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To investigate the repeatability and reproducibility of manual measurements of the reflectivity of retinal layers in healthy eyes and in eyes with acute retinal vessel occlusion via spectral-domain optical coherence tomography (SD-OCT). To reflect the full spectrum of different reflectivities seen in OCT images, for each of the following conditions, exactly one patient with a healthy and an affected eye was selected: non-ischemic central retinal vein occlusion (CRVO), ischemic CRVO, incomplete, subtotal and total central retinal artery occlusion (CRAO). For all the patients, OCT images of the healthy and affected eyes were used. Each image was presented 10 times in a randomly changing sequence to all examiners (one experienced, two nonexperienced). The obtained values were analyzed via two statistical methods: Gage Repeatability & Reproducibility (Gage R&R, a measurement system analysis) and Lin’s concordance correlation coefficient (Lin’s CCC). The total gage R&R values were as follows: vitreous body (VB) 1.11%, innermost retinal layer (IMRL) 0.94%, middle retinal layer (MRL) 4.94%, inner retinal layer (IRL) 2.56% and outer retinal layer (ORL) 3.77%. The repeatability values were 0.79, 0.62, 2.80, 1.42 And 2.60, respectively. The reproducibility values were 0.32, 0.33, 2.41, 1.14 and 1.16, respectively. Our previously described method of manual measurement of SD-OCT images of retinal layers determining the level of reflectivity (and hence ischemia) in the retina without any invasive examination is reliable, repeatable, reproducible and feasible for clinical use. Registry: ClinicalTrials.gov, Protocol ID: EK 417,102,016, TRN: NCT03061526, Registration date: 19 February 2017.

Increased levels of systemic vascular endothelial growth factors (VEGFs) in patients with diabetes are associated with increased risk of microvessel disease. On the other hand, low VEGF levels after intravitreal antibody application may be associated with acute cardiovascular complications and treatment failure. Individual levels of systemic VEGF vary in a wide range depending on analytical methods and quality of diabetes control. So far only limited information exists on intraindividual fluctuations over longer periods and circadian rhythms. We analysed the intraindividual variance of VEGF-A, VEGF-C and placental growth factor (PLGF) in CTAD (citrate-theophylline-adenine-dipyridamol) plasma as well as VEGF-A in serum over a period of 6 months in patients with stable controlled type 2 diabetes (10 M, 10 F) and age and sex matched subjects with normal glucose tolerance (NGT). Furthermore, circadian levels of VEGFs were controlled hourly from 7:30 a.m. to 7:30 p.m. under standardized metabolic ward conditions. In addition, the relationship to metabolic, hormonal and inflammatory biomarkers was analyzed. VEGF-A, VEGF-C and PLGF remained stable in plasma and VEGF-A in serum over 6 months in both groups. No circadian change was observed in VEGF-A serum and plasma concentrations. A minor decrease of VEGF-C plasma levels was evident after 5 p.m. in both groups and a significant peak of PLGF concentrations occurred after lunch, which was more pronounced in T2DM. In multivariate analysis, only serum VEGF-A correlated to diabetes duration, whereas VEGF-C only correlated to HbA1c and fasting blood glucose. We did not observe significant intraindividual variances for VEGF-A in serum and VEGF-A, VEGF-C and PLGF in CTAD plasma over a period of 6 months. Taken together, a single morning measurement of systemic VEGF levels after 7:30 am appears to be a reliable parameter for the individual risk associated with abnormal VEGF concentrations in blood. NCT02325271.

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 To evaluate efficacy, durability, and safety of faricimab in Japanese patients with diabetic macular edema (DME). Study design Subgroup analysis of 2 global, multicenter, randomized, double-masked, active-comparator–controlled, phase 3 trials (YOSEMITE, NCT03622580; RHINE, NCT03622593). Methods Patients with DME were randomized 1:1:1 to intravitreal faricimab 6.0 mg every 8 weeks (Q8W), faricimab 6.0 mg per personalized treatment interval (PTI), or aflibercept 2.0 mg Q8W through week 100. Primary endpoint was best-corrected visual acuity (BCVA) change from baseline at 1 year, averaged over weeks 48, 52, and 56. This is the first time 1-year outcomes between Japanese patients (only enrolled into YOSEMITE) and the pooled YOSEMITE/RHINE cohort (N = 1891) have been compared. Results The YOSEMITE Japan subgroup included 60 patients randomized to faricimab Q8W (n = 21), faricimab PTI (n = 19), or aflibercept Q8W (n = 20). Consistent with global results, the adjusted mean (95.04% confidence interval) BCVA change at 1 year in the Japan subgroup was comparable with faricimab Q8W (+11.1 [7.6–14.6] letters), faricimab PTI (+8.1 [4.4–11.7] letters), and aflibercept Q8W (+6.9 [3.3–10.5] letters). At week 52, 13 (72%) patients in the faricimab PTI arm achieved ≥ Q12W dosing, including 7 (39%) patients receiving Q16W dosing. Anatomic improvements with faricimab were generally consistent between the Japan subgroup and pooled YOSEMITE/RHINE cohort. Faricimab was well tolerated; no new or unexpected safety signals were identified. Conclusion Consistent with global results, faricimab up to Q16W offered durable vision gains and improved anatomic and disease-specific outcomes among Japanese patients with DME.

