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Background: A characteristic of the retinal circulation is that arterial occlusion is embolic or secondary to vasculitis but rarely or never due to in situ atherosclerosis. Therefore, retinal artery occlusion suggests the presence of cardiac or large-vessel disease outside the eye. This cohort study examined the general risk of macrovascular disease in individuals with diabetes, with or without retinal artery occlusion. Methods: We retrieved data on 992 subjects with incident retinal artery occlusion and preexisting diabetes, registered in Denmark between January 1, 2000, and December 31, 2018. Each retinal artery occlusion subject was matched for age, sex, and diabetes duration, with 5 control subjects with diabetes but without retinal artery occlusion. We performed survival analyses to compare the risk of extraocular macrovascular disease between the 2 groups in a 5-year follow-up. Results: After 1 year, the incidence of macrovascular disease in subjects with retinal artery occlusion was approximately 21 per 100 person-years (95% confidence interval [CI]: 18.11-24.29), compared to 6.25 per 100 patient-years (95% CI: 5.57-7.00) in those without retinal artery occlusion. After 5 years, the cumulative incidences of macrovascular disease were 51.2% (95% CI: 47.9-54.7%) and 29.4% (95% CI: 28.0-30.8%) in patients with diabetes with or without retinal artery occlusion, respectively. Hazard rate ratios were 3.36 (95% CI: 2.79-4.05) after 1 year and 2.27 (95% CI: 2.04-2.53) after 5 years. Conclusion: Among individuals with diabetes, those diagnosed with retinal artery occlusion had a higher general risk of macrovascular complications for at least 5 years after the occlusion event compared with those without retinal artery occlusion.

Purpose: The hospital registration of retinal artery occlusions in the Danish National Patient Registry has not previously been validated. In this study, the diagnosis codes were validated to ensure the diagnoses had an acceptable validity for research. The validation was performed both for the overall diagnosis population and at the subtype diagnosis level. Methods: The medical records for all patients with retinal artery occlusion with an incident hospital record in the years 2017–2019 in Northern Jutland (Denmark) were assessed in this population-based validation study. Furthermore, fundus images and two-person verification were assessed for the included patients when available. The positive prediction values for the overall diagnosis of retinal artery occlusion, as well as for the central or branch subtypes, were calculated. Results: A total of 102 medical records were available for review. The overall positive prediction value for a retinal artery occlusion diagnosis was 79.4% (95% CI: 70.6–86.1%), while the overall positive prediction value at the subtype diagnosis level was 69.6% (95% CI: 60.1–77.7%), with 73.3% (95% CI: 58.1–85.4%) for branch retinal artery occlusion and 71.2% (95% CI: 56.9–82.9%) for central retinal artery occlusion. For the stratified analyses at the subtype diagnosis, age, sex, diagnosis year, and primary or secondary diagnosis, the positive prediction values ranged from 73.5 to 91.7%. In the stratified analyses at the subtype level, the positive prediction values ranged from 63.3 to 83.3%. The differences among the positive prediction values of the individual strata of both analyses were not statistically significant. Conclusions: the validities of the retinal artery occlusion and subtype level diagnoses are comparable to other validated diagnoses and considered acceptable for use in research.

