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AIMS: Semaglutide and empagliflozin have shown cardiovascular protection. In SUSTAIN-6, semaglutide was associated with an increased risk of diabetic retinopathy. We investigated whether changes in retinal oxygenation, retinal vascular autoregulation, and central retinal thickness are altered by semaglutide, empagliflozin or the combination.METHODS: This study was a prespecified, secondary outcome from a randomised, 32 weeks partly placebo-controlled, partly open-label, clinical trial on the effects of semaglutide and empagliflozin on arterial stiffness and kidney oxygenation. A total of 120 participants with type 2 diabetes, established or high risk of cardiovascular disease and age ≥50 years were randomised into four parallel groups (semaglutide, empagliflozin, the combination or tablet placebo, n = 30 for each group). We primarily hypothesized that semaglutide would increase venular oxygenation.RESULTS: We found no changes in retinal arteriolar, venular or venular-arteriolar oxygenation nor in retinal vessel diameter regardless of treatment group. Semaglutide increased central retinal thickness compared to placebo with ~1 % (3.8 μm 95 % CI [0.9;6.7], p = 0.009) with no changes in the empagliflozin or combination group.CONCLUSION: Neither semaglutide, empagliflozin nor the combination alters markers of retinal function. The effect of semaglutide on central retinal thickness was small, but the clinical significance is uncertain.

Purpose: The Danish Registry of Diabetic Retinopathy includes information from >200 000 patients who attends diabetic retinopathy (DR) screening in Denmark. Screening of patients with uncomplicated type 2 diabetes is often performed by practicing ophthalmologists, while patients with type 1 and complicated type 2 diabetes attends screening at hospitals. We performed a clinical reliability study of retinal images from Danish screening facilities to explore the inter-grader agreement between the primary screening ophthalmologist and a blinded, certified grader. Methods: Invitations to participate were sent to screening facilities across Denmark. The primary grader uploaded fundus photographs with information on estimated level of DR (International Clinical Diabetic Retinopathy scale as 0 [no DR], 1–3 [mild, moderate or severe nonproliferative DR {NPDR}], or 4 [proliferative DR {PDR}]), region of screening, image style, and screening facility. Images were then regraded by a blinded, certified, secondary grader. Weighted kappa analysis was performed to evaluate agreement. Results: Fundus photographs from 230 patients (458 eyes) were received from practicing ophthalmologists (52.6%) and hospital-based grading centres (47.4%) from all Danish regions. Reported levels of DR by the primary graders were 66.8%, 12.2%, 13.1%, 1.3% and 5.5% for DR levels 0–4. The overall agreement between primary and secondary graders was 93% (κ = 0.83). Based on screening facility agreement was 96% (κ = 0.89) and 90% (κ = 0.76) for practicing ophthalmologists and hospital-based graders. Conclusion: In this nationwide study, we observed a high overall inter-grader agreement and based on this, it is reasonable to assume that reported DR gradings in the screening programme in Denmark, accurately reflect the truth.

PURPOSE: The purpose of the study was to evaluate the prevalence and incidence of diabetic retinopathy (DR) along with associated markers in patients with type 2 diabetes in the Danish DR-screening programme.METHODS: We included all persons with type 2 diabetes in the Danish Registry of Diabetic Retinopathy, who had attended at least one episode of DR screening in 2013-2018. DR was classified as levels 0-4 indicating increasing severity. Data were linked with various national health registries to retrieve information on diabetes duration, marital status, comorbidity and systemic medication.RESULTS: Among 153 238 persons with type 2 diabetes, median age and duration of diabetes were 66.9 and 5.3 years and 56.4% were males. Prevalence and 5-year incidences of DR, 2-step-or-more progression of DR and progression to proliferative DR (PDR) were 8.8%, 3.8%, 0.7% and 0.2%, respectively. In multivariable models, leading markers of incident DR and progression to PDR were duration of diabetes (HR 1.98, 95% CI 1.87-2.09; HR 2.89, 95% CI 2.34-3.58 per 10 years of duration) and use of insulin (HR 1.88, 95% CI 1.76-2.01; HR 2.40, 95% CI 1.84-3.13), while the use of cholesterol-lowering medicine was a protecting marker (HR 0.87, 95% CI 0.81-0.93; HR 0.70, 95% CI 0.52-0.93). From 2013 to 2015, 3-year incidence rates of PDR decreased from 1.22 to 0.45 events per 1000 person-years.CONCLUSION: Nationally, among Danish individuals with type 2 diabetes attending DR screening, we identified duration of diabetes and use of insulin as the most important predictor for the development of DR, while cholesterol-lowering medicine was a protective factor.

PURPOSE: Knowledge of visual health in the population is necessary for designing and implementing measures to handle visual handicap. The purpose of the FORSYN (Forekomst af synshandicap og synshjaelpemidler i Danmark) project was to study visual health in the Danish population 2020-2022 after implementation of the recent advances in the management of choroidal and retinal vascular disease. The present study reports visual acuity and causes of central visual loss from this study.METHODS: A population-representative sample of 10 350 citizens living within 40 kilometres from Aarhus University Hospital were invited to answer a questionnaire about quality of life related to vision, measurement of visual acuity and a non-mydriatic examination of the eyes. The data were corrected for selection bias on the basis of demographic and socioeconomic factors so that the results could be projected to represent the adult Danish population.RESULTS: Population-adjusted visual acuity in ETDRS letters (mean ± SD) differed significantly (p CONCLUSIONS: Recent advances in the therapy of chorioretinal vascular diseases have been paralleled with a reduction in central vision loss secondary to exudative AMD and diabetic retinopathy in Denmark. The demographic development can be expected to increase the demand for treatments of vision-threatening diseases that mainly affect older persons.

