MicroRNA-2861 regulates the proliferation and apoptosis of human retinal vascular endothelial cells treated with high glucose by targeting NDUFB7.

Objectives: Although anti-VEGF and retinal laser photocoagulation are two therapeutic modalities that have been used in the clinical treatment of diabetic retinopathy (DR), it is unknown how these modalities target vascular endothelial function in DR. Methods: We first downloaded and analyzed the differential genes in two DR-related datasets, GSE60436 and GSE53257. The differential gene expression was then verified using RT-qPCR, and the most upregulated gene, NDUFB7, was selected for subsequent experiments. Subsequently, the role of NDUFB7 silencing and enforced expression on the proliferation and apoptosis of HRVECs was explored using CCK-8 assay, EDU proliferation assay and apoptotic TUNEL staining. In addition, the upstream potential miRNAs of NDUFB7 were predicted online using the Targetscan website. RT-qPCR, Western blotting (WB), and dual luciferase gene reporter assay were used to confirm the targeting connection between miR-2861 and NDUFB7. Finally, miR-2861 expression after high glucose (HG) treatment and its effect on proliferation and apoptosis of HRVECs under HG were investigated. Results: In this study, we first downloaded and analyzed the differential genes in two DR-related datasets, GSE60436 and GSE53257. We found that TUFM, PRELID1, MRPL32, NDUFB7, MRPL4, MRPL40, HSD17B10 and SLC25A13 were upregulated in DR, and RT-qPCR showed that NDUFB7 was most upregulated. Subsequent CCK-8 assay, EDU proliferation assay and TUNEL staining showed that up-picked NDUFB7 promotes proliferation and inhibits apoptosis of HRVECs. In addition, the upstream potential miRNAs of NDUFB7 were predicted online using the Targetscan website. RT-qPCR, Western blotting (WB), and dual luciferase gene reporter assay confirmed the targeting connection between miR-2861 and NDUFB7. Finally, it was observed that miR-2861 can inhibit the proliferation and promote the apoptosis of HRVECs by targeting NDUFB7. Conclusions: Our findings showed that upregulated NDUFB7 in DR promotes proliferation and inhibits apoptosis of HRVECs, and miR-2861 can rescue the pathogenic effect of NDUFB7 upregulation by targeting NDUFB7.

Polyunsaturated fatty acids and diabetic microvascular complications: a Mendelian randomization study.

Background: Observational studies and clinical trials have implicated polyunsaturated fatty acids (PUFAs) in potentially safeguarding against diabetic microvascular complication. Nonetheless, the causal nature of these relationships remains ambiguous due to conflicting findings across studies. This research employs Mendelian randomization (MR) to assess the causal impact of PUFAs on diabetic microvascular complications. Methods: We identified instrumental variables for PUFAs, specifically omega-3 and omega-6 fatty acids, using the UK Biobank data. Outcome data regarding diabetic microvascular complications were sourced from the FinnGen Study. Our analysis covered microvascular outcomes in both type 1 and type 2 diabetes, namely diabetic neuropathy (DN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). An inverse MR analysis was conducted to examine the effect of diabetic microvascular complications on PUFAs. Sensitivity analyses were performed to validate the robustness of the results. Finally, a multivariable MR (MVMR) analysis was conducted to determine whether PUFAs have a direct influence on diabetic microvascular complications. Results: The study indicates that elevated levels of genetically predicted omega-6 fatty acids substantially reduce the risk of DN in type 2 diabetes (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.47-0.82, p = 0.001). A protective effect against DR in type 2 diabetes is also suggested (OR: 0.75, 95% CI: 0.62-0.92, p = 0.005). MVMR analysis confirmed the stability of these results after adjusting for potential confounding factors. No significant effects of omega-6 fatty acids were observed on DKD in type 2 diabetes or on any complications in type 1 diabetes. By contrast, omega-3 fatty acids showed no significant causal links with any of the diabetic microvascular complications assessed. Conclusions: Our MR analysis reveals a causal link between omega-6 fatty acids and certain diabetic microvascular complications in type 2 diabetes, potentially providing novel insights for further mechanistic and clinical investigations into diabetic microvascular complications.

Comparison review of image classification techniques for early diagnosis of diabetic retinopathy.

