Retinal Vascularization Research Articles

Appropriate dose of intravitreal ranibizumab for ROP: a retrospective study

ObjectiveTo compare the recurrence rate of retinopathy of prematurity (ROP) after treatment with 0.3 mg vs. 0.25 mg ranibizumab.SubjectsAll patients with ROP who underwent intravitreal injection of ranibizumab in Hainan General Hospital between January 2014 and May 2020 were included in this retrospective study.MethodsEighty-two cases (146 eyes) who received intravitreal injection of 0.25 mg ranibizumab were included in the conventional-dose group, and 59 cases (108 eyes) who received intravitreal injection of 0.3 mg ranibizumab were included in the high-dose group. The two groups were further divided into the 25-28-week, 29-31-week, 32-34-week, and 35-36-week GA subgroups. The differences between the conventional-dose group and the high-dose group in gestational age (GA), birth weight (BW), age at initial injection (weeks), incidence of systemic diseases, the recurrence rate of ROP, and age at retinal vascularization completed (weeks) were analyzed.ResultsGA, BW, age at initial injection, and the incidence of systemic diseases were not significantly different between the conventional-dose group and the high-dose group (p > 0.05). The recurrence rates of ROP were significantly lower in the 25-28-week, 29-31-week, and 32-34-week subgroups of the high-dose group than in the same subgroups of the conventional-dose group (p < 0.05). Within the conventional-dose group, the recurrence rate of ROP was significantly lower in the 32-34-week and 35-36-week subgroups than in the 25-28-week and 29-31-week subgroups (p < 0.05). Within the high-dose group, the recurrence rate of ROP was not significantly different between the four subgroups (p > 0.05). Retinal vascularization was completed at a later age in the 32-34-week subgroup of the high-dose group than in the 32-34-week subgroup of the conventional-dose group (p < 0.05) but was not significantly different between the two groups at any other GA range (p > 0.05). No severe ocular or systemic complications occurred in any patient.ConclusionTreatment with 0.3 mg ranibizumab can reduce the recurrence rate of ROP without prolonging retinal vascularization or causing serious systemic complications. Therefore, this dose may be an appropriate therapeutic dose for ROP.

Fluorescein Angiography Findings in Treatment-Naive Premature Infants with Retinal Vascular Immaturity and Persistent Avascular Retina

ABSTRACTPurposeTo evaluate the fluorescein angiography (FA) findings in eyes with spontaneously regressed retinopathy of prematurity (ROP).MethodsFluorescein angiography images of 162 eyes of 81 treatment-naive infants who underwent FA due to retinal vascular immaturity and persistent avascular retina (PAR) despite exceeding postmenstrual age of 60 weeks were analyzed retrospectively. Disc diameter (DD), optic disc-to-fovea distance (FD), the length of temporal retinal vascularization (LTRV), and the length of measurable temporal avascular retina distance (LMTAR), were quantitatively measured.ResultsThe mean gestational age and FA imaging age were 29.39 ± 3.13 and 86.51 ± 24.80 weeks postmenstrual, respectively. The mean ratios of LTRV/FD and LMTAR /DD were 4.47 ± 0.36 and 2.21 ± 1.01, respectively. Pigmentary changes were detected in the peripheral retina in 21% of the eyes. There was at least one angiographic finding in 88% of the eyes, but these findings were usually mild. Based on the FA findings, laser photocoagulation was performed to the peripheral avascular retina in ten eyes of five patientsConclusionEven in larger preterm infants and without severe retinopathy and anti-VEGF treatment, PAR and peripheral pigmentary changes may be detected, and mild angiographic vascular activity may continue. These findings may lead to late-onset retinal pathologies that may threaten vision. In eyes with PAR, follow-up with FA and prophylactic laser application may be applicable. Further investigation is required for this topic.

Retinal Vascular Study Using OCTA in Subjects at High Genetic Risk of Developing Alzheimer's Disease and Cardiovascular Risk Factors.

