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Abstract Background Osteogenesis imperfecta (OI) is a connective tissue disorder in which the Type 1 collagen is defective. The eye is a structure rich in collagen Type 1 and is heavily impacted by the disease. Many vision-threatening eye diseases have been associated with OI. The onset of these diseases also tend to occur at an earlier age in individuals with OI. Despite the research on these risks, appropriate ophthalmological screening or care guidelines for individuals with OI remain unknown. As such, the purpose of this scoping review was to explore and describe existing ophthalmological screening and care guidelines to orient OI patient care. Main body A scoping review based on the Joanna Briggs Institute (JBI) methodology was conducted. A search of databases (PubMed and Medline) was completed in consultation with a research librarian. A total of 256 studies were imported for screening. Primary sources matching the inclusion and exclusion criteria were screened, extracted, and analyzed using Covidence. Conclusion A total of 12 primary articles met inclusion and exclusion criteria, containing case reports, case series and cohort studies. Despite the risk of blindness associated with the consequences of OI on the eye, the primary literature fails to provide detailed screening and care guidelines aimed at identifying disease early. We provide general recommendations based on the review findings to guide the ophthalmological care of patients with OI and call upon the experts to convene globally to create screening guidelines. Further investigations of ophthalmological screening are warranted to limit these vision-threatening risks with early detection and treatment. Standardized ophthalmological screening guidelines for OI remain an area for research.

Abstract Introduction This study reports our experiences with systematic retinal screening in Denmark through optometrists with access to tele-ophthalmological services before, during, and after the COVID-19 pandemic. Methods We evaluated an optometrist-based retinal screening system with a referral option for tele-ophthalmological service by a consultant ophthalmologist within the time period of August 1, 2018 to September 30, 2023. The optometrist collected patient history, refraction, best-corrected visual acuity, intraocular pressure, basic slit-lamp examination, 4-in-1 visual field report, and retinal imaging using color fundus 45° photography. Tele-ophthalmological services were provided by consultant ophthalmologists. Within pre-defined periods of pre-COVID-19, COVID-19, and post-COVID-19, we evaluated the rate of referrals to the tele-ophthalmological service, diagnoses made, and referrals to the public healthcare system. Results A total of 1,142,028 unique individuals, which corresponded to 19.1% of the entire population of Denmark, underwent screening by the optometrists; 50,612 (4.4%) of these individuals were referred to the tele-ophthalmological examination by consultant ophthalmologists. A referral for further ophthalmic examination, either at hospital or at an ophthalmic practice, was made for 10,300 individuals (20.4% of those referred for tele-ophthalmology, corresponding to 0.9% of the population screened). The referral rate from the screening to the tele-ophthalmological service increased from before COVID-19 (3.4%) to during COVID-19 (4.3%) and further after COVID-19 (6.4%). This increase coincided with an increasing prevalence of conditions seen in the tele-ophthalmological service. Conclusion During a period of 5 years, 19.1% of the entire population of Denmark underwent retinal screening. This provided an adjunctive health service during a period of severe strain on the public healthcare system, while limiting the number of excessive referrals to the public healthcare system. Temporal trends illustrated an increased pattern of use of a large-scale tele-ophthalmological system.

Abstract Background To systematically review the real-world outcomes of intravitreal faricimab treatment in patients with neovascular age-related macular degeneration (nAMD) to evaluate its efficacy and safety in clinical settings. This study was conducted due to the need for real-world evidence to complement the findings from controlled clinical phase-III trials. Methods A systematic literature search was conducted on March 17, 2024, across 11 databases, utilizing search terms specifically tailored each database. All studies were reviewed qualitatively with specific focus on the outcomes of interest: the best-corrected visual acuity (BCVA), the central retina thickness (CRT), and the burden of therapy. Results We identified a total of 22 eligible studies of 1762 eyes from 1618 patients with nAMD. Studies reported that intravitreal faricimab injections maintained BCVA in patients with previously treated eyes and demonstrated statistically significant improvement in patients with treatment-naïve eyes. The CRT was reduced after intravitreal faricimab therapy. Faricimab was well-tolerated, with no significant safety concerns identified, and reduced the overall burden of therapy. Conclusion Real-world studies corroborate the conclusions drawn from phase-III trials regarding faricimab treatment, demonstrating improvement in both visual and anatomical outcomes. Additionally, no significant safety issues were identified, as the treatment was generally well-tolerated and reduced the overall burden of therapy in the real-world settings.

