Proliferative Retinopathy Research Articles

Role Of Colour Doppler Imaging In Early Diagnosis Of Diabetic Retinopathy

Diabetic retinopathy is the most common cause of vision loss among people with diabetes and a leading cause of blindness among working-age adults in India. It is a form of microangiopathy, and is the most common ocular complication seen in diabetic patients. Diabetic retinopathy progresses from non proliferative to proliferative retinopathy. The non proliferative retinopathy is the milder form and it is reversible. As the progression to proliferative retinopathy happens, the patients are symptomatic and become irreversible. Vascular changes and subsequent ocular hemodynamic changes are critical events in the pathogenesis of diabetic retinopathy. Colour doppler imaging is one of the most widely used and well-established techniques for assessing ocular blood flow velocities in the retro bulbar vessels. This is a non-invasive, painless imaging method with highly reproducibility. Estimation of orbital blood flow velocity from colour doppler imaging of the ophthalmic artery and central retinal artery is a technique offering great potential for the identification of early retinopathy in diabetic patients.

Diabetic retinopathy and visual impairment in a Norwegian diabetic coast population with a high dietary intake of fish oils. An observational study.

To present retinal and visual findings in a Norwegian west coast diabetic population and to elucidate the effect of dietary intake of marine polyunsaturated fatty acids (PUFAs) on the development of diabetic retinopathy (DR). In an eye practice in an archipelago of 314 km², serving a population of about 40 000, we recorded the prevalence of visual impairment and DR in a referred diabetic population. 510 consecutive patients were included, 238 females and 272 males. 50 patients had type I and 460 had type II diabetes mellitus (DM). Self-reported medication, diet supplements, HbA1c and fish consumption were registered. In the type I group, the median age was 44.5 and median DM duration 11.5 years [1-44]. 48% had photographic evidence of DR, 8 patients (16%) had proliferative retinopathy (PDR), and 6 patients (12%) had diabetic macular oedema (DME). All had best-corrected visual acuity (BCVA) of 0.5 (log MAR 0.3) or better in the best eye. In the type II group, the median DM duration was 8 years [1-53], and median age was 66. 98% had best eye BCVA at or better than 0.5 (log MAR 0.3) in the best eye. None of the 510 patients had BCVA worse than 0.3 (log MAR 0.48) due to diabetic retinopathy. Compared to similar studies, we found a very low visual impairment rate. A possible protective effect of PUFA on the prevalence and progression of diabetic microangiopathy including retinopathy is discussed.

Characterization of Risk Profiles for Diabetic Retinopathy Progression.

Diabetic retinopathy (DR) is a frequent complication of diabetes and, through its vision-threatening complications, i.e., macular edema and proliferative retinopathy, may lead to blindness. It is, therefore, of major relevance to identify the presence of retinopathy in diabetic patients and, when present, to identify the eyes that have the greatest risk of progression and greatest potential to benefit from treatment. In the present paper, we suggest the development of a simple to use alternative to the Early Treatment Diabetic Retinopathy Study (ETDRS) grading system, establishing disease severity as a necessary step to further evaluate and categorize the different risk factors involved in the progression of diabetic retinopathy. It needs to be validated against the ETDRS classification and, ideally, should be able to be performed automatically using data directly from the examination equipment without the influence of subjective individual interpretation. We performed the characterization of 105 eyes from 105 patients previously classified by ETDRS level by a Reading Centre using a set of rules generated by a decision tree having as possible inputs a set of metrics automatically extracted from Swept-source Optical Coherence Tomography (SS-OCTA) and Spectral Domain- OCT (SD-OCT) measured at different localizations of the retina. When the most relevant metrics were used to derive the rules to perform the organization of the full pathological dataset, taking into account the different ETDRS grades, a global accuracy equal to 0.8 was obtained. In summary, it is now possible to envision an automated classification of DR progression using noninvasive methods of examination, OCT, and SS-OCTA. Using this classification to establish the severity grade of DR, at the time of the ophthalmological examination, it is then possible to identify the risk of progression in severity and the development of vision-threatening complications based on the predominant phenotype.

Short-and Long-Term Expression of Vegf: A Temporal Regulation of a Key Factor in Diabetic Retinopathy.