To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

Purpose: The global protein profile of the aqueous humor has been found to correlate with the severity of retinal vascular disease. Studying the aqueous humor in central retinal vein occlusion (CRVO) with proteomic techniques may bring insights to the molecular mechanisms underlying the condition.Methods: Aqueous humor samples from treatment naïve patients with CRVO complicated by macular edema (n = 28) and age-matched controls (n = 20) were analyzed by label-free quantification liquid chromatography - tandem mass spectrometry. Best corrected visual acuity (BCVA) was measured as logMAR, and the severity of macular edema was evaluated as central retinal thickness (CRT) with optical coherence tomography. Control samples were obtained prior to cataract surgery. Significantly changed proteins were identified by a permutation-based calculation with a false discovery rate of 0.05.Results: A total of 177 proteins were differentially expressed in CRVO. Regulated proteins were involved in complement activation, innate immune response, blood coagulation, and cell adhesion. Upregulated proteins that correlated with BCVA and CRT included fibrinogen alpha, beta, and gamma chains, fibronectin, Ig lambda-6 chain C region, Ig alpha-1 chain C region, and complement C7. Downregulated proteins that correlated negatively with BCVA, and CRT, included procollagen C-endopeptidase enhancer 1, clusterin, opticin, reelin, fibrillin-1, and cadherin-2. Monocyte differentiation antigen CD14 and lipopolysaccharide-binding protein were increased in CRVO.Conclusions: Fibrinogen chains, fibronectin, and immunoglobulin components correlated with BCVA and CRT, suggesting a multifactorial response. Protective anti-angiogenic proteins, including procollagen C-endopeptidase enhancer 1, clusterin, and opticin, were downregulated in CRVO and correlated negatively with BCVA and CRT. PURPOSE. The global protein profile of the aqueous humor has been found to correlate with the severity of retinal vascular disease. Studying the aqueous humor in central retinal vein occlusion (CRVO) with proteomic techniques may bring insights to the molecular mechanisms underlying the condition. METHODS. Aqueous humor samples from treatment naive patients with CRVO complicated by macular edema (n = 28) and age-matched controls (n = 20) were analyzed by labelfree quantification liquid chromatography - tandem mass spectrometry. Best corrected visual acuity (BCVA) was measured as logMAR, and the severity of macular edema was evaluated as central retinal thickness (CRT) with optical coherence tomography. Control samples were obtained prior to cataract surgery. Significantly changed proteins were identified by a permutation-based calculation with a false discovery rate of 0.05. RESULTS. A total of 177 proteins were differentially expressed in CRVO. Regulated proteins were involved in complement activation, innate immune response, blood coagulation, and cell adhesion. Upregulated proteins that correlated with BCVA and CRT included fibrinogen alpha, beta, and gamma chains, fibronectin, Ig lambda-6 chain C region, Ig alpha-1 chain C region, and complement C7. Downregulated proteins that correlated negatively with BCVA, and CRT, included procollagen C-endopeptidase enhancer 1, clusterin, opticin, reelin, fibrillin-1, and cadherin-2. Monocyte differentiation antigen CD14 and lipopolysaccharide-binding protein were increased in CRVO. CONCLUSIONS. Fibrinogen chains, fibronectin, and immunoglobulin components correlated with BCVA and CRT, suggesting a multifactorial response. Protective anti-angiogenic proteins, including procollagen C-endopeptidase enhancer 1, clusterin, and opticin, were downregulated in CRVO and correlated negatively with BCVA and CRT.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death over the world. There is a great need for biomarkers capable of early detection and as targets for treatment. Differential protein expression was investigated with two-dimensional gel electrophoresis (2D-PAGE) followed by identification with liquid chromatography–tandem mass spectrometry (LC-MS/MS) in CRC patient tissue from (i) the peripheral part of the tumor, (ii) the central part of the tumor as well as from (iii) a non-involved part of the colorectal tissue. The expression patterns of six identified proteins were further evaluated by one-dimensional Western blot (1D-WB) analysis of the CRC tissue. Proteins that were perturbed in expression level in the peripheral or in the central part of the tumor as compared with the non-involved part included S100A11, HNRNPF, HNRNPH1 or HNRNPH2, GSTP1, PKM and FABP1. These identified markers may have future diagnostic potential or may be novel treatment targets after further evaluation in larger patient cohorts.

PURPOSE: The Faroe Islands are home to 50,000 genetically isolated people in the North Atlantic. The prevalence of open-angle glaucoma (OAG) in the Faroese population is unknown. Consequently, we conducted a survey to determine the prevalence of OAG in the Faroese population. We also investigated the role of known glaucoma-causing genes in Faroese OAG.MATERIALS AND METHODS: We conducted a prospective survey of known and newly diagnosed glaucoma patients at the Faroese National Hospital, Landssjukrahusid, Tórshavn between October 1, 2015 to December 31, 2017. In addition we reviewed the only eye care provider in the Faroese Islands by scrutinizing electronic medical records between 2009 and June 15, 2014, October 1, 2015 and the partly overlapping prescriptions for ocular hypotensive medications in 2016 to identify patients with either a diagnosis of glaucoma, a diagnosis of ocular hypertension or a prescription for ocular hypotensive medications. Next, we prospectively confirmed diagnoses with complete eye examinations. Patient DNA samples were tested for variations in known glaucoma-causing genes [myocilin (MYOC), optineurin (OPTN), and TANK binding kinase 1 (TBK1)].RESULTS: We determined the age-related prevalence of OAG January 1, 2017 in individuals 40 years or older to be 10.7/1000 (1.07%) and highly age-related. A diagnosis of OAG was present in 264 patients, of whom 211 (79.9%) had primary OAG (including normal tension glaucoma), 49 (18.6%) had pseudoexfoliation glaucoma, and 4 (1.5%) had pigmentary glaucoma. Among patients receiving medications for glaucoma, nearly 50% had primary OAG, while the majority of the rest had ocular hypertension or secondary glaucoma. No disease-causing variants were detected in MYOC, OPTN, or TBK1.CONCLUSIONS: The calculated prevalence of OAG in the Faroe Islands was 1.07%. The absence of MYOC, OPTN, or TBK1 disease-causing variants in Faroese primary OAG patients suggests that a different, potentially unique set of genes may be contributing to the pathogenesis of glaucoma in this population.