Diabetic retinopathy (DR) is one of the leading causes of vision loss in adults and is one of the detrimental side effects of the mass prevalence of Diabetes Mellitus (DM). It is crucial to have an efficient screening method for early diagnosis of DR to prevent vision loss. This paper compares and analyzes the various Machine Learning (ML) techniques, from traditional ML to advanced Deep Learning models. We compared and analyzed the efficacy of Convolutional Neural Networks (CNNs), Capsule Networks (CapsNet), K-Nearest Neighbor (KNN), Support Vector Machine (SVM), decision trees, and Random Forests. This paper also considers determining factors in the evaluation, including contrast enhancements, noise reduction, grayscaling, etc. We analyze recent research studies and compare methodologies and metrics, including accuracy, precision, sensitivity, and specificity. The findings highlight the advanced performance of Deep Learning (DL) models, with CapsNet achieving a remarkable accuracy of up to 97.98% and a high precision rate, outperforming other traditional ML methods. The Contrast Limited Adaptive Histogram Equalization (CLAHE) preprocessing technique substantially enhanced the model's efficiency. Each ML method's computational requirements are also considered. While most advanced deep learning methods performed better according to the metrics, they are more computationally complex, requiring more resources and data input. We also discussed how datasets like MESSIDOR could be more straightforward and contribute to highly evaluated performance and that there is a lack of consistency regarding benchmark datasets across papers in the field. Using the DL models facilitates accurate early detection for DR screening, can potentially reduce vision loss risks, and improves accessibility and cost-efficiency of eye screening. Further research is recommended to extend our findings by building models with public datasets, experimenting with ensembles of DL and traditional ML models, and considering testing high-performing models like CapsNet.

Incidence and Clinical Characteristics of COVID-19 Ophthalmopathy Following the Termination of Dynamic Zero COVID-19 Strategy in China.

Ocular involvement is not uncommon in patients with COVID-19. However, the incidence of COVID-19 ophthalmopathy in COVID-19 patients is still not clear. In this prospective case series study, we recruited 2445 consecutive cases presenting at Neuro-ophthalmology clinic of our Eye Center during the last resurgence of SARS-CoV-2 infection from 8 December 2022 to 15 March 2023 in China, 149 cases were diagnosed as COVID-19 ophthalmopathy, 87 cases were female, with a mean age of 43.2 years, and the mean follow-up time was 15.4 weeks. One hundred and twenty of 149 cases suffered from systemic symptoms mostly manifesting as fever, cough and muscle pain prior to or soon after ocular involvement. The most common COVID-19 ophthalmopathy was optic neuritis (51/149), followed by acute zonal occult outer retinopathy complex disease (31/149), uveitis (17/149), ocular mobility disorder-related (third, fourth, or sixth) cranial nerve neuritis (15/149), anterior ischaemic optic neuropathy (9/149), retinal artery occlusion (8/149), retinal microangiopathy including retinal haemorrhage and cotton wool spot (8/149), viral conjunctivitis (7/149), retinal vein occlusion (3/149), viral keratitis (2/149), ptosis (2/149), and other rare ocular diseases. Except 5 cases with central retinal artery occlusion, other 144 COVID-19 ophthalmopathy cases showed good response to steroid therapy. Our study revealed an incidence of 6.09% for COVID-19 ophthalmopathy in outpatients at our Neuro-ophthalmology clinic during last resurgence of COVID-19 in China, and demonstrated that SARS-CoV-2 infection could induce an initial onset or a relapse of ophthalmic diseases, and that ocular involvement might manifest as the initial or even the only presentation of COVID-19.

Cost-Effectiveness of Addressing Retinopathy of Prematurity in Rwanda.

PURPOSE: With the expansion of neonatal care in sub-Saharan Africa (SSA), an increasing number of premature babies are at risk to develop retinopathy of prematurity (ROP). Previous studies have quantified the cost-effectiveness of addressing ROP in middle-income countries, but few have focused on SSA. This study estimates the cost of a national program for ROP screening and anti-VEGF injection treatment in Rwanda compared to the status quo. METHODS: Medical cost data were collected from King Faisal Hospital in Rwanda (July 2022). Societal burden of vision loss included lost productivity and quality-adjusted life years (QALYs). Published data on epidemiology and natural history of ROP were used to estimate burden and sequelae of ROP in Rwanda. Cost of a national program for screening and treating a one-year birth cohort was compared to the status quo using a decision analysis model. RESULTS: Cost of ROP screening and treatment was $738 per infant. The estimated equipment cost necessary for the startup of a national program was $58,667. We projected that a national program could avert 257 cases of blindness in the cohort and increase QALYs compared to the status quo. Screening and treatment for ROP would save an estimated $270,000 for the birth cohort from reductions in lost productivity. CONCLUSION: The cost of screening and anti-VEGF treatment for ROP is substantially less than the indirect cost of vision loss due to ROP. Allocating additional funding towards expansion of ROP screening and treatment is cost-saving from a societal perspective compared to current practice.

Assessing the importance of risk factors for diabetic retinopathy in patients with type 2 diabetes mellitus: Results from the classification and regression tree models.

