optical coherence tomography (OCT). Functional and structural improvement were assessed by collection of visual acuity and findings on OCT at determined time points until 9 years of follow-up. RESULTS: The study comprised 90 eyes of 80 patients with a mean age of 67.2 ± 6.8 years, with an average postoperative follow-up of 80.8 ± 17.4 months (range 54 to 130 months). The mean macular hole diameter was 239.7 µm ± 92.2. Macular hole reoperation occurred in four eyes (4%) at a mean duration of 5.5 ± 6 months (range 0.3 to 13 months). Over the study duration, ellipsoid zone (EZ) integrity was maintained in 67.8% of eyes, with an absence of intraretinal fluid (IRF) in 96% on final OCT. The preoperative mean Early Treatment Diabetic Retinopathy Study (ETDRS) best visual acuity (BVA) of 51 improved to a mean BVA of 76 at 5 years postoperatively, with an average gain of 24 letters at one year that remained stable over 5 years (P < 0.05). Eight years after surgical repair, more than 80% of patients achieved a BVA > 65. CONCLUSIONS: Vitreoretinal surgery for idiopathic FTMH resulted in successful hole closure and sustained visual acuity improvement over long-term follow-up. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Diabetic retinopathy: Screening, prevention, and treatment.

Internists are integral in the multidisciplinary approach to diabetic retinopathy, contributing significantly to the management of diabetes and diabetes-related complications. Effective screening processes, timely referrals, and strategic diabetes management are imperative to prevent and mitigate the consequences of diabetic retinopathy. The evolution of treatments for diabetic retinopathy has markedly improved vision outcomes and reduced the burden on patients. Despite these advances, a collaborative approach to care is essential to prevent the progression of vision impairment and manage associated complications.

American Society of Retina Specialists Artificial Intelligence Task Force Report.

Since the Artificial Intelligence Committee of the American Society of Retina Specialists developed the initial task force report in 2020, the artificial intelligence (AI) field has seen further adoption of US Food and Drug Administration-approved AI platforms and significant development of AI for various retinal conditions. With expansion of this technology comes further areas of challenges, including the data sources used in AI, the democracy of AI, commercialization, bias, and the need for provider education on the technology of AI. The overall focus of this committee report is to explore these recent issues as they relate to the continued development of AI and its integration into ophthalmology and retinal practice.

Central Retinal Thickness Variability as a Predictive Factor for Visual Acuity After Dexamethasone Implant in Retinal Vein Occlusion.

BACKGROUND AND OBJECTIVE: Investigate central retinal thickness (CRT) variability and changes in best-corrected visual acuity (BCVA) after 12 months in patients with retinal vein occlusion (RVO) treated with dexamethasone intravitreal implants. PATIENTS AND METHODS: Post hoc analyses of two randomized trials in patients with macular edema associated with branch or central RVO treated with a 0.7-mg dexamethasone implant. Central retinal thickness standard deviation (CRT-SD) and central retinal thickness amplitude (CRT-A) were measures of variability. Analyses included multinomial and simple linear regression. RESULTS: In 400 patients, CRT-SD and CRT-A were significantly associated with central RVO, second dexamethasone implant, and baseline CRT. Baseline BCVA was associated with CRT-A. CRT-SD and CRT-A were significantly correlated with a 12-month change in BCVA (effect sizes of -0.032 and -0.013 letters/µm; P < 0.001). Patients in the highest CRT-SD quartile gained significantly fewer letters (+1.88 letters; 95% CI: -0.46 to 4.23). CONCLUSION: Greater CRT variability was associated with smaller BCVA improvements in patients with RVO treated with dexamethasone implants. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Drug-Induced Intracranial Hypertension: The Adverse Effects of Acne Medications and Topical Retinoids.