PURPOSE: We aimed to investigate if diabetic retinopathy (DR), glaucoma and/or ocular hypertension (OHT) are prospectively linked, as previous studies have proposed cross-sectional associations, but longitudinal data from larger cohorts are lacking.METHODS: We performed a bidirectional 5 years prospective, registry-based cohort study. We extracted data from national registers, including the Danish Registry of Diabetic Retinopathy, the Danish Civil Registration System, the Danish National Patient Register and the Danish National Prescription Registry. DR level was defined by the highest level of the two eyes. Glaucoma and/or OHT was defined by diagnostic codes (H40*) or at least three redeemed prescriptions of glaucoma medication (S01E*) within 1 year. We included 205 970 persons with diabetes and 1 003 170 age- and gender-matched non-diabetes controls. Exposures were level-specific DR (i) and glaucoma and/or OHT (ii), and outcomes were hazard ratios (HRs) for 5 years incident glaucoma and/or OHT (i) and DR (ii).RESULTS: Persons with diabetes were more likely to develop glaucoma and/or OHT (multivariable adjusted HR 1.11, 95% CI 1.06-1.15), but this did not depend on the level of DR. In persons with diabetes, those with glaucoma and/or OHT were more likely to develop DR (multivariable adjusted HR 1.12, 95% CI 1.03-1.23) within 5 years.CONCLUSION: In a national cohort, diabetes associated with a little higher risk of upcoming glaucoma and/or OHT, and, inversely, the presence of the latter predicted a higher risk of incident DR. Nevertheless, our data do not seem to justify including glaucoma evaluation in the national Danish DR-screening programme.

Purpose: Proliferative diabetic retinopathy (PDR) can be treated by retinal photocoagulation, but in some cases, the treatment is initiated too late or is insufficient so that the disease advances to a stage requiring vitrectomy. There is a need to identify risk factors that can predict if patients with PDR will develop complications in need for vitrectomy. Methods: Survival analysis with death as competing risk was used to study systemic risk factors for PDR progression to a complication in need for vitrectomy in right eyes of all 1288 diabetic patients from the Aarhus area, Denmark, who had developed proliferative retinopathy in the right eye during the 25 years period from 1 July 1994 until 1 July 2019. Results: The overall cumulative incidence of reaching a vitrectomy end point in the right eye was 24.1% (n = 311). In 9.3% (n = 120) of the patients where vitrectomy had been performed together with the first photocoagulation, the age of onset of diabetes was significantly higher (p < 0.0001), the diabetes duration longer (p < 0.035) and BMI higher (p < 0.01) than in the patients who had been vitrectomized later than the first photocoagulation. The risk for vitrectomy was significantly increased by high variability of HbA1c before the development of PDR (p < 0.0001), but not by other parameters known to increase the risk for developing PDR. Conclusion: Increasing variability of HbA1c before the development of PDR increases the risk for progression to a complication in need of vitrectomy. The need for vitrectomy is unaffected by other risk factors known to increase the risk for developing PDR.

Purpose: Vasomotion is spontaneous oscillations in the diameter of resistance vessels with derived effects on blood flow, and it has been proposed that disturbances in vasomotion may be involved in retinal vascular disease. The purpose of this study was to investigate whether retinal vasomotion shows regional variation and is modified by activated autoregulation. Methods: Video recordings of the diameter of retinal arterioles previously obtained from 55 normal persons were subjected to Fourier analysis to characterize the frequencies and propagation of spontaneous diameter changes in retinal arterioles. The analyses were performed on peripapillary temporal retinal arterioles, on arteriolar branches toward the macular area and the retinal periphery, and were performed during rest, during an increase in the arterial blood pressure induced by isometric exercise, and during increased retinal metabolism induced by flickering light. Results: There was no propagation of diameter changes along the studied vascular segments. Isometric exercise constricted the arterioles significantly by (mean ± SD) 1.76% ± 3.56% (P = 0.02) and increased the power of diameter oscillations at very low frequencies (0.1-1.4 c/min). Flicker stimulation dilated the arterioles significantly by (mean ± SD) 5.10% ± 2.91% (P < 0.0001) and reduced the power of diameter oscillations at all but the very low frequencies (P < 0.006 for all comparisons). Flicker-induced dilation and changes in hydraulic conductance were lower in peripheral than in macular arterioles. Conclusions: Retinal vasomotion in normal persons increases during increased arterial blood pressure and decreases during flicker stimulation. The findings may act as a basis for the study of vasomotion in retinal vascular disease.

As clinical practice variation has been problematized as a symptom of suboptimal care and inefficient resource spending, consistency in the delivery of healthcare is a recurring policy goal. We examine a case where the introduction of a new treatment is most likely to provide consistency in healthcare delivery because it was introduced with a national clinical practice guideline representing consensus about best clinical practice among leading clinicians, and because care delivery was highly centralized to few high-volume treatment units. Despite the consensus on best clinical practice and care centralization, this study shows pronounced regional variation in patient outcomes and treatment costs that increased over time. Using a mixed-methods design, we find that the lack of consistency in care was largely unrelated to patient-specific characteristics, but seemed to reflect structural differences in the regional organization and financing of healthcare delivery. We conclude that the value of clinical practice guidelines is undermined when structural barriers limit the ability of clinicians and clinical managers to scale up treatment, and that some degree of decentralization may be a tool to maintain treatment intensity when the treatment effect is dependent on a high treatment intensity.