Abstract Diabetes is a prevalent global concern, with an estimated 12% of the global adult population affected by 2045. Diabetic retinopathy (DR), a sight-threatening complication, has spurred diverse screening approaches worldwide due to advances in DR knowledge, rapid technological developments in retinal imaging and variations in healthcare resources. Many high income countries have fully implemented or are on the verge of completing a national Diabetic Eye Screening Programme (DESP). Although there have been some improvements in DR screening in Africa, Asia, and American countries further progress is needed. In low-income countries, only one out of 29, partially implemented a DESP, while 21 out of 50 lower-middle-income countries have started the DR policy cycle. Among upper-middle-income countries, a third of 59 nations have advanced in DR agenda-setting, with five having a comprehensive national DESP and 11 in the early stages of implementation. Many nations use 2–4 fields fundus images, proven effective with 80–98% sensitivity and 86–100% specificity compared to the traditional seven-field evaluation for DR. A cell phone based screening with a hand held retinal camera presents a potential low-cost alternative as imaging device. While this method in low-resource settings may not entirely match the sensitivity and specificity of seven-field stereoscopic photography, positive outcomes are observed. Individualized DR screening intervals are the standard in many high-resource nations. In countries that lacks a national DESP and resources, screening are more sporadic, i.e. screening intervals are not evidence-based and often less frequently, which can lead to late recognition of treatment required DR. The rising global prevalence of DR poses an economic challenge to nationwide screening programs AI-algorithms have showed high sensitivity and specificity for detection of DR and could provide a promising solution for the future screening burden. In summary, this narrative review enlightens on the epidemiology of DR and the necessity for effective DR screening programs. Worldwide evolution in existing approaches for DR screening has showed promising results but has also revealed limitations. Technological advancements, such as handheld imaging devices, tele ophthalmology and artificial intelligence enhance cost-effectiveness, but also the accessibility of DR screening in countries with low resources or where distance to or a shortage of ophthalmologists exists.

Purpose: Controversy exists regarding the systemic safety of intravitreal VEGF inhibitors in the treatment of neovascular age-related macular degeneration (nAMD). We aimed to investigate the potential impact of VEGF inhibitor treatment on the risk of all-cause mortality and cardiovascular disease (CVD) among patients with nAMD. Design: A nationwide register-based cohort study with 16 years follow-up. Participants: Patients with nAMD exposed with VEGF inhibitors (n = 37 733) and unexposed individuals without nAMD (n = 1 897 073) aged ≥ 65 years residing in Denmark between January 1, 2007, and December 31, 2022. Methods: Cox proportional hazards analysis was conducted to assess the effect of intravitreal VEGF inhibitor treatment on all-cause mortality and incident CVD. Main Outcome Measures: In a predefined analysis plan we defined primary outcomes as hazard ratios (HRs) of all-cause mortality and a composite CVD endpoint in patients with nAMD treated with VEGF inhibitors compared with individuals without nAMD. The secondary outcomes encompassed analyses that explored the impact of the number of doses and the association between exposure and outcome over a specific time period. Results: Overall, 63.7% of patients with nAMD were women with an average age of 69.9 years (interquartile range 65.0–76.0 years). Patients exposed to VEGF inhibitors demonstrated a reduced risk of all-cause mortality compared with individuals without nAMD (HR, 0.79; 95% confidence interval [CI], 0.78–0.81), and an increased risk of composite CVD (HR, 1.04; 95% CI, 1.01–1.07). The decreased risk of all-cause mortality persisted, but there was no significant association between VEGF inhibitor treatment and CVD when patients with nAMD were grouped by the number of doses or considered exposed within 60 days postinjection. Conclusions: Our study revealed a decreased risk of all-cause mortality and a 4% increased risk of CVD among patients with nAMD exposed with VEGF inhibitors. The decreased risk of mortality is unlikely to be directly pathophysiologically related to VEGF inhibitor treatment. Instead, we speculate that patients undergoing VEGF inhibitor treatment are, on average, individuals in good health with adequate personal resources. Therefore, they also have a higher likelihood of overall survival. These findings strongly support the safety of VEGF inhibitor treatment in terms of all-cause mortality and CVD among patients with nAMD. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Abstract The port delivery system (PDS) of anti-VEGF therapy provides continuous delivery of ranibizumab (RBZ). In October of 2021, the American Food and Drug Administration (FDA) approved the PDS with RBZ as a treatment option for neovascular age-related macular degeneration (nAMD). As the field of PDS with RBZ is progressing rapidly, this narrative review provides a much-needed overview of existing clinical trials as well as ongoing and upcoming trials investigating PDS with RBZ. The phase 2 LADDER trial reported that the mean time to first refill with RBZ PDS 100 mg/ml was 15.8 months (80% CI 12.1–20.6), and pharmacokinetic profiling revealed a sustained concentration of RBZ in serum and aqueous humor. Later, the phase 3 ARCHWAY trial reported that PDS with RBZ (100 mg/ml) refilled every 24 weeks was non-inferior to monthly intravitreal injection (IVI) with RBZ (0.5 mg) in patients with nAMD over 9 months and 2 years. However, patients with PDS had a higher rate of adverse events including vitreous hemorrhage and endophthalmitis. Patients indicate high treatment satisfaction with both PDS and IVI, but the lower number of treatments with PDS was reported as a preferred choice. Several ongoing and future clinical trials, of which details are discussed in this paper, are further exploring the potentials of PDS with RBZ. We conclude that the PDS provides continuous deliverance of RBZ and that clinical efficacy levels are non-inferior to IVI therapy for nAMD. Yet, a higher rate of adverse events remains a concerning detail for widespread implementation. Future studies are warranted to better understand which patients may benefit best from this treatment approach, if long-term efficacy can be sustained, and if safety of PDS can be further improved.

