In the past, perifoveal capillary arcade morphology and ﬂ ow speed were studied with ﬂ uorescein angiography, ﬂ uorescein videoangiography 36 and digital ﬂ uorescein angiograms. 1 Speci ﬁ cally, in the diabetic eye, it can be found an increase in the area of the FAZ and the inter- capillary areas in the perifoveal region. 1,34,36 For research purpose, the authors cited below calculated areas using computer tools and thus they obtained quantitative data. However, we have not found a topographic VD analysis, despite that previous reports highlight that the presence of papillomacular ischemia was particularly associated with VA reduction. 34
Other DR clinical findings, such as arteriolar wall stain- ing, neovascularization, and intraretinal microvascular abnormalities (IRMA), have divergent appearances on OCTangiography and fluorescein angiography. Wall staining and arteriolar narrowing have been illustrated as intense attenuation of microcirculation caliber on OCTangiography. IRMA, depicted as dilated terminal ves- sels surrounded by capillary loss, were similarly identi- fied with OCTangiography and fluorescein angiography (Fig. 2) . OCT angiograms clearly visualized new ves- sels on the disc (NVD) that persisted as spiral, looped, and irregular structures after initial anti-VEGF therapy . Retinal NV is mostly detected by observing the flow signal above the internal limiting membrane. Hyperfluo- rescent lesions on fluorescein angiography that appeared indistinguishable from an MA were identified as NV usingOCTangiography. This information may help us to understand why some patients with PDR and vitre- ous hemorrhage do not have a definitive NV on fluores- cein angiography, as long as this method does not always identify all NV .
Optical Coherence Tomography (OCT) offers a non- invasive, rapid imaging modality that can provide im- aging of the cross-sectional structures of the retina by using low-coherence interferometry to capture high resolution two dimensional images from the optical scat- tering from different layers of the retina  and is an essential tool in the detection and monitoring of DME , and DMI with inner retinal thinning . Optical coherence tomography angiography (OCTA) is a novel use of OCT to visualise the microvasculature of the ret- ina and choroid without the need for dye injection . This is performed through repeated scans at the same location to detect the changes in OCT reflectance signal from the flow through blood vessels [16, 17]. It allows depth-resolved imaging of the retinal vasculature and is an ideal approach for various retinal conditions such as DR, retinal venous occlusion, uveitis, retinal arterial oc- clusion and age-related macular degeneration [18, 19].
OCTA was performed for all subjects using the RTVue XR OCT Avanti System with AngioVue version 2018.0.0.18 (Optovue, Fremont, CA, USA); AngioVue HD imaging retinal scan size 6×6 mm 2 , 400×400 pixels (two repeats/B-scan), scan time 3 s, axial resolution 5 µm and transversal resolution 15 µm. En face, A-scan and B-scan angiography images of both the super ﬁ cial capillary plexus (SCP) and deep capillary plexus (DCP) were used for analysis. The automated measured OCTA parameters were the FAZ area (mm 2 ), the super ﬁ cial capillary plexus vessel density (SCP-VD) and the deep capillary plexus vessel density (DCP-VD), in whole and parafoveal areas. The vessel density was automatically calculated in two circular rings after excluding the FAZ area: the parafoveal area in a circular zone of 3 mm diameter and the whole area in a circular zone of 6 mm diameter. The automated vessel density measurements were applied using the new AngioVue software (Optovue, USA), which includes automated algorithms for mapping capillary den- sity in the SCP and DCP, and the vessel density was demon- strated as a percentage by taking the ratio of the total vessel area to the total area of analyzed region. The central retinal thickness was recorded from a 6×6 mm 2 area on the B-scan map. OCTA images with a signal strength index (SSI) <6 were excluded from the present study.
A healthy choroid is essential for retinal function. Until recently, the choroid could only be evaluated by indocyanine green angiography, laser flowmetry, and ultrasonography. However, these techniques are only able to show us choroidal vessel abnormalities and blood flow changes; they cannot show the three-dimensional anatomy of choroid layers or the retinal pigment epithelium. Optical coherence tomography (OCT) is a noninva- sive imaging modality, which is used in acquiring high-resolution sections of retina. Recently, enhanced depth imaging (EDI) spectral-domain OCT has been described.
All subjects presented with DRIL to some degree. The extent of DRIL was not affected by the treatment, and there was no correlation with final visual acuity. This could be due to our small sample size, as the literature reported good correlation between visual acuity and DRIL extent, with a stronger predictive value than even retinal thickness . However, we found a correlation between DRIL area, capillary dropout on FA/OCTA and diminished retinal sensitivity on microperimetry. Moen et al. also demonstrated a correlation between alterations in inner retinal layer with ischemic areas. They theorized that superficial and deep capillary plexuses of the retina have a role as a framework for retinal cells; once this framework is lost, function (macular sensitivity) could be compromised .
