Attendance in a national screening program for diabetic retinopathy: a population-based study of 205,970 patients.

AIMS: A nationwide diabetic retinopathy (DR) screening program has been established in Denmark since 2013. We aimed to perform an evaluation of adherence to DR screenings and to examine whether non-adherence was correlated to DR progression. METHODS: The population consisted of a register-based cohort, who participated in the screening program from 2013 to 2018. We analyzed age, gender, marital status, DR level (International Clinical DR severity scale, none, mild-, moderate-, severe non-proliferative DR (NPDR) and proliferative DR (PDR)), comorbidities and socioeconomic factors. The attendance pattern of patients was grouped as either timely (no delays > 33%), delayed (delays > 33%) or one-time attendance (unexplained). RESULTS: We included 205,970 patients with 591,136 screenings. Rates of timely, delayed and one-time attendance were 53.0%, 35.5% and 11.5%, respectively. DR level at baseline was associated with delays (mild-, moderate-, severe NPDR and PDR) and one-time attendance (moderate-, severe NPDR and PDR) with relative risk ratios (RRR) of 1.68, 2.27, 3.14, 2.44 and 1.18, 2.07, 1.26, respectively (P < 0.05). Delays at previous screenings were associated with progression to severe NPDR or PDR (hazard ratio (HR) 2.27, 6.25 and 12.84 for 1, 2 and 3+ delays, respectively). Any given delay doubled the risk of progression (HR 2.28). CONCLUSIONS: In a national cohort of 205,970 patients, almost half of the patients attended DR screening later than scheduled or dropped out after first screening episode. This was, in particular, true for patients with any levels of DR at baseline. DR progression in patients with delayed attendance, increased with the number of missed appointments.

Endovascular Treatment for a Ruptured Lumbar Artery Aneurysm in a Patient with von Recklinghausen Disease.

INTRODUCTION: Vasculopathy, such as an aneurysm, stenosis, rupture, or arteriovenous fistula, in patients with neurofibromatosis type I (NF-1; von Recklinghausen disease) is well recognised. However, there has been no report regarding treatment for a ruptured lumbar artery aneurysm associated with NF-1. We present the first report of successful endovascular treatment by coil embolisation for a ruptured lumbar artery aneurysm in a patient with NF-I. REPORT: A 52 year old man with a history of NF-1 was referred with back pain and anaemia. The computed tomography scan showed rupture of a solitary lumbar artery aneurysm. The rupture was successfully treated by endovascular embolisation with a coil and N-butyl-2-cyanoacrylate. DISCUSSION: Endovascular treatment with coil embolisation was performed safely in this patient.

Severe hypoglycaemia is a major predictor of incident diabetic retinopathy in Japanese patients with type 2 diabetes.

AIM: Hypoglycaemia is a common complication in diabetes patients. However, its relationship with retinopathy has not been well documented in patients with type 2 diabetes (T2D). This study aimed to investigate the associations between hypoglycaemia and the incidence and progression of diabetic retinopathy (DR). METHODS: In this longitudinal cohort study, which was part of the Japan Diabetes Complications Study (JDCS), adult patients with T2D were recruited at 59 diabetes clinics across Japan. Their history of hypoglycaemia was assessed by standardized self-reported questionnaires. Severe hypoglycaemia was defined as having at least one episode with coma requiring an outpatients visit or hospitalization. Adjusted hazard ratios (HRs) for incidence and progression of DR over 8 years of follow-up were determined. RESULTS: Of 1221 patients without DR, 127 (10.4%) had experienced non-severe hypoglycaemia within the previous year, whereas 10 (0.8%) reported severe hypoglycaemia episodes. During the 8-year follow-up involving 8492 person-years, 329 patients developed DR. In 410 patients with prevalent DR, the adjusted HRs for incident DR were 4.35 (95% CI: 1.98-9.56; P<0.01) and, for progression of DR, 2.29 (95% CI: 0.45-11.78; P=0.32) with severe hypoglycaemia. CONCLUSION: Having a history of severe hypoglycaemia was one of the strongest predictors of incident DR in patients with T2D, with a fourfold increased risk. Identifying patients with greater risks of DR based on their history of hypoglycaemia may help to personalize risk evaluation in patients with diabetes.

Serum ferritin level is a prognostic marker in patients with peripheral T-cell lymphoma.

