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Management of vitreoretinal disorders (e.g., neovascular age-related macular degeneration [nAMD] and diabetic macular edema [DME]) have assumed the standard therapy of lifelong anti-VEGF injections with drugs like aflibercept, brolucizumab, ranibizumab and bevacizumab. However, the burden imposed on patients is a major deterrent for continual therapy and recovery. Faricimab, a bispecific antibody, blocking both VEGF-A and Ang-2 molecules, produces a comparable functional and anatomical results, with less injections, significantly reducing patient burden. Visual acuity, safety, adverse effects, and anatomical outcomes are discussed in the pivotal clinical trials (YOSEMITE/RHINE and TENAYA/LUCERNE), and early data from real-world studies (TRUCKEE, TAHOE, FARWIDE-DME, FARETINA and others). In YOSEMITE and RHINE, faricimab demonstrated non-inferior vision gains, better anatomical outcomes compared to aflibercept every 8 weeks. Faricimab in the personalized treatment interval (PTI), after week 96, achieved 12-week interval in 78.1% of the patients and 16-week interval in 62.3%. TENAYA and LUCERNE reported comparable best corrected visual acuity (BCVA) improvement and better anatomic outcomes during head-to-head phase, parallel to aflibercept, at its 8-week treatment schedule. Faricimab in the PTI regimen, after week 96 achieved 12-week interval in 77.8% of the patients and 16-week interval in 63.1%. Safety of faricimab has been comparable to aflibercept in these pivotal trials. Real-world data supports the data from the pivotal studies regarding the efficacy and safety profile of faricimab in heterogenous real world patient population. Moreover, in previously treated patients, it also demonstrated a faster fluid resolution, good safety profile. Considering faricimab has demonstrated anatomic and durability benefit in the treatment of nAMD and DME, additional data from ongoing extension clinical trials, AVONELLE-X and RHONE-X will help understand longer term outcomes for patients treated with faricimab as well as patients switching from aflibercept to faricimab after finishing the pivotal trials. Longer term data from the real-world studies will also continue to contribute to our understanding of long-term efficacy, safety and durability in the real world patient population.

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Recombinant adeno-associated viral vectors (rAAV) are the safest and most effective gene delivery platform to drive the treatment of many inherited eye disorders in well-characterized animal models. The use in rAAV of ubiquitous promoters derived from viral sequences such as CMV/CBA (chicken ß-actin promoter with cytomegalovirus enhancer) can lead to unwanted side effects such as pro-inflammatory immune responses and retinal cytotoxicity, thus reducing therapy efficacy. Thus, an advance in gene therapy is the availability of small promoters, that potentiate and direct gene expression to the cell type of interest, with higher safety and efficacy. In this study, we used six human mini-promoters packaged in rAAV2 quadruple mutant (Y-F) to test for transduction of the rat retina after intravitreal injection. After four weeks, immunohistochemical analysis detected GFP-labeled cells in the ganglion cell layer (GCL) for all constructs tested. Among them, Ple25sh1, Ple25sh2 and Ple53 promoted a widespread reporter-transgene expression in the GCL, with an increased number of GFP-expressing retinal ganglion cells when compared with the CMV/CBA vector. Moreover, Ple53 provided the strongest levels of GFP fluorescence in both cell soma and axons of retinal ganglion cells (RGCs) without any detectable adverse effects in retina function. Remarkably, a nearly 50-fold reduction in the number of intravitreally injected vector particles containing Ple53 promoter, still attained levels of transgene expression similar to CMV/CBA. Thus, the tested MiniPs show great potential for protocols of retinal gene therapy in therapeutic applications for retinal degenerations, especially those involving RGC-related disorders such as glaucoma.