BACKGROUND: Tetracyclines and vitamin A derivatives, major components in acne care and antiaging products, have been associated with the development of drug-induced intracranial hypertension (DIIH). Treatment practices and longitudinal visual outcomes have been highly understudied in DIIH. The purpose of this study was to provide management guidelines for DIIH and report visual outcomes of patients with DIIH. METHODS: This was a single institute ophthalmology center case-control study where patients were seen between June 1, 2012, and September 1, 2023, in the United States. Patients with an International Classification of Disease (ICD) code for IIH and meeting the IIH diagnostic criteria who were taking a tetracycline or a vitamin A derivative during their diagnosis were included in this study. Patients were stratified into the following 3 categories: tetracyclines only, vitamin A derivatives only, or both, and compared with Kruskal-Wallis rank-sum tests. Poor visual outcomes were evaluated for and defined as a visual field mean deviation (peripheral visual measure) of -7 dB or greater. Individuals were followed for up to 1.5 years after diagnosis. RESULTS: Among patients with IIH (n = 839), DIIH occurred in 8.10% of them (n = 68) with 83% taking the medication for acne. 88% of cases were female, and patients had a mean age of 24.96 years. DIIH medications were taken for an average length of 25.79 weeks before diagnosis of IIH. 20.5% of patients with DIIH were not treated with any IIH medication and were discontinued from the inducing drug. 3 patients had a poor visual outcome on follow-up with all of them taking a vitamin A derivative (P < 0.05). Patients identified as having a poor visual outcome did not report discontinuing the DIIH drug (P < 0.05). CONCLUSIONS: We propose treatment guidelines highlighting that patients taking a DIIH medication who develop headaches or visual changes should be immediately referred to ophthalmology, removal of the offending agent, and close monitoring by ophthalmology for vision loss. Importantly, vitamin A DIIH may have more severe visual outcomes, but further research is needed to corroborate this finding.

The Effect of Glucagon-Like Peptide-1 Receptor Agonists on Diabetic Retinopathy at a Tertiary Care Center.

Objective: The potential association between diabetic retinopathy (DR) worsening and glucagon-like peptide-1 receptor agonists (GLP-1RA) has affected therapeutic management of diabetic patients but remains controversial. This study compared rates of DR development or progression in patients on GLP-1RA to those on SGLT-2 inhibitors (SGLT-2I). Design: Retrospective cohort study. Subjects: Nine hundred eighty-one patients with diabetes mellitus taking GLP-1RA or SGLT-2I, the latter serving as controls, between 2012 and 2023. Methods: Patients were one-to-one greedy matched by propensity scores on race/ethnicity, age, smoking status, baseline body mass index and hemoglobin A1c %, type of diabetes mellitus, baseline DR status and history of DR procedures, duration of drug use, whether they had taken both drug types, and change in hemoglobin A1c % after 1 year on the drug. Main Outcome Measures: The primary outcome was clinical DR development or progression (termed "worsening") detected by International Classification of Diseases (ICD), 10th edition codes, confirmed by manual review, on GLP-1RA compared with SGLT-2I after propensity score matching. Secondary outcomes included DR worsening indicated by need for procedures due to complications, and time-to-first DR worsening event. Results: The study included 692 GLP-1RA users and 289 SGLT-2I users. The mean follow-up periods for GLP-1RA versus SGLT-2I use were 1.54 (standard deviation [SD] 1.82) years and 1.38 (SD 1.56) years, respectively. The rates of clinical worsening were 2.3% and 2.8%, respectively. After propensity score matching, an association was not identified between GLP1-RA and DR worsening neither clinically by ICD-10 codes (odds ratio [OR] = 0.33, 95% confidence interval [CI]: 0.11-1.03) nor by indication for procedures (OR = 0.50, 95% CI 0.13-2.00). Time-to-first DR worsening did not differ between the groups in Kaplan-Meier analysis. The most common type of clinical worsening event for both drug types was vitreous hemorrhage (43.7% and 50% of worsening events in GLP-1RA and SGLT-2I users, respectively). The most common DR procedure indicated was anti-VEGF injections (34% and 35% of GLP-1RA and SGLT-2I events, respectively). Conclusions: Diabetic retinopathy worsening, either clinically or by procedures, was not associated with GLP-1RA compared with SGLT-2I, both before and after propensity score matching on all analyses, including time-to-first worsening event. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Long-term visual outcomes and fluid compartment changes in limited-early versus early response to anti-VEGF treatment for diabetic macular edema.