Aims: This study reports the implementation of a diabetic retinopathy (DR) screening program in Aracaju, Brazil, emphasizing the challenges and premature termination. Methods: The program, a collaboration between local health authorities, national DR screening experts, private clinics, trained retinal imaging technicians, a portable retinal camera with artificial intelligence (AI), telemedicine, and AI-assisted image analysis, was established. Screening occurred at primary care centers, with free specialized treatment for high-risk DR cases. Results: After a public tender, two clinics were selected for screening, and four for secondary management. Initially, diabetic patient attendance at primary care clinics varied considerably, posing a challenge. Nonetheless, the screening continued, with 3,561 patients screened within six months. However, due to complaints and disputes between providers and authorities, the program was prematurely terminated, achieving less than a quarter of the initial screening target. Conclusions: The DR screening program faced significant challenges, including low adherence and organizational issues at primary care centers. This experience highlights the need to standardize clinical workflows, enhance organization and integration among primary care units, and address cultural factors to improve adherence rates. These insights are valuable for implementing screening programs, particularly in low- and middle-income countries.

Abstract Purpose Retinal artery occlusion (RAO) is a vision threatening disease associated with cerebral vascular dysfunction, which may reflect initial signs of cerebral pathology. Early detection of patients in risk of dementia could allow for preventative treatment. Hence, this study aimed to investigate RAO as an independent biomarker of incident dementia. Methods This study was a nationwide, 20-year longitudinal cohort study in Denmark with inclusion from 1998 to 2020 and follow up until the end of 2022. We identified 2 205 159 individuals aged 65 or older through the Danish national health registers and monitored RAO (exposure) and dementia (outcome) status. We calculated incidence rate and performed a Cox regression analysis with hazard ratio (HR) and 95% confidence interval (CI) for RAO as a marker of dementia in a crude, a semi-adjusted (age and sex), and a fully adjusted model (furthermore adjusted for marital status and systemic comorbidity.) Results We identified 8 863 individuals with RAO. Incidence rates were higher among exposed compared to unexposed individuals (12.28 and 8.18 per 1000 person-years at risk, respectively). Individuals with RAO were more likely to be male and older at inclusion, to have hypertension, dyslipidaemia, cardiovascular disease, chronic kidney disease, and diabetes (p

Abstract Introduction This review aims to assess the efficacy, durability and safety of faricimab—a dual vascular endothelial growth factor and angiopoietin 2 inhibitor—in patients with neovascular age-related macular degeneration (nAMD) and diabetic macula oedema (DMO). It summarises the findings of current studies on faricimab and discusses whether this new drug may fill a gap in current treatment options. Methods We performed a search of the PubMed, Cochrane, Web of Science and EMBASE databases for publications on faricimab between 29 November 2022 and 10 May 2023, and a search of ClinicalTrials.gov for the protocols on clinical trials for this review. We included clinical trials, case–control studies and observational studies. Results In phase 3 trials of nAMD, the efficacy of faricimab was non-inferior to aflibercept (+ 5.8–6.6 vs. + 5.1–6.6 Early Treatment Diabetic Retinopathy Study [ETDRS] letters). At study end, 80% of faricimab-treated patients were on ≥ 12-week dosing intervals, and 44.9–45.7% of faricimab-treated patients were on 16-week dosing intervals. Total adverse events, as well as serious ocular adverse events, were comparable between groups. In phase 3 trials of DMO, efficacy of faricimab was non-inferior to aflibercept (+ 10.7–11.8 vs. + 10.3–10.9 ETDRS letters). At study end, > 70% of patients in the personalised treatment interval faricimab group were on ≥ 12-week dosing intervals, and 51–53% were on 16-week dosing intervals. Total adverse events were comparable between groups, although the rate of serious ocular adverse events was higher in the faricimab groups than in the aflibercept groups (1.9–3.1% vs. 0.6–1.9%, respectively). In real-world studies of treatment-resistant nAMD or DMO, faricimab demonstrated superior efficacy compared to aflibercept. In a real-world study of mostly previously treated nAMD, faricimab demonstrated some efficacy. Conclusion Faricimab demonstrated non-inferior to superior efficacy, strong durability and acceptable safety in treatment-naïve nAMD and mostly treatment-naïve DMO, as well as superior efficacy in treatment-resistant nAMD and DMO. However, further research is needed on faricimab in real-world settings.

Abstract Introduction There is little understanding of long-term treatment persistence in patients receiving anti-vascular endothelial growth factor (anti-VEGF) injections for diabetic macular edema (DME), particularly relating to treatment intervals. The aim of this study was to investigate the association between treatment interval and discontinuation rate after 24 months of unilateral anti-VEGF treatment in patients with DME under routine clinical care in the USA. Methods This was a non-interventional, retrospective cohort study to review the health insurance claims of adults with DME linked with the IBM MarketScan® Commercial and Medicare Supplemental databases, who were continuously enrolled in a health plan for at least 6 months prior to their first anti-VEGF treatment and for a duration of at least 24 months between July 2011 and June 2017. Patients were grouped on the basis of the injection interval they achieved at 24 months of treatment. Discontinuation rate beyond 24 months and its association with treatment intervals at 24 months was estimated using the Kaplan–Meier method and Cox proportional hazards models. Results The overall discontinuation rate among the 1702 eligible patients from 24 to 60 months after treatment initiation was 30%. At 60 months, patients were more likely to remain on treatment in shorter (75.3% [4-week interval group]) versus longer treatment interval groups (62.1% [> 12-week interval group], difference = 13.2%, [95% confidence interval (CI) 1.06, 2.06], p = 0.01). Patients on a > 12-week interval were twice as likely to discontinue treatment compared with those on an 8-week interval (hazard ratio = 2.01 [95% CI 1.43, 2.82], p

