Visual outcomes of observation, macular laser and anti-VEGF in diabetic macular edema in type 1 diabetes: a real-world study.

BACKGROUND: The treatment for diabetic macular edema (DME) has revolutionized during the last 15 years after the introduction of intravitreal anti-VEGF agents. The aim of the current study is to evaluate the real-world visual outcomes of diabetic macular edema (DME) treatment in patients with type 1 diabetes (T1D) in long-term follow-up. METHODS: A real-world, descriptive, population-based cohort and follow-up of all patients with T1D and DME in 2006-2020 in 34 communities of the Northern Ostrobothnia Hospital District. The main outcome measures included age, gender, duration of T1D at the onset of DME, stage of retinopathy, treatment of DME (observation, laser, intravitreal treatments, combination), and visual outcomes. RESULTS: A total of 304 eyes of 206 T1D patients with DME were included. 75% (n=155) had non-proliferative diabetic retinopathy during the onset of DME. 15% of the cases were observed, 33% had macular laser, 41% intravitreal anti-VEGF and 12% combination of laser and intravitreal injections. Patients in anti-VEGF and in combination groups gained 4.9 and 5.5 ETDRS letters after the initial DME episode (p<0.001 and p<0.001), and the long-term visual improvements were 4.1 and 5.1 ETDRS letters (p<0.001 and p<0.001), respectively. In observation and laser groups the initial gain of 0.1 (p>0.90) and loss of 0.4 ETDRS letter (p=0.61), respectively, was noted. After the follow-up, a 3.7 ETDRS letter decrease was documented in the observation group (p>0.90) and a 1.1 (p=0.14) ETDRS letter decline in the laser group of patients. At the beginning of treatment, eyes subjected to anti-VEGF alone or in combination with laser had lower visual acuity compared to eyes subjected to observation or macular laser. The average of a 6.1±4.8 anti-VEGF injections were needed to dry DME. Visual impairment due to DME decreased from 2.4% to 1.0% during the 15-year period. CONCLUSIONS: Anti-VEGF alone or in combination with macular laser seems to be beneficial in terms of visual outcomes and treatment stability in T1D patients with central DME. Moreover, satisfying long-term visual outcomes were achieved with anti-VEGF treatment in a real-world setting.

Comparison of 21 artificial intelligence algorithms in automated diabetic retinopathy screening using handheld fundus camera.

BACKGROUND: Diabetic retinopathy (DR) is a common complication of diabetes and may lead to irreversible visual loss. Efficient screening and improved treatment of both diabetes and DR have amended visual prognosis for DR. The number of patients with diabetes is increasing and telemedicine, mobile handheld devices and automated solutions may alleviate the burden for healthcare. We compared the performance of 21 artificial intelligence (AI) algorithms for referable DR screening in datasets taken by handheld Optomed Aurora fundus camera in a real-world setting. PATIENTS AND METHODS: Prospective study of 156 patients (312 eyes) attending DR screening and follow-up. Both papilla- and macula-centred 50° fundus images were taken from each eye. DR was graded by experienced ophthalmologists and 21 AI algorithms. RESULTS: Most eyes, 183 out of 312 (58.7%), had no DR and mild NPDR was noted in 21 (6.7%) of the eyes. Moderate NPDR was detected in 66 (21.2%) of the eyes, severe NPDR in 1 (0.3%), and PDR in 41 (13.1%) composing a group of 34.6% of eyes with referable DR. The AI algorithms achieved a mean agreement of 79.4% for referable DR, but the results varied from 49.4% to 92.3%. The mean sensitivity for referable DR was 77.5% (95% CI 69.1-85.8) and specificity 80.6% (95% CI 72.1-89.2). The rate for images ungradable by AI varied from 0% to 28.2% (mean 1.9%). Nineteen out of 21 (90.5%) AI algorithms resulted in grading for DR at least in 98% of the images. CONCLUSIONS: Fundus images captured with Optomed Aurora were suitable for DR screening. The performance of the AI algorithms varied considerably emphasizing the need for external validation of screening algorithms in real-world settings before their clinical application.

What is already known on this topic? Diabetic retinopathy (DR) is a common complication of diabetes. Efficient screening and timely treatment are important to avoid the development of sight-threatening DR. The increasing number of patients with diabetes and DR poses a challenge for healthcare.What this study adds? Telemedicine, mobile handheld devices and artificial intelligence (AI)-based automated algorithms are likely to alleviate the burden by improving efficacy of DR screening programs. Reliable algorithms of high quality exist despite the variability between the solutions.How this study might affect research, practice or policy? AI algorithms improve the efficacy of screening and might be implemented to clinical use after thorough validation in a real-life setting.