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OBJECTIVE: To compare the anatomical results in patients with rhegmatogenous retinal detachment, at least grade B of proliferative vitreoretinopathy, and with a trans-surgical dexamethasone implant vs the control group. We also assessed the diminution of proliferative vitreoretinopathy and the final visual acuity (VA). METHOD: The patients were evaluated clinically and with optical coherence tomography for 10 months. Logistic regression analyses were performed to evaluate the effect of the dexamethasone implant on retinal detachment. Correlational analyses were explored depending on the variables' distribution, and an independent samples t-test was used to compare the VA in both groups. RESULTS: The study included 38 eyes of patients with proliferative vitreoretinopathy: 18 with the implant and 20 for the control group. The evaluation of the main objective showed significant differences (p < 0.05) in the anatomical success between the two groups (61.1% vs. 20%, treatment vs. control); odds ratio of 6.29; 95% confidence interval: 1.5- 26.8; p = 0.013; Nagelkerke's R2 = 0.225. The t-test showed a significant difference in the final VA of the patients (t = 2.047; df = 36; p = 0.048; Cohen's d = 0.66). CONCLUSIONS: Retinal redetachment was less frequent, and better VA was observed, in patients with the dexamethasone implant in comparison with the control group.

OBJETIVO: Comparar los resultados anatómicos en pacientes con desprendimiento de retina regmatógeno, vitreorretinopatía proliferativa a partir de grado B y aplicación de implante de dexametasona transquirúrgico frente a un grupo control. También se valoraron la disminución de la vitreorretinopatía proliferativa y la agudeza visual (AV) final. MÉTODO: Los pacientes se evaluaron clínicamente y con tomografía de coherencia óptica por 10 meses. Se realizaron análisis de regresión logística para evaluar el efecto del implante en el redesprendimiento de retina. Se exploraron análisis correlacionales dependiendo de la distribución de variables y se aplicó la prueba t de muestras independientes para comparar la AV en ambos grupos. RESULTADOS: Se incluyeron 38 ojos de pacientes con vitreorretinopatía proliferativa: 18 con el implante y 20 del grupo control. La evaluación del objetivo principal mostró diferencias significativas (p < 0.05) en el éxito anatómico entre ambos grupos (61.1% en los ojos con tratamiento frente a 20% en el grupo control); razón de momios de 6.29; intervalo de confianza del 95%: 1.5- 26.8; p = 0.013; R2 de Nagelkerke = 0.225. La prueba t mostró una diferencia significativa entre la AV final de los pacientes (t = 2.047; gl = 36; p = 0.048; d de Cohen = 0.66). CONCLUSIONES: Se observó menor redesprendimiento, así como mejor AV, en los pacientes con el implante de dexametasona en comparación con el grupo control.

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Leukemia is a common neoplasia that, in its progress, can have ocular involvement due to direct infiltration or secondary to hematological alterations typical of the disease. These findings are consistent with an involvement of the central nervous system and are thus related to the prognosis. Despite the existing systemic therapies, there needs to be more literature that shows the treatment in the ocular involvement of this disease. A case report of a child with ocular involvement due to treatment-refractory acute lymphoblastic leukemia, successfully managed with intravitreal methotrexate, is presented.

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PRO-169 is an anti-VEGF monoclonal antibody developed by Laboratorios Sophia that shares its sequence with Bevacizumab (BVZ); though, PRO-169 is intended for intravitreal administration. In this study, analytical characterization showed that PRO-169 had glycosylation differences in comparison to BVZ reference product (RP); since it had more content of G1F, G2F, sialic acid and high mannose. Further investigation was performed to evaluate if differences between both products would affect the efficacy and safety profile of PRO-169. PRO-169 had no alteration in its in vitro biological activity; moreover, no cytotoxicity or immunogenicity concerns should be expected as demonstrated by different orthogonal methods at analytical, in vitro and in vivo assays. These results support moving to the clinical testing of PRO-169 since no major complications will be expected with its clinical use for the treatment of ophthalmic diseases.