Purpose: The superior and inferior tarsal muscles are sympathetically innervated smooth muscles. Long-term diabetes often leads to microvascular complications, such as, retinopathy and autonomic neuropathy. We hypothesized that diabetes induces (1) sympathetic paresis in the superior and inferior tarsal muscles and that this measure is associated with (2) the severity of diabetic retinopathy, (3) the duration of diabetes, and (4) autonomic function. In addition, association between the severity of retinopathy and autonomic function was investigated.Methods: Forty-eight participants with long-term type 1 diabetes and confirmed distal symmetrical polyneuropathy were included. Palpebral fissure heights were measured bilaterally in response to topically applied 10% phenylephrine to the right eye. The presence of proliferative diabetic retinopathy (PDR) or nonproliferative diabetic retinopathy and disease duration were denoted. Time and frequency derived heart rate variability parameters obtained from 24-hour continuous electrocardiography were recorded.Results: The difference in palpebral fissure heights between phenylephrine treated and untreated eyes (∆PFH) was 1.02 mm ± 0.29 (P = 0.001). The ∆PFH was significantly lower in the PDR group (0.41 mm ± 0.43 vs. 1.27 mm ± 1.0), F(1,35) = 5.26, P = 0.011. The ∆PFH was lower with increasing diabetes duration, r(37) = -0.612, P = 0.000. Further, the ∆PFH was lower with diminished autonomic function assessed as total frequency power in electrocardiogram (r = 0.417, P = 0.014), and sympathetic measures of very low (r = 0.437, P = 0.010) and low frequency power (r = 0.384, P = 0.025).Conclusions: The ∆PFH is a simple ambulatory sympathetic measure, which was associated with the presence of PDR, disease duration, and autonomic function. Consequently, ∆PFH could potentially be an inexpensive and sensitive clinical indicator of autonomic dysfunction.

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.

Retinal artery occlusion (RAO) is a devastating condition with no effective treatment. The management of RAO could potentially be improved through an in-depth understanding of the molecular alterations in the condition. This study combined advanced proteomic techniques and an experimental model to uncover the retinal large-scale protein profile of RAO. In 13 pigs, RAO was induced with an argon laser and confirmed by fluorescein angiography. Left eyes serving as controls received a sham laser without inducing occlusion. Retinal samples were collected after one, three, or six days and analyzed with liquid chromatography—tandem mass spectrometry. In RAO, 36 proteins were differentially regulated on day one, 86 on day three, and 557 on day six. Upregulated proteins included clusterin, vitronectin, and vimentin, with several proteins increasing over time with a maximum on day six, including clusterin, vimentin, osteopontin, annexin-A, signal transducer, and the activator of transcription 3. On day six, RAO resulted in the upregulation of proteins involved in cellular response to stress, hemostasis, innate immune response, and cytokine signaling. Downregulated proteins were involved in transmission across chemical synapses and visual phototransduction. This study identified the upregulation of multiple inflammatory proteins in RAO and the downregulation of proteins involved in visual pathways. Retinal artery occlusion (RAO) is a devastating condition with no effective treatment. The management of RAO could potentially be improved through an in-depth understanding of the molecular alterations in the condition. This study combined advanced proteomic techniques and an experimental model to uncover the retinal large-scale protein profile of RAO. In 13 pigs, RAO was induced with an argon laser and confirmed by fluorescein angiography. Left eyes serving as controls received a sham laser without inducing occlusion. Retinal samples were collected after one, three, or six days and analyzed with liquid chromatography—tandem mass spectrometry. In RAO, 36 proteins were differentially regulated on day one, 86 on day three, and 557 on day six. Upregulated proteins included clusterin, vitronectin, and vimentin, with several proteins increasing over time with a maximum on day six, including clusterin, vimentin, osteopontin, annexin-A, signal transducer, and the activator of transcription 3. On day six, RAO resulted in the upregulation of proteins involved in cellular response to stress, hemostasis, innate immune response, and cytokine signaling. Downregulated proteins were involved in transmission across chemical synapses and visual phototransduction. This study identified the upregulation of multiple inflammatory proteins in RAO and the downregulation of proteins involved in visual pathways.

