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PurposePrediction of the early treatment response is important in neovascular age-related macular degeneration (nAMD). Hence, we aimed to test if non-invasive measurements of the retinal vascular structure were able to predict a successful outcome of initial intravitreal treatment.MethodsIn 58 eyes of 58 patients with treatment-naïve nAMD, advanced markers of retinal vascular structure were measured by Singapore I Vessel Assessment prior to initial intravitreal treatment with three monthly injections of aflibercept with subsequently categorization of patients as full treatment responders (FTR) or non/partial treatment responders (N/PR), with the former defined as loosing fewer than five Early Treatment Diabetic Retinopathy Study letters and having no residual intra- or subretinal fluid or macular haemorrhage.ResultsOf 54 eyes attending follow-up, 44.4% were categorized as FTR. Patients with FTR were older (81.5 vs. 77 years, p = 0.04), and prior to treatment those eyes had a lower retinal arteriolar fractal dimension (Fd) (1.21 vs. 1.24 units, p = 0.02) and venular length-diameter ratio (LDR) (7.3 vs. 15.9 units, p = 0.006), but did not differ with respect to other retinal vascular parameters. In multiple logistic regression models, a lower chance of FTR was independently predicted by a higher retinal venular LDR (odds ratio [OR] 0.91, 95% CI 0.82–0.99, p = 0.03, for each 1 unit increment) and marginally by a higher retinal arteriolar Fd (OR 0.83, 95% CI 0.68–1.00, p = 0.05, for each 0.01 unit increment).ConclusionRetinal venular LDR independently predicted the initial treatment response in nAMD. If confirmed by long-term, prospective studies, this might help to guide treatment.

Purpose: To evaluate treatment efficacy in diabetic macular oedema (DME) comparing a study population receiving combined intravitreal vascular endothelial growth factor (VEGF) inhibition and focal/grid photocoagulation with a matched, real-world population receiving standard of care treatment.Methods: In an exploratory study, we included 43 eyes from 32 patients from a previously published study as well as 46 eyes from 38 standard-of-care patients. The study population had received a loading dose of three monthly aflibercept injections followed by focal/grid photocoagulation and additional aflibercept pro re nata. Principal measurements at 12 months were numbers of intravitreal injections, best corrected visual acuity (BCVA) and central retinal thickness (CRT).Results: At baseline, there were no differences between groups regarding age, sex, body mass index, haemoglobin A1C, systolic pressure or type of diabetes, but the study population had a higher diastolic pressure (81.6 versus 72.1 mmHg, p = 0.03) and a lower duration of diabetes (12.3 versus 23.2 years, p = 0.03). At month 12, patients in the study group had a higher visual acuity (79.6 versus 74.3 ETDRS letters, p = 0.03), despite having received fewer aflibercept injections (4.4 versus 5.9, p Conclusion: In comparison to a matched, real-world DME-population, patients in combined treatment with intravitreal aflibercept and postloading focal/grid photocoagulation obtained a better functional outcome despite having received fewer intravitreal injections. Future randomized studies are needed to evaluate the long-term efficacy of this combined treatment regimen.

The pathophysiology of diabetic macular oedema (DME) remains poorly understood. Proteomic analysis of the vitreous using mass spectrometry (MS) can potentially identify proteins of pathophysiological importance. In this systematic review, we summarize the available evidence on protein changes in DME detected by MS. We systematically searched 13 literature databases on 19 September 2021. Eligible studies were defined as those using samples from human eyes with DME analysed with MS. Two authors assessed the studies for eligibility, extracted data and evaluated risk of bias independently. Six eligible studies were identified. All were designed in a cross-sectional fashion comparing results to either a non-diabetic control group or a control group without DME. A total of 62 eyes from 60 patients contributed as study group and 48 eyes from 48 patients served as control group. Proteomic analyses revealed significant differences in the vitreous protein levels in patients with DME when compared with controls. Three studies or more identified increased contents of apolipoprotein A-I, apolipoprotein A-II, apolipoprotein A-IV, apolipoprotein C-III, gelsolin, pigment epithelium-derived factor, serum albumin, transthyretin, vitamin D-binding protein in DME. Two studies found increased levels of complement factors B and C3. Protein changes reproduced across the studies suggested that DME was associated with retinal lipid accumulation, angiogenesis, retinal protective mechanisms, inflammation and complement activation. Proteome studies support the multifactorial pathogenesis of DME as proteins with highly different biological functions are regulated in DME. An important number of proteins differ, provide pathophysiological insight and suggest the direction for future research.