To investigate the role of vascular endothelial growth factor (VEGF) at different phases of diabetic retinopathy (DR), we assessed the retinal protein expression of VEGF-A164 (corresponding to the VEGF165 isoform present in humans, which is the predominant member implicated in vascular hyperpermeability and proliferation), HIF-1α and PKCβ/HuR pathway in Ins2 Akita (diabetic) mice at different ages. We used C57BL6J mice (WT) at different ages as control. Retina status, in terms of tissue morphology and neovascularization, was monitored in vivo at different time points by optical coherence tomography (OCT) and fluorescein angiography (FA), respectively. The results showed that VEGF-A164 protein expression increased along time to become significantly elevated (p < 0.05) at 9 and 46 weeks of age compared to WT mice. The HIF-1α protein level was significantly (p < 0.05) increased at 9 weeks of age, while PKCβII and HuR protein levels were increased at 46 weeks of age compared to WT mice. The thickness of retinal nerve fiber layer as measured by OCT was decreased in Ins2 Akita mice at 9 and 46 weeks of age, while no difference in the retinal vasculature were observed by FA. The present findings show that the retina of the diabetic Ins2 Akita mice, as expected for mice, does not develop proliferative retinopathy even after 46 weeks. However, diabetic Ins2 Akita mice recapitulate the same evolution of patients with DR in terms of both retinal neurodegeneration and pro-angiogenic shift, this latter indicated by the progressive protein expression of the pro-angiogenic isoform VEGF-A164, which can be sustained by the PKCβII/HuR pathway acting at post-transcriptional level. In agreement with this last concept, this rise in VEGF-A164 protein is not paralleled by an increment of the corresponding transcript. Nevertheless, the observed increase in HIF-1α at 9 weeks indicates that this transcription factor may favor, in the early phase of the disease, the transcription of other isoforms, possibly neuroprotective, in the attempt to counteract the neurodegenerative effects of VEGF-A164. The time-dependent VEGF-A164 expression in the retina of diabetic Ins2 Akita mice suggests that pharmacological intervention in DR might be chosen, among other reasons, on the basis of the specific stages of the pathology in order to pursue the best clinical outcome.

Gustatory sweating in people with type 1 and type 2 diabetes mellitus: Prevalence and risk factors.

ObjectiveGustatory sweating (GS) is characterized by profuse sweating during or immediately after ingestion of food and is known as a complication of diabetes mellitus (DM). This study aimed to determine the prevalence of GS and to characterize the sweating in a cohort of patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM) as compared with a control group.MethodsIn a cross‐sectional study, 665 outpatients with T1DM and 505 outpatients with T2DM filled in an 8‐point questionnaire about GS. Answers were paired with medical data from the electronic patient records to explore associations with DM complications. The control group consisted of 1158 persons without DM answering the same questionnaire in an online version.ResultsIn people with T1DM and T2DM, the prevalence of GS was 10% (95% CI 7%–12%) and 13% (95% CI 10%–16%), respectively. In the control group, the prevalence of GS was 5% (95% CI 3%–6%). Most commonly, people sweat on the face and/or head and upper body with a duration of 10–30 min albeit in the control group <10 min. In patients with T1DM, increased HbA1c was associated with GS (OR 1.3 [95% CI 1.05–1.6], p = .016), and in T2DM, younger age (OR 0.95 [95% CI 0.92–0.99), p = .006), presence of severe peripheral neuropathy (OR 2.33 [95% CI 1.04–5.2], p = .039) and absence of proliferative retinopathy were associated with GS (OR 0.22 [95% CI 0.07–0.71], p = .011).ConclusionWe found the prevalence of gustatory sweating of 11% in a hospital‐based cohort of patients with T1DM and T2DM. This was twice as high as in non‐diabetic control persons. Associations between GS and known diabetes complications could only be demonstrated in T2DM. Compared with a control group without DM, odds for GS are higher in people with DM and age >45.