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This review aimed to systematically compare the efficacy and safety of intravitreal aflibercept (IVA) and vitrectomy for treating severe vitreous hemorrhage (VH) secondary to proliferative diabetic retinopathy (PDR). The review was conducted in accordance with PRISMA guidelines. A search strategy, including the MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and US National Library of Medicine databases, was developed to identify randomized controlled trials (RCTs) that compared vitrectomy and IVA for managing VH due to PDR (participant age ≥ 18 years). The primary outcome measure was the difference in the mean visual acuity between the two treatment groups at 1, 6, and 24 months. Outcome measures included clearance of VH (in weeks), the incidence of recurrent VH, and the rate of complications. The studies were evaluated using the Cochrane Bias (ROB) tool. We identified 774 articles; six articles met the inclusion criteria, and two were ultimately included (n = 239 eyes). With or without PRP, IVA injections and vitrectomy were performed in 117 and 122 eyes, respectively. The mean BCVA at one month was significantly better in the vitrectomy group (MD=0.22, CI:0.10-0.34, p=0.0003), but no difference was found at six months (MD=0.04, CI: -0.04-0.12, p=0.356). The incidence of recurrent VH was significantly higher in the IVA group (OR=5.05, CI:2.71-9.42, p<0.0001). The probability of recurrent VH was five times greater in the IVA group than that in the vitrectomy group. There were no significant differences in the overall proportions of intra- or postoperative complications (OR=0.64, CI: 0.09-4.85, p=0.669). None of the studies had a low ROB in any of the seven domains. We conclude that IVA can be considered a viable treatment modality for diabetic VH in patients with a good follow-up. Vitrectomy initially provides better visual effect, faster VH recovery, and lower VH recurrence than IVA injections.

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INTRODUCTION: Diabetic retinopathy is a major cause of visual loss worldwide. The most important clinical findings include diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). AREAS COVERED: PubMed was used for our literature review. Articles from 1995 to 2023 were included. Pharmacologic treatment of diabetic retinopathy generally involves the use of intravitreal anti-vascular endothelial growth factor (VEGF) therapy for DME and PDR. Corticosteroids remain important second-line therapies for patients with DME. Most emerging therapies focus on newly identified inflammatory mediators and biochemical signaling pathways involved in disease pathogenesis. EXPERT OPINION: Emerging anti-VEGF modalities, integrin antagonists, and anti-inflammatory agents have the potential to improve outcomes with reduced treatment burdens.

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PURPOSE: To compare accuracy, precision, and residual volume of commonly used syringes for intravitreal injections (IVIs) and to assess the intraocular pressure (IOP) rise by variations in volumes delivered. DESIGN: Experimental laboratory study. SUBJECTS: No subjects were involved in this study. METHODS: We tested 8 syringe models with 2 different needle setups, with 2 different solutions (distilled water or glycerin) and target volumes (50 and 70 µL). To obtain the delivered and residual volumes, we weighed the syringe-needle setups with scale before liquid withdrawal, with liquid, and after liquid release. We also created an experimental eye model to determine the transient rise in IOP following stepwise 10-µL increases in injection volumes. MAIN OUTCOME MEASURES: Delivered and residual volumes, IOP rise. RESULTS: We tested a total of 600 syringe-needle setups. Becton Dickinson (BD) Ultra-Fine (0.34 ± 0.28 µL), Zero Residual (1.53 ± 1.15 µL), and Zero Residual Silicone Oil-free (1.40 ± 1.16 µL) syringes showed the lowest residual volume (P < 0.001) in comparison with the others (range: 24.86 ± 1.78 µL for Injekt-F to 51.97 ± 3.37 µL for Omnifix-F). The most accurate setups were (percentage deviation from target volume): Zero Residual Silicone Oil-free (+ 0.70%), Zero Residual 0.3 ml (+ 4.49%), BD Ultra-Fine (+ 7.83%), Injekt-F (9.42%), Norm-Ject (+ 15.88%), Omnifix-F (+ 16.96%), BD Plastipak Brazil (+17.96%), and BD Plastipak Spain syringes (+ 19.41%). There was a statistically significant difference between the Zero Residual Silicone Oil-free syringe and all other syringes (P < 0.0001), except for the Zero Residual 0.3-ml syringe (P = 0.029). The coefficient of variation was low for all syringes. The modeled IOP rise ranged from 32.3 (standard deviation [SD], 1.4) mmHg for 20-µL injection volume to 76.5 (SD, 1.0) mmHg for 80-µL injection volume. For the standard 50-µL injection volume, the peak pressure was 50.7 (SD, 0.1) mmHg, and the pressure rise duration was 28 (SD, 2) minutes. CONCLUSIONS: There were significant differences in accuracy and residual volume between syringes, whereas they showed a high precision. Volume excess results in a considerable increase in IOP rise after injection. These findings may provide a relevant overview to clinicians and to both device and drug manufacturers regarding pharmacoeconomic, safety, and efficacy issues. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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ABSTRACT Staphylococcus hominis (S. hominis) is a coagulase-negative Staphylococci and an infrequent cause of endophthalmitis. Due to its ability to produce biofilm, especially in diabetic patients, strains may acquire antibiotic resistance. We present two cases of S. hominis endophthalmitis, one with acute endophthalmitis after intravitreal bevacizumab injection and one with chronic endophthalmitis following undiagnosed penetrating ocular trauma. Although there are only four published S. hominis endophthalmitis cases in the literature, to the best of our knowledge, there has been no previously published case after intravitreal bevacizumab.