PURPOSE: Diabetic retinopathy (DR) is among the leading causes of visual loss in the working-age population. It is generally accepted that screening of DR is cost-effective and can detect DR before it becomes sight-threatening to allow timely treatment.METHODS: A group of retinal specialists was formed by the Danish Ophthalmological Society with the aim to formulate contemporary evidence-based guidelines for screening of DR in order to implement these in the Danish screening system.RESULTS: We hereby present evidence for DR-screening regarding (1) classification of DR, (2) examination techniques, (3) screening intervals and (4) automated screening. It is our recommendation that the International Clinical Retinopathy Disease Severity Scale should be used to classify DR. As a minimum, mydriatic two-field disc- and macular-centred images are required. In the case of suspected clinically significant diabetic macular oedema, supplementary optical coherence tomography can increase the diagnostic accuracy. There is solid evidence to support a flexible, individualized screening regimen. In particular, it is possible to prolong screening intervals to 24-48 months for patients with no or mild nonproliferative diabetic retinopathy (NPDR), but it is also possible to use extended intervals of 12-24 months for patients with moderate NPDR given that these are well-regulated regarding glycaemic control (HbA1c ≤ 53 mmol/mol) and blood pressure (≤130/80 mmHg). Automated screening of DR is encouraging but is not ready for implementation at present.CONCLUSION: Danish evidenced-based guidelines for screening of DR support high-quality imaging and allow flexible, individualized screening intervals with a potential for extension to patients with low risk of DR progression.

Corneal refractive surgery disrupts corneal integrity and reduces biomechanical stability in consequence of the beneficial refractive alteration. The minimal invasive cap-based refractive procedure, small-incision lenticule extraction (SMILE), has been proposed to affect corneal integrity less than flap-based procedures, due to the fibre-sparing incision of the strong anterior corneal lamellae. Flap-based procedures include laser-assisted in situ keratomileusis (LASIK), femtosecond laser-assisted in situ keratomileusis (FS-LASIK) and femtosecond lenticule extraction (FLEx). The purpose of this systematic review was to evaluate corneal biomechanical changes by noncontact air pulse tonometry after treatment of myopia/myopic astigmatism with SMILE compared to flap-based refractive surgery. A total of 220 publications were identified through a systematic search in PubMed and Embase. Two levels of screening identified nine studies (three randomised controlled trials (RCT) and six nonrandomised clinical trials) eligible for the review. All the nonrandomised clinical trials were graded to have an overall serious risk of bias. Measurements with the Corvis ST were not included in any of the eligible studies. The RCTs found no statistical significant differences between SMILE or flap-based procedures concerning corneal hysteresis (CH) or corneal resistance factor (CRF), as measured with the Ocular Response Analyzer. However, a greater reduction in CRF and CH was found in the flap-based group in five and two of the nonrandomised studies, respectively. The findings in this review illustrate that the presumed biomechanical advantages of a cap-based small incision could not be demonstrated in existing studies and by commercially available technology. However, studies with lower levels of evidence suggest less affection of corneal viscoelastic properties after SMILE when evaluating corneal stability by noncontact tonometry.

PURPOSE: To determine associations between physical activity (PA) and myopia in Danish school children and investigate the prevalence of myopia.METHODS: This is a prospective study with longitudinal data on PA in a Danish child cohort. Physical activity (PA) was measured objectively by repeated ActiGraph accelerometer measurement four times with different intervals (1-2.5 years) at the mean ages 9.7, 11.0, 12.9 and 15.4 years. Mean intensity of PA was estimated as counts/minutes, and time spent in sedentary, light, moderate and vigorous PA was summed using defined cut-off points. The ophthalmologic examination was conducted at the mean age of 15.4 ± 0.7 years and included cycloplegic autorefraction and biometry.RESULTS: A total of 307 children participated in the Childhood Health, Activity, and Motor Performance School (CHAMPS) Eye Study. The cycloplegic spherical equivalent (SE) was 0.30 ± 1.46 dioptres. The prevalence of myopia was 17.9% (SE ≤-0.5 dioptres). Mean axial length (AL) was 23.5 ± 0.9 mm. For all participants, the overall mean daily distribution of PA was 67.2% in sedentary, 25.6% in light, 4.4% in moderate and 2.9% in vigorous PA. Age- and sex-adjusted linear regression showed no association between PA and SE or AL. In a prospective slope analysis, there was no association between accumulated PA during the 7 years and AL or SE.CONCLUSION: The prevalence of myopia among Danish children was 17.9%. By logistic regression and slope analysis, we found no association between PA and myopia, in this first of its kind study based on objective and repeated PA data.