OBJECTIVE: This study assessed best visual acuity (BVA) and central subfield thickness (CST) outcomes for LER (limited early responder) and ER (early responder) patients at 24 and 36 months. DESIGN: Retrospective chart review PARTICIPANTS: One-hundred and twelve patients characterized at 3 months after their first anti-VEGF injections as either LER if they met the anatomic criteria (aLER = CST reductions ≤ 10%), visual criteria (vLER = ETDRS letter gains < 5 letter), or both (cLER). All other patients were classified as ER (aER/vER/cER). METHODS: Variables collected include CST and ETDRS letters at baseline, 3, 24, and 36 months following injections, comorbidities, smoking status, demographics, baseline systemic factors, and the type and quantity of anti-VEGF injections. Analyses were performed using Welch's t-test, multivariable linear and multivariable logistic regression. RESULTS: BVA changes from 3 months were significant between cLER versus cER and vLER versus vER groups (p < 0.05). There was a greater decrease in mean BVA from 3 months to 36 months in the cER group compared to the cLER group. Alternatively, mean BVA decreased in the vER cohort, while the vLER cohort slightly increased. CST changes from 3 months were statistically significant (p < 0.01) between all LER and ER groups with LER groups showing greater reductions compared to ER counterparts. BVA and CST changes from baseline to 24 and 36 months were not significant after controlling for baseline differences between LER and ER groups. CONCLUSION: Results highlight the value of long-term anti-VEGF treatment and the need to further explore options that may lead to continued BVA improvements beyond 3 months.

Evidence for the Hepato-Retinal Axis: A Systematic Review.

BACKGROUND AND OBJECTIVE: Liver health has been reported to be associated with retinal pathology in various ways. These include deposition of retino-toxins, neovascular drive, and disruption of the blood-retina barrier. Extrahepatic synthesis of implicated molecules and hemodynamic changes in liver dysfunction are also considered. The objective was to review the current evidence for and against a hepato-retinal axis that may guide further areas of preclinical and clinical investigation. METHODS: This was a systematic review. PubMed and Cochrane were queried for English language studies examining the connection between hepatic dysfunction and retinal pathology. RESULTS: Fourteen studies were included and examined out of 604 candidate publications. The studies selected include preclinical studies as well as clinical case series and studies. CONCLUSIONS: Several liver pathologies may be linked to retinal pathology as mediated by hepatically synthesized molecules. The hepato-retinal axis may be present and further, targeted studies of the axis are warranted. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Characterization and prevalence of ocular comorbidities and risk of legal blindness across the United States.

BACKGROUND/OBJECTIVES: Vision loss is a top disability in the United States (US). Patients commonly present with multiple ocular diseases, but the extent to which this places them at risk for vision loss, and if sex and race impacts this, is poorly understood. This exploratory analysis evaluated which ocular comorbidities and demographics are at highest risk for visual impairment. SUBJECTS/METHODS: A retrospective cross-sectional study was conducted through the TriNetX Analytics Network, an aggregated network encompassing over 90 million insured and uninsured patients across 50 healthcare organizations from all regions in the US. Patients with diabetic retinopathy (DR), age-related macular degeneration (AMD), retinal vein occlusion (RVO), glaucoma, and uveitis were included in this study. Ocular diseases and visual impairment were determined through ICD-10 codes. Prevalence and odds ratios were calculated while stratifying by sex and racial demographics. Statistical analyses were completed using RStudio and Excel with 95% confidence intervals calculated. RESULTS: The comorbid conditions with the highest prevalence of visual impairment were uveitis and RVO (39.94%), uveitis and neovascular AMD (37.61%), and uveitis and glaucoma (33.23%). The comorbidity with the highest odds for visual impairment was uveitis and RVO (POR 4.86; 95% CI 4.49, 5.26). Compared to white males, Black and Hispanic males were disproportionately affected by visual impairment across ocular comorbidities. CONCLUSION: This study quantified the prevalence and odds of visual impairment for unilateral and comorbid ocular disease, with the addition of uveitis causing the greatest increase. Black and Hispanic males were disproportionately affected by visual impairment across comorbid conditions.

Retrospective Cohort Study of Sickle Cell Disease and Large Vessel Retinal Vascular Occlusion Risk in a National United States Database.