In this study, we evaluated the anatomic and functional outcome and intraocular adverse effects after a 3-month endotamponade with Densiron 68, a mixture of F(6)H(8) with silicone oil, in complex inferior re-detachments. Forty-eight eyes of 48 patients aged 27-82 years with retinal re-detachment due to proliferative vitreoretinopathy (PVR) grades CP1 to CA7 were included. Mean duration of the Densiron endotamponade was 108.7+/-66.9 days, with a mean follow-up after removal of 102.8+/-31.9 days. Twenty-two patients (45.8%) showed stable retinal reattachment after Densiron removal. Fourteen patients (29.2%) developed retinal re-detachment after removal, generally within 1 month and in the upper circumference (n=8). In 11 patients (22.9%) recurrent re-detachment (inferior n=8) appeared during Densiron endotamponade. In one eye (2.1%) treatment was primarily unsuccessful. Visual acuity improved from mean logMAR 1.66+/-1.03 to 1.47+/-0.97 (not statistically significant, P=0.257). Side effects included temporary inflammatory reaction (n=10), fibrin accumulation (n=6), sterile hypopyon (n=2), vitreous hemorrhage (n=6), elevated IOP (n=5), emulsification (n=4) and chronic hypotony (n=4). The anatomical success rate without further interventions of 45.8% (22 of 48 patients) seems unsatisfactory. However, in evaluating the potential of Densiron, it should be considered that all patients in this study had previous surgery with standard procedures, including silicone oil, which had already failed. Intraoperative laser photocoagulation of the periphery of the upper quadrants might reduce the risk of retinal re-detachments.

The high-density silicone oil (Densiron 68), a mixture of F6H8 with silicone oil, seems to be a therapeutic option, at least in selected patients with complex inferior retinal re-detachment, where standard procedures have already failed. In an interventional case series we used Densiron as a primary endotamponade. Twelve eyes of 12 patients aged 31 years to 85 years with inferior complex rhegmatogenous retinal detachment with secondary proliferative vitreoretinopathy (PVR) grades CP2 to CA8 were included. Surgical techniques (pars plana vitrectomy, membrane peeling, retinotomy, retinectomy, endophotocoagulation, cryocoagulation, endotamponade) did not include a scleral buckling procedure (except one eye). Mean duration of the Densiron endotamponade was 78.3 +/- 29.74 days, with a mean follow up after removal of 400.6 +/- 85.4 days. After Densiron removal, four patients (33.3%) showed a stable reattached retina without further interventions, while, in six patients (50%), recurrent retinal re-detachment appeared during endotamponade, generally within 2 months. One patient (8.3%) developed re-detachment 5 months after Densiron removal. One eye (8.3%) lost light perception due to severe intraretinal fibrosis with chronic hypotonia, despite complete retinal re-attachment. Visual acuity improved from mean logarithm of the minimum angle of resolution (logMAR) of 2.95 +/- 1.21 to 1.87 +/- 1.32 (statistically significant, P = 0.022). Side effects included temporary inflammatory reaction/fibrin accumulation (n = 2/2), moderate-to-severe intraretinal fibrosis (n = 3), elevated intraocular pressure (IOP) (n = 3), emulsification (n = 2), sterile hypopyon (n = 1), vitreous haemorrhage (n = 1) and chronic hypotony (n = 1). Primary anatomical success rate of 33.3% was less encouraging than as expected. Especially, re-detachments within the posterior staphyloma in highly myopic patients were common during Densiron endotamponade. However, the surgical success increased to 75% after reintervention, even without the use of an additional encircling band. The observed adverse effects and the functional outcomes do not contraindicate the use of Densiron as an internal tamponade for a period of 3 months.