PURPOSE: This study aims to estimate the prevalence and risk factors of diabetic retinopathy (DR) in patients enrolled in a large Danish quality-assuring database for diabetes: the Funen Diabetes Database (FDDB).METHODS: All patients with type 1 (T1DM) and type 2 DM (T2DM) diabetes mellitus (DM) were included in a cross-sectional study. The level of DR per patient was determined based on the eye with highest level of DR. All ocular and non-ocular data were extracted at the latest examination that corresponded to the most recent DR-grading data.RESULTS: Data from 17 152 patients were analysed; 83.1% had T2DM. Prevalence of DR was 23.8% (T1DM: 54.3%, T2DM: 21.2%). T1/T2DM patients were statistically significantly different regarding age, duration of diabetes, BMI, systolic blood pressure (BP), cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, s-creatinine and u-albumin (p < 0.001 for all). Increasing level of DR showed statistically significant association with age, duration of diabetes, systolic BP, HbA1c, s-creatinine and u-albumine with increasing level of DR (all are p < 0.001) both T1DM/T2DM patients.CONCLUSION: The patients in FDDB had good systemic control with median values of BP, serum lipids, cholesterol and HbA1c all close to or below national guidelines at the time of data extraction, but still a high level of DR was found in this cohort. DR was more common in patients with T1DM than T2DM, but as T2DM patients are more numerous, their level of DR despite acceptable control is still concerning. Most important associated factors for higher levels of DR were age, duration of diabetes, HbA1c, s-creatinine and u-albumine.

PURPOSE: To test the validity of the eyesi surgical simulator as an assessment tool in a virtual reality vitreoretinal training programme.METHODS: In collaboration with an experienced vitreoretinal surgeon, a virtual vitreoretinal training programme was composed on the eyesi surgical simulator, software version 2.9.2 (VRmagic GmbH, Manheim, Germany). It was completed twice by three groups: 20 medical students, ten residents of ophthalmology and five trained vitreoretinal surgeons. The programme contained six training modules: navigation level 2 (Nav2), forceps training level 5 (ForT5), bimanual training level 3 (BimT3), laser coagulation level 3 (LasC3), posterior hyaloid level 3 (PostH3) and internal limiting membrane peeling level 3 (ILMP3). The scores in each module were assessed from two to five different factors (tissue treatment, efficiency, target achievement, instrument handling and microscope handling), and it was possible to achieve 100 points in each module.RESULTS: At the final training session, the highest overall median score was found for the vitreoretinal surgeons (vitreoretinal surgeons: 434 points, residents: 394.5 points, medical students: 272.5 points, p < 0.01). This was also found in four of the six modules. These were Nav2 (p = 0.03), BimT3 (p < 0.01), PostH3 (p < 0.01) and ILMP3 (p < 0.01). On the other hand, the three groups did not differ regarding ForT5 (p = 0.16) or LasC3 (p = 0.75).CONCLUSIONS: We developed a training programme with validity for the eyesi surgical simulator as an assessment tool for overall score and for four of six vitreoretinal modules. These findings could potentially make the programme a useful tool in the training of future vitreoretinal surgeons.