BACKGROUND: Diabetic retinopathy (DR) is one of the serious complications of diabetes mellitus (DM). Many studies have identified the risk factors associated with DR, but there is not much evidence on the importance of these factors for DR. This study aimed to investigate the associated factors for patients with type 2 DM (T2DM) and calculate the importance of the identified factors. MATERIALS AND METHODS: Using probability proportionate to size sampling method in this community-based cross-sectional study, 22 community health service centers were selected from 10 administrative districts in Shenzhen, China. Approximately 60 T2DM patients were recruited from each center. The participants completed a structural questionnaire, had their venous blood collected, and underwent medical examinations and fundus photography. Logistic regression models were used to identify the risk factors of DR. The classification and regression tree (CART) model was used to calculate the importance of the identified risk factors. RESULTS: This study recruited 1097 T2DM patients, 266 of whom were identified as having DR, yielding a prevalence rate of 24.3% (95% confidence interval [CI]: 21.7%-26.9%). Results showed that a longer duration of DM, indoor-type lifestyle, and higher levels of hemoglobin A1c (HbA1c) or urea increased the risk of DR. Patients with HbA1c values ≥7% were about 2.45 times (odds ratio: 2.45; 95% CI: 1.83-3.29) more likely to have DR than their counterparts. The CART model found that the values of variable importance for HbA1c, DM duration, lifestyle (i.e., indoor type), and urea were 48%, 37%, 10%, and 4%, respectively. CONCLUSION: The prevalence of DR is high for T2DM patients who receive DM health management services from the primary healthcare system. HbA1c is the most important risk factor for DR. Integration of DR screening and HbA1c testing into the healthcare services for T2DM to reduce vision impairment and blindness is urgently warranted.

The STAT1-SLC31A1 axis: Potential regulation of cuproptosis in diabetic retinopathy.

BACKGROUND: By identifying molecular biological markers linked to cuproptosis in diabetic retinopathy (DR), new pathobiological pathways and more accessible diagnostic markers can be developed. METHODS: The datasets related to DR were acquired from the Gene Expression Omnibus database, while genes associated with cuproptosis were sourced from previously published compilations. Consensus clustering was conducted to delineate distinct DR subclasses. Feature genes were identified utilizing weighted correlation network analysis (WGCNA). Additionally, two machine-learning algorithms were employed to refine the selection of feature genes. Finally, we conducted preliminary validation experiments to ascertain the involvement of cuproptosis in DR development and the transcriptional regulation of critical genes using both the streptozotocin-induced diabetic mouse model and the high glucose-induced BV2 model. RESULTS: In the STZ-induced diabetic mouse retinas, a decrease in the expression of cuproptosis signature proteins (FDX1, DLAT, and NDUFS8) suggested the occurrence of cuproptosis in DR. Subsequently, the expression of eight cuproptosis differential genes was validated through the STZ-induced diabetes and oxygen-induced retinopathy (OIR) models, with the key gene SLC31A1 showing upregulation in both models and dataset species. Further analyses, including weighted gene co-expression network analysis, GSVA, and immune infiltration analysis, indicated a close correlation between cuproptosis and microglia function. Additionally, validation in an in vitro model of microglia indicated the occurrence of cuproptosis in microglia under high glucose conditions, alongside abnormal expression of STAT1 with SLC31A1. CONCLUSION: Our findings suggest that STAT1/SLC31A1 may pave the way for a deeper comprehension of the mechanistic basis of DR and offer potential therapeutic avenues.

The association between serum 25-hydroxyvitamin D levels and retinopathy of prematurity in preterm infants.

Objective: This study aimed to investigate the correlation between serum 25-hydroxyvitamin D (25(OH)D) levels and retinopathy of prematurity (ROP) in premature infants one month after birth. Methods: Preterm infants (gestational age <32 weeks) admitted to the Affiliated Hospital of Qingdao University from 2017 to 2022 were divided into ROP and non-ROP groups based on ROP occurrence any stage. Serum 25(OH)D levels and clinical data were compared between the two groups at 1 month after birth, and the relationship between vitamin D levels and ROP was analyzed. Results: Among the 217 premature infants included, 55 (25.35%) were in the ROP group, and 162 (74.65%) were in the non-ROP group. The ROP group had lower gestational age and birth weight, longer invasive ventilation (IV), non-invasive ventilation (NIV), and oxygen therapy times compared to the non-ROP group. Apgar scores, cesarean delivery, and antenatal steroids ratios were lower in the ROP group, while sepsis and pulmonary surfactant utilization ratios were higher (all p < 0.05). Significant differences in serum 25-(OH)D levels were observed among children in the non-ROP group (14.20 ± 5.07 ng/ml), ROP treated group (7.891 ± 1.878 ng/ml), and untreated group (12.168 ± 4.354 ng/ml) (p < 0.001). Multivariate regression analysis identified antenatal steroids as protective factors and lower birth weight, serum 25-(OH)D levels, long-term invasive mechanical ventilation, and sepsis as independent risk factors for ROP in premature infants. Conclusion: Vitamin D, lower birth weight, long-term invasive mechanical ventilation, and sepsis were associated with incidence of ROP in preterm infants. Vitamin D was associated with the severity of ROP, emphasizing the importance of prudent vitamin D supplementation and regular monitoring of serum 25-(OH)D levels.