Background:To assess the prevalence of macular microcystoid lacunae in patients with autosomal dominant optic atrophy (ADOA) and its association with visual function and inner retinal morphology.Methods:The study included 140 participants with ADOA, with a mean age of 44 (SD ±19, range 7-82) years. Study participants with a genetically verified sequence variant in the OPA1 gene were examined with best-corrected visual acuity, contrast sensitivity, optical coherence tomography (Spectralis, Heidelberg) and adaptive optics fundus photography (rtx1, Imagine Eyes). Optically empty microcystoid spaces in the ganglion cell layer and inner plexiform layer were mapped by inspection of the 2 sets of images. Data were analyzed with a mixed model adjusted for age and sex with family and individual as random effect.Results:Microcystoid lacunae were present in 32 of 140 participants (23%) including 18 males and 14 females. Microcystoid lacunae were associated with younger age (P = 0.0503) and a smaller nerve fiber layer volume (P = 0.035). No association was found between presence of microcystoid lacunae and visual acuity (P = 0.2), contrast sensitivity (P = 0.8), axial length (P = 0.7), or ganglion cell layer volume (P = 0.2). The analysis showed moderately reduced visual acuity in patients with microcystoid lacunae. Normal and severely impaired visual function were seen only in participants without microcystoid lacunae.Conclusion:In ADOA, macular microcystoid lacunae were found in 23% of the study participants and tended to be present in younger participants with moderate visual acuity reduction and a smaller nerve fiber layer volume. Further studies are needed to investigate whether cavities left by dead ganglion cells are predictors of decrease in visual function.

PURPOSE: This study seeks to examine potential risk factors for the development of retinal artery occlusions (RAO).METHODS: We used data obtained from Danish nationwide registries to evaluate potential risk factors for RAO present up to 5 years prior to the RAO diagnosis. The study included 5312 patients diagnosed with RAO registered in the Danish National Patient Register and 26,560 controls assessed from the general population matched on sex and age at index date. Adjusted conditional logistic regression was used to estimate the odds ratio of included risk factors for RAO diagnosis. We conducted supplementary analyses stratified on sex and age, and on RAO subtype. In addition, interaction analyses were performed between strata in the stratified analyses.RESULTS: Risk factors associated with the development of RAO included diabetes, arterial hypertension, ischemic heart disease, peripheral artery disease, stroke, renal disease, cataract, and glaucoma, with ORs ranging from 1.33 to 4.94. Atrial fibrillation and sleep apnea yielded effect measures close to equivalence. The presence of a risk factor was generally associated with higher odds of RAO among the population ≤ 55 of age. Arterial hypertension was stronger associated with RAO in male patients than in female patients. The association with arterial hypertension was stronger for CRAO than for BRAO subtype.CONCLUSION: The investigated risk factors suggest that atherosclerosis and conditions changing the intraocular pressure are involved in the pathophysiology of RAO.

Background: Retinal artery occlusion (RAO) has been considered a stroke equivalent. This study compares risk factor profiles for thromboembolism among patients with RAO and stroke, respectively. Methods: This case-control study is based on 5683 RAO patients entered in the Danish National Patient Register between 1st of January 2000 and 31st of December 2018. Cases were matched on sex, year of birth, and age at event with 28,415 stroke patients. The Danish nationwide registries were used to collect information about age, sex, previous diagnoses, and drug prescriptions. Adjusted conditional logistic regression models were used to investigate the association between hypothesised risk factors and the patient outcome. Results: For atrial fibrillation, a substantially stronger association to stroke was found, with an odds ratio (OR) of 0.52 (95% CI: 0.47-0.58) when comparing RAO patients with stroke patients. RAO was stronger associated with arterial hypertension, peripheral artery disease, retinal vein occlusion, cataract, and glaucoma with OR's ranging from 1.21-11.70. The identified effect measures reached equivalence or was close to equivalence for diabetes, heart failure, ischemic heart disease, and renal disease. Conclusion: The differences in risk factor profiles between RAO and stroke suggests differences in the pathophysiology of the two diseases. These variations in pathophysiologies between the two diseases may indicate that different interventions are needed to ensure the optimal long-term prognosis for the patients.