PURPOSE: To examine the incidence of retinal detachments and to evaluate patient profiles and surgical characteristics.METHODS: Retrospective review of patients operated for primary retinal detachment (RD) and redetachment between 2010 and 2012 at the Department of Ophthalmology, Odense University Hospital, Denmark. We included all RD such as rhegmatogenous retinal detachment (RRD), tractional retinal detachment (TRD) and exudative retinal detachment (ERD).RESULTS: In total, 779 RD surgeries were performed: 83.7% (n = 652) primary operations and 16.3% (n = 127) reoperation. For primary operation, pars plana vitrectomy (PPV), scleral buckling and combined operations were performed in 95.1% (n = 620), 4.6% (n = 30) and 0.3% (n = 2) respectively. Over time there was less use of silicone oil and greater use of gas tamponade (p = 15 years. Retinal detachment (RD) was more common in males than females (1.8:1), and mean age at presentation was 61.8 years (standard deviations ± 12.3). The annual incidence for RRD and TRD operation was 20.72 (95% CI 19.11-22.43) and 1.25 (95% CI 0.9-1.7) per 100 000 inhabitants >15 years.CONCLUSION: This study presents the first overall incidence for RD in Denmark. The highest incidence of RRD was among males aged 60 to 79 years, whereas TRD was among females at same age. Pars plana vitrectomy (PPV) was the preferred surgical technique, and during 2012 all RD patients were treated with PPV, independent of lens status and age.

Aim: To determine the mortality rate in a Danish cohort of children and adolescents diagnosed with Type 1 diabetes mellitus compared with the general population. Methods: In 1987 and 1989 we included 884 children and 1020 adolescents aged 20 years and under, corresponding to 75% of all Danish children and adolescents with Type 1 diabetes, in two nationwide studies in Denmark. Those who had participated in both investigations (n = 720) were followed until 1 January 2014, using the Danish Civil Registration System on death certificates and emigration. We derived the expected number of deaths in the cohort, using population data values from Statistics Denmark to calculate the standardized mortality ratio. Survival analysis was performed using Cox proportional hazards model. Results: During the 24 years of follow-up, 49 (6.8%) patients died, resulting in a standardized mortality ratio of 4.8 (95% confidence interval 3.5, 6.2) compared with the age-standardized general population. A 1% increase in baseline HbA 1c (1989), available in 718 of 720 patients, was associated with all-cause mortality (hazard ratio = 1.38; 95% confidence interval 1.2, 1.6; P < 0.0001). Type 1 diabetes with multiple complications was the most common reported cause of death (36.7%). Conclusion: We found an increased mortality rate in this cohort of children and adolescents with Type 1 diabetes compared with the general population. The only predictor for increased risk of death up to 24 years after inclusion was the HbA 1c level in 1989. This emphasizes the importance of achieving optimal metabolic control in young people with Type 1 diabetes.

Purpose Pharmacological inhibition of the constitutively expressed extracellular matrix integrin ligand MFAP4 is previously shown with efficacy in mouse model of choroidal neovascularization. To evaluate the intraocular expression of MFAP4 in the anterior chamber (CA) and vitreous body (VB) in patients with nAMD (cases) as compared to controls. Methods Aqueous humour from 29 patients and vitreous humour of 54 patients were collected during elective cataract surgery and pars plana vitrectomy, respectively. Samples from the CA consisted of three cases and 26 controls and from the VB of 42 cases and 12 controls. The 42 samples from the VB were further divided into four subgroups depending on the subtype of nAMD (CNV with retinal hemorrhage, CNV without retinal hemorrhage, fibrosis, PE-detachment). Samples were analyzed by the AlphaLISA technique. Wilcoxon rank-sum test and Kruskall-Wallis test was used to test for differences between two and multiple groups, respectively. Results Median MFAP4 was significantly lower in the anterior chamber as compared to the VB (7.9 Units/ml vs. 17.9 Units/ml, p

AIMS: To examine the long-term incidence of vitrectomy in young people with Type 1 diabetes.METHODS: We prospectively studied 324 people with Type 1 diabetes who participated in baseline examinations in 1995. Surgical history was obtained from the Danish National Patient Registry in April 2012.RESULTS: During the 17-year study period, 39 people (12.0%) underwent vitrectomy at least once. The mean age and diabetes duration at first vitrectomy were 29.8 and 22.9 years, respectively, and 64.1% of the participants were men. In multivariable Cox regression analysis, baseline age (hazard ratio 0.81 per 1 year increase), BMI (hazard ratio 1.21 per 1 kg/m(2) increase), HbA1c (hazard ratio 1.72 per 1% increase) and diabetic retinopathy (hazard ratio 2.85 and 6.07 for mild and moderate/severe diabetic retinopathy vs none, respectively) were independent predictors of vitrectomy (P < 0.05 for all variables).CONCLUSIONS: Vitrectomy is a relatively common procedure in young people with Type 1 diabetes, with poor glycaemic control being the strongest modifiable risk factor.