Abstract Vascular endothelial growth factor inhibitors have substantially improved the visual outcomes in patients with macular edema (ME) caused by branch retinal vein occlusion (BRVO), but treatment outcomes are highly variable and early prediction of expected clinical outcome would be important for individualized treatment. As non-invasive metabolic, structural and functional retinal markers might act as early predictors of clinical outcomes, we performed a 12-month, prospective study aimed to evaluate if baseline retinal oximetry, optical coherence tomography angiography (OCT-A) or microperimetry were able to predict need of treatment, structural or functional outcome in patients with ME caused by treatment-näive BRVO. We evaluated 41 eyes of 41 patients with a mean age of 69.6 years and 56% females. We found a strong tendency towards a higher retinal arteriolar oxygen saturation in patients without a need of additional aflibercept treatment after the loading phase (99.8% vs. 92.3%, adjusted odds ratio 0.80 (95% confidence interval 0.64-1.00), adjusted p = 0.058), but otherwise, retinal oximetry, OCT-A or microperimetry were not able to predict need of treatment, structural nor functional outcomes. (Trial registration: clinicaltrials.gov, S-20,170,084. Registered 24 August 2014, https://clinicaltrials.gov/ct2/show/NCT03651011 )

Objectives This qualitative study aims to identify patient-reported barriers to treatment for neovascular age-related macular degeneration (nAMD) and investigate their impact on quality of life.Design Using a qualitative explorative design.Setting Semi-structured individual or dyadic interviews were conducted with patients and their relatives.Participants Twenty-one patients completed the interview, with four of them having a relative present.Interventions Gadamer’s hermeneutics guided the epistemological approach, and maximum variation sampling was employed to capture diverse patient experiences. An advisory board consisting of patients, relatives and ophthalmologists ensured the relevance of the study. Thematic analysis was conducted using NVivo software.Primary and secondary outcome measures To investigate patient-reported barriers to the recommended treatment for nAMD and impact on quality of life.Results The study included 21 patients with nAMD, with a median age of 79 years. Five themes emerged: (1) good compliance with intravitreal treatment, (2) the dual role of relatives, (3) treatment commute, (4) hospital barriers, (5) preventive health literacy.Conclusion This study highlights the resilience and adherence of patients with nAMD in Denmark to their treatment despite various barriers. While the therapy may have negative effects on their well-being, patients do not opt out of treatment. These findings underscore the importance of personalised treatment plans that provide, for example, convenient access to care and clear future agreements at the hospital. By adopting more patient-centred approaches, healthcare providers can enhance patient satisfaction and improve treatment adherence, ultimately leading to better patient outcomes and quality of life.

Purpose: To evaluate the proliferative diabetic retinopathy (PDR) progression rates and identify the demographic and clinical characteristics of patients who later developed PDR compared with patients who did not progress to that state. Design: A national 5-year register-based cohort study including 201 945 patients with diabetes. Subjects: Patients with diabetes who had attended the Danish national screening program (2013–2018) for diabetic retinopathy (DR). Methods: We used the first screening episode as the index date and included both eyes of patients with and without subsequent progression of PDR. Data were linked with various national health registries to investigate relevant clinical and demographic parameters. The International Clinical Retinopathy Disease Scale was used to classify DR, with no DR as level 0, mild DR as level 1, moderate DR as level 2, severe DR as level 3, and PDR as level 4. Main Outcome Measures: Hazard ratios (HRs) for incident PDR for all relevant demographic and clinical parameters and 1-, 3-, and 5-year incidence rates of PDR according to baseline DR level. Results: Progression to PDR within 5 years was identified in 2384 eyes of 1780 patients. Proliferative diabetic retinopathy progression rates from baseline DR level 3 at 1, 3 and 5 years were 3.6%, 10.9%, and 14.7%, respectively. The median number of visits was 3 (interquartile range, 1–4). Progression to PDR was predicted in a multivariable model by duration of diabetes (HR, 4.66 per 10 years; 95% confidence interval [CI], 4.05–5.37), type 1 diabetes (HR, 9.61; 95% CI, 8.01–11.53), a Charlson Comorbidity Index score of > 0 (score 1: HR, 4.62; 95% CI, 4.14–5.15; score 2: HR, 2.28; 95% CI, 1.90–2.74; score ≥ 3: HR, 4.28; 95% CI, 3.54–5.17), use of insulin (HR, 5.33; 95% CI, 4.49–6.33), and use of antihypertensive medications (HR, 2.23; 95% CI, 1.90–2.61). Conclusions: In a 5-year longitudinal study of an entire screening nation, we found increased risk of PDR with increasing baseline DR levels, longer duration of diabetes, type 1 diabetes, systemic comorbidity, use of insulin, and blood pressure–lowering medications. Most interestingly, we found lower risk of progression from DR level 3 to PDR compared with that in previous studies. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Migraine is a disease characterized by cerebral vasodilation. While diabetes has previously been associated with a lower risk of migraine, it is not known if diabetic retinopathy (DR), a retinal peripheral vascular occlusive disease, is a potential biomarker of protection against migraine. Therefore, we aimed to examine diabetic retinopathy as a marker of prevalent and 5-year incident migraine. In a national cohort, we compared patients with diabetes attending DR screening from The Danish National Registry of Diabetic Retinopathy (cases, n = 205,970) to an age- and gender-matched group of patients without diabetes (controls, n = 1,003,170). In the cross-sectional study, a multivariable model demonstrated a lower prevalence of migraine among cases compared with controls (OR 0.83, 95% CI 0.81–0.85), with a lower risk in cases with DR than in those without (OR 0.69, 95% CI 0.65–0.72). In the prospective study, a lower risk of incident migraine was found in a multivariable model in cases (HR 0.76, 95% CI 0.70–0.82), but this did not depend upon the presence of DR. To conclude, in a national study of more than 1.2 million people, patients screened for DR had a lower risk of present migraine, but DR was not a protective marker of incident migraine.