Intranasal dexmedetomidine reduces pain scores in preterm infants during retinopathy of prematurity screening.

Background: This study aimed to investigate the effectiveness of intranasal dexmedetomidine in reducing pain scores during retinopathy of prematurity (ROP) screening examinations in preterm infants. Methods: Infants born at ≤32 weeks of gestational age, undergoing routine ROP examinations in the neonatal intensive care unit, were included in the study and divided into two groups: the standard protocol group (n = 43) and the dexmedetomidine group (n = 56), over a 1-year period. Both groups received standard procedural preparation including swaddling, oral dextrose, and topical anesthesia with proparacaine. The dexmedetomidine group additionally received intranasal dexmedetomidine at a dose of 1 mcg/kg before the procedure. Pain scores (PIPP score), heart rate, respiratory rate, blood pressure, and oxygen saturation were compared at baseline, 1-min, and 5-min during the procedure. Results: There were no significant differences between the groups regarding descriptive and pre-procedure characteristics. In the dexmedetomidine group, the median (25-75p) PIPP score, heart rate, systolic blood pressure and mean (±SD) respiratory rate measured at the 1st minute of the procedure were significantly lower than those in the standard group [PIPP score 10 (8-13) vs. 14 (10-16), p < 0.001; heart rate 165 (153-176) beats/min vs. 182 (17-190) beats/min, p < 0.001; respiratory rate 60 (±7) breaths/min vs. 65(±9) breaths/min, p = 0.002; systolic blood pressure 78 (70-92) mmHg vs. 87 (78-96) mmHg, p = 0.024; respectively] whereas the saturation value was significantly higher (88% (81-95) vs. 84% (70-92), p = 0.036; respectively). By the 5th minute of the procedure, the median (25-75p) PIPP score [4 (2-6) vs. 6 (4-10), p < 0.001], heart rate [148 (143-166) beats/min vs. 162 (152-180) beats/min, p = 0.001] and respiratory rate [56 (54-58) breaths/min vs. 58 (54-62) breaths/min, p = 0.034] were significantly lower, and the saturation level was significantly higher [96% (94-97) vs. 93% (91-96), p = 0.003] in the dexmedetomidine group. Additionally, the frequency of adverse effects was significantly lower in the dexmedetomidine group compared to the standard protocol group (11% vs. 47%, p = 0.001). Conclusion: Administering intranasal dexmedetomidine before ROP screening examinations was associated with a decrease in pain scores among preterm infants. This suggests its potential as an effective and well-tolerated method for pain management during ROP screenings.

Visual motion sensitivity as an indicator of diabetic retinopathy in type 2 diabetes mellitus.

Objectives: This current study is based on a set of visual motion sensitivity tests, investigating the correlation between visual motion sensitivity and diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM), thereby furnishing a scientific rationale for preventing and controlling DR. Methods: This research was conducted by a combination of questionnaire collection and on-site investigation that involved 542 T2DM recruited from a community. The visual motion sensitivity determined the visual motion perception of the participants across three spatial frequencies (low, medium, and high) for both the first- and second-order contrast. The logistic regression model was adopted to investigate the relationship between visual motion sensitivity and DR prevalence. Besides, the Pearson correlation analysis was used to analyze the factors influencing visual motion sensitivity and restricted cubic spline (RCS) functions to assess the dose-response relationship between visual motion sensitivity and glycated hemoglobin. Results: Among 542 subjects, there are 162 cases of DR, with a prevalence rate of 29.89%. After adjusting factors of age, gender, glycated hemoglobin, duration of diabetes, BMI, and hypertension, we found that the decline in first- and second-order high spatial frequency sensitivity increased the risk for DR [odds ratio (OR): 1.519 (1.065, 2.168), 1.249 (1.068, 1.460)]. The decline in perceptual ability of second-order low, medium, and high spatial frequency sensitivity is a risk factor for moderate to severe DR [OR: 1.556 (1.116, 2.168), 1.388 (1.066, 1.806), 1.476 (1.139, 1.912)]. The first-order and the second-order high spatial frequency sensitivity are significantly positively correlated with glycated hemoglobin (r = 0.105, p = 0.015 and r = 0.119, p = 0.005, respectively). Conclusion: Visual motion sensitivity especially for the second-order high spatial frequency stimuli emerges as a significant predictor of DR in T2DM, offering a sensitive diagnostic tool for early detection.

Changes of the peripapillary vascular parameters in premature infants without retinopathy of prematurity using U-net segmentation.