Diabeticretinopathy (DR) is the most important cause of blindness in type 1 DM patients [1, 2]. It has been postulated that selective loss of pericytes and thickening of the basement membrane in retinal capillaries occur as a result of exposure to elevated blood glucose over an extended period of time, damaging the retinal vessels and affecting the retinal blood flow in a time-dependant manner . To evaluate the vascular flow in the retina of diabetic patients, fluorescein angiography (FA) re- quires an intravenous injection and has been relegated by the advent of non-invasive retinal imaging techniques [4–10] Optical coherence tomography (OCT) is a light- based technique that provides pseudo-histologic images of the retinal structure, which has become the main diagnostic tool in the management of retinal diseases . Unfortunately, the information given by conven- tional OCT images is merely structural, and no informa- tion about blood flow or perfused areas can be obtained, being difficult to detect early changes in the retinal vas- cular network of diabetic patients.
duration was found to be the only signi ﬁ cant contributor to DR in multivariate regression. Lower rates of DR among patients with DM and HCV with concurrent cirrhosis or HIV related to the shorter duration of DM in these groups, perhaps due to increased mortality related to cirrhosis or HIV itself. This ﬁ nding supports the potential for survival bias to yield fewer DM-related complications among HCV patients with cirrhosis or HIV. Relatedly, Marchesini et al noted reduced rates of retinopathy among DM patients with cirrho- sis than in DM controls without cirrhosis, although the etiol- ogy of cirrhosis (hepatitis or non-hepatitis) was not speci ﬁ ed. 15 Similarly, Burgess et al reported a negative asso- ciation between HIVand DR (OR=0.16, p=0.02). 19 In further support of a potential role for survival bias, Greca et al reported signi ﬁ cantly lower rates of DR among the subset of HCV patients on dialysis compared to patients without HCV. 12
Diabeticretinopathy (DR) is a vision-threatening microvascu- lar complication of type 1 and type 2 diabetes mellitus. 1 It affects ~93 million people worldwide and is a leading cause of new-onset blindness. 2–5 Patients with either non-proliferative DR (NPDR) or proliferative DR (PDR) can develop diabetic macular edema (DME) which, if left untreated, is a major cause of vision impairment and legal blindness in patients with DR. In the United States from 2005 to 2008, 4.2 million adults with diabetes aged ≥ 40 years had DR; of these, 655,000 patients had advanced vision-threatening DR. 5 Ranibizumab is a recombinant humanized monoclonal antibody fragment that binds and inhibits the biologic activ- ity of all isoforms of human vascular endothelial growth factor (VEGF)-A. Ranibizumab 0.3 mg was approved by the US Food and Drug Administration for the treatment of DME in 2012 and for DR in patients with DME in 2015. In 2017, the US Food and Drug Administration broadened the DR indication, approving ranibizumab for the treatment of DR with or without DME. Evidence to support these approvals included the RIDE and RISE Phase III clinical trials (NCT00473382 and NCT00473330), which demon- strated that intravitreous ranibizumab every 4 weeks resulted in substantial visual acuity (VA) gains, on average, in patients with DME over 2 years, which were maintained through year 3. 6,7 Additional supporting evidence for the broader DR indication was provided by the DiabeticRetinopathy Clinical Research (DRCR) Network Protocol S study (NCT01489189), which demonstrated the ef ﬁ cacy of ranibi- zumab for DR in patients with and without DME. 8
The fMRI data preprocessing was performed using the tool- box for Data Processing & Analysis of Brain Imaging (http://www.rfmri.org/dpabi), 45 which is based on Statistical Parametric Mapping 8 (http://www. ﬁ l.ion.ucl. ac.uk) implemented in MATLAB 2013a (MathWorks, Natick, MA, USA). Brie ﬂ y, following these steps: 1) DICOM format of the functional images were converted to NIFTI format, and the ﬁ rst ten volumes were discarded to reach equilibrium. 2) The remaining BOLD images were corrected for slice timing effects and then realigned to the ﬁ rst volume to correct for head motion. Data from subjects whose head motion was >2 mm or for whom rotation exceeded 2° during scanning were excluded. 46,47 3) Individual 3D-BRAVO structural images were registered to the mean fMRI data, and the resulting aligned structural images were segmented using the Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra toolbox to improve spatial precision in the
The present analysis also found that a 2-step or greater DR improvement at month 6 was more common among eyes with DME resolution by month 3 than in those who still had DME at month 3. Corresponding data, consistent with the results of our new predictive analysis, were reported by Ip et al, 24 who found that resolution of DME and signi ﬁ cant improvement in best-corrected visual acuity (BCVA) is more common in eyes with an at least 2- or 3-step DR improvement at month 24. In fact, addi- tional analyses on RIDE/RISE data demonstrated that among eyes that had both resolution of DME and a 2-step or greater DR improvement at month 3, only 17.5% experienced an additional 2-step or greater DR improvement between months 3 and 24 (unpublished data). This is expected because most of these eyes had improved to the point that they no longer had room to improve by an additional 2 or more steps in DR severity. These data are in accord with and supportive of the RIDE/ RISE analyses published by Ip et al, 24 which show that DR step improvements in patients with DME correlate with BCVA letter improvements, indicating the clinical impor- tance of DR severity regression. Together, these ﬁ ndings show that there is a correlation between DME and DR responses to ranibizumab; this is consistent with the fact that both are associated with a VEGF-driven pathophysiol- ogy and that DME occurs as a complication of DR. Based on the existing data, we hypothesize that eyes that have early resolution of DME accompanied by early improve- ments in DR could be potentially good candidates for less frequent (less-than-monthly) ranibizumab treatment, while some eyes that do not have early resolution of DR and DME may bene ﬁ t from continued treatment with anti- VEGF therapy for up to 12 – 18 months (when the plateau of the population response is reached; Figure 1).