IMPORTANCE: Thyroid eye disease (TED) is a serious condition that can cause proptosis and strabismus and, in rare cases, lead to blindness. Incidence data for TED and strabismus and surgical interventions after TED are sparce. OBJECTIVE: To investigate the nationwide incidence of TED, strabismus, and surgical interventions associated with TED. DESIGN, SETTING, AND PARTICIPANTS: A Danish nationwide registry-based cohort study between 2000, which marks the beginning of uniform coding for the decompression surgery nationwide, and 2018. The cohort consisted of a mean 4.3 million people aged 18 to 100 years with no prior TED diagnosis each year. Total observation time was 8.22 × 10(7) person-years (women, 4.18 × 10(7) person-years; men, 4.04 × 10(7) person-years). MAIN OUTCOME MEASURES: The annual numeric and age-standardized incidence of hospital-treated TED and cumulative incidence of strabismus, strabismus surgery, and orbital decompression surgery in patients with TED. The incidence was stratified by sex, thyroid diagnosis, and age. RESULTS: A total of 4106 incident diagnoses of TED were identified during 19 years among 3344 women (81.4%) and 762 men (18.6%). The mean numeric annual nationwide incidence rate of TED was 5.0 per 100 000 person-years overall, 8.0 per 100 000 person-years in women, and 1.9 per 100 000 person-years in men, resulting in a 4:1 ratio of women to men with TED. The age-standardized incidence was similar. The mean (SD) age at onset was 51.3 (14.5) years. At the time of TED diagnosis, 611 patients (14.9%) were euthyroid, 477 (11.6%) were hypothyroid, and 3018 (73.5%) were hyperthyroid. In patients with TED who were euthyroid, the 4-year cumulative incidence was 41% for antithyroid medication and 13% for L-thyroxine. In patients with TED, the 4-year cumulative incidence for strabismus was 10%. The 4-year cumulative incidence of surgical interventions after TED was 8% for strabismus surgery and 5% for orbital decompression. At 4 years, strabismus surgery was more common in men (13.3%; 95% CI, 10.75-15.86) than in women (7.2%; 95% CI, 6.24-8.08), and the absolute difference was 6.1% (95% CI, 3.42-8.14; P

Purpose: Previous studies have shown that the retinal oxygen saturation in central retinal vein occlusion treated with anti-VEGF compound has no predictive value for visual outcome after 12 months. It is of interest to evaluate whether this conclusion is similar for patients with branch retinal vein occlusion among whom only some patients are treated. Methods: Retinal oxygen saturation, visual acuity and central retinal thickness were studied at the time of referral and after six and 12 months in 111 patients successively referred to the Department of Ophthalmology, Aarhus University Hospital, with a venous occlusion affecting branches peripheral from the central retinal venule. The predictive value of the oxygen saturation at referral was investigated in treated and untreated patients. Results: Seventy-three patients with visual acuity between 35 and 70 ETDRS letters at referral were treated with intravitreal injection of anti-VEGF compound. Over 12 months, the venous oxygen saturation improved in parallel with central retinal thickness and visual acuity but had no predictive value for visual outcome. In 12 untreated patients with visual acuity >70 ETDRS letters, younger age and high oxygen saturation at the time of referral were positive predictors for the visual outcome after 12 months. Conclusion: Oxygen saturation, visual acuity and central retinal thickness improve in parallel during treatment of branch retinal vein occlusion with intravitreal anti-VEGF medication. Retinal oximetry at referral cannot predict visual acuity after 12 months in treated patients but may perhaps become a tool for predicting the visual prognosis in a subgroup of patients where treatment is omitted because of a too high visual acuity at the time of diagnosis of the disease.

Purpose: To identify parameters that can predict the postoperative risk for progression of retinopathy to a vision-threatening stage after cataract surgery. This may optimize the timing of surgery and the postoperative follow-up strategy in diabetic patients. Methods: Multi-state survival analysis with death as competing risk was used to investigate how year of onset and age of onset of diabetes, gender, body mass index, HbA1c and blood pressure had affected the risk for developing diabetic macular oedema (DME) and proliferative diabetic retinopathy (PDR) among 2540 right eyes from 2797 diabetic patients operated for cataract on one or both eyes during 25 years until July 1. 2019. Results: Cataract surgery had been performed in 98.8% of patients reaching 90 years of age. The risk for developing both DME and PDR was increased by cataract surgery. The risk was highest during the first postoperative years and increased by pre-operative variability in HbA1c. The risk after more than 20 years postoperatively increased by increased cumulative HbA1c pre-operatively. The other studied risk factors contributed differently to the development of the two complications. Conclusions: Decision models for the timing of cataract surgery in diabetic patients should consider that the risk for developing vision-threatening retinopathy depends on follow-up time. Differences in the risk profiles for developing DME and PDR after cataract surgery support that the two complications should be regarded as separate late complications.

Purpose: Clustering of vision threatening diabetic retinopathy within specific families can be the result of similarities in life style but may also be due to a common genetic background. An evaluation of the role of heredity for the development of diabetic retinopathy may help adjusting control intervals in screening program to each patient's individual risk profile. Methods: Survival analysis was used to study whether family history of diabetes among men and women with type 1 or type 2 diabetes together with the degree of heredity could be added as risk factors to improve the prediction of the risk for developing proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). The study was conducted on data from 12,281 patients followed in the Aarhus area, Denmark, from 1 January 2003 to 1 July 2019. Results: The risk for developing PDR was significantly reduced 2–11 years after known onset of diabetes in the presence of female family members with type 1 diabetes, and the risk for developing DME significantly increased 4–24 years after onset of diabetes in the presence of family members with type 2 diabetes of any sex. These hereditary factors were independent of other studied risk factors such as previous cataract surgery, age of onset of diabetes, metabolic regulation and blood pressure. Conclusions: The presence of family members with diabetes affects the risk for developing vision threatening diabetic retinopathy and affects the risk for developing PDR and DME differently. This evidence may help individualizing the control intervals in screening programmes for diabetic retinopathy.