OBJECTIVE: To determine if differences exist in the risk of developing large vessel retinal vascular occlusions in patients with sickle cell states. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with sickle cell disease (SCD) or trait evaluated by an ophthalmologist were compared with matched controls without SCD or sickle cell trait (SCT) also evaluated by an ophthalmologist. METHODS: This study used deidentified data from a national database (2006-2024), using International Classification of Diseases 10 codes to select for retinal vascular occlusions. Propensity score matching was performed with respect to age, sex, race, ethnicity, smoking, hypertension, diabetes, dyslipidemias, and obesity, resulting in hemoglobin SS (HbSS), hemoglobin SC (HbSC), and SCT cohorts and matched control cohorts. MAIN OUTCOME MEASURES: Risk ratios (RRs) and 95% confidence intervals (CIs) of retinal vascular occlusion diagnosis, including central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO), central retinal vein occlusion, branch retinal vein occlusion, and corneal dystrophy as a negative control, given SCD or SCT. RESULTS: After propensity score matching, HbSS (n = 10 802; mean age ± standard deviation, 38.6 ± 20.6 years), HbSC (n = 4296, 34.3 ± 17.8 years), and SCT (n = 15 249, 39.8 ± 23.7 years) cohorts were compared with control cohorts (n = 10 802, 38.7 ± 20.7 years; n = 4296, 34.6 ± 18.0 years; n = 15 249, 39.9 ± 23.8 years, respectively). Patients with SCD (HbSS) had higher risk of developing any retinal vascular occlusion (RR, 2.33; 95% CI, 1.82-3.00), CRAO (RR, 2.71; 95% CI, 1.65-4.47), and BRAO (RR, 4.90; 95% CI, 2.48-9.67) than matched controls. Patients with HbSC disease had higher risk (RR, 3.14; 95% CI, 1.95-5.06) of developing any retinal vascular occlusion than matched controls without SCD. Patients with SCT did not have higher risk of developing retinal vascular occlusions (RR, 1.01; 95% CI, 0.81-1.26) than matched controls. CONCLUSIONS: In a retrospective cohort study, patients with HbSS SCD have an increased risk of developing retinal vascular occlusions, and more specifically CRAO and BRAO, compared with patients without SCD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A pre-B acute lymphoblastic leukemia cell line model reveals the mechanism of thalidomide therapy-related B-cell leukemogenesis.

Lenalidomide, a thalidomide derivative, is prescribed as maintenance therapy for multiple myeloma (MM). Patients with MM receiving lenalidomide were found to develop a distinct therapy-related B cell acute lymphoblastic leukemia (B-ALL). However, the molecular mechanism by which lenalidomide drives B-ALL is unknown. We show that thalidomide treatment of B cell lines increased CD34 expression and fibronectin adhesion. This resembled the effects of Ikzf1 loss of function mutations in B-ALL. IKZF1 is a transcription factor that can act as both a transcriptional activator and a repressor depending upon the target loci. In our experiments, thalidomide-induced degradation of IKZF1 increased the expression of its transcriptional repression targets Itga5 and CD34 explaining the increased adhesion and stemness. Strikingly, withdrawal of thalidomide lead to the mis-localization of IKZF1 to the cytoplasm. Moreover, chromatin immunoprecipitation data showed a long-term effect of thalidomide treatment on IKZF1 target loci. This included decreased chromatin occupancy at early B cell factor 1 (EBF1) and Spi1 (PU.1). Consequently, B-cell lineage specifying transcription factors including Pax5, Spi1 and EBF1 were downregulated even after 7 days of thalidomide withdrawal. Our study thus provides a molecular mechanism of thalidomide-induced B-ALL whereby thalidomide alters the chromatin occupancy of IKZF1 at key B-cell lineage transcription factors leading to a persistent block in B-cell differentiation.

Cardiovascular risk in anti-VEGF treatment of neovascular age-related macular degeneration.

