Clinical serum lipidomic profiling revealed potential lipid biomarkers for early diabetic retinopathy.

Diabetic retinopathy (DR) is a serious complication of diabetes featuring abnormal lipid metabolism. However, the specific lipid molecules associated with onset and progression remain unclear. We used a broad-targeted lipidomics approach to assess the lipid changes that occur before the proliferative retinopathy stage and to identify novel lipid biomarkers to distinguish between patients without DR (NDR) and with non-proliferative DR (NPDR). Targeted lipomics analysis was carried out on serum samples from patients with type I diabetes, including 20 NDRs and 20 NPDRs. The results showed that compared with the NDR group, 102 lipids in the NPDR group showed specific expressions. Four lipid metabolites including TAG58:2-FA18:1 were obtained using the Least Absolute Shrink And Selection Operator (LASSO) and Support Vector Machine Recursive Feature Elimination (SVM-RFE) methods. The four-lipid combination diagnostic models showed good predictive ability in both the discovery and validation sets, and were able to distinguish between NDR patients and NPDR patients. The identified lipid markers significantly improved diagnostic accuracy within the NPDR group. Our findings help to better understand the complexity and individual differences of DR lipid metabolism.

Nuclear proteins and diabetic retinopathy: a review.

Diabetic retinopathy (DR) is an eye disease that causes blindness and vision loss in diabetic. Risk factors for DR include high blood glucose levels and some environmental factors. The pathogenesis is based on inflammation caused by interferon and other nuclear proteins. This review article provides an overview of DR and discusses the role of nuclear proteins in the pathogenesis of the disease. Some core proteins such as MAPK, transcription co-factors, transcription co-activators, and others are part of this review. In addition, some current advanced treatment resulting from the role of nuclear proteins will be analyzes, including epigenetic modifications, the use of methylation, acetylation, and histone modifications. Stem cell technology and the use of nanobiotechnology are proposed as promising approaches for a more effective treatment of DR.

Intravitreal conbercept injection with panretinal photocoagulation for high-risk proliferative diabetic retinopathy with vitreous hemorrhage.

AIM: To assess the clinical efficacy and safety of combining panretinal photocoagulation (PRP) with intravitreal conbercept (IVC) injections for patients with high-risk proliferative diabetic retinopathy (HR-PDR) complicated by mild or moderate vitreous hemorrhage (VH), with or without diabetic macular edema (DME). METHODS: Patients diagnosed with VH with/without DME secondary to HR-PDR and received PRP combined with IVC injections were recruited in this retrospective study. Upon establishing the patient's diagnosis, an initial IVC was performed, followed by prompt administration of PRP. In cases who significant bleeding persisted and impeded the laser operation, IVC was sustained before supplementing with PRP. Following the completion of PRP, patients were meticulously monitored for a minimum of six months. Laser therapy and IVC injections were judiciously adjusted based on fundus fluorescein angiography (FFA) results. Therapeutic effect and the incidence of adverse events were observed. RESULTS: Out of 42 patients (74 eyes), 29 were male and 13 were female, with a mean age of 59.17±12.74y (33-84y). The diabetic history was between 1wk and 26y, and the interval between the onset of visual symptoms and diagnosis of HR-PDR was 1wk-1y. The affected eye received 2.59±1.87 (1-10) IVC injections and underwent 5.5±1.02 (4-8) sessions of PRP. Of these, 68 eyes received PRP following 1 IVC injection, 5 eyes after 2 IVC injections, and 1 eye after 3 IVC injections. Complete absorption of VH was observed in all 74 eyes 5-50wk after initial treatment, with resolution of DME in 51 eyes 3-48wk after initial treatment. A newly developed epiretinal membrane was noted in one eye. Visual acuity significantly improved in 25 eyes. No complications such as glaucoma, retinal detachment, or endophthalmitis were reported. CONCLUSION: The study suggests that the combination of PRP with IVC injections is an effective and safe modality for treating diabetic VH in patients with HR-PDR.

Evaluation of nail fold capillaroscopy changes in patients with diabetic retinopathy and healthy controls, and its correlation with disease duration, HbA1c levels and severity of diabetic retinopathy: An observational study.