RESUMO Staphylococcus hominis (S. hominis) é um estafilococo coagulase-negativo e uma causa pouco frequente de endoftalmite. Devido à sua capacidade de produzir biofilme, especialmente em pacientes diabéticos, cepas dessa bactéria podem adquirir resistência a antibióticos. Este relato apresenta dois casos de endoftalmite por S. hominis: um de endoftalmite aguda após injeção intravítrea de bevacizumabe e outro de endoftalmite crônica após trauma ocular penetrante não diagnosticado. Embora existam apenas quatro casos de endoftalmite por S. hominis publicados na literatura, até onde sabemos não houve nenhum caso publicado anteriormente após bevacizumabe intravítreo.

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ABSTRACT Purpose: To compare viscotrabeculotomy with anterior chamber irrigation to Ahmed glaucoma valve implantation for secondary glaucoma following silicone oil removal. Methods: A prospective study was conducted on 43 vitrectomized pseudophakic eyes with persistent glaucoma after silicone oil removal. Patients were randomized to either viscotrabeculotomy with anterior chamber irrigation or Ahmed glaucoma valve implantation. All patients were examined on day 1, week 1, and months 1, 3, 6, 9, 12, 18, and 24 postoperatively. Postoperative complications were noted. Success was defined as an intraocular pressure between 6 and 20 mmHg and with an intraocular pressure reduction of >30% compared with the preoperative intraocular pressure. Results: There were 22 eyes in the viscotrabeculotomy with anterior chamber irrigation and 21 eyes in the Ahmed glaucoma valve implantation group. The mean preoperative and postoperative intraocular pressure in the viscotrabeculotomy with anterior chamber irrigation and Ahmed glaucoma valve implantation groups were 35.5 ± 2.6 mmHg and 35.5 ± 2.4 mmHg and 16.9 ± 0.7 mmHg and 17.9 ± 0.9 mmHg respectively (p˂0.0001). There was a statistically significant intraocular pressure reduction at all follow-up time points compared to preoperative values (p˂0.0001) in both groups. The unqualified success rate in the viscotrabeculotomy with anterior chamber irrigation and Ahmed glaucoma valve implantation groups were 72.73% and 61.9%, respectively. A minimal self-limited hyphema was the most common complication. Conclusions: Both viscotrabeculotomy with anterior chamber irrigation and Ahmed glaucoma valve implantation are effective in lowering the intraocular pressure in glaucoma after silicone oil removal with viscotrabeculotomy with anterior chamber irrigation providing greater reduction, higher success rates, and minimal complications.