AIM: To quantitatively assess the changes in mean vascular tortuosity (mVT) and mean vascular width (mVW) around the optic disc and their correlation with gestational age (GA) and birth weight (BW) in premature infants without retinopathy of prematurity (ROP). METHODS: A single-center retrospective study included a total of 133 (133 eyes) premature infants [mean corrected gestational age (CGA) 43.6wk] without ROP as the premature group and 130 (130 eyes) CGA-matched full-term infants as the control group. The peripapillary mVT and mVW were quantitatively measured using computer-assisted techniques. RESULTS: Premature infants had significantly higher mVT (P=0.0032) and lower mVW (P=0.0086) by 2.68 (104 cm-3) and 1.85 µm, respectively. Subgroup analysis with GA showed significant differences (P=0.0244) in mVT between the early preterm and middle to late preterm groups, but the differences between mVW were not significant (P=0.6652). The results of the multiple linear regression model showed a significant negative correlation between GA and BW with mVT after adjusting sex and CGA (P=0.0211 and P=0.0006, respectively). For each day increase in GA at birth, mVT decreased by 0.1281 (104 cm-3) and for each 1 g increase in BW, mVT decreased by 0.006 (104 cm-3). However, GA (P=0.9402) and BW (P=0.7275) were not significantly correlated with mVW. CONCLUSION: Preterm birth significantly affects the peripapillary vascular parameters that indicate higher mVT and narrower mVW in premature infants without ROP. Alterations in these parameters may provide new insights into the pathogenesis of ocular vascular disease.

Key genes and regulatory networks for diabetic retinopathy based on hypoxia-related genes: a bioinformatics analysis.

AIM: To prevent neovascularization in diabetic retinopathy (DR) patients and partially control disease progression. METHODS: Hypoxia-related differentially expressed genes (DEGs) were identified from the GSE60436 and GSE102485 datasets, followed by gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Potential candidate drugs were screened using the CMap database. Subsequently, a protein-protein interaction (PPI) network was constructed to identify hypoxia-related hub genes. A nomogram was generated using the rms R package, and the correlation of hub genes was analyzed using the Hmisc R package. The clinical significance of hub genes was validated by comparing their expression levels between disease and normal groups and constructing receiver operating characteristic curve (ROC) curves. Finally, a hypoxia-related miRNA-transcription factor (TF)-Hub gene network was constructed using the NetworkAnalyst online tool. RESULTS: Totally 48 hypoxia-related DEGs and screened 10 potential candidate drugs with interaction relationships to upregulated hypoxia-related genes were identified, such as ruxolitinib, meprylcaine, and deferiprone. In addition, 8 hub genes were also identified: glycogen phosphorylase muscle associated (PYGM), glyceraldehyde-3-phosphate dehydrogenase spermatogenic (GAPDHS), enolase 3 (ENO3), aldolase fructose-bisphosphate C (ALDOC), phosphoglucomutase 2 (PGM2), enolase 2 (ENO2), phosphoglycerate mutase 2 (PGAM2), and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Based on hub gene predictions, the miRNA-TF-Hub gene network revealed complex interactions between 163 miRNAs, 77 TFs, and hub genes. The results of ROC showed that the except for GAPDHS, the area under curve (AUC) values of the other 7 hub genes were greater than 0.758, indicating their favorable diagnostic performance. CONCLUSION: PYGM, GAPDHS, ENO3, ALDOC, PGM2, ENO2, PGAM2, and PFKFB3 are hub genes in DR, and hypoxia-related hub genes exhibited favorable diagnostic performance.

Differential distribution of fibrovascular proliferative membranes in 25-gauge vitrectomy for proliferative diabetic retinopathy.

AIM: To analyze the distribution of fibrovascular proliferative membranes (FVPMs) in proliferative diabetic retinopathy (PDR) patients that treated with pars plana vitrectomy (PPV), and to evaluate the outcomes separately. METHODS: This was a retrospective and cross-sectional study. Consecutive 25-gauge (25-G) PPV cases operated for PDR from May 2018 to April 2020. According to the FVPMs images outlined after operations, subjects were assigned into three groups: arcade type group, juxtapapillary type group, and central type group. All patients were followed up for over one year. General characteristics, operation-related variables, postoperative parameters and complications were recorded. RESULTS: Among 103 eyes recruited, the FVPMs distribution of nasotemporal and inferiosuperioral was significantly different (both P<0.01), with 95 (92.23%) FVPMs located in the nasal quadrants, and 74 (71.84%) in the inferior. The eyes with a central FVPM required the longest operation time, with silicon oil used in most patients, generally combined with tractional retinal detachment (RD) and rhegmatogenous RD, the worst postoperative best-corrected visual acuity (BCVA) and the highest rates of recurrent RD (all P<0.05). FVPM type, age of onset diabetes mellitus, preoperative BCVA, and combined with tractional RD and rhegmatogenous RD were significantly associated with BCVA improvement (all P<0.05). Compared with the central type group, the arcade type group had higher rates of BCVA improvement. CONCLUSION: FVPMs are more commonly found in the nasal and inferior mid-peripheral retina in addition to the area of arcade vessels. Performing 25-G PPV for treating PDR eyes with central FVPM have relatively worse prognosis.