Background Diabetic retinopathy (DR) is an important microvascular complication of long-term type 2 diabetes mellitus (T2DM) leading to blindness if not properly diagnosed and managed. It can develop as early as 7 years before the diagnosis of diabetes. Nail fold capillaroscopy (NFC) is a non-invasive technique for observing capillary microvasculature and there are few studies which have explored the use of NFC in diabetes mellitus patients. Objective To study the nail fold capillaroscopic alterations in patients with T2DM having diabetic retinopathy and compare them to healthy controls. The secondary objective was to correlate the NFC findings with the duration of diabetes, haemoglobin A1c (HbA1c) levels and the severity of DR. Materials and methods This cross-sectional observational study enrolled 200 patients - 100 cases with T2DM having diabetic retinopathy (as per the American Diabetes Association criteria and Diabetic Retinopathy Disease Severity Scale) and 100 healthy age and sex-matched controls. All patients were subjected to NFC and ophthalmological assessment. Results NFC revealed that patients with DR showed significantly higher frequencies of tortuous, dilated, bushy, meandering, angulated capillaries, avascular areas and micro-haemorrhages as compared to healthy controls (p < 0.05). In proliferative DR (PDR), the frequency of tortuous, bushy capillaries, and avascular areas was statistically high and the capillary density was reduced as compared to non-proliferative DR. The DR patients with longer disease duration (>20) years had a significantly higher frequency of tortuous capillaries, avascular areas, meandering, angulated and dilated capillaries. The frequency of tortuosity, avascular areas, and bushy areas was significantly higher in patients with poor glycaemic control (HbA1c >11). Limitations A larger sample size study with different demographic populations could have provided a broader picture of NFC changes in T2DM patients with DR. Discussion NFC may act as a surrogate marker of retinal involvement in patients with DM and should be performed at regular intervals. Conclusion NFC is a quick, simple, safe, and non-invasive method to assess the capillaroscopic alterations in diabetic patients which inturn can help in assessing the severity of DR.

Impact of anti-VEGF treatment on development of proliferative diabetic retinopathy in routine clinical practice.

BACKGROUND: This study evaluated impact of anti-vascular endothelial growth factor (VEGF) treatment on proliferative diabetic retinopathy (PDR) development among patients with non-proliferative diabetic retinopathy (NPDR) in US real-world clinical practice. METHODS: This was a retrospective analysis of electronic medical records (Vestrum Health; January 2013 to June 2019) of eyes with baseline NPDR, without DME, and naïve to anti-VEGF treatment at index DR diagnosis. Eyes that received anti-VEGF and/or laser treatment over the course of study before development of PDR constituted the treated cohort while the remaining including those treated with laser constituted the anti-VEGF naïve cohort. Survival analysis via Kaplan-Meier method evaluated time to DME and PDR development by baseline NPDR severity, with anti-VEGF treatment as censoring variable. Baseline factors affecting PDR development were analyzed using Cox multivariable regression, censoring for anti-VEGF treatment. RESULTS: Among anti-VEGF-naive eyes, cumulative incidence of DME in eyes with mild (n = 70,050), moderate (n = 39,116), and severe NPDR (n = 10,692) at baseline was 27.1%, 51.2%, and 60.6%. Multivariable regression analysis identified baseline NPDR severity as the most significant predictor of PDR development over 48 months (hazard ratio [HR] [95% confidence interval {CI}] of 2.69 (2.65-2.72) for moderate vs mild NPDR and 6.51 (6.47-6.55) for severe vs mild NPDR). Cumulative incidence (95% CI) of PDR was 7.9% (7.4%-8.3%), 20.9%, (20.0%-21.7%) and 46.8% (44.4%-49.2%) over 48 months in eyes with mild, moderate, and severe NPDR at baseline, respectively. Among treated eyes with baseline severe NPDR, cumulative incidence of PDR at 48 months was 50.1% in eyes treated with laser (n = 546; HR [95% CI] vs no treatment: 0.8 [0.7-1.0]), 27.4% in eyes treated with anti-VEGF (n = 923; HR [95% CI]: 0.4 [0.4-0.5]), and 25.6% in eyes treated with anti-VEGF plus laser (n = 293; HR [95% CI]: 0.5 [0.4-0.7]) compared with 49.9% in eyes with no treatment (n = 8930). CONCLUSIONS: DME and PDR development rates increased with increasing baseline NPDR severity. Approximately half of anti-VEGF‒naive eyes with severe NPDR progressed to PDR within 4 years in US clinical practice. The progression rate from severe NPDR to PDR was approximately halved with anti-VEGF versus no treatment.