In 103 subjects with a high genetic risk of developing Alzheimer’s disease (AD), family history (FH) of AD and ApoE ɛ4 characterization (ApoE ɛ4) were analyzed for changes in the retinal vascular network by OCTA (optical coherence tomography angiography), and AngioTool and Erlangen-Angio-Tool (EA-Tool) as imaging analysis software. Retinal vascularization was analyzed by measuring hypercholesterolemia (HCL) and high blood pressure (HBP). Angio-Tool showed a statistically significant higher percentage of area occupied by vessels in the FH+ ApoE ɛ4- group vs. in the FH+ ApoE ɛ4+ group, and EA-Tool showed statistically significant higher vascular densities in the C3 ring in the FH+ ApoE ɛ4+ group when compared with: i)FH- ApoE ɛ4- in sectors H3, H4, H10 and H11; and ii) FH+ ApoE ɛ4- in sectors H4 and H12. In participants with HCL and HBP, statistically significant changes were found, in particular using EA-Tool, both in the macular area, mainly in the deep plexus, and in the peripapillary area. In conclusion, OCTA in subjects with genetic risk factors for the development of AD showed an apparent increase in vascular density in some sectors of the retina, which was one of the first vascular changes detectable. These changes constitute a promising biomarker for monitoring the progression of pathological neuronal degeneration.

Factors associated with refractive outcome in children treated with bevacizumab for retinopathy of prematurity: the importance of retinal vascularization.

To evaluate the factors that may be associated with refractive outcome in eyes treated with intravitreal bevacizumab (IVB) injection for retinopathy of prematurity (ROP). Retrospective case series. Refractive outcomes of 181 infants who were treated with primary IVB for Type I ROP or aggressive ROP, were retrospectively evaluated. According to the pretreatment retinal vascularization, eyes were classified into zone I, zone I-zone II, and zone II groups. The first year, third year, and final refractive error were analyzed. Univariate logistic regression test was performed to evaluate the effect of factors on the development of ≥ 1 diopter (D) myopia. At the final examination, the mean age was 22.9 ± 10.9months. The zone II group was more hyperopic than the zone I-zone II and zone I zone groups (P = 0.001). Of the 331 eyes, 17 eyes (5.1%) had high myopia, 50 eyes (15.1%) had low myopia, and 83 eyes (25.1%) had emmetropia. During follow-up, 110 (33.2%) eyes underwent laser treatment. Gestational age, birth weight, neonatal intensive care unit type, the presence of additional laser treatment, number of injections, the type of ROP, and the dose of IVB were not associated with the development of ≥ 1 D myopia. The pretreatment and prelaser retinal zones were associated with the development of ≥ 1 D myopia. The most important factors affecting the refractive outcome in infants who underwent primary IVB treatment was the extent of pretreatment and prelaser retinal vascularization.

Dapagliflozin protects neural and vascular dysfunction of the retina in diabetes.

IntroductionDapagliflozin, a sodium-glucose transporter inhibitor, effectively reduces blood glucose and is indicated for individuals with kidney diseases and cardiovascular disorders. In this study, we further expand the therapeutic benefit of dapagliflozin in the neural and vascular retina, with the potential to effectively manage diabetic retinopathy (DR), the most common complication of diabetes.Research design and methodsDb/db mice, an animal model of type 2 diabetes, were treated with dapagliflozin orally, and the electroretinogram (ERG) response and acellular capillary numbers were assessed. Messenger RNA levels of inflammatory cytokines were studied using real-time quantitative (q)PCR. We assessed endothelial cell migration in a scratch wound assay and retinal glucose uptake using human retinal endothelial cells.ResultsThe dapagliflozin treatment improved the ERG b-wave amplitude and decreased acellular capillary numbers. The scratch wound assay demonstrated a reduction in wound closure after dapagliflozin treatment. Retinal glucose uptake reduced after dapagliflozin treatment compared with the respective controls.ConclusionsOur studies suggest that dapagliflozin treatment effectively corrects neural and vascular dysfunction of the retina in diabetes. This effect is mediated by a decrease in inflammation and improved glycemic control. In addition, dapagliflozin exhibits decreased wound healing and glucose uptake, which could benefit the retina. Thus, dapagliflozin could be helpful in the management of DR, with multimodal therapeutic effects.

