Quality-adjusted life years in macular oedema due to age-related macular degeneration, diabetes and central retinal vein occlusion: the impact of anti-VEGF agents in a tertiary centre in Greece.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME), and macular oedema due to central retinal vein occlusion (CRVO) are leading causes of vision loss, currently managed with anti-vascular endothelial growth factor injections (anti-VEGF). The aim of this study was to calculate QALYs in patients with nAMD, DME, and CRVO treated with anti-VEGF agents (QALYs+) in a Greek tertiary hospital setting and compare them to theoretical QALYs that the patients would have without treatment (QALYs-). MATERIAL AND METHODS: The study included 143 treatment-naive patients with macular oedema due to nAMD (n = 79), DME (n = 57), and CRVO (n = 7), who received anti-VEGF injections as monotherapy according to the Treat-and-Extend (T&E) protocol. The anti-VEGF agents were ranibizumab and aflibercept in equivalent fractions. QALYs where calculated by the formula QALY = Utility Value × Time, where "Time" refers to the follow-up period of the study. For QALYs-, we assumed that visual acuity remained unchanged during this period. RESULTS: Mean follow-up time was 1.3 ± 1.2 years in the nAMD group, 1 ± 1.3 years in the DME group, and 0.5 ± 1 years in the CRVO group. There was no statistically significant difference between QALYs- and QALYs+ in all three ocular pathologies for the study period (p > 0.05 for each of the three statistical tests performed). DISCUSSION/CONCLUSION: Possible explanations for the lack of significant difference between QALYs - and QALYs + in nAMD, DME, and CRVO groups, may be the short time horizon used in this analysis, the inclusion of data from the better-seeing eye (BSE) and the specific socio-economic, geographical and health care characteristics of this rural Greek area.

SLC2A1 Tag SNPs in Greek Patients with Diabetic Retinopathy and Nephropathy.

Backround: Genetic variants are implicated in the development of diabetic retinopathy (DR) and nephropathy (DN). The role of solute carrier family 2-facilitated glucose transporter member 1 (SLC2A1), also known as glucose transporter (GLUT1), on DR and DN remain controversial. OBJECTIVE: Examination of the influence of tag SLC2A1 single-nucleotide polymorphisms (SNPs) on the development of DR and DN during the course of type 2 diabetes mellitus (T2DM). METHODS: A total of 169 patients with DR or DN, 107 uncomplicated T2DM patients, and 315 controls were recruited and genotyped for 14 SLC2A1 tag SNPs. SNPs and haplotypes were tested for associations with microvascular diabetes' complications. RESULTS: rs3768029 TT genotype was associated with a lower risk of DR + DN, compared to the CC wild-type (p = 0.0024). Moreover, CT and TT rs841847 genotypes were associated with a higher risk of DR + DN compared to the CC genotype (p = 0.0028). A common haplotype (GGCCCGCATCAAT) was associated with an increased risk of DR, DN, DR ± DN, and DR + DN phenotypes. Mutational loads of rs3768029, rs3729548, rs841853, and rs841847 were found to influence the development of microvascular complications during the T2DM course. CONCLUSIONS: This study provides evidence that SLC2A1 gene variants might be implicated in the development of T2DM microvascular complications.

Macular Ischemia Changes in Patients with Diabetic Macular Edema Treated with Aflibercept and Ranibizumab.

Τhis study aims to assess changes in the fovea avascular zone (FAZ) in treatment naïve patients receiving aflibercept or ranibizumab injections for diabetic macular edema (DME). Best corrected visual acuity (BCVA) testing, OCT, and OCT-angiography imaging were performed at baseline and 1 month after each injection. Injections of either aflibercept or ranibizumab were administered monthly for 6 consecutive months. FAZ in the superficial (SCP) and the deep capillary plexus (DCP) using OCT angiography was recorded for each visit. Fifty eyes from fifty patients with a mean age of 67.0 ± 10.7 years were included in the study. Twenty-five patients received aflibercept and twenty-five received ranibizumab. BCVA was 40.8 ± 10.0 and increased to 52.1 ± 7.9 ETDRS letters at the last visit (p < 0.001). CRT was 295.6 ± 34.0 at baseline and 247.9 ± 29.7 at the last study visit (p < 0.001). SCP FAZ was 350.6 ± 79.5 µm2 at baseline and 339.0 ± 71.3 µm2 after sox monthly injections (p = 0.132). DCP FAZ was 558.6 ± 199.0 µm2 at baseline and 459.5 ± 156.1 µm2 after six monthly injections (p < 0.001). There was no effect of the choice of ranibizumab or aflibercept on DCP FAZ change (p = 0.277). In conclusion, treatment with 6 monthly injections of ranibizumab and aflibercept led to an increase in BCVA and a decrease in CRT and DCP FAZ area. Both drugs led to an improvement in DCP ischemia.

Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration.

Vitamin D has been shown to have anti-angiogenic properties and to play a protective role in several types of cancer, including breast, prostate and cutaneous melanoma. Similarly, vitamin D levels have been shown to be protective for risk of a number of conditions, including cardiovascular disease and chronic kidney disease, as well as numerous autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases and type 1 diabetes mellitus. A study performed by Parekh et al. was the first to suggest a role for vitamin D in age-related macular degeneration (AMD) and showed a correlation between reduced serum vitamin D levels and risk for early AMD. Based on this study and the protective role of vitamin D in diseases with similar pathophysiology to AMD, we examined the role of vitamin D in a family-based cohort of 481 sibling pairs. Using extremely phenotypically discordant sibling pairs, initially we evaluated the association of neovascular AMD and vitamin D/sunlight-related epidemiological factors. After controlling for established AMD risk factors, including polymorphisms of the genes encoding complement factor H (CFH) and age-related maculopathy susceptibility 2/HtrA serine peptidase (ARMS2/HTRA1), and smoking history, we found that ultraviolet irradiance was protective for the development of neovascular AMD (p = 0.001). Although evaluation of serum vitamin D levels (25-hydroxyvitamin D [25(OH)D]) was higher in unaffected individuals than in their affected siblings, this finding did not reach statistical significance. Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurse's Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.

COVID-19 hemodynamic and thrombotic effect on the eye microcirculation after hospitalization: A quantitative case-control study.

BACKGROUND & OBJECTIVE: To quantify the hemodynamic and thrombotic effect of COVID-19 on the eye microcirculation of patients with thromboprophylaxis, shortly after hospital discharge. METHODS: This case-control study included 17 COVID-19 survivors (named "COVID-19 Group") and 17 healthy volunteers (named "Control Group"). Axial blood velocity (Vax) and percentage of occluded vessels (POV) were quantified by Conjunctival Video Capillaroscopy (CVC). Microvessels were identified and classified as "capillaries" (CAP), "postcapillary venules of size 1" (PC1), and "postcapillary venules of size 2" (PC2). RESULTS: The COVID-19 Group did not differ significantly in basic demographics from the Control Group. In the COVID-19 Group, there was a statistically significant (p < 0.001) reduction of Vax (39%, 49% and 47%, for CAP, PC1, and PC2, respectively) in comparison to the Control Group and a sizeable (p < 0.001) increase of POV (600%) in comparison to the Control Group. CONCLUSIONS: COVID-19 not only reduces significantly axial blood velocity in the capillaries and postcapillary venules of the eye but has also a devastating effect on microthrombosis (POV) despite thromboprophylaxis treatment. This gives a possible explanation for long COVID and a hint about the existence of a possibly unknown coagulation factor.

Plasma and aqueous humour levels of ghrelin in open-angle glaucoma patients.