Knockdown of fibrillin-1 suppresses retina-blood barrier dysfunction by inhibiting vascular endothelial apoptosis under diabetic conditions.

AIM: To investigate the effects of fibrillin-1 (FBN1) deletion on the integrity of retina-blood barrier function and the apoptosis of vascular endothelial cells under diabetic conditions. METHODS: Streptozotocin (STZ)-induced diabetic mice were used to simulate the diabetic conditions of diabetic retinopathy (DR) patients, and FBN1 expression was detected in retinas from STZ-diabetic mice and controls. In the Gene Expression Omnibus (GEO) database, the GSE60436 dataset was selected to analyze FBN1 expressions in fibrovascular membranes from DR patients. Using lentivirus to knock down FBN1 levels, vascular leakage and endothelial barrier integrity were detected by Evans blue vascular permeability assay, fluorescein fundus angiography (FFA) and immunofluorescence labeled with tight junction marker in vivo. High glucose-induced monkey retinal vascular endothelial cells (RF/6A) were used to investigate effects of FBN1 on the cells in vitro. The vascular endothelial barrier integrity and apoptosis were detected by trans-endothelial electrical resistance (TEER) assay and flow cytometry, respectively. RESULTS: FBN1 mRNA expression was increased in retinas of STZ-induced diabetic mice and fibrovascular membranes of DR patients (GSE60436 datasets) using RNA-seq approach. Besides, knocking down of FBN1 by lentivirus intravitreal injection significantly inhibited the vascular leakage compared to STZ-DR group by Evans blue vascular permeability assay and FFA detection. Expressions of tight junction markers in STZ-DR mouse retinas were lower than those in the control group, and knocking down of FBN1 increased the tight junction levels. In vitro, 30 mmol/L glucose could significantly inhibit viability of RF/6A cells, and FBN1 mRNA expression was increased under 30 mmol/L glucose stimulation. Down-regulation of FBN1 reduced high glucose (HG)-stimulated retinal microvascular endothelial cell permeability, increased TEER, and inhibited RF/6A cell apoptosis in vitro. CONCLUSION: The expression level of FBN1 increases in retinas and vascular endothelial cells under diabetic conditions. Down-regulation of FBN1 protects the retina of early diabetic rats from retina-blood barrier damage, reduce vascular leakage, cell apoptosis, and maintain vascular endothelial cell barrier function.

High-normal serum bilirubin is a useful indicator to assess the risk of diabetic retinopathy in type 2 diabetes: A real-world study.

Background: To investigate the association of serum bilirubin within normal range, especially unconjugated bilirubin (UCB), with diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods: In this cross-sectional, real-world study, 7617 T2DM patients were stratified into quartiles based on serum UCB levels. DR was determined by digital fundus photography and further classified into non-proliferative diabetic retinopathy (NPDR) and PDR. The associations of serum bilirubin levels and UCB quartiles with DR were investigated by logistic regression analysis. Results: After controlling for age, sex, and diabetes duration, the DR prevalence was significantly decreased across the serum UCB quartiles (40.4 %, 33.4 %, 29.7 %, 26.6 % for each quartile, respectively, p < 0.001 for trend). The subjects with DR had lower serum total bilirubin (TB) and UCB, rather than conjugated bilirubin (CB), compared with those without DR (p = 0.003 for TB, p < 0.001 for UCB, and p = 0.528 for CB, respectively), while all three types of serum bilirubin in the subjects with PDR were obviously lower than those with NPDR (p = 0.006 for TB, and p < 0.001 for UCB and CB, respectively). After adjustment for confounding factors, logistic regression demonstrated negative associations of serum TB and UCB levels, rather than CB, with the presence of DR (OR: 0.844, 95%CI: 0.774-0.920, p < 0.001 for TB; OR: 0.828, 95%CI: 0.763-0.899, p < 0.001 for UCB; and OR: 0.984, 95%CI: 0.900-1.074, p = 0.713 for CB, respectively). Additionally, a fully-adjusted analysis revealed a negative correlation between UCB quartiles and DR (p < 0.001). Conclusion: High-normal serum TB and UCB were closely associated with the decreased odds of DR, while all types of serum bilirubin were negatively correlated with the severity of DR in T2DM patients. Serum bilirubin may be used as a potential indicator to assess the risk and severity of DR in T2DM.