Background: High-density silicone oils are newly developed long-term tamponade agents for the treatment of complicated retinal detachment in the inferior retina. Previous studies describe satisfying anatomical and functional results. In this study we examined the largest cohort so far for a 9-month follow-up and performed a comparison to conventional silicone oil. Methods: Our study documents results and adverse effects after vitreoretinal surgery and endotamponade with Densiron® 68 in 99 cases of complicated retinal detachment. A 9-month follow-up was performed. Data of 21 patients with intraocular conventional silicone oil tamponade in complicated retinal detachment were retrospectively analyzed and served as control. Results: Anatomical success was achieved in 78 of 89 eyes (87.6%) with completed follow-up; visual acuity did not change significantly (from mean preoperative logMAR 1.88 to postoperative logMAR 1.96 (p = 0.9). Compared to control a higher anatomical success but a similar number of adverse effects were observed with heavy silicone oil in vitreous. Nevertheless, patients who received Densiron 68 twice due to redetachment showed a significantly higher rate of intraocular inflammation with the tamponade agent in situ. Conclusion: Our results support the hypothesis of Densiron 68 as potent tamponade agent for complicated retinal detachment in the inferior retinal segments especially in eyes where a previous operation failed.

Background: To investigate whether vaccination against SARS-CoV-2 is associated with the onset of retinal vascular occlusive disease (RVOD). Methods: In this multicentre study, data from patients with central and branch retinal vein occlusion (CRVO and BRVO), central and branch retinal artery occlusion (CRAO and BRAO), and anterior ischaemic optic neuropathy (AION) were retrospectively collected during a 2-month index period (1 June–31 July 2021) according to a defined protocol. The relation to any previous vaccination was documented for the consecutive case series. Numbers of RVOD and COVID-19 vaccination were investigated in a case-by-case analysis. A case–control study using age- and sex-matched controls from the general population (study participants from the Gutenberg Health Study) and an adjusted conditional logistic regression analysis was conducted. Results: Four hundred and twenty-one subjects presenting during the index period (61 days) were enrolled: one hundred and twenty-one patients with CRVO, seventy-five with BRVO, fifty-six with CRAO, sixty-five with BRAO, and one hundred and four with AION. Three hundred and thirty-two (78.9%) patients had been vaccinated before the onset of RVOD. The vaccines given were BNT162b2/BioNTech/Pfizer (n = 221), followed by ChadOx1/AstraZeneca (n = 57), mRNA-1273/Moderna (n = 21), and Ad26.COV2.S/Johnson & Johnson (n = 11; unknown n = 22). Our case–control analysis integrating population-based data from the GHS yielded no evidence of an increased risk after COVID-19 vaccination (OR = 0.93; 95% CI: 0.60–1.45, p = 0.75) in connection with a vaccination within a 4-week window. Conclusions: To date, there has been no evidence of any association between SARS-CoV-2 vaccination and a higher RVOD risk.

Purpose: To retrospectively evaluate the re-injection interval, efficacy and safety of dexamethasone (DEX) intravitreal implant 0.7 mg in the treatment of macular oedema (ME) due to retinal vein occlusion (RVO) in Germany in 2009-2012. Methods: Retrospective, multicentre, anonymised observational study of data collected from the first DEX implant 0.7 mg injection through 3-6 months following the last injection. Data were included if the patient was >18 years old, had a diagnosis of ME secondary to branch or central RVO, and received at least 2 DEX implant 0.7 mg injections during routine practice. Results: Data from 87 patients were analysed. Mean time to re-injection between first and second treatments was 5.03 months in the total RVO population, and 5.46 and 4.52 months for the branch and central RVO subpopulations, respectively. An intraocular pressure increase of >25 mm Hg was recorded in 20% of patients, and 34% of patients began treatment with anti-glaucoma medication, but surgery was not needed for this condition. Conclusions: DEX implant 0.7 mg was found to be well tolerated and effective with repeat treatments in clinical practice.

An irregular corneal surface compromises IOP measurement by Goldmann applanation tonometry. In such cases accurate measurement without corneal contact would be desirable. The new eyelid tonometer TGDc-01 measures IOP without corneal contact through the eyelid. The aim of the study was to evaluate the accuracy of the eyelid tonometer compared with Goldmann applanation tonometry (cornea thickness-corrected values) in subjects without corneal alterations. IOP was measured in 199 eyes of 103 subjects without corneal alterations by means of two different methods. Measurements with the transpalpebral tonometer TGDc-01 and the Goldmann applanation tonometer were performed within 5 min in random order. The mean difference between lid tonometry and Goldmann applanation tonometry was 0.71 mmHg, SD +/-2.467 mmHg. In the reliability analysis the intraclass correlation coefficient was 0.8620. Compared with Goldmann applanation tonometry 66.4% of the IOP readings measured by lid tonometry were in an interval of +/-2 mmHg, 81.0% in an interval of +/-3 mmHg. The maximum of deviation was -6 mmHg and +6 mmHg, respectively. The Bland and Altman plots are shown. Lid tonometry correlates sufficiently with Goldmann applanation tonometry, but in more than 10% of the measurements the IOP readings differed by more than 3 mmHg. The eyelid tonometer may be helpful as a screening tool when Goldmann applanation tonometry is not applicable.