Normalization of Oxygen‐Induced Retinopathy in the Mouse Supplementation with Myo/Nog Cells

IntroductionRetinopathy of Prematurity (ROP) is the leading cause of blindness in children, affecting 50% of infants born prior to gestational week 32. ROP is the result of postpartum supplemental oxygen administered to compensate for underdeveloped lungs. However, hyperoxia inhibits proper development supplying the retina. When the infants are returned to ambient air, an imbalance is present between the oxygen concentration and metabolic demands of retinal neurons. This leads to a rapid induction of angiogenesis, leaky blood vessels, neovascular tuft formation, and cell death. Myo/Nog cells that express MyoD, Noggin, and brain‐specific angiogenesis inhibitor 1 (BAI1) exhibit neuroprotective properties in the eye and brain and are proposed to play a role in regulating angiogenesis in ROP.MethodsAn Oxygen‐induced retinopathy (OIR) protocol was implemented in neonatal C57BL/6J mice by exposing them on postnatal days 7‐12 (P7‐P12) to hyperoxia (75% oxygen) and then returning them to normal air (21% oxygen) from P12 until P21. On P15, groups receiving treatments were intravitreally injected with 1 µL of phosphate‐buffered saline (PBS) containing 2000 Myo/Nog cells isolated from the brain with the BAI1 antibody (BAI1+ group), 2000 unsorted brain cells (BAI1‐ group), or PBS alone (PBS group). Electroretinography (ERG) was conducted on P21 to assess retinal function. Eyes were extracted and either dissected for flat‐mount observation of vasculature and tufts, or processed for histology. The thickness of the retina and number of TUNEL+ apoptotic cells were quantified in tissue sections of eyes processed for histology. Adobe Photoshop (Adobe, San Jose, CA) was used to splice together 9 images that made up each whole retina from flat‐mounted eyes. The blood vessels were selected using the “Lasso tool” on photoshop, quantified by number of pixels, and then compared to the total number of pixels in the whole retina.ResultsOIR induced neovascular tuft formation. Exogenously added Myo/Nog cells normalized the retinopathy induced by the OIR model, reducing the number of tufts and improving the quality of the vasculature. The vasculature was most developed in retinas injected with brain derived Myo/Nog cells. ERG data shows a trend towards improvement of visual function with Myo/Nog cell injection.ConclusionMyo/Nog cell regulation of retinal vascularization may be related to the production of BAI1. Improved visual function seen with injection of Myo/Nog cells may be related to both a reduction of neovascular tufts and direct effects on retinal neurons. Therefore Myo/Nog cells have therapeutic potential in the prevention of ROP by normalizing the vasculature and preventing neuronal cell death.

Quantitative evaluation of retinal and choroidal vascularity and retrobulbar blood flow in patients with myopic anisometropia by CDI and OCTA

AimsTo investigate the association between the myopic severity and retinal microvascular density, choroidal vascularity and retrobulbar blood flow in adult anisomyopes.MethodsThis study comprised 90 eyes of 45 myopic anisomyopes who...

Repeated intravitreal ranibizumab for reactivated retinopathy of prematurity after intravitreal ranibizumab monotherapy: vascular development analysis.