Abstract: Proliferative diabetic retinopathy and diabetic macular edema can be a potentially sightthreatening disease if not treated correctly. It is directly correlated to the duration of diabetes and how well managed the patients' diabetes is. In the last 15 years, the treatment of diabetic eye disease has taken a quantum leap in methodology due to the group of biological agents named antivascular endothelial growth factor (anti-VEGF). The introduction of the first biological agent has revolutionized the treatment, not only in diabetic eye disease but also across most inflammatory eye diseases, causing leakage of fluid from the blood vessels i.e., in age-related macular degeneration. The availability of these biological agents, despite their considerable costs, have significantly improved the outcomes measured in visual acuity compared to more traditional treatments of diabetic retinopathy in the form of sole laser treatment and glycemic control. The agents demonstrate a favorable safety profile, but if the rarest and most severe side effects occur, there is a potential total loss of vision. This review aims to make an overview of the current pharmaceutical therapeutic options in the treatment of diabetic macular edema. This includes laser therapy, intravitreal steroids, and a primary focus on intravitreal antivascular endothelial growth factors.

Purpose Theophylline has been suggested to have a neuroprotective effect in ischemic stroke; however, results from animal stroke models and clinical trials in humans are controversial. The aim of this study was to assess the effect of theophylline on the cerebral perfusion with multiparametric magnetic resonance imaging (MRI). Methods The relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative mean transit time (rMTT) in the infarct core, penumbra, and unaffected tissue were measured using multi-parametric MRI at baseline and 3‑h follow-up in patients treated with theophylline or placebo as an add-on to thrombolytic therapy. Results No significant differences in mean rCBF, rCBV, and rMTT was found in the penumbra and unaffected tissue between the theophylline group and the control group between baseline and 3‑h follow-up. In the infarct core, mean rCBV increased on average by 0.05 in the theophylline group and decreased by 0.14 in the control group (p Conclusion The results indicate that theophylline does not change the perfusion in potentially salvageable penumbral tissue but only affects the rCBV in the infarct core. In contrast to the penumbra, the infarct core is unlikely to be salvageable, which might explain why theophylline failed in clinical trials.

Introduction Infective endocarditis (IE) has high mortality, partly due to delayed diagnosis. No biomarker can identify IE in patients with fever and clinical picture of infection. To find putative biomarkers we analyzed serum levels of two proteins found in cardiac valves, fibulin-1 (n = 696) and osteoprotegerin (n = 689) among patients on clinical suspicion of IE. Proteomic analyses were performed in 24 patients with bacteremia, 12 patients with definite IE and 12 patients with excluded IE. Methods Fibulin-1 and osteoprotegerin were studied by enzyme linked immunosorbent assay (ELISA). Proteomic analyses were conducted by 2-dimensional polyacrylamid gel electrophoresis (2D-PAGE) and label-free quantitative liquid chromatography - tandem mass spectrometry (LFQ LC-MS/MS). Controls for 2D 2D-PAGE and LFQ LC-MS/MS had bacteremia and excluded IE. Results Osteoprotegerin levels were significantly increased in IE patients compared with non-IE patients. Fibulin-1 showed no difference. 2D-PAGE showed significant differences of 6 proteoforms: haptoglobin, haptoglobin-related protein, α-2-macroglobulin, apolipoprotein A-I and ficolin-3. LFQ LC-MS/MS analysis revealed significant level changes of 7 proteins: apolipoprotein L1, complement C1q subcomponent B and C, leukocyte immunoglobulin-like receptor subfamily A member 3, neuropilin-2, multimerin-1 and adiponectin. Conclusions The concentration changes in a set of proteoforms/proteins suggest that stress and inflammation responses are perturbed in patients with IE compared to patients with bacteremia without IE.