Association between gut microbiota and diabetic microvascular complications: a two-sample Mendelian randomization study.

Background: Gut microbiota (GM) homeostasis in the human body is closely associated with health, which can be used as a regulator for preventing the onset and progression of disease. Diabetic microvascular complications bring about not only a huge economic burden to society, but also miserable mental and physical pain. Thus, alteration of the GM may be a method to delay diabetic microvascular complications. Objective: A two-sample Mendelian randomization (MR) analysis was conducted to reveal the causal inference between GM and three core diabetic microvascular complications, namely, diabetic kidney disease (DKD), diabetic retinopathy (DR), and diabetic neuropathy (DNP). Methods: First, genome-wide association study (GWAS) summary statistics for GM from the MiBioGen consortium and three main diabetic microvascular complications acquired from the FinnGen research project were assessed. Second, a forward MR analysis was conducted to assess the causality of GM on the risk of DKD, DR, and DNP. Third, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and leave-one-out analyses, were further conducted to assess the accuracy of MR analysis. Finally, Steiger tests and reverse MR analyses were performed to appraise the possibility of reverse causation. Results: A total of 2,092 single-nucleotide polymorphisms related to 196 bacterial traits were selected as instrumental variables. This two-sample MR analysis provided strongly reasonable evidence that 28 genetically predicted abundance of specific GM that played non-negligible roles in the occurrence of DKD, DR, and DNP complications were causally associated with 23 GM, the odds ratio of which generally ranged from 0.9 to 1.1. Further sensitivity analysis indicated low heterogeneity, low pleiotropy, and high reliability of the causal estimates. Conclusion: The study raised the possibility that GM may be a potential target to prevent and delay the progression of diabetic microvascular complications. Further experiments of GM therapy on diabetic microvascular complications are warranted to clarify their effects and specific mechanisms.

Hyperreflective choroidal foci in diabetic eyes with and without macular edema: Novel insights on diabetic choroidopathy.

Histopathologic studies of diabetic choroid suggest that diabetic choroidopathy is a key aspect secondary to diabetes. Recently, hyperreflective choroidal foci (HCF) have been introduced as novel optical coherence tomography (OCT) parameter. The aim of this study was to identify and quantify HCF in diabetic subjects with retinopathy, with or without diabetic macular edema (DME). Eighty-five diabetic subjects with different degrees of DR were enrolled: 37 without DME and 48 with DME. All subjects underwent full ophthalmologic examination including spectral domain optical coherence tomography (OCT). OCT images were analyzed to quantify and localize HCF. Each image was analyzed by two independent, masked examiners. OCT images showed that all subjects (100%) had HCF in the different layers of the choroid. The number of HCF was significantly higher in diabetics with DME versus those without DME (p < 0.0001). HCF showed variable size, shape and location inside the choroid. They were mainly located in choriocapillaris and Sattler's layer, on the edges of blood vessels. The intraobserver and interobserver agreement was almost perfect (ICC >0.9). This study suggests that hyperreflective foci in the choroid of subjects with DR may be accurately identified with structural OCT. Their number significantly increases with the progression of DME. These HCF may represent, as in the retina, a sign of infiltration of inflammatory cells (mainly migrating microglia) into the choroid, according to the hypothesis raised by Jerry Lutty. HCF may confirm in vivo the histopathologic findings suggesting that diabetic choroidopathy may be primarily a neuroinflammatory disorder.

Follow-up in a point-of-care diabetic retinopathy program in Pittsburgh: a non-concurrent retrospective cohort study.

BACKGROUND: The Point-of-Care Diabetic Retinopathy Examination Program (POCDREP) was initiated in 2015 at the University of Pittsburgh/UPMC in response to low diabetic retinopathy (DR) examination rates, a condition affecting a quarter of people with diabetes mellitus (PwDM) and leading to blindness. Early detection and treatment are critical with DR prevalence projected to triple by 2050. Approximately, half of PwDM in the U.S. undergo yearly examinations, and there are reported varying follow-up rates with eye care professionals, with limited data on the factors influencing these trends. POCDREP aimed to address screening and follow-up gap, partnering with diverse healthcare entities, including primary care sites, free clinics, and federally qualified health centers. METHODS: A non-concurrent retrospective cohort study spanning 2015-2018 examined data using electronic health records of patients who underwent retinal imaging. Imaging was performed using 31 cameras across various settings, with results interpreted by ophthalmologists. Follow-up recommendations were made for cases with vision-threatening DR (VTDR), incidental findings, or indeterminate results. Factors influencing follow-up were analyzed, including demographic, clinical, and imaging-related variables. We assessed the findings at follow-up of patients with indeterminate results. RESULTS: Out of 7,733 examinations (6,242 patients), 32.25% were recommended for follow-up. Among these, 5.57% were classified as having VTDR, 14.34% had other ocular findings such as suspected glaucoma and age-related macular degeneration (AMD), and 12.13% were indeterminate. Of those recommended for follow-up, only 30.87% were assessed by eye care within six months. Older age, marriage, and severe DR were associated with higher odds of following up. Almost two thirds (64.35%) of the patients with indeterminate exams were found with a vision-threatening disease at follow-up. CONCLUSION: The six-month follow-up rate was found to be suboptimal. Influential factors for follow-up included age, marital status, and the severity of diabetic retinopathy (DR). While the program successfully identified a range of ocular conditions, screening initiatives must extend beyond mere disease detection. Ensuring patient follow-up is crucial to DR preventing programs mission. Recommended strategies to improve follow-up adherence include education, incentives, and personalized interventions. Additional research is necessary to pinpoint modifiable factors that impact adherence and to develop targeted interventions.