Cognitive impairment; Diabetes mellitus; Diabetic retinopathy Discapacidad cognitiva; Diabetes mellitus; Retinopatía diabética Discapacitat cognitiva; Diabetis mellitus; Retinopatia diabètica Background: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD). Objective: To investigate diabetes and DR as a risk marker of present and incident AD. Methods: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes. Results: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59–0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81–0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08–1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18–1.53). Conclusion: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR. This work was supported by VELUX FONDEN (grant number 00028744) and Odense University Hospital PhD Foundation (grant number 4339).

Background: To investigate the relationship between risk factors of retinal artery occlusion (RAO) and retinal vein occlusion (RVO) and thereby identify similarities and differences between the two types of retinal vascular occlusions.Methods: In this case-control study, 5997 RAO patients were included and matched with three RVO patients each. The RVO patients were matched on sex and age at index date. All patients, personal information, diagnoses, and prescriptions were obtained from the Danish nationwide registries. Adjusted conditional logistic regression was used to investigate the association of RAO and RVO with the included risk factors.Results: RAO was stronger associated with arterial hypertension, heart failure, ischemic heart disease, peripheral artery disease, renal disease, and stroke than RVO, with effect measures ranging from 1.13-2.08. RVO was inversely associated with atrial fibrillation, cataract, and glaucoma with effect measures of 0.84 (95% CI: 0.75-0.95), 0.83 (95% CI: 0.76-0.90) and 0.45 (95% CI: 0.40-0.52), respectively. Conclusion: Differences in the level of associations with the included risk factors suggests differences in the pathophysiologies of the two diseases. The main pathophysiology associated with RAO was atherosclerosis, whereas the main pathophysiology associated with RVO were changes in the pressure gradients of the eyes.

INTRODUCTION: Risk factors for retinal vein occlusion have been extensively studied, with varying population sizes. Smaller populations result in less certain measures of associations. The present review included studies with a relevant population size to identify clinically relevant risk factors for retinal vein occlusion. Understanding the risk factors of retinal vein occlusion is important for the management of these patients.AREAS COVERED: A comprehensive literature review was conducted through a systematic literature search in PubMed and Embase. Additional studies were selected from cross references in the assessed studies. Weighted effect measures were calculated for all included risk factors.Risk factors associated with retinal vein occlusion included cardiovascular diseases, eye diseases, systemic diseases, medical interventions, and sociodemographic factors.EXPERT OPINION: This review provided an extensive overview of a wide variety of risk factors increasing the risk of developing retinal vein occlusion. The severity of the identified risk factors indicated that these patients have been in contact with the health care system before their retinal vein occlusion event. Therefore, the clinical course for patients with retinal vein occlusion may benefit from a multidisciplinary collaboration between ophthalmologists and especially cardiologists.

he effect and safety of low-dose atropine in myopia control have not been studied in randomized, placebo-controlled trials outside Asia. We investigated the efficacy and safety of 0.1% atropine loading dose and 0.01% atropine compared with a placebo in a European population. Investigator-initiated, randomized, double-masked, placebo-controlled, equal-allocation, multicenter study comparing 0.1% atropine loading dose (six months) followed by 0.01% atropine (18 months), 0.01% atropine (24 months), and placebo (24 months). Participants were monitored for a 12-months washout period. Outcome measures were axial length (AL), cycloplegic spherical equivalent (SE), photopic and mesopic pupil size, accommodation amplitude, visual acuity, intraocular pressure (IOP), and adverse reactions and events. We randomized 97 participants (mean [standard deviation] age, 9.4 [1.7] years; 55 girls (57%) and 42 boys (43%)). After six months, AL was 0.13 mm shorter (95% confidence interval [CI], −0.18 to −0.07 [adjusted p < 0.001]) with 0.1% atropine loading dose and 0.06 mm shorter (95% CI, −0.11 to −0.01 [adjusted p = 0.06]) with 0.01% atropine than in the placebo group. We observed similar dose-dependent changes in SE, pupil size, accommodation amplitude, and adverse reactions. No significant differences in visual acuity or IOP were found between groups, and no serious adverse reactions were reported. We found a dose-dependent effect of low-dose atropine in European children without adverse reactions requiring photochromatic or progressive spectacles. Our results are comparable to those observed in East Asia, indicating that results on myopia control with low-dose atropine are generalizable across populations with different racial backgrounds.Keywords: myopia; myopia control; low-dose atropine; axial length; spherical equivalent The effect and safety of low-dose atropine in myopia control have not been studied in randomized, placebo-controlled trials outside Asia. We investigated the efficacy and safety of 0.1% atropine loading dose and 0.01% atropine compared with a placebo in a European population. Investigator-initiated, randomized, double-masked, placebo-controlled, equal-allocation, multicenter study comparing 0.1% atropine loading dose (six months) followed by 0.01% atropine (18 months), 0.01% atropine (24 months), and placebo (24 months). Participants were monitored for a 12-months washout period. Outcome measures were axial length (AL), cycloplegic spherical equivalent (SE), photopic and mesopic pupil size, accommodation amplitude, visual acuity, intraocular pressure (IOP), and adverse reactions and events. We randomized 97 participants (mean [standard deviation] age, 9.4 [1.7] years; 55 girls (57%) and 42 boys (43%)). After six months, AL was 0.13 mm shorter (95% confidence interval [CI], −0.18 to −0.07 [adjusted p < 0.001]) with 0.1% atropine loading dose and 0.06 mm shorter (95% CI, −0.11 to −0.01 [adjusted p = 0.06]) with 0.01% atropine than in the placebo group. We observed similar dose-dependent changes in SE, pupil size, accommodation amplitude, and adverse reactions. No significant differences in visual acuity or IOP were found between groups, and no serious adverse reactions were reported. We found a dose-dependent effect of low-dose atropine in European children without adverse reactions requiring photochromatic or progressive spectacles. Our results are comparable to those observed in East Asia, indicating that results on myopia control with low-dose atropine are generalizable across populations with different racial backgrounds.