English

BACKGROUND Diabetes mellitus is a heterogeneous group of diseases, characterized by a state of chronic hyperglycemia, resulting from varied aetiologies. Diabetic retinopathy (DR) is the most common ocular complication of diabetes with 5 % of diabetics, progressing to severe visual loss of 5/200 or less. 3 Very few studies have been conducted on optical coherence tomography (OCT) changes in diabetic retinopathy in Indian scenario. We wanted to evaluate the association of retinal nerve fibre layer (RNFL) thickness with diabetic retinopathy and assess the possibility of RNFL thickness changes being a precursor to diabetic retinal changes. METHODS A cross sectional study was conducted at the Department of Ophthalmology, Acharya Vinobha Bhave Rural Hospital. A total of 120 patients were enrolled for the study and divided into four groups of equal population as controls / non-diabetics (NDM), diabetics without retinopathy (NDR), diabetics with non-proliferative diabetic retinopathy (NPDR) and diabetics with proliferative retinopathy (PDR). Patients were evaluated for visual acuity, RNFL thickness, intraocular pressure(IOP), cup disc ratio in each case and data was statistically analysed. RESULTS Mean temporal RNFL thickness in PDR group was 73.72 ± 15.22 and was statistically significant (P = 0.0001) than temporal RNFL thickness in controls (60.41 ± 7.56), NDR (61.06 ± 6.51) and NPDR (59.01 ± 5.51). Mean cup-disc disc ratio was 0.26 ± 0.08 in controls, was 0.28 ± 0.11 in NDR group, 0.32 ± 0.08 in NPDR group and 0.36 ± 0.11 in PDR group and was statistically significant (P = 0.026). However no statistically significant difference was seen in global average RNFL thickness across groups though it was more in NPDR and PDR when compared to NDM group, and was least in NDR group. CONCLUSIONS There was statistically significant increase in temporal RNFL thickness in diabetic group which worsens with the disease. Hence temporal RNFL thickness may be estimated in diabetic patients to predict transformation to diabetic retinopathy and intervene at an early stage. KEY WORDS Diabetes Mellitus, Retinal Nerve Fibre Layer, Proliferative Diabetic Retinopathy, Non Proliferative Diabetic Retinopathy

Retinopathy of prematurity shows alterations in Vegfa164 isoform expression

BackgroundPathologic ocular neovascularization in retinopathy of prematurity (ROP) and other proliferative retinopathies are characterized by dysregulation of vascular endothelial growth factor-A (VEGF-A). A study of Vegfa isoform expression during oxygen-induced ischemic retinopathy (OIR) may enhance our understanding of Vegf dysregulation.MethodsFollowing induction of OIR, immunohistochemistry and polymerase chain reaction (PCR) was performed on room air (RA) and OIR mice.ResultsTotal Vegfa messenger RNA (mRNA) expression was stable in RA mice, but increased in OIR mice with a peak at postnatal day 17 (P17), before returning to RA levels. Vegfa164a expression was similar in both OIR and RA mice at P10 (Phase 1 OIR), but 2.4-fold higher in OIR mice compared to RA mice at P16 (Phase 2 OIR). At P10, Vegfa164b mRNA was similar in OIR vs RA mice, but was expressed 2.5-fold higher in OIR mice compared to RA mice at P16. At P10 and P16, Vegfr2/Vegfr1 expression was increased in OIR mice compared to RA mice. Increased activation of microglia was seen in OIR mice.ConclusionsVegfa164a, Vegfa164b, and Vegfr1 were overexpressed in OIR mice, leading to abnormal signaling and angiogenesis. Further studies of mechanisms of Vegf dysregulation may lead to novel therapies for ROP and other proliferative retinopathies.ImpactVegfa164 has two major isoforms, a proangiogenic, Vegfa164a, and an antiangiogenic, Vegfa164b, with opposing receptors, inhibitory Vegfr1, and stimulatory Vegfr2, but their role in OIR is unclear.In Phase 1 OIR, both isoforms and receptors are expressed similarly.In Phase 2 OIR, both isoforms are overexpressed, with an increased ratio of inhibitory Vegfr1.Modulation of angiogenesis by Vegf regulation enables pruning of excess angiogenesis during physiology, but results in ineffective angiogenesis during OIR. Knowledge of VEGF dysregulation may have novel therapeutic implications in the management of ROP and retinal proliferative diseases.