INTRODUCTION: The prognostic value of serum ferritin level in patients with peripheral T-cell lymphoma (PTCL) remains unknown. METHODS: We retrospectively analyzed clinical data from 78 consecutive patients with newly diagnosed PTCL that were treated with anthracycline-containing regimens between 1998 and 2011. RESULTS: The patients consisted of 50 males and 28 females with a median age of 64 years (range, 16-83 years). The subtypes of PTCL were 39 PTCL, not otherwise specified and 39 angioimmunoblastic T-cell lymphoma (AITL). The median observation period for the surviving patients was 50 months. The overall survival (OS) was poorer in patients with serum ferritin level above the upper normal limit (n = 28), compared with patients with serum ferritin level within normal range (n = 50; 4-year OS: 23% vs. 72%; P < 0.001). In the multivariate analysis, poor performance status (P = 0.006) and elevated serum ferritin level (P = 0.018) were independent risk factors for poor OS. CONCLUSION: Serum ferritin level is a useful prognostic marker for PTCL.

Development of Health Parameter Model for Risk Prediction of CVD Using SVM.

Current methods of cardiovascular risk assessment are performed using health factors which are often based on the Framingham study. However, these methods have significant limitations due to their poor sensitivity and specificity. We have compared the parameters from the Framingham equation with linear regression analysis to establish the effect of training of the model for the local database. Support vector machine was used to determine the effectiveness of machine learning approach with the Framingham health parameters for risk assessment of cardiovascular disease (CVD). The result shows that while linear model trained using local database was an improvement on Framingham model, SVM based risk assessment model had high sensitivity and specificity of prediction of CVD. This indicates that using the health parameters identified using Framingham study, machine learning approach overcomes the low sensitivity and specificity of Framingham model.

Retinal arteriolar narrowing is associated with a 4-year risk of incident metabolic syndrome.

We aimed to determine whether retinal microvascular changes in vessel calibers at baseline are associated with the future risk of developing the metabolic syndrome over 4 years in an adult cohort of Japanese individuals (n=90) who attended a health-screening program. Retinal vessel caliber was calculated as the central retinal artery equivalent and vein equivalent (CRAE) from non-mydriatic digital fundus images using semiautomated standardized software. There were 18 cases (20%) that developed metabolic syndrome over 4 years. Narrower arteriolar caliber at baseline was associated with an increased risk of incident metabolic syndrome over 4 years after adjusting for potential confounding risk factors including individual cardiovascular risk factors related to the metabolic syndrome (adjusted odds ratio per 1 s.d. change in CRAE: 2.92, 95% confidence interval 1.03, 8.24; P=0.043). Persons with wider venular caliber at baseline were more likely to have incident metabolic syndrome, but this was not statistically significant. Retinal vascular caliber might provide independent and useful information to predict incident metabolic syndrome in a health screening program.

Age-related rarefaction in retinal vasculature is not linear.

The fractal dimension is a global measure of complexity and is useful for quantifying anatomical structures, including the retinal vascular network. A previous study found a linear declining trend with aging on the retinal vascular fractal dimension (DF); however, it was limited to the older population (49 years and older). This study aimed to investigate the possible models of the fractal dimension changes from young to old subjects (10­73 years). A total of 215 right-eye retinal samples, including those of 119 (55%) women and 96 (45%) men, were selected. The retinal vessels were segmented using computer-assisted software, and non-vessel fragments were deleted. The fractal dimension was measured based on the log­log plot of the number of grids versus the size. The retinal vascular DF was analyzed to determine changes with increasing age. Finally, the data were fitted to three polynomial models. All three models are statistically significant (Linear: R(2) = 0.1270, 213 d.f., p < 0.001, Quadratic: R(2) = 0.1536, 212 d.f., p < 0.001, Cubic: R(2) = 0.1529, 211 d.f., p < 0.001). The quadratic regression is significantly better than the linear regression (p < 0.001); however, the increase in R(2) from the quadratic model to the cubic model is not significant (p = 0.97). These results suggest that the decreasing trend of the fractal dimension associated with aging is better explained by the quadratic model than by the linear and cubic models in a sample with a broader age spectrum.

Age-related rarefaction in retinal vasculature is not linear.

The fractal dimension is a global measure of complexity and is useful for quantifying anatomical structures, including the retinal vascular network. A previous study found a linear declining trend with aging on the retinal vascular fractal dimension (DF); however, it was limited to the older population (49 years and older). This study aimed to investigate the possible models of the fractal dimension changes from young to old subjects (10-73 years). A total of 215 right-eye retinal samples, including those of 119 (55%) women and 96 (45%) men, were selected. The retinal vessels were segmented using computer-assisted software, and non-vessel fragments were deleted. The fractal dimension was measured based on the log-log plot of the number of grids versus the size. The retinal vascular DF was analyzed to determine changes with increasing age. Finally, the data were fitted to three polynomial models. All three models are statistically significant (Linear: R2 = 0.1270, 213 d.f., p < 0.001, Quadratic: R2 = 0.1536, 212 d.f., p < 0.001, Cubic: R2 = 0.1529, 211 d.f., p < 0.001). The quadratic regression is significantly better than the linear regression (p < 0.001); however, the increase in R2 from the quadratic model to the cubic model is not significant (p = 0.97). These results suggest that the decreasing trend of the fractal dimension associated with aging is better explained by the quadratic model than by the linear and cubic models in a sample with a broader age spectrum.