Purpose: The purpose of the study was to evaluate vision-related quality of life and visual ability in patients with OPA1 autosomal dominant optic atrophy (ADOA). Methods: This cross-sectional, observational study included 145 participants with a mutation in the OPA1 gene associated with ADOA, 63 mutation-free first-degree relatives and 92 healthy subjects unrelated to the families. Participants underwent a clinical eye examination, and adult participants completed the National Eye Institute Visual Function Questionnaire (NEI-VFQ-39), while children completed the Cardiff Visual Ability Questionnaire for Children (CVAQC). Results: In adults with ADOA, both mean visual acuity (VA) and mean contrast sensitivity (CS) were significantly inferior to both first-degree relatives and unrelated controls (p < 0.001). In children with ADOA, mean VA was significantly lower compared with first-degree relatives (p = 0.0052), whereas CS was not (0.127). Adults with ADOA scored lower than both comparator groups on composite score (p < 0.001), general health subscale (p = 0.0075) and all vision-related subscales (p < 0.001) except the ocular pain subscale (p = 0.2). In children with ADOA, the median CVAQC logit score was significantly lower compared with first-degree relatives (p = 0.037). The science lessons subscale was significantly lower for children with ADOA compared with first-degree relatives (p = 0.046), as well as the language lessons subscale (p = 0.038). For adults, composite score and subscale scores were significantly associated with both VA, CS and fixation status. Conclusion: OPA1 mutation is associated with lower quality of life and visual ability in patients with ADOA compared with both first-degree relatives and unrelated controls. VA, CS and fixation status affect quality of life in patients with ADOA.

This study seeks to examine potential risk factors for the development of retinal artery occlusions (RAO).We used data obtained from Danish nationwide registries to evaluate potential risk factors for RAO present up to 5 years prior to the RAO diagnosis. The study included 5312 patients diagnosed with RAO registered in the Danish National Patient Register and 26,560 controls assessed from the general population matched on sex and age at index date. Adjusted conditional logistic regression was used to estimate the odds ratio of included risk factors for RAO diagnosis. We conducted supplementary analyses stratified on sex and age, and on RAO subtype. In addition, interaction analyses were performed between strata in the stratified analyses.Risk factors associated with the development of RAO included diabetes, arterial hypertension, ischemic heart disease, peripheral artery disease, stroke, renal disease, cataract, and glaucoma, with ORs ranging from 1.33 to 4.94. Atrial fibrillation and sleep apnea yielded effect measures close to equivalence. The presence of a risk factor was generally associated with higher odds of RAO among the population ≤ 55 of age. Arterial hypertension was stronger associated with RAO in male patients than in female patients. The association with arterial hypertension was stronger for CRAO than for BRAO subtype.The investigated risk factors suggest that atherosclerosis and conditions changing the intraocular pressure are involved in the pathophysiology of RAO.

Background: The purine adenosine triphosphate (ATP) plays a significant role in retinal blood flow regulation and recent evidence suggests that the vasoactive effect of the compound differs in vessels at different branching level. However, the cellular basis for the regulation of retinal blood flow mediated by ATP has only been scarcely studied. Methods: Perfused porcine hemiretinas (n = 60) were loaded with the calcium-sensitive fluorophore Oregon Green ex vivo. Spontaneous oscillations in fluorescence were studied in perivascular cells at five different vascular branching levels ranging from the main arteriole to the capillaries, before and after the addition of intra- and extravascular ATP alone or in the presence of a P2-purinergic receptor antagonist. Results: Intravascular ATP induced an overall significant (p < 0.01) constriction of (mean ± SD) −9.79 ± 13.40% and extravascular ATP an overall significant (p < 0.01) dilatation of (mean ± SD) 19.62 ± 13.47%. Spontaneous oscillations of fluorescence in perivascular cells were significantly more intense around third order arterioles than around vessels at both lower and higher branching levels (p < 0.05 for all comparisons). ATP increased intracellular fluorescence in perivascular cells of first and second order arterioles after extravascular application, and the increase correlated with the accompanying vasodilatation (p < 0.03). Blocking of P2-receptors reduced oscillating fluorescence in pre-capillary arterioles secondary to intravascular ATP (p = 0.03). Conclusions: Spontaneous oscillations of calcium-sensitive fluorescence in perivascular retinal cells differ at different vascular branching levels. Extravascular ATP increases fluorescence in cells around the larger retinal arterioles exposed to the retinal surface. Future studies should investigate calcium signaling activity in perivascular retinal cells during interventions that simulate retinal pathology such as hypoxia.