ERG was performed using the MonPack3 system (Metrovision, Pérenchies, France). ERGs were done at baseline (pre-treatment), 1 week after each PRP session, and 6 weeks after the last PRP treatment. Dark-adapted 0.01 ERG, Dark-adapted 3 ERG, Dark-adapted 10 ERG, Light-adapted 3 ERG, and Light-adapted 30 Hz ﬂ icker ERG were recorded. ERGs were done in accordance with International Society for Clinical Electrophysiology of Vision (ISCEV) standard in an electrically shielded room to avoid additional sound and noise. 10 All ERG tests were performed by an experienced examiner and the peaks of the wave amplitude were selected. To quantify the overall response waveform, root mean square (RMS) was calcu- lated which was de ﬁ ned as the area under the curve [amplitude (nV)] in Dark-adapted 10 ERG.
In the present study, 60% of studied sample consulted eye specialists and 35.4% of them had eye examinations at least within one year. This could be explained by the fact that patients were aware of the effect of DM on their eyes. The study agreed with Mwangi MW et al, 29 who reported that 50% of all the respondents went for eye checkups. Of the 50% who went for eye checkups, 27% of them went once a year. Also, it agrees with Al Zarea BK, 12 who observed that about 95% of all the participants went for regular ocular examinations. However, the results dis- agreed with those of Prabhu M et al, 23 who reported that only 16.5% of diabetic patients were referred for an eye examination by their physicians.
Some studies have suggested that these changes are due to neural damage in ganglion cells and nerve ﬁ ber layers of the retina, especially in patients with proliferative diabeticretinopathy. 14,15 In addition, the PRP plays an important role in the visual evoked potential components changes. Matsubara et al 15 showed that the effects of PRP on the levels of cytochrome oxidase (CO), Zif268, synaptophysin and growth-associated protein 43 (GAP-43) in the primary visual cortex of adult monkeys could result in metabolic activity changes and redistribution of neurochemicals in the visual cortex. These changes result in an anomalous visual functional loss that alters the visual evoked potential com- ponents and can also explain the degradation of a currently damaged visual system that was mentioned in the present study. It should also be taken into account that PRP by using argon lasers can further stabilize peripheral retinal lesions, and, therefore, the central retinal changes after PRP may also continue, which in turn can cause changes in visual evoked potential components. 28
Netrin receptors have been expressed in developing retina and Netrin-neogenin signaling, which might stimulate retinal ganglion cell axon growth into and along the optic nerve. 20,21 Netrin-1/UNC5B may activate retinal vessel development and they can stimulate pro-angiogenesis. 22 The guidance of retinal ganglion cell axons through the optic disc is depen- dent on the DCC/Netrin-1 axonal guidance system. 21 Furthermore, netrin-1 contributes to steering axons out of the retina. 23 Under hypoxic conditions, the Netrin-1 level increases and it might be a key factor in inducing retinal neovascularization. 25,26 Retinal neovascularization is the major pathological condition of several diseases including diabeticretinopathy, retinal vein occlusion, and age-related macular degeneration. 8,24,27 Netrin-1 promotes retinal angio- genesis in oxygen-induced retinopathy. 28,29
carcinogenic status. 25 On this basis, we collected the serum level of CA125 in patients with type 2 diabetes and examined possible associations between this tumor biomarker and the presence as well as severity of DR. Serum CA125 level was signi ﬁ cantly related to the presence of DR in Chinese adult patients with type 2 diabetes. In addition, when DR was analyzed categorically, a statistically signi ﬁ cant association between CA125 level and different DR severity strata was also observed. CA125 level was exceedingly higher in parti- cipants with more advanced DR such as VTDR, and there was no difference in mild or moderate NPDR participants inver- sely. After using multiple adjusted models and accounting for clinical confounders, there was still an increasing trend of VTDR risk, accompanying with the improvement of CA125 quartiles. Therefore, it was speculated that elevated CA125 level was consider as an independent predictor for the pre- sence of DR and VTDR. Serum CA125 is an easily assessed laboratory parameter in clinical practice and could be expected to become a potential indicator to early detection of DR, enabling the clinicians to make timely treatment, and prevent the development of vision impairment.