To evaluate the retinal vascularization of repeated intravitreal ranibizumab (IVR) for reactivated retinopathy of prematurity (ROP) treated with IVR monotherapy. The retrospective study reviewed ROP infants who accepted IVR injection as the first treatment in our department from January 2017 to December 2018. The ratio of the distance from the center of the optic disc to the border of the vascularized zone (DB) to the distance from the center of the disc to the fovea (DF) was used for the vascular outgrowth analysis. Seventy-eight infants were included in the study. A total of 54.3% of the reactivated ROP patients could achieve complete vascularization after repeated IVR injections. Gestational age (GA) > 29weeks and a temporal DB/DF ratio ≥ 3 in the first IVR were potential predictors for complete retinal vascularization after IVR monotherapy. The temporal DB/DF ratio ≥ 3.6 in the second IVR injection was a potential predictor for complete retinal vascularization after repeated IVR for ROP reactivation. Reactivated ROP after IVR monotherapy can be treated successfully with repeated IVR injections. GA and temporal DB/DF ratio are potential predictors of complete retinal vascularization in ROP infants treated with IVR.

NDP-related retinopathies: clinical phenotype of female carriers

Background/aimsNorrin cysteine knot growth factor (NDP) located on the X chromosome, was previously reported to cause Norrie disease and familial exudative vitreoretinopathy (FEVR), which are blindness-causing ocular disorders, in males....

Omega-3/Omega-6 Long-Chain Fatty Acid Imbalance in Phase I Retinopathy of Prematurity.

There is a gap in understanding the effect of the essential ω-3 and ω-6 long-chain polyunsaturated fatty acids (LCPUFA) on Phase I retinopathy of prematurity (ROP), which precipitates proliferative ROP. Postnatal hyperglycemia contributes to Phase I ROP by delaying retinal vascularization. In mouse neonates with hyperglycemia-associated Phase I retinopathy, dietary ω-3 (vs. ω-6 LCPUFA) supplementation promoted retinal vessel development. However, ω-6 (vs. ω-3 LCPUFA) was also developmentally essential, promoting neuronal growth and metabolism as suggested by a strong metabolic shift in almost all types of retinal neuronal and glial cells identified with single-cell transcriptomics. Loss of adiponectin (APN) in mice (mimicking the low APN levels in Phase I ROP) decreased LCPUFA levels (including ω-3 and ω-6) in retinas under normoglycemic and hyperglycemic conditions. ω-3 (vs. ω-6) LCPUFA activated the APN pathway by increasing the circulating APN levels and inducing expression of the retinal APN receptor. Our findings suggested that both ω-3 and ω-6 LCPUFA are crucial in protecting against retinal neurovascular dysfunction in a Phase I ROP model; adequate ω-6 LCPUFA levels must be maintained in addition to ω-3 supplementation to prevent retinopathy. Activation of the APN pathway may further enhance the ω-3 and ω-6 LCPUFA’s protection against ROP.

Automated Diagnosis of Optical Coherence Tomography Angiography (OCTA) Based on Machine Learning Techniques.

Diabetic retinopathy (DR) refers to the ophthalmological complications of diabetes mellitus. It is primarily a disease of the retinal vasculature that can lead to vision loss. Optical coherence tomography angiography (OCTA) demonstrates the ability to detect the changes in the retinal vascular system, which can help in the early detection of DR. In this paper, we describe a novel framework that can detect DR from OCTA based on capturing the appearance and morphological markers of the retinal vascular system. This new framework consists of the following main steps: (1) extracting retinal vascular system from OCTA images based on using joint Markov-Gibbs Random Field (MGRF) model to model the appearance of OCTA images and (2) estimating the distance map inside the extracted vascular system to be used as imaging markers that describe the morphology of the retinal vascular (RV) system. The OCTA images, extracted vascular system, and the RV-estimated distance map is then composed into a three-dimensional matrix to be used as an input to a convolutional neural network (CNN). The main motivation for using this data representation is that it combines the low-level data as well as high-level processed data to allow the CNN to capture significant features to increase its ability to distinguish DR from the normal retina. This has been applied on multi-scale levels to include the original full dimension images as well as sub-images extracted from the original OCTA images. The proposed approach was tested on in-vivo data using about 91 patients, which were qualitatively graded by retinal experts. In addition, it was quantitatively validated using datasets based on three metrics: sensitivity, specificity, and overall accuracy. Results showed the capability of the proposed approach, outperforming the current deep learning as well as features-based detecting DR approaches.