[Biomechanics of diabetic vitreopapillary traction syndrome]. / Biomekhanika diabeticheskogo vitreopapillyarnogo traktsionnogo sindroma.

Diabetic vitreopapillary traction syndrome (VPT) is a variant of diabetic retinopathy (DR) that can lead to vision loss in advanced stages. This review reports on the biomechanics of the vitreous in the pathogenesis of proliferative DR, in particular diabetic VPT. The article analyzes and summarizes literature data, presents the views of different authors on this problem, and provides the results of Russian and foreign scientific research on this pathology. It is concluded that further research in this area can lead to a significant improvement in the results of therapy, timely diagnosis, and preservation of vision in patients with DR.

Effectiveness and safety of early lens extraction during par plana vitrectomy for proliferative diabetes retinopathy with mild cataract: a randomized clinical trial.

AIM: To evaluate the effectiveness and safety of early lens extraction during pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) compared to those of PPV with subsequent cataract surgery. METHODS: This multicenter randomized controlled trial was conducted in three Chinese hospitals on patients with PDR, aged >45y, with mild cataracts. The participants were randomly assigned to the combined (PPV combined with simultaneously cataract surgery, i.e., phacovitrectomy) or subsequent (PPV with subsequent cataract surgery 6mo later) group and followed up for 12mo. The primary outcome was the change in best-corrected visual acuity (BCVA) from baseline to 6mo, and the secondary outcomes included complication rates and medical expenses. RESULTS: In total, 129 patients with PDR were recruited and equally randomized (66 and 63 in the combined and subsequent groups respectively). The change in BCVA in the combined group [mean, 36.90 letters; 95% confidence interval (CI), 30.35-43.45] was significantly better (adjusted difference, 16.43; 95%CI, 8.77-24.08; P<0.001) than in the subsequent group (mean, 22.40 letters; 95%CI, 15.55-29.24) 6mo after the PPV, with no significant difference between the two groups at 12mo. The overall surgical risk of two sequential surgeries was significantly higher than that of the combined surgery for neovascular glaucoma (17.65% vs 3.77%, P=0.005). No significant differences were found in the photocoagulation spots, surgical time, and economic expenses between two groups. In the subsequent group, the duration of work incapacity (22.54±9.11d) was significantly longer (P<0.001) than that of the combined group (12.44±6.48d). CONCLUSION: PDR patients aged over 45y with mild cataract can also benefit from early lens extraction during PPV with gratifying effectiveness, safety and convenience, compared to sequential surgeries.

The Genetic Variants of Long Noncoding RNA MEG3 and Its Association to the Clinical Features of Diabetic Retinopathy.

PURPOSE: This study aimed to investigate the potential correlation between the single-nucleotide polymorphism (SNP) of maternally expressed gene 3 (MEG3) and the clinical manifestations of diabetic retinopathy (DR). METHODS: Five loci of MEG3 SNPs including rs4081134 (G/A), rs10144253 (T/C), rs7158663 (G/A), rs3087918 (T/G) and rs11160608 (A/C) were genotyped by TaqMan allelic discrimination in 457 non-DR patients and 280 DR individuals. RESULTS: The distribution frequency of MEG3 SNP rs7158663 GA (AOR: 0.683, 95% CI: 0.478-0.975, p = 0.036) and MEG3 SNP rs7158663 GA + AA (AOR: 0.686, 95% CI: 0.487-0.968, p = 0.032) were significantly lower in the DR group. And the MEG3 SNP rs7158663 GA + AA (AOR: 0.610, 95% CI: 0.377-0.985, p = 0.043) demonstrated a significantly lower distribution frequency in the male DR group. Besides, the DR patients with MEG3 SNP rs7158663 GA + AA genotype showed a significantly lower HbA1c level than the DR patients with MEG3 SNP rs7158663 GG genotype (7.29 ± 1.23 versus 7.74 ± 1.49, p = 0.013). Moreover, in the analysis using data from gene expression data series database, a higher MEG3 level was significantly correlated to a lower miR-182 level in the database (p = 0.0114). CONCLUSIONS: In this study, the distribution frequency of MEG3 SNP rs7158663 GA + AA genotype was lower in DR, while the DR would develop under lower HbA1c level in DM patients with this MEG3 SNP variant.