RESUMO Objetivo: Comparar a viscotrabeculotomia com irrigação da câmara anterior com o implante de válvula de glaucoma de Ahmed para glaucoma secundário após remoção de óleo de silicone. Métodos: Foi realizado um estudo prospectivo de 43 olhos pseudofácicos vitrectomizados com glaucoma persistente após a remoção de óleo de silicone. Os pacientes foram randomizados para viscotrabeculotomia com irrigação da câmara anterior ou implante de válvula de Ahmed. Todos os pacientes foram examinados no primeiro dia, na primeira semana e 1, 3, 6, 9, 12, 18 e 24 meses após a cirurgia. Observaram-se complicações pós-operatórias. O sucesso foi definido como uma pressão intraocular entre 6 e 20 mmHg e uma redução da pressão intraocular >30% em comparação com a pressão intraocular pré-operatória. Resultados: Foram designados 22 olhos para o grupo da viscotrabeculotomia com irrigação da câmara anterior e 21 olhos para o grupo do implante de válvula de Ahmed. A pressão intraocular média pré-operatória foi de 35,5 ± 2,6 mmHg para o grupo da viscotrabeculotomia com irrigação da câmara anterior e pós- e de 35,5 ± 2,4 mmHg no grupo do implante de válvula de Ahmed. e Os valores pós-ope­ratórios foram de 16,9 ± 0,7 mmHg e 17,9 ± 0,9 mmHg para esses mesmos grupos, respectivamente (p<0,0001). Ambos os grupos tiveram uma redução estatisticamente significativa da pressão intraocular em relação aos valores pré-operatórios (p<0,0001) em todos os momentos do acompanhamento. A taxa de sucesso não qualificado nos grupos da viscotrabeculotomia com irrigação da câmara anterior e do implante de válvula de Ahmed foi de 72,73% e 61,9%, respectivamente. A complicação mais comum foi o hifema, autolimitado e mínimo. Conclusões: Tanto a viscotrabeculotomia com irrigação da câmara anterior quanto o implante de válvula de Ahmed são eficazes na redução da pressão intraocular no glaucoma após injeção de óleo de silicone, mas a viscotrabeculotomia com irrigação em câmara anterior proporcionou maior redução da pressão intraocular e maiores taxas de sucesso, com complicações mínimas.

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ABSTRACT Purpose: We aimed to evaluate the factors influencing the visual gain following pars plana vitrectomy for vitreous hemorrhage in patients with proliferative diabetic retinopathy. Methods: A retrospective study was conducted on 172 eyes of 143 consecutive patients with diabetes mellitus between January 2012 and January 2018. Demographic data, ophthalmological findings, surgery details, and visual outcomes were gathered after consulting the patients' records. The main outcome measured was the improvement of best corrected visual acuity and the secondary outcomes measured were rebleeding and complications. Results: Best corrected visual acuity improved in 103 eyes (59.88%), worsened in 45 eyes (26.16%), and remained unchanged in 24 eyes (13.95%). Type 2 diabetes mellitus was significantly associated with better final best corrected visual acuity (p=0.0244). Previous treatment by pan-retinal laser photocoagulation or intravitreal bevacizumab determined better final best corrected visual acuity, but not significantly (p>0.05). Preoperative rubeosis iridis and neovascular glaucoma did not influence the outcomes. The lack of fibrovascular proliferation requiring dissection was a significant factor for better final best corrected visual acuity (p=0.0006). Rebleeding occurred in 37.1% of the eyes and it was not influenced by the antiplatelet drugs (p>0.05). Postoperative neovascular glaucoma was a negative prognostic factor (p=0.0037). Conclusion: The final best corrected visual acuity was influenced positively by type 2 diabetes mellitus and the absence of preoperative extensive fibrovascular proliferation and negatively by postoperative neovascular glaucoma.

RESUMO Objetivo: Avaliar os fatores que influenciam o ganho visual após vitrectomia via pars plana para hemorragia vítrea em pacientes com retinopatia diabética proliferativa. Métodos: Foi realizado um estudo retrospectivo de 172 olhos de 143 pacientes consecutivos com diabetes mellitus entre janeiro de 2012 e janeiro de 2018. Dados demográficos, achados oftalmológicos, detalhes da cirurgia e resultados visuais foram coletados através de consulta aos prontuários dos pacientes. A principal medida de desfecho foi o aumento da melhor acuidade visual corrigida e as medidas de desfecho secundário foram a recidiva da hemorragia e a ocorrência de complicações. Resultados: A melhor acuidade visual corrigida aumentou em 103 olhos (59,88%), diminuiu em 45 olhos (26,16%) e permaneceu inalterada em 24 olhos (13,95%). O diabetes mellitus tipo 2 foi significativamente associado a maiores valores finais da melhor acuidade visual corrigida (p=0,0244). O tratamento prévio por fotocoagulação panretiniana com laser ou bevacizumabe intravítreo determinou maiores valores da melhor acuidade visual final corrigida, mas não significativamente (p>0,05). A presença de rubeose iridiana pré-operatória ou de glaucoma neovascular não influenciou os desfechos. A ausência de proliferação fibrovascular com necessidade de dissecção foi um fator significativo para maiores valores da melhor acuidade visual final corrigida (p=0,0006). Ocorreu recidiva da hemorragia em 37,1% dos olhos e não foi influenciada por fármacos antiplaquetários (p>0,05). O glaucoma neovascular pós-operatório foi um fator prognóstico negativo (p=0,0037). Conclusão: O resultado final da melhor acuidade visual corrigida foi influenciado positivamente pelo diabetes mellitus tipo 2 e pela ausência de proliferação fibrovascular extensa no pré-operatório, e negativamente pela ocorrência de glaucoma neovascular pós-operatório.