Retinal vascular changes following intravitreal ranibizumab injections for neovascular AMD over a 1-year period.

PURPOSE: To assess retinal vascular calibre changes in eyes with neovascular age-related macular degeneration (AMD), treated with intravitreal anti-vascular endothelial growth factor agents, over a 1-year period and compare any such changes to untreated fellow eyes. METHODS: Treatment naïve patients with neovascular AMD received three consecutive intravitreal injections of ranibizumab, followed by a pro re nata dosing regimen up to 1 year, with the aim of maintaining a 'fluid-free' macula. Retinal arteriolar and venular calibre was measured from digital fundus photographs at baseline and at three monthly intervals to 1 year, and summarised as central retinal artery equivalent (CRAE) and central retinal venular equivalent (CRVE), respectively. RESULTS: A total of 53 injected eyes and 41 fellow, non-injected eyes were analysed. At baseline, there were no differences in retinal vascular calibre between injected and non-injected eyes (mean CRAE (SD) 144.93 (14.07) vs 145.74 (13.10) µm, P=0.80 and mean CRVE (SD) 216.23 (25.93) vs 219.91 (22.82) µm, P=0.53). Over a 12-month period, retinal venular calibre dilatation occurred in injected eyes (mean CRVE change +5.71 (14.71) µm, P=0.007), with no change in retinal arterioles, +0.69 (14.71) µm, P=0.68. In non-injected eyes, arteriolar narrowing occurred as a whole, mean CRAE change -4.20 (7.00) µm, P=0.001, over 12 months, with a trend for narrowing in venules, -2.16 (11.56) µm, P=0.28. In injected eyes, after controlling for covariates, the changes in CRVE over 12 months mirrored improvements in macular thickness, -0.06 (-0.005, -0.11) µm, P=0.04, and visual acuity, +9.66 (-0.30, +19.32) µm, P=0.06. CONCLUSION: Intravitreal ranibizumab significantly dilated retinal venules after a 1-year period.

Republished article: The impact of diabetic retinopathy: understanding the patient's perspective.

Understanding the impact of a condition from the patient's perspective is important, and different types of patient-reported outcomes or instruments are available to help with this. This review article summarises the current evidence on the impact of diabetic retinopathy (DR) and its associated vision impairment on patient-reported outcomes. We have included research that has used a range of outcome measures to assess the impact of DR on generic health-related quality of life, utility, vision-functioning and vision-specific quality of life. This review also offers clarification on frequently misused psychometric terminologies to help clinicians and researchers better understand the literature associated with patient-reported outcome research. Overall, the evidence suggests that DR, particularly in its vision-threatening stages, has a substantial, negative impact on the patient. However, our understanding of the impact of DR is currently restricted due to limitations inherent in currently available patient-reported outcome measures. We conclude by discussing potential directions for future research in this area, such as item banking and computer adaptive testing.

Incidence and progression of diabetic retinopathy in Japanese adults with type 2 diabetes: 8 year follow-up study of the Japan Diabetes Complications Study (JDCS).

AIMS/HYPOTHESIS: The aim of this study was to determine the incidence and progression rates of diabetic retinopathy and their associations in Japanese individuals with type 2 diabetes. METHODS: This is a part of the Japan Diabetic Complications Study (JDCS), a multi-centred randomised trial of type 2 diabetes patients aged 40-70 years with an 8 year follow-up. There were 1,221 patients without diabetic retinopathy at baseline; incidence of diabetic retinopathy was defined as the development of any diabetic retinopathy. There were 410 patients with mild non-proliferative diabetic retinopathy at baseline; progression of diabetic retinopathy was defined as the development of severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy. We used multivariate proportional Cox hazard models, and generalised additive models were also applied to identify potential threshold effect. RESULTS: The incidence and progression rate of diabetic retinopathy was 38.3/1,000 person-years and 21.1/1,000 person-years, respectively. Higher HbA(1c) (adjusted HR [aHR] per 1% [10.9 mmol/mol] 1.36 [95% CI 1.28-1.45]), longer duration of diabetes (aHR per 5 year period 1.26 [95% CI 1.17-1.35]), higher systolic blood pressure (aHR per +10 mmHg 1.01 [95% CI 1.00-1.02]) and higher body mass index (aHR per 1 kg/m(2) 1.05 [95% CI 1.00-1.09]) were associated with incident diabetic retinopathy. The association between HbA(1c) and incident diabetic retinopathy was linear; the association with duration of diabetes increased rapidly between 5 and 10 years. Higher HbA(1c) was also associated with progression of diabetic retinopathy (aHR per 1% [10.9 mmol/mol] 1.66 [95% CI 1.41-1.96]). CONCLUSIONS: Observed incidence and progression rates of diabetic retinopathy seemed lower than that in western populations. HbA(1c) was the only factor associated with both incidence and progression of diabetic retinopathy. The strength of the association between duration of diabetes and incidence of diabetic retinopathy increased rapidly during a period of 5 to 10 years duration of diabetes. TRIAL REGISTRATION: C000000222 ( www.umin.ac.jp ) FUNDING: This study is supported by the Ministry of Health, Labour and Welfare, Japan.