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.

In this study we investigated brain morphology in adults with diabetic neuropathy. We aimed to characterize gray matter volume (GMV) and cortical thickness, and to explore associations between whole brain morphology and clinical characteristics. 46 adults with type 1 diabetes and distal symmetric peripheral neuropathy (DSPN) and 28 healthy controls underwent magnetic resonance imaging scans. GMV and cortical thickness were estimated using voxel-/surface-based morphometry. Associations between total GMV and clinical characteristics were explored. Adults with DSPN had reduced total GMV compared with controls (627.4 ± 4.1 mL vs. 642.5 ± 5.2 mL, P = 0.026). GMV loss was more pronounced for participants with painful neuropathy compared with controls (619.1±8.9 mL vs. 642.4±5.2 mL, P = 0.026) and for those with proliferative vs. non-proliferative retinopathy (609.9 ± 6.8 mL vs. 636.0 ± 4.7 mL, P = 0.003). Characteristics such as severity of neuropathy and decreased parietal N-acetylaspartate/creatine metabolite concentration seem to be related to GMV loss in this cohort. Regional GMV loss was confined to bilateral thalamus/putamen/caudate, occipital and precentral regions, and decreased cortical thickness was identified in frontal areas. Since the observed total GMV loss influenced with clinical characteristics, brain imaging could be useful for supplementary characterization of diabetic neuropathy. The regional brain changes could suggest that some areas are more vulnerable in this cohort.

OBJECTIVE The aim of the study was to identify factors associated with nonattendance in a Danish nationwide screening program for diabetic retinopathy among people with type 2 diabetes. RESEARCH DESIGN AND METHODS A retrospective observational study linking individual-level register data was performed. First, we compared characteristics of 156,878 people with type 2 diabetes divided into attenders and never-attenders on the basis of their screening history over a 6-year period. Second, we assessed 230,173 screening intervals within the same 6-year period. Mixed-effects models were used to investigate the effect of sociodemographic and health-related factors on the likelihood of having a nonattender interval (i.e., failing to attend screening within the recommended interval). RESULTS A total of 42,068 (26.8%) people were identified as never-attenders, having no registered eye screening over a 6-year period. Compared with attenders, never-attenders were more frequently divorced/widowed, lived in the Capital Region of Denmark, and had poorer health. A total of 62,381 (27.1%) screening intervals were identified as nonattender intervals. Both sociodemographic and health-related factors were significantly associated with the likelihood of having a nonattender interval. The largest odds ratios for nonattendance were seen for mental illness, nonwestern descent, divorce, comorbidity, and place of residence. CONCLUSIONS Our findings suggest that never- and nonattendance of screening for diabetic retinopathy are more common among people who are divorced/widowed and of poorer health. Additionally, nonattendance is more frequent among people of nonwestern decent. These population subgroups may benefit from targeted interventions aimed at increasing participation in diabetic retinopathy screening.

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.

Purpose: Liraglutide treatment has shown promising anti-inflammatory and nerve regenerative results in preclinical and clinical trials. We sought to assess if liraglutide treatment would induce nerve regeneration through its anti-inflammatory and neurotrophic mechanisms by increasing peripapillary retinal nerve fiber layer (RNFL) thickness in individuals with long-term type 1 diabetes. Methods: Secondary analyses were performed on a prospective, double-blinded, randomized, placebo-controlled trial on adults with type 1 diabetes, distal symmetric polyneuropathy (DSPN), and confirmed diabetic retinopathy, who were randomized 1:1 to either 26 weeks placebo or liraglutide treatment. The primary endpoint was a change in peripapillary RNFL thickness between treatments, assessed by optical coherence tomography. Results: Thirty-seven participants were included in the secondary analysis. No differences in mean peripapillary RNFL thickness (overall ΔMean RNFL thickness; liraglutide -1 (±8) μm (-1%) vs. placebo -1 (±5) μm (-1%), P = 0.78, n = 37) or any of the quadrants. Peripapillary RNFL thicknesses were shown between treatments in either nonproliferative (ΔMean RNFL thickness; liraglutide -1 (±5) μm (-1%) vs. placebo 0 (±4) μm (0%), P = 0.80, N = 26) or proliferative diabetic retinopathy subgroup (ΔMean RNFL thickness; liraglutide -2 (±14) μm (-3%) vs. placebo -1 (±6) μm (-2%), P = 0.88, N = 11). Conclusions: In this study, 26 weeks of liraglutide treatment did not induce measurable changes in the assessed optic nerve thickness. Thus, this methodology does not support the induction of substantial nerve regeneration in this cohort with established retinopathy and DSPN. The trial was approved by the Danish Health and Medicines Authority. Informed consent was obtained from all participants.