Visual Outcomes of Anti-VEGF Treatment on Neovascular Age-Related Macular Degeneration: A Real-World Population-Based Cohort Study.

Neovascular age-related macular degeneration (nAMD) leads to visual impairment if not treated promptly. Intravitreal anti-VEGF drugs have revolutionized nAMD treatment in the past two decades. We evaluated the visual outcomes of anti-VEGF treatment in nAMD. A real-life population-based cohort study. The data included parameters for age, sex, age at diagnosis, laterality, chronicity, symptoms, visual outcomes, lens status, and history of intravitreal injections. A total of 1088 eyes (827 patients) with nAMD were included. Visual acuity was stable or improved in 984 eyes (90%) after an average of 36 ± 25 months of follow-up. Bevacizumab was the first-line drug in 1083 (99.5%) eyes. Vision improved ≥15 ETDRS letters in 377 (35%), >5 ETDRS letters in 309 (28%), and was stable (±5 ETDRS letters) in 298 (27%) eyes after anti-VEGF treatment. The loss of 5 ≤ 15 ETDRS letters in 44 (4%) eyes and ≥15 ETDRS letters in 60 (6%) eyes was noted. At the diagnosis of nAMD, 110 out of 827 patients (13%) fulfilled the criteria for visual impairment, whereas 179 patients (22%) were visually impaired after the follow-up. Improvement or stabilization in vision was noted in 90% of the anti-VEGF-treated eyes with nAMD. In addition, anti-VEGF agents are crucial in diminishing nAMD-related visual impairment.

Incidence and prevalence of neovascular age-related macular degeneration: 15-year epidemiological study in a population-based cohort in Finland.

BACKGROUND/OBJECTIVES: Neovascular age-related macular degeneration (nAMD) is a common cause for visual impairment in the ageing population. An increasing number of nAMD patients causes significant health burden, although intravitreal anti-VEGF agents have revolutionized nAMD treatment during the past 15 years. We aimed to define incidence and prevalence of nAMD in different age-categories in the anti-VEGF era and to estimate the number of the individuals over 75 years of age in 2050. PATIENTS AND METHODS: We conducted an epidemiological study of the nAMD cohort (n = 2121) in a Finnish population of 410,000 inhabitants. Demographic and clinical data were gathered from Oulu University Hospital's database during 2006-2020. The incidence and prevalence rates were calculated using population data from national registers. The three-year moving average of incidence of nAMD per 100,000 person years was estimated. Prevalence figures were calculated per 100,000 age-specific inhabitants. RESULTS: The average age at the diagnosis of nAMD was 788 years, and 62% of the patients were women. The incidence of nAMD was 71 (95% CI 55-90) and 102 (95% CI 88-118) per 100,000 person years in 2006 and 2020, respectively. During 2006-2020, 1.2- and 2.4-fold increases in nAMD incidence were noted in 75-84 and in 85-96 age groups, respectively. In the oldest 75-84 and 85-96 age categories the nAMD prevalence was 2865/100,000 (3%, 95% CI 2665-3079) and 2620/100,000 (3%, 95% CI 2323-2956), respectively. The proportion of the inhabitants >75 years old is estimated to increase from 10% in 2020 to 17% by 2050. CONCLUSIONS: Our results indicate constant 1.2- and 2.4-fold increases in nAMD incidence during the past 15 years in age groups of 75-84 and 85-96 years, respectively, and 3% prevalence of nAMD in 2020. An almost two-fold increase in the ageing population by the year 2050 may also predict the trends in nAMD.KEY MESSAGESThe results of the current population-based study indicate 1.2- and 2.4-fold increases in the incidence of neovascular AMD (nAMD) during the last 15 years in the Finnish population aged 75-84 and 85-96 years and 3% prevalence of nAMD in 2020.An almost two-fold increase in the number of individuals over 75 years of age by the year 2050 is estimated, which may also predict the trends in nAMD.Intravitreal anti-vascular endothelial growth factor (anti-VEGF)- agents have revolutionized the treatment and prognosis of nAMD. Timely recognition and referral of nAMD patients to ophthalmologist can ensure vision-related functionality especially among the ageing population.

Outcomes of 35-year duration of type 1 diabetes and proliferative diabetic retinopathy on functional vision and quality of life: Benefits of good glycemic control.