OBJECTIVE: Assess 5-year all-cause mortality (ACM), hemorrhagic stroke, ischemic stroke, and myocardial infarction (MI) risks in nAMD patients receiving anti-VEGF injections compared with controls. DESIGN: Population-based retrospective cohort study using a U.S. federated health research network, containing de-identified data of 96 million patients from 1/1/2003 to 3/6/2023. PARTICIPANTS: nAMD Patients with anti-VEGF injections. Controls included nAMD patients without anti-VEGF injections, non-exudative AMD patients, and patients without AMD. METHODS: Patients were identified using nAMD ICD-10 and anti-VEGF CPT codes and matched for age, sex, and comorbidities. Five-year relative risk of ACM (RR1), hemorrhagic stroke (RR2), ischemic stroke (RR3), and MI (RR4) in nAMD patients receiving anti-VEGF injections were calculated. RESULTS: A total of 27,609 nAMD patients (mean diagnosis age [SD], [78.2 (10.3)]) received anti-VEGF injections; 769 nAMD patients without injections (75.8 [12.2]), 27,599 non-exudative AMD patients (78.2 [10.3]), and 21,902 no-AMD patients (76.1 [10.5]) were identified. After matching, nAMD patients receiving injections did not show increased risk versus nAMD patients without injections (RR1, 0.66; 95% CI [0.53, 0.82]), (RR2, 1.00 [0.42, 2.38]), (RR3, 1.70 [0.92,3.13]), (RR4, 0.63 [0.33, 1.18]). No increased risk was found compared to non-exudative AMD patients (RR1, 0.99 [0.95, 1.03]), (RR2, 0.94 [0.83,1.07]), (RR3, 1.04 [0.96, 1.12]), (RR4, 0.99 [0.91, 1.08]). Increased risk for ACM was observed versus no-AMD patients (RR1, 1.21 [1.15, 1.27]), but no other differences were found (RR2, 0.81 [0.70, 0.93]), (RR3, 1.00 [0.92, 1.09]), (RR4, 0.986 [0.90, 1.09]). CONCLUSION: Anti-VEGF injections were not associated with major cardiovascular events in nAMD patients over 5 years.

Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis. Recent evidence supports the hypothesis that targeting both VEGF and Ang-2 may improve clinical outcomes in DME and nAMD compared with targeting VEGF alone by enhancing vascular stability, resulting in reduced macular leakage, prevention of neovascularization, and diminished inflammation. Faricimab, a novel bispecific antibody that targets VEGF-A and Ang-2, has been evaluated in clinical trials for DME (YOSEMITE/RHINE) and nAMD (TENAYA/LUCERNE). These trials evaluated faricimab against the anti-VEGFA/B and anti-placental growth factor fusion protein aflibercept, both administered by intravitreal injection. In addition to faricimab efficacy, safety, and pharmacokinetics, durability was evaluated during the trials using a treat-and-extend regimen. At 1 year, faricimab demonstrated non-inferior vision gains versus aflibercept across YOSEMITE/RHINE and TENAYA/LUCERNE. In YOSEMITE/RHINE, faricimab improved anatomic parameters versus aflibercept. Reduction of central subfield thickness (CST), and absence of both DME and intraretinal fluid were greater in faricimab- versus aflibercept-treated eyes. In TENAYA/LUCERNE, CST reductions were greater for faricimab than aflibercept at the end of the head-to-head phase (0-12 weeks), and were comparable with aflibercept at year 1, but with less frequent dosing. CST and vision gains were maintained during year 2 of both YOSEMITE/RHINE and TENAYA/LUCERNE. These findings suggest that dual Ang-2/VEGF-A pathway inhibition may result in greater disease control versus anti-VEGF alone, potentially addressing the unmet needs and reducing treatment burden, and improving real-world outcomes and compliance in retinal vascular diseases. Long-term extension studies (RHONE-X, AVONELLE-X) are ongoing. Current evidence suggests that dual inhibition with faricimab heralds the beginning of multitargeted treatment strategies inhibiting multiple, independent components of retinal pathology, with faricimab providing opportunities to reduce treatment burden and improve outcomes compared with anti-VEGF monotherapy.

Melatonin and Risk of Age-Related Macular Degeneration.