BACKGROUND: To compare aqueous humour and plasma levels of ghrelin, a peptide recently identified in human eyes, in patients with open-angle glaucoma and controls. DESIGN: Cross-sectional, controlled, hospital-based study. PARTICIPANTS: Twenty-four open-angle glaucoma (17 primary open-angle and 7 pseudo-exfoliation glaucoma) patients and 30 controls were included. All participants were patients scheduled for cataract or glaucoma surgery. Patients with other ocular pathology, previous ocular surgery or diabetes were excluded. METHODS: Blood samples were collected before elective surgery. Aqueous humour was aspirated from the anterior chamber through a paracentesis with a 27-G needle under sterile conditions before any tissue manipulation. Ghrelin quantification was performed with commercially available Radioimmunoassay kits. MAIN OUTCOME MEASURE: Ghrelin levels in aqueous humour and plasma. RESULTS: Plasma levels of ghrelin were 490.5 ± 156.0 pg/mL in the open-angle glaucoma and 482.2 ± 125.4 pg/mL in the control group (Mann-Whitney test, P = 0.897). Aqueous humour levels of ghrelin were 85.5 ± 15.4 and 123.4 ± 25.5 pg/mL in the respective groups (P < 0.001). The ratio of plasma/aqueous humour ghrelin concentration was higher in the open-angle glaucoma versus the control group (5.75 ± 1.92 vs. 4.00 ± 1.04, P < 0.001). There was no difference in aqueous humour levels of ghrelin between primary open-angle glaucoma and pseudo-exfoliation glaucoma patients (P = 0.494). CONCLUSIONS: Aqueous humour levels of ghrelin were significantly lower in open-angle glaucoma patients, compared with controls. This difference may manifest a role of ghrelin in the disease process or a consequence of antiglaucoma treatment.

Optical coherence tomography angiography reveals vascular alterations in pediatric commotio retinae.

INTRODUCTION: Aim of this study is to present the acute and long-term swept-source optical coherence tomography angiography findings in pediatric commotio retinae. MATERIALS AND METHODS: Two children presented with reduced visual acuity and Berlin edema after blunt trauma. RESULTS: Swept-source optical coherence tomography revealed hyperreflectivity of the retinal nerve fiber layer and disruption of the ellipsoid zone and the retinal pigment epithelium. Swept-source optical coherence tomography angiography showed enlarged superficial foveal avascular zone in both cases. In the more severe case, there was enlargement of both superficial and deep foveal avascular zone, and reduction of the superficial vascular plexus density. CONCLUSION: The present findings suggest that pediatric commotio retinae may be associated with retinal vascular changes, that is, foveal avascular zone enlargement and decreased vessel density. The extent of the microvascular alterations is possibly related to trauma severity.

Blood velocity pulse quantification in the human conjunctival pre-capillary arterioles.

Axial red blood cell velocity pulse was quantified throughout its period by high speed video microcinematography in the human eye. In 30 conjunctival precapillary arterioles (6 to 12 microm in diameter) from 15 healthy humans, axial velocities ranged from 0.4 (the minimum of all the end diastolic values) to 5.84 mm/s (the maximum of all the peak systolic values). With the velocity pulse properly quantified, two parameters can be estimated: (1) the average velocity of the pulse during a cardiac cycle AVV (average velocity value) and (2) the magnitude of the pulsation using Pourcelot's resistive index RI. These parameters are important for the estimation of other hemodynamic parameters such as the average volume flow and the average shear stress. The results of this study revealed that the AVV in the human precapillary arterioles ranged between 0.52 and 3.26 mm/s with a mean value for all microvessels of 1.66 mm/s+/-0.11(SE). The RI ranged between 35.5% and 81.8% with a mean value of 53.1%+/-2.2. Quantitative information was obtained for the first time on the velocity pulse characteristics just before the human capillary bed.

Evaluation of MMP1 and MMP3 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma.

PURPOSE: To investigate possible genetic associations of matrix metalloproteinase-1 (MMP1) and MMP3 gene polymorphisms with exfoliation syndrome (XFS) with (XFS/+G) and without (XFS/-G) glaucoma in a cohort of Greek patients. METHODS: A total of 182 unrelated Greek patients with XFS, including 92 patients with XFS/+G, and 214 unrelated age- and gender-matched controls were enrolled in the study. MMP1 -1607 1G/2G (rs1799750) and MMP3 -1171 5A/6A (rs3025058) polymorphisms were determined using standard PCR/restriction fragment length polymorphism methods. Differences in allele and genotype distributions were analyzed using logistic regression. RESULTS: The distribution of genotypes and alleles in MMP1 and MMP3 polymorphisms was not significantly different between cases with exfoliation syndrome, with or without glaucoma, and controls. However, the allele contrast for the MMP1 variant showed a trend for a significant association with XFS/-G (Odds Ratio=1.47 [1.03-2.10]), since after correction for multiple comparisons, this association was no longer statistically significant. CONCLUSIONS: Our study provided some evidence of a possible role of the MMP1 variant in the development of exfoliation syndrome in Greek patients.