Purpose: Diabetic retinopathy (DR) is a hypoxic retinal disease, but so far, the association with systemic hypoxia is poorly understood. Hence, the aim of this study was to evaluate cross-sectional and longitudinal associations between DR and chronic respiratory failure (CRF) in a national cohort. Design: Cross-sectional and 5-year longitudinal register-based cohort study. Methods: Between 2013 and 2018, we included patients with diabetes from the Danish Registry of Diabetic Retinopathy, who were each age and sex matched with five controls without diabetes. At index date, the prevalence of CRF was compared between cases and controls, and the longitudinal relationship between DR and CRF was assessed in a five-year follow-up. Results: At baseline, we identified 1,980 and 9,990 patients with CRF among 205,970 cases and 1,003,170 controls. The prevalence of CRF was higher among cases than controls (OR 1.75, 95% CI 1.65–1.86), but no difference between cases with and without DR was found.During follow-up, we identified 1,726 and 5,177 events of CRF among cases and controls, respectively. The incidence of CRF was higher among both cases with and without DR compared to controls (DR level 0: HR 1.24, 95% CI 1.16–1.33, DR level 1–4: HR 1.86, 95% CI 1.63–2.12), and higher among cases with DR compared to cases without DR (HR 1.54, 95% CI 1.38–1.72). Conclusion: In this study based on nationwide data, we found an increased risk of present and incident CRF in patients with diabetes with or without DR, and we identified DR as a predictor of future CRF.

Bevacizumab is a frequently used inhibitor of vascular endothelial growth factor (VEGF) in the management of macular edema in central retinal vein occlusion (CRVO). Studying retinal protein changes in bevacizumab intervention may provide insights into mechanisms of action. In nine Danish Landrace pigs, experimental CRVO was induced in both eyes with argon laser. The right eyes received an intravitreal injection of 0.05 mL bevacizumab (n = 9), while the left control eyes received 0.05 mL saline water (NaCl). Retinal samples were collected 15 days after induced CRVO. Label-free quantification nano-liquid chromatography–tandem mass spectrometry identified 59 proteins that were regulated following bevacizumab treatment. Following bevacizumab intervention, altered levels of bevacizumab components, including the Ig gamma-1 chain C region and the Ig kappa chain C region, were observed. Changes in other significantly regulated proteins ranged between 0.58–1.73, including for the NADH-ubiquinone oxidoreductase chain (fold change = 1.73), protein-transport protein Sec24B (fold change = 1.71), glycerol kinase (fold change = 1.61), guanine-nucleotide-binding protein G(T) subunit-gamma-T1 (fold change = 0.67), and prefoldin subunit 6 (fold change = 0.58). A high retinal concentration of bevacizumab was achieved within 15 days. Changes in the additional proteins were limited, suggesting a narrow mechanism of action.

Purpose: To examine the real-world performance of a support vector machine learning software (RetinaLyze) in order to identify the possible presence of diabetic retinopathy (DR) in patients with diabetes via software implementation in clinical practice. Methods: 1001 eyes from 1001 patients—one eye per patient—participating in the Danish National Screening Programme were included. Three independent ophthalmologists graded all eyes according to the International Clinical Diabetic Retinopathy Disease Severity Scale with the exact level of disease being determined by majority decision. The software detected DR and no DR and was compared to the ophthalmologists’ gradings. Results: At a clinical chosen threshold, the software showed a sensitivity, specificity, positive predictive value and negative predictive value of 84.9% (95% CI: 81.8–87.9), 89.9% (95% CI: 86.8–92.7), 92.1% (95% CI: 89.7–94.4), and 81.0% (95% CI: 77.2–84.7), respectively, when compared to human grading. The results from the routine screening were 87.0% (95% CI: 84.2–89.7), 85.3% (95% CI: 81.8–88.6), 89.2% (95% CI: 86.3–91.7), and 82.5% (95% CI: 78.5–86.0), respectively. AUC was 93.4%. The reference graders Conger’s Exact Kappa was 0.827. Conclusion: The software performed similarly to routine grading with overlapping confidence intervals, indicating comparable performance between the two groups. The intergrader agreement was satisfactory. However, evaluating the updated software alongside updated clinical procedures is crucial. It is therefore recommended that further clinical testing before implementation of the software as a decision support tool is conducted.