Further Analysis on Characteristic of Diabetic Reinopathy - A Case in Thai Binh Province in Vietnam

Objective: to study the characteristics of the diabetic retinopathy and some related factors in patients with type 2 diabetes. Subject and research methods: a cross-sectional descriptive study on 80 patients with type 2 diabetes to be examined and treated at the Internal Medicine Department of Thai Binh Medical University Hospital from January to December 2019. Result: • The percentage of patients with damage to the retina accounts for 42.5%; of which, 38.8% were nonproliferative retinopathy, 17.5% were macular disease, 2.5% were pre-proliferative retinopathy and 1.2% were proliferative retinopathy. • The risk of retinal damage increased higher in women than in men; the OR coeffecient of subgroups, namely age ≥ 70 years; diabetic duration ≥ 10 years; BMI ≥ 23 (kg/m2), hypertension, was 1.4; 2.5; 4.0; 4.5; 2.5, respectively. Patients with blood glucose ≥ 7 mmol/L, HbA1c ≥ 7%; total cholesterol &gt; 5.2 mmol/L, triglyceride &gt; 1.88 mmol/L had higher risk of retinopathy with OR coefficient of 2.3; 2.5; 3.2; 2.0, respectively. Patients who were non-compliance with treatment had 3.8 times higher risk of retinopathy than those who complied with treatment. Conclusion: the percentage of patients with retinopathy was 42.5%, the risk of retinopathy increased in patients with one of the following characteristics: female, age ≥ 70 years, duration of diabetes ≥ 10 years, BMI ≥ 23 (kg / m2), hypertension, blood glucose concentration ≥ 7 mmol/L, HbA1c ≥ 7%; cholesterol&gt; 5.2 mmol/L, triglyceride&gt; 1.88 mmol/L.

Type 2 diabetes and neonatal hypoglycemia: role of route of delivery and insulin infusion

Objective To compare the rate of neonatal hypoglycemia among newborns delivered by individuals with Type 2 diabetes mellitus (T2DM) in two clinical scenarios: who attempted vaginal delivery vs. had a planned cesarean delivery (CD); who had intrapartum insulin infusion vs. who did not. Methods This was a retrospective cohort study of individuals with insulin-treated T2DM who had non-anomalous singleton pregnancy and delivered at a single tertiary center (March 2012 and May 2018). Individuals with chronic renal failure, proliferative retinopathy, or major congenital anomalies were excluded. The primary outcome was neonatal hypoglycemia (blood glucose < 40 mg/dl <24 h of age or < 50 mg/dl >24 h of age). Secondary outcomes included neonatal outcomes. Multivariable Poisson regression models with robust error variance were used to examine the association between groups and the primary outcome. Adjusted relative risk (aRR) and 95% confidence intervals (CI) were calculated. Results Of 233 individuals with T2DM, 215 (92.2%) met the inclusion criteria, of whom 95 (44%) attempted vaginal delivery and 120 (56%) had a planned CD. Individuals who labored had a higher gestational age at delivery (36.6 vs. 35.8 weeks, p = .005), and higher blood glucose levels upon admission (125 vs 103, p < .001) compared to those with a planned CD. After adjustment for potential confounders, there was no difference in risk of neonatal hypoglycemia between the groups (41.2 vs 44.1%, aRR 1.05, 95% CI = 0.75–1.45). Among those who attempted vaginal delivery, 34 (35.8%) required insulin infusion. There was no difference in the risk of neonatal hypoglycemia (aRR = 0.79, 95% CI = 0.45–1.37) between newborns delivered by individuals who required insulin infusion and those who did not. Conclusion Over 40% of newborns delivered by individuals with insulin-dependent T2DM had hypoglycemia; however, there was no significant difference in the risk of hypoglycemia, irrespective of the route of delivery and the use of insulin infusion.

High Systolic Blood Pressure, Anterior Segment Changes and Visual Impairment Independently Predict Sickle Cell Retinopathy

Sickle cell disease is often complicated by retinopathy, which can be proliferative or non proliferative. Proliferative sickle cell retinopathy potentially leads to blindness. There is a paucity of data on sickle cell disease-related retinopathy from Africa, where the disease is most prevalent. We aimed to determine the clinical, ophthalmic, and laboratory predictors of sickle cell retinopathy in an African population. We conducted a cross-sectional study of 262 participants, aged 13 years and above, with sickle cell disease. Demographic and clinical data were collected using a structured questionnaire and standard physical examinations. Vitreo-retinal specialists performed eye examinations on all the participants. Hematological and biochemical assessments were conducted using standard methods. A multivariate stepwise forward logistic regression was performed to determine the predictors of retinopathy. The median age of the participants was 20 years (interquartile range: 17–25 years). Most of the participants had a homozygous Hb S (HBB: c.20A>T) genotype (96.9%), with 3.1% who carried a Hb S/Hb C (HBB: c.19G>A) genotype. The prevalence of non proliferative sickle cell retinopathy was 24.4%. Only 1.9% had proliferative sickle cell retinopathy (PSCR). Elevated systolic blood pressure (BP) [odds ratio (OR): 6.85, 95% confidence interval (95% CI): 1.05–44.45, p = 0.059], moderate visual impairment (OR: 5.2, 95% CI: 1.39–19.63, p = 0.015), and anterior segment changes (OR: 2.21, 95% CI: 1.19–4.13, p = 0.012) were independently predictive of retinopathy. This study provides new insight into predictors of retinopathy in sickle cell disease, with implications on early screening and prevention.