AIMS: To evaluate clinical outcomes, functional vision and quality of life (QoL) after 35-year duration of type 1 diabetes (T1D) and proliferative diabetic retinopathy (PDR). METHODS: A population-based cohort study of T1D. Data from laboratory tests, ophthalmic examinations, multifunctional vision-test, and 15D-QoL measurements were analysed. RESULTS: 35 % of the original cohort (n = 216) had PDR, and 48 % of them were re-evaluated. They were 41 ± 3 [34-46] years old and 62 % were males. The duration of T1D was 35 ± 4 [29-41] years. 76 % had transdermal glucose monitoring. HbA1c had decreased from 80.1 mmol/mol to 63.6 mmol/mol (p < 0.001). Visual acuity was 73-77 ETDRS-letters. Two patients had visual impairment. Visual field sensitivities were lower in PDR vs. healthy controls (23.2 ± 3.9 dB vs. 26.9 ± 1.0 dB, and 14.9 ± 5.6 dB vs. 21.0 ± 2.0 dB, respectively, p < 0.001). Contrast sensitivity was similar, but the reaction time was longer in the PDR group (490.5 ms vs. 462.8 ms, p = 0.004). QoL-parameters concerning sleeping, usual activities, discomfort and symptoms, and sexual activity had decreased, but improved for mobility and distress. CONCLUSIONS: Long-term visual prognosis and QoL remained good despite the declined functional vision caused by PDR.

Role of reactive oxygen species in the regulation of cardiac contractility.

Increased production of reactive oxygen species (ROS) has been linked to the pathogenesis of contractile dysfunction in heart failure. However, it is unclear whether ROS can regulate physiological cellular processes in the myocardium. Here, we characterized the role of endogenous ROS production in the acute regulation of cardiac contractility in the intact rat heart. In isolated perfused rat hearts, endothelin-1 (ET-1, 1nmol/L) stimulated ROS formation in the left ventricle, which was prevented by the antioxidant N-acetylcysteine and the NAD(P)H oxidase inhibitor apocynin. N-acetylcysteine, the superoxide dismutase mimetic MnTMPyP, and apocynin significantly attenuated ET-1-mediated inotropic effect, which was accompanied by inhibition of extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. Moreover, the mitochondrial K(ATP) channel blocker 5-HD, and the mitochondrial large conductance calcium activated potassium channel blocker paxilline, but not the sarcolemmal K(ATP) channel blocker HMR 1098 attenuated the inotropic response to ET-1. However, ET-1-induced ROS generation was not abolished by inhibiting mitochondrial K(ATP) channel opening. In contrast to ET-1 stimulation, the positive inotropic effect of ß(1)-adrenergic receptor agonist dobutamine (250nmol/L) was significantly augmented by N-acetylcysteine and apocynin. Moreover, dobutamine-induced phospholamban phosphorylation was markedly enhanced by apocynin. In conclusion, NAD(P)H oxidase-derived ROS play a physiological role in the acute regulation of cardiac contractility in the intact rat heart. Our results reveal that ET-1-induced increase in cardiac contractility is partially dependent on enhanced ROS generation, which in turn, activates the ERK1/2 pathway. On the other hand, ß-adrenergic receptor-induced positive inotropic effect and phospholamban phosphorylation is enhanced by NAD(P)H oxidase inhibition.

Handheld fundus camera performance, image quality and outcomes of diabetic retinopathy grading in a pilot screening study.

PURPOSE: To compare the performance and image quality of the handheld fundus camera to standard table-top fundus cameras in diabetic retinopathy (DR) screening. The reliability and diagnostic accuracy of DR grading performed by an ophthalmologist and a photographer reader were evaluated. MATERIALS AND METHODS: 157 patients with diabetes, attending screening or follow-up of DR, were evaluated by fundus photographs taken in mydriasis by Optomed Aurora and Canon or Zeiss Visucam fundus cameras. The image quality and the severity of DR were evaluated independently by an ophthalmologist and experienced photographer. The sensitivity, specificity and reliability of the assessments were determined. RESULTS: 1884 fundus images from 314 eyes were analysed. In 53% of all eyes, DR was not present. 10% had mild non-proliferative diabetic retinopathy (NPDR), 16% moderate NPDR, 6% severe NPDR and 16% proliferative diabetic retinopathy (PDR). The DR grading outcomes by Aurora highly equalled to those of Canon or Zeiss (κ = 0.93, 95% CI 0.91 to 0.94), and there was almost perfect agreement in grading between the ophthalmologist and photographer (κ = 0.96, 95% CI 0.95 to 0.97). The image quality of Aurora was sufficient for reliable assessment according to both graders in 84-88% of the cases. CONCLUSION: The Optomed Aurora fundus camera seems appropriate for DR screening. The sufficient image quality and high diagnostic accuracy for DR grading are supportive for a less expensive and easily transportable screening system for DR. Immediate image grading carried out by a photographer would further improve and speed up the screening process in all settings.

Central Nervous System and Ocular Manifestations in Puumala Hantavirus Infection.