Abstract Background The purpose of this study was to evaluate the area of retinal neovascularization in patients with treatment-naïve proliferative diabetic retinopathy (PDR) as measured by optical coherence tomography angiography (OCT-A) as a marker of subsequent treatment response after panretinal photocoagulation (PRP), and to examine if this area correlated with area of retinal neovascularization as measured by fluorescein angiography (FA). Methods En face OCT-A scans (4.5 × 4.5 mm) of neovascularizations were obtained at baseline (BL) before PRP and at month (M) 3 and M6 after treatment. Progression of PDR were defined as lesion growth (assessed by ophthalmoscopy and wide-field fundus photo) or increasing leakage by Optos ultra-widefield FA, and patients were divided into two groups; progression or non-progression. Mann–Whitney U test and Wilcoxon signed-rank test were used to analyse differences between groups and between time points. Areas of retinal neovascularizations (OCT-A and FA) were calculated by algorithms developed in Python (version 3.6.8, The Python Software Foundation, USA). Results Of 21 eyes included, 14 had progression of disease. Median OCT-A area did not differ between the two groups (progression vs. non-progression) at BL (76.40 ± 162.03 vs. 72.62 ± 94.15, p = 0.43) but were statistically significantly larger in the progression group at M6 (276.69 ± 168.78 vs. 61.30 ± 70.90, p = 0.025). Median FA area did not differ in the progression vs. the non-progression group at BL (111.42 ± 143.08 vs. 60.80 ± 54.83, p = 0.05) or at M6 (200.12 ± 91.81 vs. 123.86 ± 162.16, p = 0.62). Intraclass correlation between area by OCT-A and FA was −5.99 (95% CI: −35.28–0.993), p = 0.71. Conclusions In this study of patients with treatment-naïve PDR, we showed that increasing area of retinal neovascularizations measured by OCT-A at M6 indicated progression of disease after PRP treatment. Our results suggest that area by OCT-A reflects disease activity and that it can be used as an indicator to monitor the progression of PDR over time, and to evaluate treatment response six months after PRP. Trial registration https://clinicaltrials.gov (identifier: NCT03113006). Registered April 13, 2017.

Giant cell arteritis (GCA) is a potential sight-threatening disease. Although it is associated with polymyalgia rheumatica (PMR), visual loss is not common in PMR. A retinal oximeter can be used to conduct a direct, non-invasive, in vivo assessment of the vascular system. In a cross-sectional study, we measured the retinal oxygen saturation and retinal vessel calibers in GCA patients, PMR patients, and control participants. Twenty GCA patients (38 eyes), 19 PMR patients (33 eyes), and 12 controls (20 eyes) were investigated. Images were analyzed using Oxymap Analyzer software 2.5.0 (Oxymap ehf., Reykjavik, Iceland). Groups were compared using an age- and sex-adjusted linear mixed model regression. The median (IQR) age for GCA patients was 69.0 (66.5–76.5) years, for PMR 69.0 (67.0–72.0) years, and for the controls 75.5 (71.5–81.0) years, respectively. As compared to the controls (115.3 µm), the retinal arterioles were significantly wider in patients with GCA (124.4 µm; p = 0.023) and PMR (124.8 µm; p = 0.049). No difference was found in the retinal venular caliber or vascular oxygen saturation. These results indicate that GCA and PMR patients differ similarly in the retinal arteriolar diameter compared to controls. Further studies are needed in order to clarify the underlying inflammatory mechanisms in retinal arteriolar vessels and if these parameters can be used to predict clinical outcomes.

Central retinal vein occlusion (CRVO) is a visually disabling condition resulting from a thrombus in the major outflow vessel of the eye. The inflammatory response in CRVO is effectively treated with a dexamethasone (DEX) intravitreal implant. Uncovering the proteome changes following DEX implant intervention in CRVO may identify key proteins that mediate the beneficial effects of DEX. In six Göttingen minipigs, CRVO was induced in both eyes with an argon laser using a well-established experimental model. The right eyes were treated with a DEX intravitreal implant (Ozurdex, Allergan), while the left control eyes received a sham injection. Eight weeks after DEX intervention, retinal samples were collected and analyzed with tandem mass tag-based mass spectrometry. DEX implant intervention resulted in the upregulation of peptidyl-prolyl cis–trans isomerase FKBP5 (FKBP5) and ubiquilin-4. Immunohistochemistry showed expression of FKBP5 in the nuclei in all cellular layers of the retina. Cell adhesion molecule 3, tumor necrosis factor receptor superfamily member 16, and trans-1,2-dihydrobenzene-1,2-diol dehydrogenase were downregulated following DEX intervention. The upregulation of the corticosteroid-sensitive protein FKBP5 suggests that the implant remained active at the molecular level after eight weeks of treatment. Future studies may investigate if FKBP5 regulates the efficacy and duration of the DEX implant.

Abstract Background The purpose of this study was to perform a systematic review of the current literature on simulator-based training in vitreoretinal surgery (VRS). We examined the results regarding simulated VRS and provided an overview of how the current results may be employed in VRS training. Lastly, we evaluated the quality of these results. Methods The databases of Pubmed, Embase and Cochrane Library were searched for articles in English involving simulated VRS training. A qualitative analysis was performed, since the studies which met our inclusion criteria did not allow for a quantitative meta-analysis. Results We identified 203 articles of which seven met the inclusion criteria. Of these, six studies investigated simulation with EyeSi® Surgical (VRMagic, Mannheim, Germany). Six studies reported positive performance curves. Four studies showed construct validity. One study attempted to show skill transfer from simulator to vitrectomies performed on cadavers. Methodological quality of the included studies was moderate but lacking in instrument validation. Conclusion Simulator-based training in VRS can assess and possibly assist acquisition of a variety of VRS skills. Further research is needed to support transfer from simulator to operating room. Future studies should strive to follow established validation frameworks and streamline study designs.