Pars-plana vitrectomy combined with retinectomy in severe open-globe injuries: A systematic review and meta-analysis.

This review summarized prophylactic retinectomy technique and its effect on anatomic and functional outcomes in severe open globe injuries (OGIs). A comprehensive search in PubMed (MEDLINE), Embase, Scopus, and EuropePMC databases was performed up until 8 January 2020. Enrolled studies include case series, studies involving pars plana vitrectomy (PPV) combined with retinectomy in severe penetrating injuries with or without IOFB, perforating injuries, and globe ruptures. Primary outcome was best-corrected visual acuity (BCVA) ⩾20/200 at the end of the study. Secondary outcomes were the rate of proliferative retinopathy (PVR), globe survival rate and retinal reattachment rate. A total of seven studies, involving 275 eyes with severe OGIs, is included in this study. Meta-analysis indicates that final BCVA ⩾20/200 was achieved in 61% (95% CI 49%-73%). Meta-regression analysis showed that improvement was inversely affected by the presence of pre-operative direct macular injury (p = 0.001) and corneal scar (p = 0.015). The proportion of pre-operative BCVA <20/200 was statistically insignificant to the final BCVA ⩾20/200 (p = 0.569). One study showed that the rate is higher in the retinectomy group than the non-retinectomy group (54% vs 11%). Meta-analysis showed that anatomical success can be achieved in 85% (95% CI 78%-91%) of the patients. Meta-regression analysis indicates that the anatomical success did not vary with age (p = 0.653), retinal detachment (p = 0.525), corneal scar (p = 0.596), and lens involvement (p = 0.450). Early PPV combined with retinectomy was associated with acceptable visual improvement and anatomical success.

Novel Reclassification of Adult Diabetes Is Useful to Distinguish Stages of β-Cell Function Linked to the Risk of Vascular Complications: The DOLCE Study From Northern Ukraine.

BackgroundPresently, persons with diabetes are classified as having type 1 (T1D) or type 2 diabetes (T2D) based on clinical diagnosis. However, adult patients exhibit diverse clinical representations and this makes treatment approaches challenging to personalize. A recent Scandinavian study proposed a novel classification of adult diabetes into five clusters based on disease pathophysiology and risk of vascular complications. The current study aimed to characterize new subgroups of adult diabetes using this strategy in a defined population from northern Ukraine.MethodsWe analyzed 2,140 patients with established diabetes from the DOLCE study (n = 887 with new-onset diabetes and n = 1,253 with long duration). We used the k-means approach to perform clustering analyses using BMI, age at onset of diabetes, HbA1c, insulin secretion (HOMA2-B), and insulin resistance (HOMA2-IR) indices and glutamic acid decarboxylase antibodies (GADA) levels. Risks of macro- (myocardial infarction or stroke) and microvascular [retinopathy, chronic kidney disease (CKD) and neuropathy] complications and associations of genetic variants with specific clusters were studied using logistic regression adjusted for age, sex, and diabetes duration.ResultsSevere autoimmune diabetes (SAID, 11 and 6%) and severe insulin-deficient diabetes (SIDD, 25 and 14%) clusters were twice as prevalent in patients with long-term as compared to those with new-onset diabetes. Patients with long duration in both SAID and SIDD clusters had highest risks of proliferative retinopathy, and elevated risks of CKD. Long-term insulin-resistant obese diabetes 1 (IROD1) subgroup had elevated risks of CKD, while insulin-resistant obese diabetes 2 (IROD2) cluster exhibited the highest HOMA2-B, lowest HbA1c, and lower prevalence of all microvascular complications as compared to all other clusters. Genetic analyses of IROD2 subgroup identified reduced frequency of the risk alleles in the TCF7L2 gene as compared to all other clusters, cumulatively and individually (p = 0.0001).ConclusionThe novel reclassification algorithm of patients with adult diabetes was reproducible in this population from northern Ukraine. It may be beneficial for the patients in the SIDD subgroup to initiate earlier insulin treatment or other anti-diabetic modalities to preserve β-cell function. Long-term diabetes cases with preserved β-cell function and lower risk for microvascular complications represent an interesting subgroup of patients for further investigations of protective mechanisms.