The effect of adjuvant Mitomycin C during vitrectomy on functional and anatomical outcomes in patients with severe diabetic tractional retinal detachment.

PURPOSE: To evaluate the effect of adjuvant Mitomycin C (MMC) use on the anatomical and functional success of vitreoretinal surgery (VRS) in severe diabetic tractional retinal detachment (dTRD) patients. METHODS: A retrospective analysis of consecutive patients undergoing VRS due to severe dTRD was conducted. Patients were categorized into those who received 20 µg/0.1 mL MMC via MMC sandwich method (Group 1) and those who did not (Group 2). Demographics, surgical characteristics, visual outcomes, and complications that may related to MMC were analyzed. RESULTS: A total of 25 eyes were included, 13 in Group 1 and 12 in Group 2. No statistical difference was observed in baseline characteristics between the groups. The mean best-corrected visual acuity was 1.90 ± 0.43 logMAR and 1.93 ± 0.41 logMAR preoperatively and 1.60 ± 0.78 logMAR and 1.56 ± 0.78 logMAR postoperatively in Groups 1 and 2, respectively (p = 0.154). The postoperative mean intraocular pressure was 16.23 ± 2.55 mmHg and 13.08 ± 4.94 mmHg in Groups 1 and 2, respectively (p = 0.225). The rate of re-surgery was significantly lower in Group 1 (0% vs. 41.7% in Group 2, p = 0.015). Retina was attached in all patients at the last visit. No MMC-related complication was recorded. CONCLUSION: Intraoperative adjuvant MMC application for severe dTRD significantly reduces re-surgery rates with good anatomical and functional outcomes safely.

Diabetes and further risk of cancer: a nationwide population-based study.

BACKGROUND: Individuals with diabetes have a significantly higher risk of developing various forms of cancer, and the potential biological links between these two diseases are not completely understood. METHODS: This was a longitudinal retrospective nationwide cohort study, a study design that allows us to examine the natural course of cancer development over an extended period of time with a large sample size. Initially, 3,111,975 and 22,208,395 eligible patients aged ≥ 20 years with and without diabetes, respectively, were matched by age, sex, and the Charlson comorbidity index. Ultimately, 1,751,457 patients were selected from each group. Stratified populations for diabetic retinopathy (DR) (n = 380,822) and without DR (n = 380,822) as well as proliferative DR (PDR) (n = 141,150) and non-proliferative DR (NPDR) (n = 141,150) were analyzed in this study. The main outcome measure was the first-time diagnosis of cancer during the follow-up period. RESULTS: We observed a 20% higher risk of total cancer incidence [hazard ratios (HR), 1.20; p < 0.001] in the diabetes cohort compared to the non-diabetes cohort. The highest HR was observed for liver and pancreas cancers. Moderately increased risks were observed for oral, colon, gallbladder, reproductive (female), kidney, and brain cancer. Furthermore, there was a borderline significantly increased risk of stomach, skin, soft tissue, female breast, and urinary tract (except kidney) cancers and lymphatic and hematopoietic malignancies. The stratified analysis revealed that the total cancer incidence was significantly higher in the DR cohort compared to the non-DR cohort (HR, 1.31; p < 0.001), and there was a borderline increased risk in the PDR cohort compared to the NPDR cohort (HR, 1.13; p = 0.001). CONCLUSIONS: This study provides large-scale, nationwide, population-based evidence that diabetes is independently associated with an increased risk of subsequent development of total cancer and cancer at specific sites. Notably, this risk may further increase when DR develops.

[Outcomes of bimanual vitreoretinal surgery in the treatment of diabetic retinopathy complications]. / Rezul'taty bimanual'noi vitreoretinal'noi khirurgii v lechenii oslozhnenii diabeticheskoi retinopatii.