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PURPOSE: The aim of this study is to investigate the safety of combined intravitreal injection of dexamethasone aqueous-solution (IVD) and bevacizumab (IVB) in patients with refractory diabetic macular edema (DME) and its effect on intraocular pressure (IOP), best-corrected visual acuity (BCVA) and central subfield thickness (CSFT). METHODS: This prospective study included 10 patients (10 eyes) with DME refractory to laser photocoagulation and/or anti-vascular endothelial growth factor (anti-VEGF) therapy. A complete ophthalmological examination was performed at baseline, during the first week of treatment, and monthly through week 24. Therapy consisted of monthly injections of combined IVD and IVB "pro re nata" (PRN) if CST > 300 µm. We investigated the impact of the injections on intraocular pressure (IOP), cataract development, Early Treatment Diabetic Retinopathy Study (ETDRS) best corrected visual acuity (BCVA), and central sub-foveal thickness (CSFT) measured by spectral-domain optical coherence tomography (OCT). RESULTS: Eight patients (80%) completed 24 weeks of follow-up. Compared to baseline, mean IOP increased significantly (p < 0.05) and anti-glaucomatous eye drops were necessary for 50% of the patients, CSFT was significantly reduced at all follow-up visits (p < 0.05), although mean BCVA showed no significant improvement. One patient developed dense cataract progression and another showed vitreoretinal traction at week 24. No inflammation or endophthalmitis was observed. CONCLUSION: Treatment of DME refractory to laser and/or anti-VEGF therapy with combined PRN IV dexamethasone aqueous solution and bevacizumab was associated with adverse effects related to the use of corticosteroids. However, there was a significant improvement in CSFT meantime best-correct visual acuity remained stable or improved in 50% of patients.

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Introduction: Ocular and periocular traumatisms may result in loss of vision. Our previous work showed that therapeutic hypothermia prevents retinal damage caused by traumatic neuropathy. We also generated and characterized small molecules that elicit the beneficial effects of hypothermia at normal body temperature. Here we investigate whether one of these mimetic molecules, zr17-2, is able to preserve the function of eyes exposed to trauma. Methods: Intraorbital optic nerve crush (IONC) or sham manipulation was applied to Sprague-Dawley rats. One hour after surgery, 5.0 µl of 330 nmol/L zr17-2 or PBS, as vehicle, were injected in the vitreum of treated animals. Electroretinograms were performed 21 days after surgery and a- and b-wave amplitude, as well as oscillatory potentials (OP), were calculated. Some animals were sacrificed 6 days after surgery for TUNEL analysis. All animal experiments were approved by the local ethics board. Results: Our previous studies showed that zr17-2 does not cross the blood-ocular barrier, thus preventing systemic treatment. Here we show that intravitreal injection of zr17-2 results in a very significant prevention of retinal damage, providing preclinical support for its pharmacological use in ocular conditions. As previously reported, IONC resulted in a drastic reduction in the amplitude of the b-wave (p < 0.0001) and OPs (p < 0.05), a large decrease in the number of RGCs (p < 0.0001), and a large increase in the number of apoptotic cells in the GCL and the INL (p < 0.0001). Interestingly, injection of zr17-2 largely prevented all these parameters, in a very similar pattern to that elicited by therapeutic hypothermia. The small molecule was also able to reduce oxidative stress-induced retinal cell death in vitro. Discussion: In summary, we have shown that intravitreal injection of the hypothermia mimetic, zr17-2, significantly reduces the morphological and electrophysiological consequences of ocular traumatism and may represent a new treatment option for this cause of visual loss.