Aflibercept is a frequently used inhibitor of vascular endothelial growth factor (VEGF) in the treatment of macular edema following central retinal vein occlusion (CRVO). Retinal proteome changes following aflibercept intervention in CRVO remain largely unstudied. Studying proteomic changes of aflibercept intervention may generate a better understanding of mechanisms of action and uncover aspects related to the safety profile. In 10 Danish Landrace pigs, CRVO was induced in both eyes with an argon laser. Right eyes were treated with intravitreal aflibercept while left control eyes received isotonic saline water. Retinal samples were collected 15 days after induced CRVO. Proteomic analysis by tandem mass tag-based mass spectrometry identified a total of 21 proteins that were changed in content following aflibercept intervention. In retinas treated with aflibercept, high levels of aflibercept components were reached, including the VEGF receptor-1 and VEGF receptor-2 domains. Fold changes in the additional proteins ranged between 0.70 and 1.19. Aflibercept intervention resulted in a downregulation of pigment epithelium-derived factor (PEDF) (fold change = 0.84) and endoplasmin (fold change = 0.91). The changes were slight and could thereby not be confirmed with less precise immunohistochemistry and Western blotting. Our data suggest that aflibercept had a narrow mechanism of action in the CRVO model. This may be an important observation in cases when macular edema secondary to CRVO is resistant to aflibercept intervention.

Purpose: In previous smaller studies, associations were demonstrated between diabetic retinopathy (DR) and obstructive sleep apnea (OSA), but longitudinal relationships have not been evaluated in larger cohorts. The aim of the present study was to assess the cross-sectional and prospective associations between DR and OSA in a national cohort of patients with type 2 diabetes. Design: Cross-sectional and 5-year longitudinal registry-based cohort study. Participants: For cases, we included 153 238 patients with type 2 diabetes who had attended diabetic eye screening and were registered in the Danish Registry of Diabetic Retinopathy (DiaBase). Each of these were matched by 5 control participants without diabetes of the same age and gender (n = 746 148). Methods: Exposure and outcome data as well as systemic morbidity and use of medications were identified in national registers, including the DiaBase, the Danish National Patient Register, the Danish National Prescription Registry, and the Danish Civil Registration System. The index date was defined as the date of the first DR screening registered in DiaBase. Main Outcome Measures: Exposure was defined as present and level-specific DR, and main outcomes were crude, age- and gender-adjusted, and multivariable adjusted odds ratios (ORs) for prevalent OSA as well as hazard ratios (HR) for 5-year incident OSA and DR. Results: Patients with type 2 diabetes independently were more likely to have prevalent OSA (OR, 2.01; 95% confidence interval [CI], 1.95–2.08) and to develop OSA within 5 years (HR, 1.55; 95% CI, 1.46–1.64). Patients with type 2 diabetes and DR at baseline were less likely to have prevalent OSA (OR, 0.57; 95% CI, 0.52–0.62) or to demonstrate incident OSA (HR, 0.86; 95% CI, 0.74–0.99). Likewise, patients with OSA had a lower risk to develop DR (HR, 0.83; 95% CI, 0.74–0.92). Conclusions: In a registry-based national cohort study, patients with type 2 diabetes had a higher risk of OSA. However, a 43% decreased risk of prevalent OSA was demonstrated in patients with DR, and prospectively, OSA and DR both were related inversely with each other.

Objective Given the increasing burden of repetitive intravitreal injections in diabetic macular oedema (DMO) treatment, non-invasive markers of treatment outcome are needed. Hence, we aimed to examine retinal oximetry parameters as markers of need for intravitreal aflibercept in patients with DMO.Methods This study was based on data from a 12-month clinical trial including 35 eyes of 25 patients with centre involving DMO. Retinal oximetry, visual acuity (VA) and central retinal thickness (CRT) were performed at baseline (BL). Patients then received 3 monthly injections of aflibercept followed by focal/grid laser photocoagulation. From month 4 (M4) through 12 (M12), patients were followed monthly and additional injections were given pro re nata if criteria of retreatment were met. We evaluated the difference in need for intravitreal aflibercept in groups of eyes with the highest and lowest retinal arteriolar and venular oxygen saturations, respectively.Results From BL-M12, overall VA letter score improved by 8.7 (7.2–10.2). Likewise CRT reduced by 100.7 (68.2–133.3) µm and the mean number of injections was 4.3 (3.8–4.8). Overall retinal arteriolar and venular oxygen saturations were 95.7 (93.0–98.4)% and 62.7 (59.4–65.9)% at BL. Eyes with the highest retinal arteriolar oxygen saturations had significantly more injections between BL and M12 compared with eyes with the lowest retinal arteriolar oxygen saturations (5.0 (4.2–5.8) vs 3.6 (3.1–4.0), p=0.002).Conclusion Higher retinal arteriolar oxygen saturation independently predicted the need for more intravitreal aflibercept during the first year of DMO treatment and may serve as a valuable adjunctive to established procedures for retinal imaging in terms of individualised treatment plans.Trial registration number NCT02554747