Prevalence of risk factors associated with ocular problems in males and females in type 1 & 2 diabetes

Background: The aim of current study was exploring the ocular abnormalities in individuals with Type 1 &amp; 2 diabetes. Methods: Patients referred for diabetic ocular abnormalities (retinopathy, cataract, glaucoma and refractive error) on fundoscopy from LRBT eye hospital Korangi, Karachi were randomly included in the study. Retinopathy, cataract and refractive error were evaluated by slit lamp biomicroscope or indirect ophthalmoscope, &amp; categorized into lacking, non-proliferative, proliferative retinopathy, maculopathy, capsular or sub capsular cataract, myopia and hypermetropia. While glaucoma was assessed by tonometry. Prevalence of eye complication has been seen in subjects. Outcome of substantial risk factors on the diverse phases of retinopathy, multivariate regression analysis was performed. Results: 200 diabetic subjects (106 males and 94 females) when the compared; diabetic subjects and subjects with hypertension; 28.0 % retinopathy, 9.75 % cataract, 7.31 % with glaucoma, and about 2.43% refractive error were found out among the diabetic males. 47.61 % retinopathy, 11.9% Cataract, 40.47% refractive error were found in females. In males with diabetes and hypertension were found 60.46 % retinopathy, 27.9 5% cataract, 11.62 % refractive error &amp; in females 46.15% retinopathy, 19.23 % cataract, and 34.61 % with refractive error. Conclusions: This current study emphasizes screening of diabetic subjects regularly so as to distinguish ocular abnormalities and increasing public awareness.

Transcriptome Analysis of Endothelial Colony-Forming Cells Isolated from Patients with HbSC Hemoglobinopathy and Proliferative Retinopathy

Introduction: Retinopathy is one of the major clinical manifestations of sickle cell disease. Although systemic disease is more severe in sickle cell anemia, ocular disease is apparently more severe in hemoglobin SC disease (HbSC). Sickle cell retinopathy can be classified as non-proliferative or proliferative. In the non-proliferative form, the most common clinical findings are salmon patch hemorrhages, iridescent spots and black sunbursts, which can be observed in the peripheral retina. In the proliferative form, peripheral retinal neovascularization develops after vaso-occlusion and grows anteriorly from perfused to non-perfused retina. These new vessels can lead to vitreous hemorrhage, retinal breaks, tractional or rhegmatogenous retinal detachments, and consequently vision loss can occur. The precise pathogenesis of neovascular formation in sickle cell disease is not fully understood. Endothelial Colony-Forming Cells (ECFC) have been shown to play a role in angiogenesis and could become accessible informers of vascular status and enable the study of vascular disorders. Objective: The aim of this study was to compare differential gene expression profiles of ECFC from HbSC patients with and without retinopathy. Methods: ECFCs were cultured after isolation from peripheral blood samples of three HbSC patients with proliferative retinopathy and five HbSC patients without retinopathy. RNA was extracted from the cell cultures and transcriptome analysis was performed with HiSeq 2500 sequencer (Illumina, Inc., San Diego, CA, USA) with eight RNA-seq libraries per lane (2 × 101-bp paired-end reads). Results: Ten genes were upregulated in cultures from patients with retinopathy when compared with those without retinopathy: ROBO1, SLC38A5, SLC38A5, DDR2, PEG3, PLPP7, TRBJ2-1, PLPP4, APCDD1L and SEMA3B . Discussion and Conclusion: Among these genes, we highlight the most upregulated gene encoding Robo1, a member of the roundabout (Robo) family that serves as a neuronal guidance receptor and has been reported to mediate tumor and retinal angiogenesis. The Robo1-mediated pathway has been proposed as a target for the treatment of several ocular neovascular diseases, so our data support that sickle cell proliferative retinopathy may also benefit from therapeutic strategies blocking this pathway. DisclosuresOzelo:Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behing: Consultancy; Roche: Consultancy, Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Grifols: Speakers Bureau. Fertrin:Alexion Pharmaceuticals: Consultancy.