Bi-allelic mutation of CTNNB1 causes a severe form of syndromic microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia

BackgroundInherited vitreoretinopathies arise as a consequence of congenital retinal vascularisation abnormalities. They represent a phenotypically and genetically heterogeneous group of disorders that can have a major impact on vision. Several genes encoding proteins and effectors of the canonical Wnt/β-catenin pathway have been associated and precise diagnosis, although difficult, is essential for proper clinical management including syndrome specific management where appropriate. This work aimed to investigate the molecular basis of disease in a single proband born to consanguineous parents, who presented with microphthalmia, persistent foetal vasculature, posterior lens vacuoles, vitreoretinal dysplasia, microcephaly, hypotelorism and global developmental delay, and was registered severely visually impaired by 5 months of age.MethodsExtensive genomic pre-screening, including microarray comparative genomic hybridisation and sequencing of a 114 gene panel associated with cataract and congenital ophthalmic disorders was conducted by an accredited clinical laboratory. Whole exome sequencing (WES) was undertaken on a research basis and in vitro TOPflash transcriptional reporter assay was utilised to assess the impact of the putative causal variant.ResultsIn the proband, WES revealed a novel, likely pathogenic homozygous mutation in the cadherin-associated protein beta-1 gene (CTNNB1), c.884C>G; p.(Ala295Gly), which encodes a co-effector molecule of the Wnt/β-catenin pathway. The proband’s parents were shown to be heterozygous carriers but ophthalmic examination did not detect any abnormalities. Functional assessment of the missense variant demonstrated significant reduction of β-catenin activity.ConclusionsThis is the first report of a biallelic disease-causing variation in CTNNB1. We conclude that this biallelic, transcriptional inactivating mutation of CTNNB1 causes a severe, syndromic form of microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia that results in serious visual loss in infancy.

Sequential Short Interval Anti-VEGF for the Treatment of Stage 4 Retinopathy of Prematurity.

A 23-month-old girl born at 23 weeks' gestational age with a birth weight of 453 g and retinopathy of prematurity (ROP) stage 4A in 360° and plus disease in both eyes was treated in another institution with laser; her treatment was complicated with two cardiac arrests during the procedure. The patient was referred and treated at 31 weeks with repeated intravitreal bevacizumab injection in both eyes secondary to progressive ROP. Treatment with multiple anti-vascular endothelial growth factor (VEGF) therapy as monotherapy led to the resolution of a retinal detachment and full vascularization of the retina in both eyes. To the best of the authors' knowledge, this is the first description of a patient with stage 4A ROP treated solely with anti-VEGF after failed laser treatment that led to complete resolution of a retinal detachment without surgical intervention. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:159-163.].

Morphology and Vessel Density of the Macula in Preterm Children Using Optical Coherence Tomography Angiography.