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ABSTRACT Purpose: Since particles are released in syringes during intravitreal injections, we assessed them quantitatively after agitating syringes commonly used for intravitreal injections. Methods: With and without agitation, the SR 1-ml insulin, Becton-Dickinson Ultra-Fine 0.3-ml Short Needle with a half-unit scale, HSW Norm-Ject Tuberculin, and Becton-Di­ckinson 1-ml Luer Lok Tip were examined with buffer and bevacizumab, aflibercept, and ziv-aflibercept. Flow imaging microscopy was performed to assess the particle numbers, concentrations, morphology, and size distribution. Results: Using the Becton-Dickinson Ultra-Fine syringe, the average particle count after agitation was higher than in the no-agitation group. For particles greater than 10 and 25 µm, differences were observed using the SR syringe between the two studied conditions. There were no significant differences in the means for the other syringes. Without agitation, the SR syringe had the highest number of particles (2,417,361.7 ± 3,421,575.5) followed by the Becton-Dickinson Ultra-Fine with 812.530,9 ± 996.187,2. The Becton-Dickinson Luer Lok Tip and HSW Norm-Ject performed equally with 398,396.8 ± 484,239.2 and 416,016.4 ± 242,650.1 particles, respectively. Conclusions: Flicking syringes to eliminate air bubbles results in increased numbers of particles released during intravitreal injections into the human vitreous.

RESUMO Objetivo: Visto que partículas são liberadas nas seringas durante as injeções intravítreas (IVIs), estas foram avaliadas quantitativamente após a agitação das seringas mais comumente usadas para injeções intravítreas. Métodos: A seringa SR de 1 ml de insulina, a agulha curta Becton-Dickinson Ultra-Fine 0,3 ml com escala de meia unidade, HSW Norm-Ject Tuberculin e a Becton-Dickinson Luer Lok Tip de 1 ml foram estudadas com placedo e com bevacizumabe, aflibercept e ziv-aflibercept, com e sem agitação. MicroFlow Imaging Mi­croscopy foi realizada para avaliar o número de partículas, con­centração, morfologia e distribuição das mesmas por tamanho. Resultados: A contagem média de partículas após agitação foi maior do que no grupo sem agitação usando a seringa Becton-Di­ckinson Ultra-Fine. Diferenças foram observadas usando a seringa SR entre as duas condições estudadas para partículas maiores que 10 e 25 µm. Para as demais seringas, não foram observadas diferenças significativas nas médias. A seringa SR apresentou o maior número de partículas sem agitação (2.417.361,7 ± 3.421.575,5) seguida da Becton-Dickinson Ultra-Fine com 812.530,9 ± 996.187,2. A BD Luer Lok Tip e a HSW Norm-Ject se comportaram de forma semelhante com 398.396,8 ± 484.239,2 e 416.016,4 ± 242.650,1 partículas, respectivamente. Conclusões: Agitar seringas para remover bolhas de ar resulta em um maior número de partículas liberadas durante Becton-Dickinson no vítreo humano.

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PURPOSE: To investigate ocular safety of intravitreal metoprolol in eyes with central serous chorioretinopathy. METHODS: Five eyes of five patients diagnosed with chronic central serous chorioretinopathy (cCSC) previously treated unsuccessfully with oral spironolactone, micropulse laser and intravitreal anti-vascular endothelial growth factor agents were enrolled and received off-label intravitreal metoprolol (50 µg/0.05 ml). Baseline and follow-up examinations included measurement of best-corrected visual acuity (BCVA), intraocular pressure, anterior chamber cellular/flare scores, vitritis classification, fluorescein and indocyanine green angiography, spectral domain optical coherence tomography and electroretinography (ERG), recorded by means of DTL electrodes and following the standard suggested by the International Society for Clinical Electrophysiology of Vision (ISCEV). The total follow-up period was 4 weeks. RESULTS: There were no significant differences between baseline and follow-up ERG parameters: scotopic or photopic, a- and b-wave amplitude and implicit time, nor oscillatory potentials amplitude, or whatsoever. No intraocular inflammation sign was observed. In addition, BCVA showed small improvement in 4 or kept baseline values in 1 patient. The subretinal and/or intraretinal fluid volume reduced in all patients at 1 month after treatment. CONCLUSION: Patients with refractory cCSC treated with intravitreal 50 µg/0.05 ml metoprolol showed no signs of acute ocular toxicity, along with intraretinal fluid reduction and slight BCVA improvement 1 month after injection. This data suggest that intravitreal metoprolol may be a safe alternative for cCSC.