signi ﬁ cant associations were observed for the ﬁ rst major car- diovascular event (a priori composite of cardiovascular death, non-fatal myocardial infarction, or nonfatal ischaemic stroke) individually for retinopathy (HR: 1.39, 95% CI: 1.09 – 1.76), peripheral neuropathy (1.40, 1.19 – 1.66) and nephropathy (1.35, 1.15 – 1.58). The ﬁ ndings showed that the cumulative burden of microvascular disease is a determinant of future cardiovascular risk. 48 This present study adds to the evidence that atherosclerosis is associated with diabetic microvascular complications. The exact mechanisms underlying the associa- tion between the two remains unclear. A possible explanation is that atherosclerosis and microvascular complication share same physiopathologic mechanism (for example, endothelial injury, chronic in ﬂ ammation and enhanced oxidative stress) and other independent accelerating risk factors (for example, smoking, hypertension and hyperlipidemia). 49
The strengths of the automated software developed by MATLAB program lie in its simplicity and reduction in cost. It can be operated independently and does not need web-based setting. It does not need plenty of resources and much time for learning as in the case of artificial intel- ligence and deep learning. Another strength of this software is at the preprocessing stage. Although fundus images in this study were obtained with various image qualities, for example, color, light and shadow, they were normalized in the preprocessing stage using image enhancement techniques to adjust image quality so that the regions of interest were suitable for further analysis. In addition, the software can process a group of fundus images at a time and generate a result report to the user.
Two groups were identified from the general practice dataset, ie, people with a record of screening within three years (from July 2010), and people with no record of screening within three years. These groups were chosen to compare those people who are “true” nonattenders compared with recent attenders (to distinguish a clear group of people who are at risk from not being screened for a significant period of time from those who might usually attend screening, but had just missed one screening episode). To assess the validity of this assumption, we conducted sensitivity analyses with a cutoff of those screened within two years. Age was divided into ten-year bands (except the 12–19-year age group, because diabeticretinopathy screening begins at age 12 years). Where type of diabetes was not recorded, we imputed type based on age and date of diagnosis (those with a new diag- nosis after the age of 30 years were categorized as type 2 diabetics). This assumption was checked by repeating the analyses using the original data without imputation of type. Basic demographic details were presented with frequencies and percentages for both the screened and the nonscreened groups. Comparisons were made for the dimensions of equity using logistic regression. Three models were constructed to adjust by sociodemographic, clinical, and service factors using SPSS version 18 (SPSS Inc, Chicago, IL). The final model included deprivation based on the IMD at the LSOA level. We conducted a sensitivity analysis to consider the effect of the missing deprivation data by repeating the main model using only those data that contained a deprivation record, because the number with a deprivation score was considerably less than the total database. A further model used the limited proportion of records that included ethnicity. Odds ratios (OR) and 95% confidence intervals (CI) were
Exclusion criteria: subjects with amblyopia, distant or near strabismus, anisometropia greater than 1.00 D, refrac- tive error more than ± 3.00 D sphere and – 2.00 D cylinder, near phorias greater than 4 Δ eso and 9 Δ exo, 25 history of corneal opacity, lens opacity, glaucoma, history of ocular surgery, any retinal disease, based on EDTRS, the presence of diabeticretinopathy at level 35 and above (level 35 [mild diabeticretinopathy] has been de ﬁ ned as the presence of hard exudates, cotton wool spots, and/or mild retina hemor- rhage; above level 35 includes different levels of retinal hemorrhage, intra-retinal microvascular abnormalities [IRMA], venous beading, new vessels elsewhere, neovascu- larization of the disc, peri-retinal hemorrhage, and vitreous hemorrhage), 25 or presence of clinically signi ﬁ cant macular edema (de ﬁ ned as 1) retinal thickening within 500 µm of the macular center; 2) Hard exudates within 500 µm of the macular center with adjacent retinal thickening; 3) one or more disc diameters of retinal thickening, part of which is within one disc diameter of the macular center).