Background: Retinal morphology changes may be associated with prematurity and can lead to visual impairment. Optical coherence tomography angiography may contribute to understanding the pathomechanism of structural and vascular retinal impairment in premature children. The aim of this study was to assess an influence of prematurity, neonatal clinical characteristics, and a history of retinopathy of prematurity (ROP) on the morphology and retinal vascularity of macula in children. Methods: A case–control study of 123 preterm children and 86 full-term children was performed. The age of the subjects was 10.45 years (IQR: 8.12–12.77), while the age of the control group was 11.78 years (IQR: 8.81–13.79). Optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA, angio-OCT) were performed using RTVueXR Avanti (Optovue, Fremont, CA, USA). Ganglion cell complex (GCC), foveal thickness (FT), parafoveal thickness (PFT), size of foveal avascular zone (FAZ) in superficial plexus, superficial capillary vessel density (sVD), deep capillary vessel density (dVD), central choroidal thickness (CCT), and presence of macular hypoplasia were analyzed. The association between OCT/angio-OCT results and clinical characteristics including the degree of ROP and therapy requirements was assessed in preterm infants. Results: Foveal morphology was affected in preterm children with high incidence of foveal hypoplasia (24.77%). GCC was thinner in preterm children compared to controls: avgGG 93 μm vs. 100 μm, p < 0.001. No associations between GCC and gestational age (R = −0.085; p = 0.228) and birth weight (R = −0.054; p = 0.446) were found. FAZ in preterm group was smaller than in controls (0.13 ± 0.09 vs. 0.22 ± 0.09; p < 0.001). FAZ area correlated with gestational age (R = 0.456; p < 0.001) and birth weight (R = 0.472; p < 0.001). Deep vessel density in the fovea was higher in preterm children than in control group (p < 0.001). PFT was significantly lower in preterm children compared to control group. However, increased thickness in the fovea was noted in preterm children (p < 0.001). FT was inversely correlated with gestational age (R = −0.562; p < 0.001) and birth weight (R = −0.508, p < 0.001). CCT was lower in preterm children (312 μm vs. 337.5 μm, p < 0.001) Parameters of GCC and FT were higher in patients with ROP required treatment compared to patients without ROP and spontaneously regressed retinopathy. FAZ was smaller in patients with retinopathy than in preterm children without ROP. Conclusion: Prematurity has a significant negative impact on GCC, macular morphology, and vascularization. In premature children, decreased FAZ, increased FT, and vessel density were strongly associated with gestational age, birth weight, Apgar score, ROP stage, and treatment requirement. Optical coherence tomography angiography is a useful tool for detecting retinal changes in premature children.

Progression of retinal vascularization after intravitreal anti-vascular-endothelial growth factor therapy in retinopathy of prematurity

BackgroundAnti-vascular endothelial growth factor (Anti-VEGF) therapy is now considered as one of standard therapies in approaching infants with retinopathy of prematurity (ROP). The purpose of this study was to assess the time to full retinal vascularization in infants with ROP who were treated with intravitreal bevacizumab (IVB).MethodsThis retrospective cohort study evaluated premature infants with ROP who were treated with IVB between 2012 and 2019. Demographic and clinical data were collected from the medical records and analyzed. Main outcomes were defined as time to complete vascularization and time of zone shift.ResultsEight hundred sixty-five eyes from 441 patients were included. Average gestational age and birth weight were 28 ± 4 weeks and 1121 ± 624 g, respectively. Primary treatment failure and reactivation occurred in 35 eyes (4.0%) and 33 eyes (3.8%), respectively. Recurrent ROP occurred significantly more frequently in infants with pre-treatment zone 1 ROP compared to those with zone 2 ROP (7.6% versus 3%, p < 0.01). Patients with pre-treatment zone 2 reached zone 3 faster than those with pre-treatment zone 1 (142 ± 152 days versus 181 ± 174 days, p < 0.01); however, the time until full retinal vascularization did not significantly differ between the groups (p = 0.10).ConclusionThis study revealed that pre-treatment ROP zone was associated with ROP reactivation rate but not with time to full vascularization in those treated with IVB.Trial registration Retrospectively registered; IR.TUMS.FARABI.REC.1399.040

Comparison of Fluorescein Angiography Findings in Stage 3 Retinopathy of Prematurity in Zone II Treated With or Without Anti-VEGF.