Perinatal famine is associated with excess risk of proliferative retinopathy in patients with type 2 diabetes.

Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long-term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR). We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932-1933) and the WWII (1941-1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942-1945. During the Holodomor and WWII, perinatal famine was associated with a 1.76-fold (p = 0.019) and 3.02-fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66-fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05). In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications.

HIF-1α and HIF-2α redundantly promote retinal neovascularization in patients with ischemic retinal disease.

Therapies targeting VEGF have proven only modestly effective for the treatment of proliferative sickle cell retinopathy (PSR), the leading cause of blindness in patients with sickle cell disease. Here, we shift our attention upstream from the genes that promote retinal neovascularization (NV) to the transcription factors that regulate their expression. We demonstrated increased expression of HIF-1α and HIF-2α in the ischemic inner retina of PSR eyes. Although both HIFs participated in promoting VEGF expression by hypoxic retinal Müller cells, HIF-1 alone was sufficient to promote retinal NV in mice, suggesting that therapies targeting only HIF-2 would not be adequate to prevent PSR. Nonetheless, administration of a HIF-2-specific inhibitor currently in clinical trials (PT2385) inhibited NV in the oxygen-induced retinopathy (OIR) mouse model. To unravel these discordant observations, we examined the expression of HIFs in OIR mice and demonstrated rapid but transient accumulation of HIF-1α but delayed and sustained accumulation of HIF-2α; simultaneous expression of HIF-1α and HIF-2α was not observed. Staggered HIF expression was corroborated in hypoxic adult mouse retinal explants but not in human retinal organoids, suggesting that this phenomenon may be unique to mice. Using pharmacological inhibition or an in vivo nanoparticle-mediated RNAi approach, we demonstrated that inhibiting either HIF was effective for preventing NV in OIR mice. Collectively, these results explain why inhibition of either HIF-1α or HIF-2α is equally effective for preventing retinal NV in mice but suggest that therapies targeting both HIFs will be necessary to prevent NV in patients with PSR.

980-P: Existing Microvascular Complications and Risk of Subsequent Heart Failure (HF) in Type 1 Diabetes (T1D)

We aimed to quantify the association between existing microvascular diseases and risk of subsequent HF in adults with T1D. Participants from Pittsburgh Epidemiology of Diabetes Complication (EDC) Study without known baseline HF (n=655) were classified into 4 groups based on the number (n=0-3) of existing microvascular diseases, i.e., overt nephropathy, proliferative retinopathy, and confirmed distal symmetric polyneuropathy (CDSP). Overt nephropathy was defined as an AER &amp;gt;300mg/24h in ≥ 2 of three validated timed biennial urine collections. Proliferative retinopathy was based on stereoscopic fundus photographs or a history of receiving laser therapy for proliferative diabetes retinopathy. CDSP was identified by following the Michigan Neuropathy Screening Instrument and the Michigan Diabetes Neuropathy Score. HF was determined by hospitalization, cause-of-death records, clinic exams, and/or self-reports of physician diagnosis. We applied Cox PH models to quantify the association between the number of existing microvascular diseases and risk of subsequent HF over 25 years follow-up controlling for diabetes duration (or age), sex, HbA1c, and CAD comorbidity. Mean baseline age and T1D duration were 27 years and 19 years. The 25-year cumulative incidence of HF was 6.6% (43/655). Over half didn’t have any microvascular disease at baseline; 19.7%, 16.7% and 10.8% had 1, 2 and 3 microvascular diseases, respectively. In participants with 1, 2, and 3 microvascular diseases, the adjusted HR (95%CI) of any clinically defined HF was 3.1 (1.3, 7.6), 2.5 (0.9, 6.9), and 4.0 (1.3, 11.9), compared with those without any microvascular disease. The HR (95%CI) of hospitalization or death for HF was 2.0 (0.6, 7.3), 2.2 (0.6, 8.7), and 4.1 (1.0, 16.4). As microvascular disease burden increases so does the risk of HF, independently of diabetes duration, sex, HbA1c, and CAD among adults with long-duration childhood-onset T1D. Disclosure J. Guo: None. T. Costacou: None. R. G. Miller: None. T. J. Orchard: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK034818)

Management of Patients with Newly Diagnosed Diabetic Mellitus: Ophthalmologic Outcomes in Intensive versus Conventional Glycemic Control.