The impact of diabetic retinopathy: understanding the patient's perspective.

Understanding the impact of a condition from the patient's perspective is important, and different types of patient-reported outcomes or instruments are available to help with this. This review article summarises the current evidence on the impact of diabetic retinopathy (DR) and its associated vision impairment on patient-reported outcomes. We have included research that has used a range of outcome measures to assess the impact of DR on generic health-related quality of life, utility, vision-functioning and vision-specific quality of life. This review also offers clarification on frequently misused psychometric terminologies to help clinicians and researchers better understand the literature associated with patient-reported outcome research. Overall, the evidence suggests that DR, particularly in its vision-threatening stages, has a substantial, negative impact on the patient. However, our understanding of the impact of DR is currently restricted due to limitations inherent in currently available patient-reported outcome measures. We conclude by discussing potential directions for future research in this area, such as item banking and computer adaptive testing.

Robust methodology for fractal analysis of the retinal vasculature.

We have developed a robust method to perform retinal vascular fractal analysis from digital retina images. The technique preprocesses the green channel retina images with Gabor wavelet transforms to enhance the retinal images. Fourier Fractal dimension is computed on these preprocessed images and does not require any segmentation of the vessels. This novel technique requires human input only at a single step; the allocation of the optic disk center. We have tested this technique on 380 retina images from healthy individuals aged 50+ years, randomly selected from the Blue Mountains Eye Study population. To assess its reliability in assessing retinal vascular fractals from different allocation of optic center, we performed pair-wise Pearson correlation between the fractal dimension estimates with 100 simulated region of interest for each of the 380 images. There was Gaussian distribution variation in the optic center allocation in each simulation. The resulting mean correlation coefficient (standard deviation) was 0.93 (0.005). The repeatability of this method was found to be better than the earlier box-counting method. Using this method to assess retinal vascular fractals, we have also confirmed a reduction in the retinal vasculature complexity with aging, consistent with observations from other human organ systems.

Fusion of multiscale wavelet-based fractal analysis on retina image for stroke prediction.

In this paper, we present a novel method of analyzing retinal vasculature using Fourier Fractal Dimension to extract the complexity of the retinal vasculature enhanced at different wavelet scales. Logistic regression was used as a fusion method to model the classifier for 5-year stroke prediction. The efficacy of this technique has been tested using standard pattern recognition performance evaluation, Receivers Operating Characteristics (ROC) analysis and medical prediction statistics, odds ratio. Stroke prediction model was developed using the proposed system.

Retinal fractal dimension is increased in persons with diabetes but not impaired glucose metabolism: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study.

AIMS/HYPOTHESIS: The fractal dimension (D(f)) of the retinal vasculature is a global measure of its branching pattern complexity. We examined the relationship of retinal D(f) with diabetes. METHODS: We conducted a cross-sectional study of 1,577 participants with diabetes and impaired glucose metabolism and normal controls from the population-based Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Retinal D(f) was quantified from fundus photographs using a computer-based programme and diabetes status was determined by oral glucose tolerance test based on the WHO criteria. RESULTS: After adjustment for age, sex and vascular risk factors, persons with higher retinal D(f) were more likely to have diabetes (OR 1.56; 95% CI 1.14-2.14, highest vs lowest fractal tertile). This relationship remained with further adjustment for retinal arteriolar calibre and presence of retinopathy (OR 1.64; 95% CI 1.19-2.27), and after excluding participants with retinopathy (OR 1.60; 95% CI 1.16-2.21). Retinal D (f) was not related to impaired glucose tolerance or impaired fasting glucose (OR 1.19; 95% CI 0.85-1.67). CONCLUSIONS/INTERPRETATION: Individuals with diabetes, but not with impaired glucose metabolism, have greater retinal D(f), reflecting greater complexity of the retinal vasculature. Our findings suggest the presence of early microvascular changes in the retinal vasculature of persons with diabetes, even in the absence of overt retinopathy.