To define late-stage fluorescein angiography (FA) findings in patients who received anti-vascular endothelial growth factor (VEGF) agents (intravitreal bevacizumab or aflibercept) as a treatment for stage 3 retinopathy of prematurity (ROP) in zone II. We also compared the findings of untreated eyes. Infants with a history of ROP who underwent fluorescein angiography were evaluated retrospectively. The patients were divided into 2 groups: those who received anti-VEGF treatment and those who regressed spontaneously without treatment. Vascular abnormalities, such as vascular leakage, shunts at the vascular-avascular junction, periarteriolar areas with hypoperfusion, fine branching and blunt termination of the vessels and, were recorded. Angiography evaluations revealed leakage in the eyes of 27.69% of the infants in the anti-VEGF-treated group and in 21.7% of the untreated group (p = .638). Among the abnormal vascular findings in the peripheral retina, the ratios of fine branching and blunt termination, numbers of shunts along the vascular-avascular junction, and sizes of periarteriolar areas of hypoperfusion were significantly larger in the untreated group than in the treated group (p < .05; p < .01). The gestational ages and birth weights were significantly lower (p ≤ .05) in infants with vascular findings in both groups. Vascular abnormalities in the peripheral retina are likely due to the ROP itself. Although these abnormalities were detected by FA imaging in both treated and untreated infants with ROP, they were significantly less frequent in patients treated with anti-VEGF, indicating that anti-VEGF treatments have a partially positive effect on the retinal vascularization process.

Transfusion-Free Survival Predicts Severe Retinopathy in Preterm Neonates.

Repeated red blood cell (RBC) transfusions are thought to increase the risk for retinopathy of prematurity (ROP), likely due to a critical fetal hemoglobin (HbF) reduction. In this study, we investigated if the postmenstrual age (PMA) of neonates at transfusion influences the risk for ROP. We estimated the cumulative transfusion-free survival (TFS) in a series of 100 preterm neonates receiving one or more RBC units. TFS was calculated by censoring patients at first transfusion and expressing the time between birth and transfusion as either PMA or postnatal day. Then, we investigated if TFS predicted the occurrence of severe ROP, defined as ROP stage 3 or higher. We found that neonates with severe ROP displayed a significantly shorter TFS expressed according to their PMA (p = 0.001), with similar TFS according to postnatal days. At receiver operating characteristic (ROC) curve analysis, receiving an RBC unit before week 28 of PMA predicted severe ROP with a sensitivity of 64% and a specificity of 78%. In addition, receiving a second RBC unit before the PMA of 29 weeks predicted severe ROP with a sensitivity of 75% and a specificity of 69%. At multivariate analysis, PMA at the second transfusion was even more informative than at first transfusion and outperformed all other variables in predicting severe ROP, with an odds ratio of 4.554 (95% CI 1.332–15.573, p = 0.016). Since HbF decrease is greater after multiple RBC transfusions, it is conceivable that neonates receiving more than one unit before the PMA of 29 weeks may be exposed to a greater disturbance of retinal vascularization. Any strategy aimed at preventing the critical HbF decrease at this low age might potentially reduce the risk for severe ROP.

Morphological outcome and indication for laser following intravitreal bevacizumab monotherapy for posterior retinopathy of prematurity.

The purpose of this study is to determine the natural course of retinal vascular development and recurrence requiring laser in eyes receiving intravitreal bevacizumab (IVB) for posterior retinopathy of prematurity (ROP). Data of babies receiving IVB for posterior ROP was retrospectively analyzed. Birth weight, gestational age (GA) and post-menstrual age (PMA) at injection, need for laser, retinal maturation, and their timing were recorded. The study included 63 eyes of 32 babies, born at a median GA of 31 (IQR 29-32) weeks, and birth weight 1410 (1280-1697.5) g. Aggressive posterior ROP was seen in 36 (57%) eyes and staged ROP in 27 (43%). IVB was injected at a median PMA of 36 (34.5-37) weeks. Complete retinal vascularization was seen in 33 (52.4%) at a median PMA of 52 (47-60) weeks, prophylactic laser was needed in 17 (27%) at 61 (55.5-63) weeks, and only 13 (20.6%) eyes had recurrence needing treatment laser, at 42 (39-57) weeks respectively. Babies requiring laser had a significantly lower birth weight (p = 0.033) and received injection earlier (p = 0.08). Retinal vascular development progresses with IVB monotherapy with 21% of eyes developing recurrence that requires laser in this subset of Indian babies. Following IVB, monotherapy laser can be selectively performed only in cases with recurrence or failure to mature.