Importance: Melatonin has been shown to oppose several processes that are known to mediate age-related macular degeneration (AMD), but whether melatonin can confer benefits against AMD remains unclear. Objective: To examine the association between melatonin supplementation and the risk of the development or progression of AMD. Design, Setting, and Participants: This retrospective cohort study accessed data from TriNetX, a national database of deidentified electronic medical records from both inpatient and outpatient health care organizations across the US, between December 4, 2023, and March 19, 2024. Patients aged 50 years or older, 60 years or older, and 70 years or older with no history of AMD (AMD-naive group) and with a history of nonexudative AMD (nonexudative AMD group) were queried for instances of melatonin medication codes between November 14, 2008, and November 14, 2023. Patients were then classified into either a melatonin group or a control group based on the presence of medication codes for melatonin. Propensity score matching (PSM) was performed to match the cohorts based on demographic variables, comorbidities, and nonmelatonin hypnotic medication use. Exposure: The presence of at least 4 instances of melatonin records that each occurred at least 3 months apart. Main Outcomes and Measures: After PSM, the melatonin and the control cohorts were compared to evaluate the risk ratios (RRs) and the 95% CIs of having an outcome. For the AMD-naive group, the outcome was defined as a new diagnosis of any AMD, whereas for the nonexudative AMD group, the outcome was progression to exudative AMD. Results: Among 121 523 patients in the melatonin-naive group aged 50 years or older (4848 in the melatonin cohort [4580 after PSM; mean (SD) age, 68.24 (11.47) years; 2588 female (56.5%)] and 116 675 in the control cohort [4580 after PSM; mean (SD) age, 68.17 (10.63) years; 2681 female (58.5%)]), melatonin use was associated with a reduced risk of developing AMD (RR, 0.42; 95% CI, 0.28-0.62). Among 66 253 patients aged 50 years or older in the nonexudative AMD group (4350 in the melatonin cohort [4064 after PSM; mean (SD) age, 80.21 (8.78) years; 2482 female (61.1%)] and 61 903 in the control cohort [4064 patients after PSM; mean (SD) age, 80.31 (8.03) years; 2531 female (62.3%)]), melatonin was associated with a reduced risk of AMD progression to exudative AMD (RR, 0.44; 95% CI, 0.34-0.56). The results were consistent among subsets of individuals aged 60 years or older (AMD-naive cohort: RR, 0.36 [95% CI, 0.25-0.54]; nonexudative AMD cohort: RR, 0.38 [95% CI, 0.30-0.49]) and 70 years or older (AMD-naive cohort: RR, 0.35 [95% CI, 0.23-0.53]; nonexudative AMD cohort: RR, 0.40 [95% CI, 0.31-0.51]). Conclusions and Relevance: Melatonin use was associated with a decreased risk of development and progression of AMD. Although lifestyle factors may have influenced this association, these findings provide a rationale for further research on the efficacy of using melatonin as a preventive therapy against AMD.

Longitudinal Trends and Disparities in Diabetic Retinopathy Within an Aggregate Health Care Network.

Importance: Diabetic retinopathy (DR) is a leading cause of blindness in the US, warranting updates on its prevalence and incidence in the setting of advancements in diabetic care over recent years. Objective: To determine recent trends in DR prevalence stratified by baseline demographics to identify those populations at greater risk. Design, Setting, and Participants: This was a cross-sectional epidemiologic evaluation conducted using deidentified data from the large federated TriNetX Analytics health research network composed of 56 health care organizations in the US. Patients from 2015 to 2022 who had an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code of type 1 DR (T1DR) or type 2 DR (T2DR) were included in this analysis. Patients were further stratified by age cohorts (20-29 years, 30-39 years, 40-49 years, 50-59 years, 60-69 years, and 70 years or older), race and ethnicity, and sex. Main Outcomes and Measures: Prevalence per 100 000 patients and prevalence odds ratios (ORs) were calculated in Microsoft Excel and Posit (formerly RStudio). Results: A total of 359 126 patients with T1DR or T2DR (mean [SD] age, 67 [14] years; 52% female) were included in this study between January 1, 2015, and December 21, 2022. T1DR increased in prevalence from 2015 to 2022, with T1DR increasing 1.15-fold affecting 70.4 patients per 100 000 in 2022. T2DR increased 1.07-fold affecting 461.7 patients per 100 000 in 2022. For T1DR, the cohort aged 20 to 39 years had the most substantial increase at 4.7 and 1.96 fold. Overall, White males had the largest prevalence ORs of T1DR at 1.41 (95% CI, 1.36-1.47) compared with White females (reference group). In T2DR, patients aged 20 to 39 years again had a 2.5- and 1.6-fold prevalence increase from 2015 to 2022. Regardless of age group, Hispanic males demonstrated larger prevalence OR at 4.08 (95% CI, 3.97-4.19) compared with White females followed by Hispanic females at 2.49 (95% CI, 2.42-2.56), Black males at 2.23 (95% CI, 2.17-2.29), and Black females at 2.00 (95% CI, 1.95-2.05). Conclusion and Relevance: The prevalence of both T1DR and T2DR increased in this network from 2015 to 2022, with individuals aged 20 to 39 years showing large increases. Additionally, T2DR was associated with greater increases in both Hispanic and Black communities. These findings support DR screening in young adults and for T2DR interventions specifically designed for racial and ethnic minoritized patients most affected by disease. Future investigations are warranted to further investigate these trends among young adults.