Retinal vessel calibre and micro- and macrovascular complications in type 1 diabetes.

AIMS/HYPOTHESIS: The purpose of the study was to evaluate the association between retinal vascular calibre and micro- and macrovascular complications in a population-based cohort of Danish type 1 diabetic patients. METHODS: This was a cross-sectional study of 208 long-surviving type 1 diabetic patients from a population-based Danish cohort. Retinal photographs were obtained at a clinical examination attended by each participant in 2007-2008, and retinal vascular calibre was measured and summarised as the central retinal artery or vein equivalent (CRAE or CRVE) using a computer-based program and a standardised protocol. Associations between retinal vascular calibre and micro- and macrovascular complications were examined after adjusting for confounding clinical characteristics. RESULTS: Retinal photographs were gradable for 188 of 208 patients (90.3%). The median age and duration of diabetes for patients with gradable photos were 57.9 and 42 years, respectively. After multivariate adjustments, individuals with narrower retinal arterioles were more likely to have nephropathy (OR 2.17, 95% CI 1.29-3.68, per SD decrease in CRAE) and macrovascular disease (OR 3.17, 95% CI 1.59-6.34, per SD decrease in CRAE), but not neuropathy (OR 1.10, 95% CI 0.70-1.71, per SD decrease in CRAE). Retinal venular calibre was not associated with any micro- or macrovascular complications. CONCLUSIONS/INTERPRETATION: In type 1 diabetic patients, retinal arteriolar narrowing is associated with nephropathy and macrovascular disease independently of other clinical characteristics. If supported by further prospective studies, measurement of retinal vessel diameter may allow a non-invasive evaluation of the risk of diabetes-related complications.

Prevalence and associations of epiretinal membranes in an adult Japanese population: the Funagata study.

PURPOSE: To determine the prevalence and risk factors of epiretinal membranes (ERM) in a Japanese population. PATIENTS AND METHODS: The Funagata Study examined 1758 Japanese aged 35 years or older (42% of eligible) from June 2000 to June 2002. A total of 1723 (98.0%) participants had non-mydriatic fundus photographs of the right eye to grade the presence of ERM, using the Blue Mountains Eye Study (BMES) protocol. After age standardization, the prevalence of ERM in the right eyes of the participants included in this study was compared with that reported from right eyes of participants in the BMES and the Beaver Dam Eye Study (BDES). ERM detected in eyes with diabetic retinopathy and other retinal lesions were excluded from the analysis of associations. Multiple logistic regression models were used to determine risk factors for the presence of ERM, adjusting for age and gender. RESULTS: There were 84 right eyes with ERM, representing 5.44% of this sample. After age standardization, the prevalence rate (5.7%) was within the range reported in the BMES (3.5%) and the BDES (6.9%). Older age (gender-adjusted odds ratio (OR) per 10 years: 1.72, 95% confidence interval (CI): 1.40-2.11) and diabetes (age-gender-adjusted OR: 1.84, 95% CI: 1.01-3.37) were the only two factors associated with ERM. CONCLUSIONS: We found a similar prevalence of ERM in the Japanese as in mainly white populations. Increasing age and diabetes were risk factors for ERM in this adult Japanese population.

Angiotensin-converting enzyme gene and retinal arteriolar narrowing: the Funagata Study.

The purpose of this study is to determine whether the angiotensin-converting enzyme (ACE) gene polymorphism is associated with retinal arteriolar narrowing, a subclinical marker of chronic hypertension. The Funagata Study examined a population-based sample of Japanese aged 35+ years; 368 participants had both retinal vessel diameter measurements and ACE insertion/deletion (ACE I/D) polymorphism analyses performed. Assessment of retinal vessel diameter and retinal vessel wall signs followed the protocols used in the Blue Mountains Eye Study. ACE gene polymorphisms D/D, I/D and I/I were present in 34 (9.2%), 170 (46.2%) and 164 (44.5%) participants, respectively, distributed in Hardy-Weinberg equilibrium. After multivariable adjustment, retinal arteriolar diameter was significantly narrower in subjects with the D/D genotype compared to subjects with I/D and I/I genotypes (mean difference -6.49 microm, 95% confidence interval (CI): -12.86 microm, -0.11 microm). Our study suggests that the ACE I/D polymorphism may be associated with subclinical structural arteriolar changes related to chronic hypertension.