BACKGROUND AND AIMS: Attenuated retinal vasoreactivity in patients with type 2 diabetes preceding diabetic retinopathy development has been proposed to reflect local endothelial dysfunction. Whether retinal vessel reactivity is associated with peripheral endothelial dysfunction and large artery stiffness in patients with type 2 diabetes remains to be elucidated.METHODS: Twenty patients with type 2 diabetes without retinopathy and 20 sex- and age matched controls (diabetes duration: 9.9 years (range 6.0;12.4), 40% male, age: 66.5 ± 7.3 (diabetes) and 65.2 ± 7.6 years (controls)) were included. Endothelial function was assessed using EndoPAT. Arterial stiffness was assessed by carotid-femoral pulse wave velocity using the SphygmoCor. Retinal blood supply regulation was examined by retinal arteriolar diameter change during 1) isometric exercise (hand-weight lifting), 2) exposure to flickering lights, and 3) a combined stimulus of 1) + 2) using the Dynamic Vessel Analyzer.RESULTS: No significant differences were observed in retinal vessel reactivity in T2DM patients compared to controls. Endothelial function was associated with mean arteriolar diameter change during only the combination intervention, (Beta = 0.033 [0.0013;0.064], p = 0.042) in the overall population of patients and controls. When groups were analyzed separately, the associations was statistically significant only in controls. However, formal test for interaction was not statistically significant, p = 0.40. No association was observed between pulse wave velocity and retinal arteriolar %-diameter change in patients or controls.CONCLUSION: Peripheral endothelial function was associated with retinal arteriolar diameter change in the combined sample. The association seemed to be driven primarily by the controls. Our findings indicate that peripheral endothelial function is reflective of endothelial function in the retina mainly in subjects without T2DM, whereas an association in T2DM without retinopathy was not observed. Further studies are needed in T2DM patients with more advanced retinopathy.

Background: The neurotransmitter adenosine has been proposed to be involved in the pathogenesis of diabetic retinopathy, which may be due to the vasoactive properties of the compound. Previous studies have shown that adenosine can affect the tone of retinal arterioles in vitro to induce dilatation mediated by A2A and A2Breceptors and constriction mediated by A1 and A3 receptors. Purpose: To investigate effects of intravenous administration of the adenosine A2A receptor agonist regadenoson on the diameter of retinal vessels in vivo. Method: The diameter responses of larger retinal arterioles and venules were evaluated using the dynamic vessel analyser in 20 normal persons (age 22–31 years) after intravenous administration of the adenosine A2A receptor agonist regadenoson during exposure to systemic normoxia and hypoxia. Results: The diameter of retinal arterioles and venules increased significantly during stimulation with flickering light (p < 0.0001). Regadenoson reduced the flicker-induced dilatation of venules during normoxia (p = 0.0006), but otherwise had no effect on vessel diameters (p > 0.08 for all comparisons). Conclusions:Intravenous administration of the adenosine A2A receptor agonist regadenoson had no significant effect on the diameter of retinal arterioles. Future studies should investigate differential effects of intra- and extravascular administration of adenosine receptor agonists on retinal vessels.

Here, we evaluate if microfabricated 3D pyrolytic carbon electrodes are suitable for application in sub-retinal photovoltaic prosthesis. This is done by measuring the charge storage capacity (CSC) and the maximum injectable charge, which indicate if the electrodes allow accumulation of sufficiently high charges in the charge cycle and are able to provide sufficiently fast discharge to stimulate neurons, respectively. The CSC was determined to 10.9 mC/cm2 for carbon pillars and 6.4 mC/cm2 for planar carbon electrodes. These values are comparable with values obtained for state-of-the-art electrode materials applied for retinal stimulation such as iridium oxide (IrOx). The maximum injectable charge was determined from cyclic voltammograms (CV) with values of 1.0 and 1.7 mC/cm2 for planar and pillar carbon electrodes, respectively. The measured contact resistance between carbon and n + doped Si confirms that pyrolytic carbon is a possible candidate for integration as a 3D electrode material on photovoltaic silicon retinal implants. The elemental composition of the fabricated pyrolytic carbon pillars was analyzed by X-ray photoelectron spectroscopy (XPS). The analysis showed that the Al2O3 passivated sample with fabricated pyrolytic carbon pillars only contained aluminum, oxygen and carbon, indicating a successful pyrolysis process without any unwanted elements. The study shows promising potential for pyrolytic carbon as a material for 3D electrodes in retinal, photovoltaic implants. Keywords: Retinal prosthesis, Photovoltaic, 3D electrodes, Pyrolytic carbon, Sub-retinal stimulation

Purpose: Animal models of choroidal neovascularization (CNV) are extensively used to characterize the pathophysiology of chorioretinal diseases with CNV formation and to evaluate novel treatment strategies. This systematic review aims to give a detailed overview of contemporary animal models of CNV.Methods: A systematic search was performed in PubMed and EMBASE from November 20, 2015, to November 20, 2020, for mammalian animal models of CNV. Following inclusion by two investigators, data from the articles were extracted according to a predefined protocol.Results: A total of 380 full articles, representing 409 independent animal models, were included. Mice were by far the most utilized animal (76%) followed by rats and non-human primates. The median age of rodents was 8 weeks but with a wide range. Male animals were used in 44% of the studies, but 32% did not report the sex. CNV was laser induced in 89% of the studies, but only 44% of these reported sufficiently on standard laser parameters. Surprisingly, 28% of the studies did not report a sample size for quantitative CNV evaluation. Less than half of the studies performed quantitative in vivo evaluation, and 73% evaluated CNV quantitatively ex vivo. Both in vivo and ex vivo evaluations were conducted primarily at day 7 and/or day 14.Conclusions: The laser-induced mouse model is the predominant model for experimental CNV. The widespread use of young, healthy male animals may complicate clinical translation, and inadequate reporting challenges reproducibility. Definition and implementation of standardized methodologic and reporting guidelines are attractive.