Tumor-derived Hsp70-CD14 interaction enhances the antitumor potential of cytotoxic T cells by activating tumor-associated macrophages to express CC chemokines and CD40 costimulatory molecules.

Heat shock proteins are a widely distributed group of proteins. It is constitutively expressed in almost all organisms and shows little variation throughout evolution. Previously, HSPs, particularly Hsp70, were recognized as molecular chaperones that aid in the proper three-dimensional folding of newly synthesized polypeptides in cells. Recently, researchers have focused on the potential induction of immune cells, including macrophages, antigen-specific CD8+ cytotoxic T cells, and PBMCs. It induces the expression of CC chemokines such as MIP-1α and RANTES, which are responsible for the chemotactic movement and migration of immune cells at the site of infection to neutralize foreign particles in vivo and in vitro in several cell lines but their effect on tumor-associated macrophages is still not known. These cytokines are also known to influence the movement of several immune cells, including CD8+ cytotoxic T cells, toward inflammatory sites. Therefore, the effect of tumor-derived autologous Hsp70 on the expression of MIP-lα and RANTES in tumor-associated macrophages (TAMs) was investigated. Our results indicated that Hsp70 treatment-induced MIP-lα and RANTES expression was significantly greater in TAMs than in NMOs. According to the literature, the CC chemokine shares the same receptor, CCR5, as HIV does for their action, and therefore could provide better completion to the virus for ligand binding. Furthermore, Hsp70-preactivated TAMs induced increased IL-2 and IFN-γ expression in T cells during coculture for 48 h and upregulated the antitumor immune response of the host. Therefore, the outcome of our study could be useful for developing a better approach to restricting the growth and progression of tumors.

Long-term Treatment Patterns for Diabetic Macular Edema: Up to 6-Year Follow-up in the IRIS® Registry.

OBJECTIVE: To characterize anti-VEGF intravitreal therapy (IVT) patterns and long-term visual outcomes among patients with diabetic macular edema (DME) in routine clinical practice in the United States. DESIGN: Retrospective analysis of the American Academy of Ophthalmology's IRIS® (Intelligent Research in Sight) Registry. PARTICIPANTS: Treatment-naïve patients with DME (no previous IVT in the past 12 months) initiating anti-VEGF IVT from January 1, 2015, to March 31, 2021. METHODS: Baseline characteristics, treatment patterns, and long-term visual acuity (VA) outcomes were reported for up to 6 years of follow-up. MAIN OUTCOME MEASURES: Outcomes included the annualized number of injections, change in VA, and anti-VEGF agents. RESULTS: A total of 190 345 eyes met the inclusion criteria. After 1 year of anti-VEGF IVT initiation, eyes received a mean of 3.9 (±2.8) injections and gained +3.2 (±16.4) letters of vision. Of the 1236 eyes with year 6 data, eyes received a mean of 2.9 (±2.1) injections in year 6 and gained +0.5 (±19.7) letters from baseline. The number of injections decreased, and injection intervals increased year over year up to 6 years regardless of baseline VA initiation. The average injection interval was 10 weeks in year 1 and increased to 13.2 weeks in year 2 before plateauing in years 3 to 6 (12.6, 12.3, 12.2, and 12.3 weeks, respectively). Improvements in VA from baseline were greatest in eyes that received 5 or more injections each year. At the end of follow-up, eyes with good baseline vision (>20/25) lost vision, whereas those with worse baseline vision (<20/25) gained vision. Although 51.7% of patients with DME discontinued IVT after a mean of 6 months, 32.8% reinitiated anti-VEGF IVT. Worse VA outcomes were associated with patients of Hispanic ethnicity (-1.08; 95% confidence interval: -1.34, -0.83] compared with non-Hispanic), Medicaid insurance (-1.15; 95% confidence interval: -1.48, -0.81 compared with commercial), and older age (-0.06; 95% confidence interval: -0.07, -0.05] each additional year). CONCLUSIONS: Patients with DME in routine clinical settings receive fewer injections than those in clinical trials and fewer than recommended per the label of US Food and Drug Administration-approved anti-VEGF IVT. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references in the Footnotes and Disclosures at the end of this article.