The incidence of diabetic retinopathy (DR) requiring vitreorentinal surgery is increasing. The search for new effective and safe methods of treatment, the choice of the optimal time for surgery, and the assessment of long-term treatment outcomes are relevant problems. PURPOSE: This study evaluates the long-term results of vitreorentinal surgery using the bimanual technique in DR with different stages of fibrovascular proliferation. MATERIAL AND METHODS: The study included 135 patients (135 eyes) who were divided into groups depending on the predominant type of proliferation - vascular or fibrous. Patients underwent vitrectomy with membranectomy using the bimanual technique, with peripheral panretinal endolaser coagulation of the retina and tamponade of the vitreous cavity with balanced salt solution. The postoperative observation period lasted up to 12 months. RESULTS: Both groups showed statistically significant improvement in visual function and anatomical changes in central retinal thickness. A statistically significant improvement in best corrected visual acuity (BCVA) was found in patients with initially predominantly vascular proliferation. Correlation analysis showed that initially higher BCVA tends to persist in the postoperative period. A negative correlation was found between the final BCVA and the presence of type 2 diabetes mellitus, fibrous stage of proliferation, high central retinal thickness, and the presence of diabetic macular edema (DME) - both initially and after treatment. The frequency of complications in the groups was comparable, except for postoperative DME, which was more often detected in patients with fibrous proliferation. CONCLUSION: The bimanual technique of vitreorentinal surgery for complications of DR allows achieving high anatomical and functional results. Higher BCVA is noted in patients with the vascular stage of proliferation and initially high BCVA. The obtained data allow us to form a hypothesis about the possibility of earlier surgery in patients with high BCVA, but require further investigation.

Aqueous humor proteomics analyzed by bioinformatics and machine learning in PDR cases versus controls.

BACKGROUND: To comprehend the complexities of pathophysiological mechanisms and molecular events that contribute to proliferative diabetic retinopathy (PDR) and evaluate the diagnostic value of aqueous humor (AH) in monitoring the onset of PDR. METHODS: A cohort containing 16 PDR and 10 cataract patients and another validation cohort containing 8 PDR and 4 cataract patients were studied. AH was collected and subjected to proteomics analyses. Bioinformatics analysis and a machine learning-based pipeline called inference of biomolecular combinations with minimal bias were used to explore the functional relevance, hub proteins, and biomarkers. RESULTS: Deep profiling of AH proteomes revealed several insights. First, the combination of SIAE, SEMA7A, GNS, and IGKV3D-15 and the combination of ATP6AP1, SPARCL1, and SERPINA7 could serve as surrogate protein biomarkers for monitoring PDR progression. Second, ALB, FN1, ACTB, SERPINA1, C3, and VTN acted as hub proteins in the profiling of AH proteomes. SERPINA1 was the protein with the highest correlation coefficient not only for BCVA but also for the duration of diabetes. Third, "Complement and coagulation cascades" was an important pathway for PDR development. CONCLUSIONS: AH proteomics provides stable and accurate biomarkers for early warning and diagnosis of PDR. This study provides a deep understanding of the molecular mechanisms of PDR and a rich resource for optimizing PDR management.

Impact of Bariatric Surgery on Treatment Burden and Progression of Diabetic Retinopathy.

Purpose: To assess the severity, progression, and treatment burden of diabetic retinopathy (DR) in patients after bariatric surgery compared with controls. Methods: A retrospective cohort study was performed of patients with type 2 diabetes and DR seen at the Duke Eye Center between 2014 and 2023. Clinical data included hemoglobin A1c (HbA1c), diagnostic stage of DR, diabetic macular edema (DME) or vitreous hemorrhage (VH), visual acuity (VA), and treatment burden at baseline and follow-up. Generalized estimating equation analysis was used to account for the correlation between 2 eyes of the same patient. Results: Sixteen patients who had bariatric surgery were matched by age, sex, and duration of diabetes with 60 control patients managed medically during the same time period. The HbA1c level, severity of DR, presence of DME or VH, VA, and treatment burden were not significantly different (all P > .05) at the baseline examination. On average, patients were followed for 6 years. The HbA1c level at the follow-up was significantly lower in the bariatric surgery group (6.4% vs 8.5%; P < .001). At the follow-up, the treatment burden was reduced in the bariatric surgery group compared with the control group (P = .04). There was a clear trend toward reduced progression of DR and treatment burden in the bariatric surgery group over the follow-up. Conclusions: Bariatric surgery may improve glycemic control, stabilize DR progression, and reduce the treatment burden, which may have a significant impact on quality of life for patients with DR.