The incidence of type 1 diabetes is rising all over the world. Furthermore, the increased life-expectancy of type 1 diabetic patients is likely to cause a higher number of diabetes-related micro- and macrovascular complications in the years to come. In order to examine the level of long-term complications in type 1 diabetes as well as potential markers of micro- and macroangiopathy, a population-based cohort of Danish type 1 diabetic patients was examined in order to achieve the following aims: 1 To evaluate diabetic retinopathy as a long-term marker of all-cause mortality in type 1 diabetes (Paper I). 2 To estimate the long-term incidence and associated risk factors of blindness (Paper II) and cataract surgery (Paper III) in type 1 diabetes. 3 To use retinal vascular analyses in order to investigate the associations of long-term micro- and macrovascular complications and retinal vascular diameters (Paper IV) and retinal fractals (Paper V) in type 1 diabetes. 4 To examine N-terminal pro brain natriuretic peptide (Paper VI) and osteoprotegerin (Paper VII) as non-invasive markers of micro- and macrovascular complications in type 1 diabetes. In Paper I it was a major finding that, despite a mean age of only 38.3 years at baseline, 44.7% of the patients died during the 25-year follow-up. Patients who had proliferative retinopathy as well as proteinuria at the baseline examination had a significantly higher mortality. For these, the 10-year survival was only 22.2%. As demonstrated in Paper II, blindness is an important issue in type 1 diabetes. The 25-year cumulative incidence of blindness was 7.5%. Glycaemic regulation and maculopathy at baseline were both identified as risk factors of blindness. Finally, mortality was higher in patients who went blind during the follow-up. Cataract surgery is quite common in type 1 diabetes. In Paper III a 25-year cumulative incidence of 20.8% was found. Adjusted for mortality, this was even higher (29.4%). As compared to patients without diabetes, cataract surgery takes place approximately 20 years earlier in type 1 diabetic patients. Age and maculopathy at baseline were both identified as predictors of cataract surgery. In Paper IV it was demonstrated that patients with retinal arteriolar narrowing were 2.17 and 3.17 times more likely to have nephropathy and macrovascular disease, respectively. This was an important finding that suggests that retinal fundus photos may be used in order to predict the risk of non-ophthalmological complications in type 1 diabetes. Retinal fractal analysis is another way to evaluate the vascular system of the retina. In Paper V we found associations between retinal fractal and microvascular - but not macrovascular - disease. For instance, patients with lower fractal dimensions were more likely to have proliferative retinopathy (OR 1.45, 95% CI 1.04-2.03) and neuropathy (OR 1.42, 95% CI 1.01-2.01). NT-proBNP is likely to be a future predictor of diabetes-related complications. In Paper VI higher levels of NT-proBNP were related to nephropathy (OR 5.03, 95% CI 1.77-14.25), neuropathy (OR 4.08, 95% CI 1.52-10.97) and macrovascular disease (OR 5.84, 95% CI 1.65-20.74). These associations should be confirmed in future prospective studies. As opposed to NT-proBNP, osteoprotegerin is less likely to be a predictor of either micro- or macrovascular disease in type 1 diabetes. As demonstrated in Paper VII, even though association between higher levels of OPG and nephropathy were found in an age- and sex-adjusted model (OR 2.54, 95% CI 1.09-5.90), this was no longer statistically significant when other factors were taken into account. Overall, it was demonstrated that various complications such as mortality, blindness and cataract surgery were high in type 1 diabetes. Furthermore, retinal arteriolar narrowing, decreased retinal fractals and plasma NT-proBNP were associated with various micro- and macrovascular complications. If confirmed by prospective studies, these modalities may be used in order to identify patients at risk of diabetes-related complications. This could, ultimately, lead to decreased mortality and morbidity in type 1 diabetic patients.