Type 2 diabetes: is obesity for diabetic retinopathy good or bad? A cross-sectional study.

BACKGROUND: The relationship between obesity and diabetic retinopathy (DR) remains controversial, and the relationship between sarcopenic obesity and DR is still unclear. The purpose of this study is to investigate the relationship between obesity, sarcopenic obesity, and DR in patients with type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional study was conducted on patients with T2DM. Obesity was assessed by body mass index (BMI), fat mass index (FMI), android fat mass, gynoid fat mass, and visceral adipose tissue (VAT) mass. Sarcopenia was defined according to the criteria of Consensus of the Asian Working Group for Sarcopenia (AWGS 2019). Sarcopenic obesity was defined as the coexistence of sarcopenia and obesity. The association between obesity, sarcopenic obesity, and DR was examined using univariable and multivariable logistic regression models. RESULTS: A total of 367 patients with T2DM (mean age 58.3 years; 57.6% male) were involved in this study. The prevalence of DR was 28.3%. In total patients, significant adverse relationships between obesity and DR were observed when obesity was assessed by BMI (adjusted odds ratio [aOR] 0.54, 95% confidence interval [CI] 0.31 to 0.96, p = 0.036), FMI (aOR 0.49, 95% CI 0.28 to 0.85, p = 0.012), android fat mass (aOR 0.51, 95% CI 0.29 to 0.89, p = 0.019), gynoid fat mass (aOR 0.52, 95% CI 0.30 to 0.91, p = 0.021) or VAT mass (aOR 0.45, 95% CI 0.25 to 0.78, p = 0.005). In patients with T2DM and obesity, the prevalence of sarcopenic obesity was 14.8% (n = 23) when obesity was assessed by BMI, 30.6% (n = 56) when assessed by FMI, 27.9% (n = 51) when assessed by android fat mass, 28.4% (n = 52) when assessed by gynoid fat mass, and 30.6% (n = 56) when assessed by VAT mass. Sarcopenic obesity was associated with DR when obesity was assessed by BMI (aOR 2.61, 95% CI 1.07 to 6.37, p = 0.035), android fat mass (aOR 3.27, 95% CI 1.37 to 7.80, p = 0.007), or VAT mass (aOR 2.50, 95% CI 1.06 to 5.92, p = 0.037). CONCLUSIONS: Patients with T2DM showed a substantial inverse relationship between DR and obesity, and sarcopenic obesity was considerably favorably associated with DR. Detection of sarcopenia in patients with T2DM, especially in obese T2DM, is essential to guide clinical intervention in DR.

Delayed manifestation of proliferative retinopathy associated with chronic myeloid leukemia.

Purpose: This report highlights a rare case of delayed manifestation of proliferative retinopathy associated with chronic myeloid leukemia (CML) during remission. Observations: Case report and review of the literature; In this case report, we outline the delayed manifestation and clinical progression of proliferative retinopathy in a 52-year-old male patient with a history of CML diagnosed in 2001. Initially, the patient presented with a white blood cell count (WBC) of 402,200/µl, and the leukocytosis persisted until 2005. Thereafter, the patient remained in remission for over 15 years without any visual complaints until 2022. At that time, the patient sought medical attention due to a ten-day history of left eye visual impairment, leading to the discovery of peripheral neovascularization in both eyes and vitreous hemorrhage in the left eye during fundus examination. The WBC count at the time of presentation to the Emergency Department was 10,460/µl. The patient was treated with fluorescein angiography guided panretinal photocoagulation to the areas of ischemic retina. Subsequent follow-up after eight months demonstrated regression of neovascularization. Conclusions and Importance: Our findings highlight the occurrence of proliferative retinopathy in the context of CML, uniquely manifesting during remission. This case emphasizes the importance of ophthalmological assessments not only at the time of CML diagnosis but also during subsequent follow-ups, recognizing the potential for delayed presentation of ocular complications.