Background: Damage to axonal cells releases neurofilament light chain (NFL) into the cerebrospinal fluid and plasma. The objective of this study was to investigate NFL as a potential biomarker of disease activity in neurosarcoidosis. MRIs were graded according to enhancing lesions at different central nervous system (CNS) sites. Results: In cerebrospinal fluid, levels of NFL were higher in neurosarcoidosis patients (n = 20) median 2304 pg/mL (interquartile range (IQR) 630–19,612) compared to 426 pg/mL (IQR 261-571) in extra-neurologic sarcoidosis patients (n = 20) and 336 pg/mL (IQR 194–402) in healthy controls (n = 11) (p = 0.0002). In plasma, levels of NFL were higher in neurosarcoidosis patients median 28.2 pg/mL (IQR 11.5–49.3) compared to 6.2 pg/mL (IQR 4.3–8.2) in extra-neurologic sarcoidosis patients and 7.1 pg/mL (IQR 6.2–9.0) in healthy controls (p = 0.0001). Levels in both cerebrospinal fluid and plasma were higher in neurosarcoidosis patients with moderate/severe enhancement than patients with mild enhancement on MRI (p = 0.009 and p = 0.005, respectively). To distinguish neurosarcoidosis patients from extra-neurologic patients and healthy controls, a cut-off level of 630 pg/mL in cerebrospinal fluid had 94% specificity and 79% sensitivity, while a cut-off level of 11.4 pg/mL in plasma had 97% specificity and 75% sensitivity. Conclusions: NFL levels in cerebrospinal fluid and plasma are significantly higher in neurosarcoidosis patients compared to extra-neurologic patients and healthy controls, and the levels correlate to the extent of inflammation on MRI.

The main aim of this study was to evaluate the ability of serum biomarkers to predict the worsening of retinal neurodysfunction in subjects with type 2 diabetes. For this purpose, we measured selected molecules (N-epsilon-carboxy methyl lysine (CML), laminin P1 (Lam-P1), and asymmetric dimethylarginine (ADMA)) in the serum of 341 participants of the EUROCONDOR study at baseline, 24, and 48 weeks. Retinal neurodysfunction was assessed by measuring implicit time (IT) using multifocal electroretinography, and structural changes were examined by spectral domain–optical coherence tomography. The values of IT at baseline were directly correlated with baseline serum concentrations of CML (r = 0.135, p = 0.013). Furthermore, in the placebo group, increase in CML concentration throughout follow-up correlated with the IT (r = 0.20; p = 0.03). Baseline serum levels of CML also correlated with macular retinal thickness (RT) (r = 0.231; p < 0.001). Baseline Lam-P1 levels correlated with the increase of the RT at the end of follow-up in the placebo group (r = 0.22; p = 0.016). We provide evidence that CML may be a biomarker of both retinal neurodysfunction and RT, whereas Lam-P1 was associated with RT only. Therefore, circulating levels of these molecules could provide a complementary tool for monitoring the early changes of diabetic retinopathy (DR).

The retinal vascular system is the only part of the human body available for direct, in vivo inspection. Noninvasive retinal markers are important to identity patients in risk of sight-threatening diabetic retinopathy. Studies have correlated structural features like retinal vascular caliber and fractals with micro- and macrovascular dysfunction in diabetes. Likewise, the retinal metabolism can be evaluated by retinal oximetry, and higher retinal venular oxygen saturation has been demonstrated in patients with diabetic retinopathy. So far, most studies have been cross-sectional, but these can only disclose associations and are not able to separate cause from effect or to establish the predictive value of retinal vascular dysfunction with respect to long-term complications. Likewise, retinal markers have not been investigated as markers of treatment outcome in patients with proliferative diabetic retinopathy and diabetic macular edema. The Department of Ophthalmology at Odense University Hospital, Denmark, has a strong tradition of studying the retinal microvasculature in diabetic retinopathy. In the present paper, we demonstrate the importance of the retinal vasculature not only as predictors of long-term microvasculopathy but also as markers of treatment outcome in sight-threatening diabetic retinopathy in well-established population-based cohorts of patients with diabetes.

Chronic inflammatory diseases (CIDs), including Crohn’s disease and ulcerative colitis (inflammatory bowel diseases, IBD), rheumatoid arthritis, psoriasis, psoriatic arthritis, spondyloarthritides, hidradenitis suppurativa, and immune-mediated uveitis, are treated with biologics targeting the pro-inflammatory molecule tumour necrosis factor-α (TNF) (i.e., TNF inhibitors). Approximately one-third of the patients do not respond to the treatment. Genetics and lifestyle may affect the treatment results. The aims of this multidisciplinary collaboration are to identify (1) molecular signatures of prognostic value to help tailor treatment decisions to an individual likely to initiate TNF inhibitor therapy, followed by (2) lifestyle factors that support achievement of optimised treatment outcome. This report describes the establishment of a cohort that aims to obtain this information. Clinical data including lifestyle and treatment response and biological specimens (blood, faeces, urine, and, in IBD patients, intestinal biopsies) are sampled prior to and while on TNF inhibitor therapy. Both hypothesis-driven and data-driven analyses will be performed according to pre-specified protocols including pathway analyses resulting from candidate gene expression analyses and global approaches (e.g., metabolomics, metagenomics, proteomics). The final purpose is to improve the lives of patients suffering from CIDs, by providing tools facilitating treatment selection and dietary recommendations likely to improve the clinical outcome.