Glycemic Control in Patients After Initiation of Treatment for Vision-Threatening Diabetic Retinopathy.

Purpose: To understand changes in glycemic control in patients being managed with vision-threatening diabetic retinopathy (DR). Methods: A retrospective cohort study was performed of patients with type 2 diabetes mellitus who were at least 18 years old. Patients who started treatment for vision-threatening DR were matched with controls based on age, sex, race/ethnicity, duration of diabetes, history of diabetes, and history of hypertension. The primary outcome was the difference in hemoglobin A1c (HbA1c) change after 12 months between cases and controls. Results: Four hundred fifty patients were included (225 cases paired with 225 controls); 58.7% of patients were men, and 33.8% were Hispanic. The mean (±SD) baseline HbA1c was 8.12% ± 1.57%. Patients receiving retinal interventions did not experience a significant change in HbA1c compared with controls 12 months after starting treatment (0.11% ± 1.51% vs -0.02% ± 1.52%; P = .31). In addition, there was not a significant difference in HbA1c change between cases and controls when considering the number of interventions: 2 or fewer interventions (+0.08% ± 1.30% vs -0.07% ± 1.15%; P = .46), 3 to 6 interventions (+0.41% ± 1.71% vs +0.01% ± 2.0%; P = .08), and 7 or more interventions (-0.17% ± 1.49% vs 0.0% ± 1.31%; P = .50). Conclusions: Patients who received treatment for vision-threatening DR did not experience a change in HbA1c. Increasing number of retinal interventions also did not appear to impact glycemic control. There appears to be a missed opportunity for improving diabetes management in patients with vision-threatening DR.

The Predictors of Early Treatment Effectiveness of Intravitreal Bevacizumab Application in Patients with Diabetic Macular Edema.

The aim of this study was to establish whether multiple blood parameters might predict an early treatment response to intravitreal bevacizumab injections in patients with diabetic macular edema (DME). Seventy-eight patients with non-proliferative diabetic retinopathy (NPDR) and DME were included. The treatment response was evaluated with central macular thickness decrease and best corrected visual acuity increase one month after the last bevacizumab injection. Parameters of interest were the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), vitamin D, and apolipoprotein B to A-I ratio (ApoB/ApoA-I). The NLR (2.03 ± 0.70 vs. 2.80 ± 1.08; p < 0.001), MLR (0.23 ± 0.06 vs. 0.28 ± 0.10; p = 0.011), PLR (107.4 ± 37.3 vs. 135.8 ± 58.0; p = 0.013), and SII (445.3 ± 166.3 vs. 675.3 ± 334.0; p < 0.001) were significantly different between responder and non-responder groups. Receiver operator characteristics analysis showed the NLR (AUC 0.778; 95% CI 0.669-0.864), PLR (AUC 0.628; 95% CI 0.511-0.735), MLR (AUC 0.653; 95% CI 0.536-0.757), and SII (AUC 0.709; 95% CI 0.595-0.806) could be predictors of response to bevacizumab in patients with DME and NPDR. Patients with severe NPDR had a significantly higher ApoB/ApoA-I ratio (0.70 (0.57-0.87) vs. 0.61 (0.49-0.72), p = 0.049) and lower vitamin D (52.45 (43.10-70.60) ng/mL vs. 40.05 (25.95-55.30) ng/mL, p = 0.025). Alterations in the NLR, PLR, MLR, and SII seem to provide prognostic information regarding the response to bevacizumab in patients with DME, whilst vitamin D deficiency and the ApoB/ApoA-I ratio could contribute to better staging.

Upregulation of HMOX1 associated with M2 macrophage infiltration and ferroptosis in proliferative diabetic retinopathy.