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.

Proteomics has gone through tremendous development during recent decades [...]

Purpose: To evaluate the risk of future stroke, myocardial infarction (MI), and death of patients with retinal artery occlusion (RAO) and the effect of various antithrombotic treatments as secondary prevention. Methods: This cohort study was based on nationwide health registries and included the entire Danish population from 2000 to 2018. All patients with RAO were identified and their adjusted risks of stroke, MI, or death in time periods since RAO were compared with those of the Danish population. Furthermore, antithrombotic treatment of patients with RAO was determined by prescription claims, and the association with the risk of stroke, MI, or death was assessed using multivariate Poisson regression models and expressed as rate ratios (RR) with 95% confidence intervals (95% CIs). Results: After inclusion, 6628 individuals experienced a first-time RAO, of whom 391 had a stroke, 66 had a MI, and 402 died within the first year after RAO. RAO was associated with an increased risk of stroke, MI, or death which persisted for more than 1 year for all three outcomes but was highest on days 3 to 14 after RAO for stroke, with an adjusted RR of 50.71 (95% CI, 41.55–61.87), and on days 14 to 90 after RAO for MI and death, with adjusted RRs of 1.98 (95% CI, 1.25–3.15) and 1.64 (95% CI, 1.28–189), respectively. Overall, antithrombotic treatment was not associated with any protective effect the first year. Conclusions: Patients with RAO had an increased risk of stroke, MI, or death. No protective effect of antithrombotic treatment was shown. Translational Relevance: These findings are relevant to the management of patients with RAO.

The serine protease high-temperature requirement protein A1 (HtrA1) is associated with protein-misfolding disorders such as Alzheimer's disease and transforming growth factor b-induced protein (TGFBIp)-linked corneal dystrophy. In this study, using several biochemical and biophysical approaches, including recombinant protein expression, LC-MS/MS and 2D-PAGE analyses and thioflavin-T (ThT) fluorescence assays for amyloid fibril detection, and FTIR assays, we investigated the role of HtrA1 both in normal TGFBIp turnover and in corneal amyloid formation. We show that HtrA1 can cleave wild-type TGFBIp but prefers amyloidogenic variants. Corneal TGFBIp is extensively processed in healthy people, resulting in C-terminal degradation products spanning the FAS1-4 domain of TGFBIp. We show here that HtrA1 cleaves the wild-type FAS1-4 domain only inefficiently, whereas the amyloidogenic FAS1-4 mutations transform this domain into a considerably better HTRA1 substrate. Moreover, HtrA1 cleavage of the mutant FAS1-4 domains generated peptides capable of forming in vitro amyloid aggregates. Significantly, these peptides have been previously identified in amyloid deposits in vivo, supporting the idea that HtrA1 is a causative agent for TGFBIp-associated amyloidosis in corneal dystrophy. In summary, our results indicate that TGFBIp is an HtrA1 substrate and that some mutations in the gene encoding TGFBIp cause aberrant HtrA1-mediated processing that results in amyloidogenesis in corneal dystrophies.

Background and Purpose: The theophylline in acute ischemic stroke trial investigated the neuroprotective effect of theophylline as an add-on to thrombolytic therapy in patients with acute ischemic stroke. The aim of this pre-planned subgroup analysis was to use predictive modeling to virtually test for differences in the follow-up lesion volumes.Materials and Methods: A subgroup of 52 patients from the theophylline in acute ischemic stroke trial with multi-parametric MRI data acquired at baseline and at 24-h follow-up were analyzed. A machine learning model using voxel-by-voxel information from diffusion- and perfusion-weighted MRI and clinical parameters was used to predict the infarct volume for each individual patient and both treatment arms. After training of the two predictive models, two virtual lesion outcomes were available for each patient, one lesion predicted for theophylline treatment and one lesion predicted for placebo treatment.Results: The mean predicted volume of follow-up lesions was 11.4 ml (standard deviation 18.7) for patients virtually treated with theophylline and 11.2 ml (standard deviation 17.3) for patients virtually treated with placebo (p = 0.86).Conclusions: The predicted follow-up brain lesions for each patient were not significantly different for patients virtually treated with theophylline or placebo, as an add-on to thrombolytic therapy. Thus, this study confirmed the lack of neuroprotective effect of theophylline shown in the main clinical trial and is contrary to the results from preclinical stroke models.