The incidence of type 1 diabetes is increasing in Denmark as well as the rest of the world. Due to diabetes-related micro- and macrovascular complications, the morbidity and the mortality is higher among type 1 diabetic patients. The aim of this thesis was to examine a population-based cohort of 727 type 1 diabetic patients from Fyn County, Denmark, with an onset of diabetes before 1 July 1973 in order to: 1 Evaluate the all-cause mortality rates and the influence of sex, duration of diabetes and calendar year of diagnosis in a 33-year follow-up (Paper I). 2 Examine glycaemic regulation, lipids and renal dysfunction as risk factors for all-cause mortality, cardiovascular mortality and IHD (Paper II). 3 Estimate the prevalence of DR as well as the 25-year incidence of PDR and associated risk factors in long-time surviving patients (Paper III). 4 To compare the grading of DR between ETDRS seven standard field 30° stereoscopic colour films and nine field 45° monoscopic digital colour images in long-term surviving patients (Paper IV). In the years 1973–2006 an overall MR of 22.3 per 1000 person-years was found. Furthermore a relative mortality of 3.4 was found as compared to the general population in Denmark. The relative mortality was especially high for patients aged 30–39 (SMR 9.8). There was a tendency towards a better survival for patients diagnosed after 1964. This was especially seen for men. Diabetes was the most common cause of death for those who died in the group. In 1993–1996 blood samples were drawn and glycaemic regulation, lipids and renal markers were subsequently used as predictors of all-cause mortality, cardiovascular mortality and ischaemic heart disease. Glycaemic regulation, dyslipidaemia and creatinine were all significantly associated with all three endpoints. Furthermore, variations in glycaemic control were also identified as a risk factor for overall mortality. Two hundred and one patients were examined for diabetic retinopathy in 1981–1982 and 2007–2008. At follow-up, 97.0% had DR and 42.9% of all patients without PDR at baseline developed this during the follow-up period. Patients who had had a poor glycaemic regulation as well as those who had NPDR at baseline were more likely to develop PDR than the remaining patients. On the other hand, other risk factors such as high blood pressure and proteinuria did not predict PDR. In the comparative study between ETDRS seven standard field 30° stereoscopic colour films and nine field 45° monoscopic digital colour images, 43 eyes of 43 patients were examined in 2008. A poor correlation was found between the two methods: only 29.3% were graded alike. In the remaining, the level of DR was graded higher in the digital photos. Among these, PDR was detected in three eyes using digital photos but remained undetected on all films. This suggests that digital photos with wide fields are the best way to detect DR in long-term type 1 diabetic patients. Overall, it is concluded that mortality is still higher among type 1 diabetic patients. This depends, among other things, on glycaemic regulation, lipid status and, partly, renal dysfunction. Diabetic retinopathy is almost universal in long-term type 1 diabetic patients, and almost half of all patients will develop PDR in 25 years. Nine field digital photos provide the best grading of retinopathy in long-term type 1 diabetic patients.

Acta Ophthalmol. 2011: 89: 25–29 Abstract. Purpose: To estimate the long-term cumulative incidence of cataract surgery and associated risk factors in a 25-year follow-up of a population-based cohort of patients with type 1 diabetes. Methods: Based on insulin prescriptions, a population-based cohort of 727 patients with type 1 diabetes was identified in 1973. In 1981–1982 diabetic retinopathy was graded and other markers of diabetes were measured in 573 patients who participated in a clinical baseline examination. Based on data from the Danish National Patient Registry, patients were followed until November 2006 and cataract surgery was evaluated during follow-up. Results: The 25-year crude cumulative incidence of cataract surgery was 20.8% (117 of 562 patients at risk), corresponding to a mortality-adjusted incidence of 29.4% [95% confidence interval (CI) 25.6–33.1%]. Median age and duration of diabetes at the time of surgery were 59.3 and 42 years, respectively. Cataract surgery in the cohort took place approximately 20 years earlier compared to non-diabetic persons. In a multivariate regression analysis, baseline age [hazard ratio (HR) 1.89 per 10 years, 95% CI 1.46–2.27] and maculopathy (HR 1.89, 95% CI 1.05–3.40) were the only statistically significant predictors of cataract surgery. Duration of diabetes, gender, glycaemic regulation, proteinuria, smoking, blood pressure and level of retinopathy were not associated with cataract surgery. Conclusion: Type 1 diabetes is associated with a high long-term incidence of cataract surgery. The association between maculopathy and subsequent cataract surgery is a novel finding and should be addressed in future studies.