The roles of immune cell infiltration and ferroptosis in the progression of proliferative diabetic retinopathy (PDR) remain unclear. To identify upregulated molecules associated with immune infiltration and ferroptosis in PDR, GSE60436 and GSE102485 datasets were downloaded from the Gene Expression Omnibus (GEO). Genes associated with immune cell infiltration were examined through Weighted Gene Co-expression Network Analysis (WGCNA) and CIBERSORT algorithm. Common differentially expressed genes (DEGs) were intersected with ferroptosis-associated and immune cell infiltration-related genes. Localization of cellular expression was confirmed by single-cell analysis of GSE165784 dataset. Findings were validated by qRT-PCR, ELISA, Western blotting, and immunofluorescence staining. As a result, the infiltration of M2 macrophages was significantly elevated in fibrovascular membrane samples from PDR patients than the retinas of control subjects. Analysis of DEGs, M2 macrophage-related genes and ferroptosis-related genes identified three hub intersecting genes, TP53, HMOX1 and PPARA. qRT-PCR showed that HMOX1 was significantly higher in the oxygen-induced retinopathy (OIR) mouse model retinas than in controls. Single-cell analysis confirmed that HMOX1 was located in M2 macrophages. ELISA and western blotting revealed elevated levels of HMOX1 in the vitreous humor of PDR patients and OIR retinas, and immunofluorescence staining showed that HMOX1 co-localized with M2 macrophages in the retinas of OIR mice. This study offers novel insights into the mechanisms associated with immune cell infiltration and ferroptosis in PDR. HMOX1 expression correlated with M2 macrophage infiltration and ferroptosis, which may play a crucial role in PDR pathogenesis.

Comparative Effectiveness of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter 2 Inhibitors, Dipeptidyl Peptidase-4 Inhibitors, and Sulfonylureas for Sight-Threatening Diabetic Retinopathy.

OBJECTIVE: To investigate whether the choice of glucose-lowering agent for type 2 diabetes (T2D) impacts a patient's risk of developing sight-threatening diabetic retinopathy complications. DESIGN: Retrospective observational database study emulating an idealized target trial. SUBJECTS: Adult (≥21 years) enrollees in United States commercial, Medicare Advantage, and Medicare fee-for-service plans from January 1, 2014, to December 31, 2021, with T2D and moderate cardiovascular disease (CVD) risk who had no baseline history of advanced diabetic retinal complications, initiating treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RA), sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and sulfonylureas. METHODS: We used inverse propensity scoring weights in time-to-event Cox proportional hazards models. MAIN OUTCOME MEASURES: Treatment for either diabetic macular edema or proliferative diabetic retinopathy. RESULTS: The final study population included 371 698 patients, of whom 42 265 initiated GLP-1 RA, 53 476 initiated SGLT2i, 78 444 initiated DPP-4i, and 197 513 initiated sulfonylurea agents. The probability of treatment for sight-threatening retinopathy within 2 and 5 years was 0.3% and 0.7% for patients initiating SGLT2i (median follow-up 830 [interquartile range (IQR), 343-1401] days), 0.4% and 1.0% for GLP-1 RA (669 [IQR, 256-1167] days), 0.4% and 0.9% for DPP-4i (1263 [IQR, 688-1938] days), and 0.5% and 1.2% for sulfonylurea (1223 [IQR, 662-1879] days). Sodium-glucose cotransporter 2 inhibitors use was associated with a lower risk of treatment for sight-threatening retinopathy compared with all other medication classes, including GLP-1 RA (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.55-0.97), DPP-4i (HR, 0.79; 95% CI, 0.64-0.97), and sulfonylurea (HR, 0.61; 95% CI, 0.50-0.74). Glucagon-like peptide-1 receptor agonists use was associated with a similar risk of sight-threatening retinopathy as DPP-4i (HR, 1.07; 95% CI, 0.85-1.35) and sulfonylurea (HR, 0.83; 95% CI, 0.67-1.03). CONCLUSIONS: Sodium-glucose cotransporter 2 inhibitors use was associated with a lower risk of sight-threatening diabetic retinopathy among adults with T2D and moderate CVD risk compared with other glucose-lowering therapies. Glucagon-like peptide-1 receptor agonists do not confer increased retinal risk, relative to DPP-4i and sulfonylurea medications. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Loss to Follow up in Patients with Proliferative Diabetic Retinopathy Treated with Anti-VEGF Therapy and/or Panretinal Photocoagulation in the United States.