Detection of macular photocoagulation scars with confocal infrared reflection imaging.

BACKGROUND AND OBJECTIVE: To study the diagnostic reliability (specificity and sensitivity) of confocal infrared reflection in detecting threshold argon laser photocoagulation scars in the macula. PATIENTS AND METHODS: Fifty-six maculae with diabetic macular edema were evaluated by biomicroscopic slit-lamp fundus examination, digital color fundus photography, digital fundus fluorescein angiography, and digital infrared reflection images. Three examiners evaluated whether the eye had undergone any laser photopexy in the macula. RESULTS: Sensitivity, specificity, and false-positive and false-negative results were calculated for each method. Fluorescein fundus angiography and infrared imaging, although using different approaches, both detect pigment epithelium changes such as laser scars. It seems that both methods are of equal specificity. On the other hand, both biomicroscopic fundus examination and digital color photography showed poor reliability. CONCLUSION: Infrared reflection imaging is an easy, noninvasive method with excellent sensitivity and specificity in detecting photocoagulation scars from previous threshold laser treatment. It may be useful in estimating photocoagulated areas, especially if threshold treatment has been applied.

Resolution of macular edema in idiopathic juxtafoveal telangiectasis using PDT.

A 57-year-old woman was treated by photodynamic therapy for macular edema due to idiopathic juxtafoveal telangiectasis (presumed type 1A) without subretinal neovascularization. Initial visual acuity of the treated eye was 20/200 and it improved to 20/40 by 3 months after the photodynamic therapy session. Visual acuity remained stable 32 months after the treatment. Color photographs and fundus fluorescein angiography before and after photodynamic therapy revealed regression of hemorrhages, exudates, and fluorescein leakage. Photodynamic therapy has long-term benefits for the patient with idiopathic juxtafoveal telangiectasis, presumed type 1A, because it can improve visual acuity and macular edema.

Parecoxib has non-significant long-term effects on bone healing in rats when administered for a short period after fracture.

INTRODUCTION: Selective and non-selective cyclo-oxygenase (COX) inhibitors impair bone healing by inhibiting prostaglandin synthesis. The purpose of this study was to evaluate the long-term effect of parecoxib, a selective COX-2 inhibitor, on bone healing in rats, when it is applied in a pattern similar to clinical treatment patterns, that is, in a high dose and for a short period after bone fracture. METHOD: Closed non-displaced mid-diaphyseal fractures in the middle of the left femoral shaft were generated in each animal. In the study group, parecoxib sodium (1.06 mg/kg) was administered intra-peritoneally every day for 7 days. In the control group, normal saline was administered intra-peritoneally every day for 7 days. In both groups fracture healing (bone union and callus formation) was evaluated with X-rays 28 and 42 days after surgery. RESULTS: Bone healing was lower in the study group (60 vs. 80% in the control group 28 days after fracture and 80 vs. 90% 42 days after fracture) but this difference was not statistically significant (P > 0.05). CONCLUSION: Parecoxib does not have a significant long-term effect on bone healing in rats, when it is administered in a high dose and for a short period after bone fracture.

Volume flow and wall shear stress quantification in the human conjunctival capillaries and post-capillary venules in vivo.