Background and ObjectiveDiabetic retinopathy, a microvascular complication of diabetes mellitus, is one of the most important causes of visual loss in developed countries. Our objective is to evaluate the efficacy of intensive versus conventional glycemic control of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients in terms of ophthalmologic outcome, pathogenesis of the early worsening of diabetic retinopathy, risk factors for early worsening and diabetic retinopathy progression.MethodsA literature search on publications concerning glycaemic control in diabetic retinopathy and management of newly diagnosed diabetes mellitus by intensive versus conventional glycaemic control.ResultsA total of 22 articles were reviewed after curation by the authors for relevance. Nineteen articles are randomized control trial, 2 articles are observational studies and 1 is clinical trial. Fifteen articles investigated the glycaemic control in T1DM-related diabetic retinopathy and 8 on T2DM-related diabetic retinopathy. The level of glycemia (in terms of HbA1c level) is significantly related to the diabetic retinopathy progression in both T1DM and T2DM. Intensive glycemic control was found to reduce the development of severe diabetic retinopathy, including severe non-proliferative diabetic retinopathy, neovascularization, clinically significant macular edema and loss of vision. Early worsening of diabetic retinopathy commonly occurs during the first year of intensive treatment, especially those initially present with proliferative or severe non-proliferative retinopathy. However, most patients with early worsening can recover and their long-term ophthalmologic outcomes are better when compared to conventional glycemic control.ConclusionThe current guideline on HbA1c level is considered sufficient for the minimization of diabetic retinopathy progression. More frequent monitoring for early worsening should be recommended for newly diagnosed diabetes cases already presenting with retinopathy.

Decentralizing diabetes care from tertiary to primary care: how many persons with diabetes can be down-referred to primary care settings?

In a cohort of persons with diabetes (PWDs) seeking care at a tertiary care center, we aimed to determine the proportion of PWDs eligible and willing for down referral to primary health centers (PHCs). We conducted a cross-sectional analytical study among PWDs on treatment for at least 1 year. PWDs with stable blood sugar, no history of cardiovascular events and proliferative retinopathy were considered as 'eligible' for primary care management. Of the total 1002 PWDs, mean (SD) age was 56 (12) years; 62% were male and 81% were from rural areas. About half (49%) of them were on insulin, and 52% had comorbidities. In total, 45.6% (95% CI: 42.3-48.8%) were eligible to be managed at PHCs. Among those who were eligible, 46.6% were willing to go back to PHCs. Males (APR=1.16), people with diabetes for more than 10 years (APR=1.23), and the presence of comorbidities (APR=1.13) were significantly associated with unwillingness. Quality of medicines (46%) and poor facilities (40%) at PHCs were the main reasons for unwillingness. About half of the PWDs availing care at tertiary hospitals can be managed at primary care settings; of those, only half were willing to receive care at PHCs.

Microaneurysm Turnover in Mild Non-Proliferative Diabetic Retinopathy is Associated with Progression and Development of Vision-Threatening Complications: A 5-Year Longitudinal Study.

Background: Analysis of retinal microaneurysm turnover (MAT) has been previously shown to contribute to the identification of eyes at risk of developing clinically significant complications associated with diabetic retinopathy (DR). We propose to further characterize MAT as a predictive biomarker of DR progression and development of vision-threatening complications. Methods: 212 individuals with type 2 diabetes (T2D; ETDRS grades 20 and 35) were evaluated annually in a 5-year prospective, longitudinal study, by color fundus photography and optical coherence tomography. Endpoints were diabetic macular edema (DME) or proliferative retinopathy (PDR). MAT analysis included determination of MA formation and disappearance rates, automatically assessed using the RetMarkerDR®. Retinopathy severity progression was evaluated using step increases in ETDRS severity levels. Results: Of the 212 individuals, 172 completed the 5-year follow-up study or developed an endpoint (n = 27). MAT calculated at 1 year showed a significant difference between groups of endpoint developments (p = 0.018), particularly MA disappearance rate (p = 0.007). MAT also showed a significant difference between eyes with different ETDRS severity progression in the 5-year period (p = 0.035). Conclusions: MAT is an indicator of the development of DME and/or PDR as well as of DR severity progression in T2D individuals with mild retinopathy.