Aflibercept is an inhibitor of vascular endothelial growth factor (VEGF) used to treat macular edema following branch retinal vein occlusion (BRVO). Despite well-documented efficacy, there is limited knowledge about proteome changes following aflibercept intervention in BRVO. Proteome changes may provide insights into mechanisms of action as well as aspects related to safety profile. In seven Danish Landrace pigs, BRVO was induced with a well-established experimental model of argon laser-induced BRVO. BRVO was induced in both eyes. Three days after the induced BRVO, aflibercept was injected intravitreally in the right eyes, while the left eyes received intravitreal isotonic saline water. Retinas were collected 15 days after the induced BRVO and analyzed with label-free quantification liquid chromatography tandem mass spectrometry (LFQ LC-MS/MS). Fourteen proteins were changed in expression following aflibercept intervention in the BRVO model. LFQ LC-MS/MS identified an upregulation of DnaJ homolog subfamily C member 17 (DNAJC17) (fold change = 6.19) and a modest downregulation of isoform 2 of the protein encoded by N-myc downstream regulated gene 2 (NDRG2) (fold change = 0.40). NDRG2 was unchanged by Western blotting. In the additional significantly regulated proteins, only discrete changes were observed (fold changes 0.52–1.59). Our study is the first to report an association between aflibercept intervention and the heat shock protein DNAJC17. Our results indicate that the role of heat shock proteins in the treatment of BRVO should be further explored.

Sorting protein-related receptor containing LDLR class A repeats (SORLA; also known as LR11) exerts intraneuronal trafficking functions in the central nervous system. Recently, involvement of SORLA in retinogenesis was proposed, but no studies have examined yet in detail the expression pattern of this sorting receptor in the retina. Here, we provide a spatio-temporal characterization of SORL1 mRNA and its translational product SORLA in the postnatal mouse retina. Using stereological analysis, we confirmed previous studies showing that receptor depletion in knockout mice significantly reduces the number of cells in the inner nuclear layer (INL), suggesting that functional SORLA expression is essential for the development of this retinal strata. qPCR and Western blot analyses showed that SORL1/SORLA expression peaks at postnatal day 15, just after eye opening. Interestingly, we found that transcripts are somatically located in several neuronal populations residing in the INL and the ganglion cell layer, whereas SORLA protein is also present in the synaptic plexiform layers. In line with receptor expression in dendritic terminals, we found delayed stratification of the inner plexiform layer in knockout mice, indicating an involvement of SORLA in neuronal connectivity. Altogether, these data suggest a novel role of SORLA in synaptogenesis. Receptor dysfunctions may be implicated in morphological and functional impairments of retinal inner layer formation associated with eye disorders.

In the western world, colorectal cancer (CRC) is the third most common cause of cancer-related deaths. Survival is closely related to the stage of cancer at diagnosis striking the clinical need for biomarkers capable of early detection. To search for possible biological parameters for early diagnosis of CRC we evaluated protein expression for three CREC (acronym: Cab45, reticulocalbin, ERC-55, calumenin) proteins: reticulocalbin, calumenin, and ERC-55 in a cellular model consisting of a normal derived colon mucosa cell line, NCM460, and a primary adenocarcinoma cell line of the colon, SW480. Furthermore, this cellular model was analyzed by a top-down proteomic approach, 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and liquid chromatography&ndash, tandem mass spectrometry (LC&ndash, MS/MS) for novel putative diagnostic markers by identification of differentially expressed proteins between the two cell lines. A different colorectal carcinoma cell line, HCT 116, was used in a bottom-up proteomic approach with label-free quantification (LFQ) LC&ndash, MS/MS. The two cellular models gave sets of putative diagnostic CRC biomarkers. Various of these novel putative markers were verified with increased expression in CRC patient neoplastic tissue compared to the expression in a non-involved part of the colon, including reticulocalbin, calumenin, S100A6 and protein SET. Characterization of these novel identified biological features for CRC patients may have diagnostic potential and therapeutic relevance in this malignancy characterized by a still unmet clinical need.