Understanding the mathematical relationships of volume blood flow and wall shear stress with respect to microvessel diameter is necessary for the study of vascular design. Here, for the first time, volume flow and wall shear stress were quantified from axial red blood cell velocity measurements in 104 conjunctival microvessels of 17 normal human volunteers. Measurements were taken with a slit lamp based imaging system from the post capillary side of the bulbar conjunctiva in microvessel diameters ranging from 4 to 24 micrometers. The variation of the velocity profile with diameter was taken into account by using a profile factor function. Volume flow ranged from 5 to 462 pl/s with a mean value of 102 pl/s and gave a second power law best fitting line (r=0.97) deviating significantly from the third power law relation with diameter. The estimated wall shear stress declined hyperbolically (r=0.93) from a maximum of 9.55 N/m(2) at the smallest capillaries, down to a minimum of 0.28 N/m(2) at the higher diameter post capillary venules. The mean wall shear stress value for all microvessels was 1.54 N/m(2).

Plasminogen Activator Inhibitor Type-1 Tag Single-Nucleotide Polymorphisms in Patients with Diabetes Mellitus Type 2 and Diabetic Retinopathy.

BACKGROUND: There is accumulating evidence for genetic susceptibility to the development of diabetic retinopathy (DR). The role of plasminogen activator inhibitor-1 (PAI-1) in DR risk remains controversial. OBJECTIVE: The present study was designed to investigate possible influence of PAI-1 gene region polymorphisms on the risk of DR and on the risk of developing DR early vs late in the course of type 2 diabetes mellitus (T2DM). METHODS: A total of 138 patients with DR, 107 patients with T2DM without DR, and 315 healthy controls were recruited. To cover the majority of the genetic variability across the extended region of PAI-1 gene, five tag single-nucleotide polymorphisms (SNPs) from the HapMap using a pairwise approach and an r2 ≥ 0.8 and a minor allele frequency (MAF) of >0.05 were identified. Using logistic regression analyses, tag SNPs and haplotypes were tested for associations with DR risk and risk of DR development early or late in the course of T2DM. The generalized odds ratio (ORG) was calculated to estimate the mutational load effect on DR development among all participants. Corrections for multiple comparisons were carried out (p-value < 0.01). RESULTS: A significant effect of rs2070682 on the risk of early DR onset was found in the codominant model of inheritance [odds ratio, OR (95% confidence interval, CI): 5.04 (1.47-17.28), p = 0.018]. However, this association marginally did not survive multiple testing corrections. No other significant association between PAI-1 tag-SNPs and haplotypes was revealed. Furthermore, no significant mutational load effect of PAI-1 tag SNPs on the risk of DR development in T2DM course was found. CONCLUSIONS: In conclusion, the present study does not provide any strong evidence that PAI-1 gene variants are implicated in the risk of DR or the development of DR during T2DM course.

Metabolic control of diabetes is associated with an improved response of diabetic retinopathy to panretinal photocoagulation.

OBJECTIVE: To study the influence of glycemic control and the presence of microalbuminuria on the initial response to panretinal photocoagulation (PRP) in patients with a high-risk proliferative diabetic retinopathy (PDR). RESEARCH DESIGN AND METHODS: This was a prospective cohort study with a two-by-two factorial design. We used full-scattered PRP to treat 115 eyes of type 2 diabetic patients who have high-risk PDR. HbA1c (A1C) and albumin levels in 24-h urine were constantly monitored during the pre-enrollment, treatment, and posttreatment periods. At a follow-up visit 12 weeks after the last PRP session, the fundus was examined for characteristics of regression from high-risk PDR and the response to PRP was determined to be successful or unsuccessful. The eyes were categorized into four groups based on average A1C levels and the presence or absence of microalbuminuria. The data were analyzed using a logistic regression model. Our statistical analysis determined the probability of achieving a satisfactory response to PRP in association with A1C levels and the presence or absence of microalbuminuria. RESULTS: Of the 115 eyes examined, 65 (56.5%) had a successful initial response to PRP and 50 (43.5%) did not. The probability of a satisfactory response to PRP was related to A1C levels (P < 0.05) but not to microalbuminuria and its interaction with hemoglobin glycosylation (P > or = 0.05). CONCLUSIONS: Low levels of hemoglobin glycosylation (A1C <8%) during the pretreatment, treatment, and posttreatment periods are associated with a regression of proliferative diabetic retinopathy after PRP.

FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression.

PURPOSE: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway. METHODS: Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis. RESULTS: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway. CONCLUSIONS: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.