PURPOSE: To determine the rate of loss to follow up (LTFU) in patients with proliferative diabetic retinopathy (PDR) treated with anti-VEGF therapy and/or panretinal photocoagulation (PRP) in the United States. DESIGN: Retrospective cohort study using the national IRIS® (Intelligent Research in Sight) Registry data. SUBJECTS: A total of 73 595 eyes of 56 590 patients with PDR diagnosed between 2013 and 2015 and treated between 2013 and 2018. METHODS: Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). MAIN OUTCOME MEASURES: Loss to follow up was no follow up within 12 months from last treatment. RESULTS: For patient eyes treated for PDR, 11.7% (95% CI, 11.5-12.0) were LTFU. Among patients with PDR treated with anti-VEGF therapy alone, PRP alone, and anti-VEGF and PRP, the rates of LTFU were 12.3% (95% CI, 11.8-12.7), 12.6% (95% CI, 12.1-13.0), and 10.8% (95% CI, 10.4-11.1), respectively. Risk factors for LTFU include Black or African American race/ethnicity (odds ratio [OR], 1.26; 95% CI, 1.13-1.41; P < 0.001), Hispanic ethnicity (OR, 1.28; 95% CI, 1.16-1.42; P < 0.001), Native American/Alaska Native or Native Hawaiian/Other Pacific Islander race/ethnicity (OR, 2.69; 95% CI, 2.14-3.38; P < 0.001), and unilateral disease (OR, 2.05; CI, 1.88-2.23; P < 0.001). Odds for LTFU were higher with patients with baseline vision of 20/50 to 20/200 (OR, 1.25; 95% CI, 1.15-1.36; P < 0.001) and with vision worse than 20/200 (OR, 1.22; 95% CI, 1.05-1.42; P = 0.01) than for patient eyes with a baseline visual acuity of 20/40 or better. Odds for LTFU were lower for Medicare Fee-for-Service (OR, 0.71; 95% CI, 0.64-0.79; P < 0.001) and Medicare Managed (OR, 0.66; 95% CI, 0.56-0.78; P < 0.001) compared with private insurance. Odds for LTFU were lower for patients treated in the Midwest (OR, 0.72; 95% CI, 0.64-0.81; P < 0.001) and West (OR, 0.83; 95% CI, 0.74-0.94; P = 0.003) compared with in the South region. CONCLUSIONS: The rate of LTFU is between 10% and 12% among patients with PDR who were treated with anti-VEGF injections and/or PRP. Risk factors include Black or African American race/ethnicity, Hispanic ethnicity, baseline vision worse than 20/40, private insurance, South region, and unilateral disease. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Risk factors of internal carotid artery stenosis in patients with proliferative diabetic retinopathy: an analysis using optical coherence tomography and optical coherence tomography angiography.

BACKGROUND: This research investigates the correlation between the severity of internal carotid artery (ICA) stenosis and retinal parameters in patients with proliferative diabetic retinopathy (PDR), aiming to uncover potential risk factors. METHODS: A retrospective analysis of 68 patients (136 eyes) diagnosed with bilateral PDR from January 1, 2017, to December 31, 2021, was conducted. Carotid artery stenosis (CAS) was assessed using neck computed tomography angiography (CTA) and carotid duplex ultrasound (CDUS), with stenosis classified into two groups: normal (group 1) and mild or above (group 2), based on the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Optical coherence tomography (OCT) and OCT angiography (OCTA) measured several retinal parameters, including sub foveal choroidal thickness (SFCT), retinal nerve fiber layer (RNFL) thickness, ganglion cell-inner plexiform layer (GCIPL) thickness, vessel density (VD), and foveal avascular zone (FAZ) area. Statistical analyses determined correlations between ICA degrees and retinal parameters. RESULTS: This study showed significant differences between groups in total VD, FAZ area, total RNFL thickness, and temporal RNFL thickness, indicating that patients with more severe ICA stenosis had noticeable retinal changes. Other parameters such as hyperlipidemia, total cholesterol levels, and intraocular pressure (IOP) also differed significantly, while no notable differences were observed in SFCT, central VD, average GCIPL, and superior, nasal, and inferior RNFL thickness. CONCLUSION: The study findings highlight retinal changes, such as an increased FAZ area, decreased total VD, and a total and thinner temporal RNFL, which suggest the need for carotid artery evaluation in patients. These findings have important clinical implications for the need for carotid work up in patients with PDR.