Retinal Vascularization Abnormalities Studied by Optical Coherence Tomography Angiography (OCTA) in Type 2 Diabetic Patients with Moderate Diabetic Retinopathy.

Diabetic retinopathy (DR) is the most severe and frequent retinal vascular disease that causes significant visual loss on a global scale. The purpose of our study was to evaluate retinal vascularization in the superficial capillary plexus (SCP), the deep capillary plexus (DCP) and the choriocapillaris (CC) and changes in the foveal avascular zone (FAZ) by optical tomography angiography (OCTA) in patients with type 2 diabetes mellitus (DM2) with moderate DR but without diabetic macular oedema (DME). Fifty-four eyes of DM2 with moderate DR (level 43 in the ETDRS scale) and without DME and 73 age-matched healthy eyes were evaluated using OCTA with swept-source (SS)-OCT to measure microvascularization changes in SCP, DCP, CC and the FAZ. The mean ages were 64.06 ± 11.98 and 60.79 ± 8.62 years in the DM2 and control groups, respectively. Visual acuity (VA) was lower in the DM2 patients (p = 0.001), OCTA showed changes in the SCP with a significant diminution in the vascular density and the FAZ area was significantly higher compared to healthy controls, with p < 0.001 at the SCP level. The most prevalent anatomical alterations were peripheral disruption in the SCP (83.3%), microaneurysms (MA) in the SCP and in the DCP (79.6% and 79.6%, respectively) and flow changes in the DCP (81.5%). A significant positive correlation was observed between the DM2 duration and the FAZ area in the SCP (0.304 with p = 0.025). A significant negative correlation was also found between age and CC central perfusion (p < 0.001). In summary, a decrease in the vascular density in DM2 patients with moderate DR without DME was observed, especially at the retinal SPC level. Furthermore, it was found that the FAZ was increased in the DM2 group in both retinal plexuses and was greater in the SCP group.

Synoviolin inhibits the inflammatory cytokine secretion of Müller cells by reducing NLRP3.

The pro-inflammatory cytokines secreted by Müller cells aggregate retinal cell loss and vascularization in diabetic retinopathy (DR). The deubiquitinase BRCA1-BRCA2-containing complex subunit 3 (BRCC3)-mediated nucleotide-binding domain and leucine-rich repeat receptor containing a pyrin domain 3 (NLRP3) inflammasome activation participate in this progress. This study aims to clarify whether the E3 ubiquitin ligase synoviolin (SYVN1) relieves DR via regulating the BRCC3/NLRP3 axis. The DR model was established using streptozotocin-induced mice. Immunofluorescence staining with anti-CD31, anti-glutamine synthetase, and anti-vimentin was performed to identify DR and Müller cells. Levels of pro-inflammatory cytokines, including interleukin-1β, tumor necrosis factor-α, IL-6, and IL-18, in murine serum and Müller cell supernatants were determined. Co-immunoprecipitation (Co-IP) and ubiquitination assays were used to clarify the interactions among SYVN1, BRCC3, and NLRP3. SYVN1 was reduced and BRCC3 was increased in DR retina and high glucose (HG)-induced Müller cells. Overexpressing 1 promoted the ubiquitination and degradation of BRCC3 and reduced the secretion of proinflammatory cytokines in HG-induced Müller cells. The simultaneous overexpression of 1 and Brcc3 restored the reduction of pro-inflammatory cytokines caused by the overexpression of 1 alone. Co-IP experiments confirmed the interaction between BRCC3 and NLRP3. SYVN1-mediated BRCC3 downregulation promoted NLRP3 ubiquitination and reduced pro-inflammatory cytokine secretion. 1 overexpression reduced retinal vascularization and inflammatory cytokine secretion in DR mice. SYVN1 has a protective effect on DR, whose molecular mechanisms are partly through SYVN1-mediated ubiquitination of BRCC3 and the subsequent downregulation of NLRP3.