Puumala hantavirus (PUUV), carried and spread by the bank vole (Myodes glareolus), causes a mild form of hemorrhagic fever with renal syndrome (HFRS) called nephropathia epidemica (NE). Acute high fever, acute kidney injury (AKI), thrombocytopenia, and hematuria are typical features of this syndrome. In addition, headache, blurred vision, insomnia, vertigo, and nausea are commonly associated with the disease. This review explores the mechanisms and presentations of ocular and central nervous system involvement in acute NE.

Functionally opposing roles of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in the regulation of cardiac contractility.

BACKGROUND: Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38-MAPK) have been shown to regulate various cellular processes, including cell growth, proliferation, and apoptosis in the heart. However, the function of these signaling pathways in the control of cardiac contractility is unclear. Here, we characterized the contribution of ERK1/2 and p38-MAPK to the inotropic effect of endothelin-1 (ET-1). METHODS AND RESULTS: In isolated perfused rat hearts, infusion of ET-1 (1 nmol/L) for 10 minutes increased contractility and phosphorylation of ERK1/2 and their downstream target p90 ribosomal S6 kinase (p90RSK). Suppression of ERK1/2 activation prevented p90RSK phosphorylation and attenuated the inotropic effect of ET-1. Pharmacological inhibition of epidermal growth factor receptor kinase activity abolished ET-1-induced epidermal growth factor receptor transactivation and ERK1/2 and p90RSK phosphorylation and reduced ET-1-mediated inotropic response. Moreover, inhibition of the p90RSK target Na(+)-H(+) exchanger 1 attenuated the inotropic effect of ET-1. In contrast to ERK1/2 signaling, suppression of p38-MAPK activity further augmented ET-1-enhanced contractility, which was accompanied by increased phosphorylation of phospholamban at Ser-16. CONCLUSIONS: MAPKs play opposing roles in the regulation of cardiac contractility in that the ERK1/2-mediated positive inotropic response to ET-1 is counterbalanced by simultaneous activation of p38-MAPK. Hence, selective activation of ERK1/2 signaling and inhibition of p38-MAPK signaling may represent novel means to support cardiac function in disease.

Prolactin-releasing peptide regulates cardiac contractility.

High levels of specific prolactin-releasing peptide (PrRP) binding sites have been found in the myocardium; however, the functional importance of PrRP in the regulation of cardiac function is unknown. In isolated perfused rat hearts, infusion of PrRP (1-100 nM) induced a dose-dependent positive inotropic effect. Inhibition of cAMP catabolism by IBMX, a phosphodiesterase inhibitor, failed to augment the contractile effect of PrRP. The protein phosphatase (PP1/PP2A) inhibitor calyculin A increased the inotropic response to PrRP, whereas the PP2A inhibitor okadaic acid had no effect. Ro32-0432, a protein kinase C alpha (PKC alpha) inhibitor, significantly enhanced the inotropic effect of PrRP as well as the phosphorylation of phospholamban at Ser-16. In conclusion, the present data define a hitherto unrecognized role for PrRP in the regulation of cardiovascular system by showing that PrRP exerts a direct positive inotropic effect. Moreover, our results suggest that the cAMP-independent inotropic response to PrRP is suppressed by concurrent activation of PKC alpha and PP1.

Divergent effects of losartan and metoprolol on cardiac remodeling, c-kit+ cells, proliferation and apoptosis in the left ventricle after myocardial infarction.

There is strong evidence for the use of angiotensin converting enzyme inhibitors and beta-blockers to reduce morbidity and mortality in patients with myocardial infarction (MI), whereas the effect of angiotensin receptor blockers is less clear. We evaluated the effects of an angiotensin receptor blocker losartan and a beta-blocker metoprolol on left ventricular (LV) remodeling, c-kit+ cells, proliferation, fibrosis, apoptosis, and angiogenesis using a model of coronary ligation in rats. Metoprolol treatment for 2 weeks improved LV systolic function. In contrast, losartan triggered deleterious structural remodeling and functional deterioration of LV systolic function, ejection fraction being 41% and fractional shortening 47% lower in losartan group than in controls 2 weeks after MI. The number of c-kit+ cells as well as expression of Ki-67 was increased by metoprolol. Losartan-induced thinning of the anterior wall and ventricular dilation were associated with increased apoptosis and fibrosis, while losartan had no effect on the expression of c-kit or Ki-67. Metoprolol or losartan had no effect on microvessel density. These results demonstrate that beta-blocker treatment attenuated adverse remodeling via c-kit+ cells and proliferation, whereas angiotensin receptor blocker-induced worsening of LV systolic function was associated with increased apoptosis and fibrosis in the peri-infarct region.