Purpose: The purpose of this study was to develop a porcine model for photocoagulationinduced choroidal neovascularization (CNV) with high success rate and minimalthermic damage to the neuroretina.Methods: Experimental CNV was induced by laser photocoagulation in both eyes of 16domestic pigs. In the left eyes, photocoagulation was preceded by subretinal injectionof saline to protect the neuroretina from thermic damage, whereas the right eyes weretreated with photocoagulation only. The development of the CNV after 3, 7, 14, 28, and42 days was evaluated by optical coherence tomography (OCT) scanning, fluoresceinangiography, and OCT angiography, and by histology after enucleation.Results: From day 7 after the photocoagulation, OCT showed subretinal density in alllesions of 14 alive animals, and either fluorescein or OCT angiography confirmed CNVformation in 11 of 14 of the eyes that had received photocoagulation alone and thosein which photocoagulation had been preceded by subretinal injection of saline. In allcases pretreated with subretinal saline, the neuroretina was protected from immediatethermic damage. The formation of CNVs were confirmed by histology. For both groups,the largest lesions were observed within 14 days after photocoagulation.Conclusions: Injection of subretinal saline can protect the retina fromthermic damageinduced by retinal photocoagulation without reducing the success rate in producingexperimental CNV. The effect of interventional studies aimed at reducing photocoagulationinduced experimental CNV in pigs can be evaluated within 2 weeks after photocoagulation.Translational Relevance: This model provides a fundament to develop and evaluatenovel treatment methods for neovascular retinal diseases.

PURPOSE. Convergence insufficiency (CI) is characterized by abnormal vergence eye movement frequently accompanied by abnormal accommodation and subjective symptoms, such as headache, blurred vision, and diplopia. CI is treated with vergence and accommodation exercises that are integrated so that the relative contributions of vergence and accommodation exercises to the outcome are concealed. The purpose of the present study was to determine the individual contributions of vergence and accommodation exercises for the treatment of CI in school children. METHODS. In a prospective crossover study 44 children aged 9 to 13 years with CI were randomized to perform either vergence exercises followed by accommodation exercises each for 6 weeks or the 2 treatment regimes in the reverse order. The outcome measures were recovery from CI and the parameters vergence facility, positive fusional vergence, near point of convergence, monocular amplitude, and facility of accommodation. RESULTS. After the first 6-week period, full recovery from CI was significantly more frequent in the group commencing vergence exercises than in the group commencing monocular accommodation exercises (p = 0.01), whereas there was no significant difference between these proportions after the second 6-week period (p = 0.45). Vergence facility and positive fusional vergence improved significantly more after the period with vergence exercises than after the accommodation exercises, whereas there was no significant difference between the effects of the two types of exercises on the other studied parameters. CONCLUSIONS. Vergence treatment induces a faster recovery of CI than accommodation treatment in school children. This may be used to improve compliance and success rate of the treatment.

PURPOSE. Recent evidence suggests that the smaller retinal vessels are significantly involved in the regulation of retinal blood flow and that this regulation may differ among the macular area and the retinal periphery. An alternative to studying blood flow regulation in smaller retinal vessels that are difficult to resolve is to assess the metabolic consequences of changes in the microcirculation using oximetry. METHODS. In 20 normal persons aged (mean ± SD, range) 30.1 ± 3.8 (24-37) years, the oxygen saturation and diameter of retinal arterioles and venules to the macular area and the retinal periphery were studied before and during an increase in the arterial blood pressure induced by isometric exercise. RESULTS. The isometric exercise increased the mean arterial blood pressure by (mean ± SEM) 10.0 ± 1.1 mm Hg but induced no significant changes in the diameter of the arterioles (P = 0.83). The isometric exercise had no significant effect on the oxygen saturation in the arterioles supplying the macular area and the retinal periphery (P > 0.42 for both comparisons). However, there was a significant increase in the oxygen saturation in venules draining the retinal periphery to reduce the oxygen extraction from (mean ± SEM) 36.0% ± 2.3% to 30.6% ± 2.1% (P = 0.002) but no significant change in the preexisting low oxygen extraction in the macular area that changed from (mean ± SEM) 18.2% ± 3.0% to 16.2% ± 1.9% (P = 0.37). CONCLUSIONS. Minor changes in the arterial blood pressure can induce changes in retinal rheology with significant regional variation. The finding may help explain regional variations in manifestations of retinal vascular disease such as hyperpermeability in the macular area and capillary occlusion in the retinal periphery.

Purpose: Central retinal vein occlusion (CRVO) entails retinal hypoxia that often causes visual impairment. It has been shown that oxygen saturation in larger retinal vessels correlates with the visual acuity at the time of diagnosis of CRVO but has no predictive value for the visual outcome in patients treated with anti-VEGF medication after 3 months. However, assessing the predictive value of retinal oxygen saturation after 12 months is essential because this is when the main restitution after CRVO occurs. Methods: Retinal oximetry was performed in 117 patients referred with CRVO to three European centres. The correlation between oxygen saturation and visual acuity at baseline and the predictive value of oxygen saturation in larger retinal vessels for the 12-month visual outcome after treatment with anti-VEGF medication were studied. Results: In the affected eye, the oxygen saturation was significantly higher in the arterioles, significantly lower in the venules, and the arterio-venous (A-V) significantly higher than in the unaffected eye (p