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BACKGROUND: Noninfectious endophthalmitis may be misdiagnosed, leading to serious clinical implications. So far, its causative factors remain unknown. Therefore, this study assessed the role of silicone oil and syringe agitation in the development of inflammation after intravitreal injection of aflibercept. METHODS: A randomized, double-blind, controlled clinical trial included subjects with an indication of intravitreal antiangiogenic therapy prior to vitrectomy for proliferative diabetic retinopathy. Aflibercept was injected 48 h before surgery. The control group received the injection without agitation, while the intervention group was injected with a previously agitated syringe by flicking with either a siliconized or silicone oil-free syringe. The primary endpoint was the presence of anterior chamber reaction (ACR) at 48 h. Aqueous samples were collected and underwent cytometric bead array analysis for quantification of interleukins and chemokines. RESULTS: Forty-one individuals were included (21 in the agitation group and 20 in the no-agitation group). None of the included eyes showed baseline signs of AC cells, hyperemia or pain complaint, while 10% of control group and 80% of agitation group showed AC cells 48 h after injection of aflibercept with SR syringe. There were no differences in the mean variations of all cytokines and chemokines by agitation status. However, there was a marginally significant increase between the mean variations of IP-10 (p = 0.057) and IL-8 (p = 0.058) in the siliconized one. CONCLUSION: This clinical trial discloses a potential role of agitation and siliconized syringes in the development of inflammation after an intravitreal injection of aflibercept. These findings have important clinical implications for all healthcare practitioners who perform intravitreal injections. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials, RBR-95ddhp. Registered 12 May 2019, http://www.ensaiosclinicos.gov.br/rg/RBR-95ddhp/.

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ABSTRACT Purpose: To evaluate contrast sensitivity in non-high-risk, treatment-naïve proliferative diabetic retinopathy patients treated with panretinal photocoagulation and intravitreal injections of ranibizumab) versus panretinal photocoagulation alone. Methods: Sixty eyes of 30 patients with bilateral proliferative diabetic retinopathy were randomized into two groups: one received panretinal photocoagulation and ranibizumab injections (study group), while the other received panretinal photocoagulation alone (control group). All eyes were treated with panretinal photocoagulation in three sessions according to the Early Treatment Diabetic Retinopathy Study guidelines. Contrast sensitivity measurements were performed under photopic conditions (85 cd/m2) with the Visual Contrast Test Sensitivity 6500 chart, allowing for the evaluation of five spatial frequencies with sine wave grating charts: 1.5, 3.0, 6.0, 12.0, and 18.0 cycles per degree (cpd). Outcomes were measured in contrast sensitivity threshold scores among and within groups, from baseline to 1, 3, and 6 months. Results: Fifty-eight eyes (28 in the study group and 30 in the control group) reached the study endpoint. A comparative analysis of changes in contrast sensitivity between the groups showed significant differences mainly in low frequencies as follows: at month 1 in 1.5 cpd (p=0.001) and 3.0 cpd (p=0.04); at month 3 in 1.5 cpd (p=0.016), and at month 6 in 1.5 cpd (p=0.001) and 3.0 cpd (p=0.026) in favor of the study group. Conclusions: In eyes of patients with non-high-risk proliferative diabetic retinopathy, panretinal photocoagulation treatment with ranibizumab appears to cause less damage to contrast sensitivity compared with panretinal photocoagulation treatment alone. Thus, our evaluation of contrast sensitivity may support the use of ranabizumab as an adjuvant to panretinal photocoagulation for the treatment of proliferative diabetic retinopathy.

RESUMO Objetivos: Avaliar a sensibilidade ao contraste em pacientes virgens de tratamento com retinopatia diabética proliferativa de não alto risco, submetidos a panfotocoagulação retiniana com injeções intravítreas de ranibizumabe versus pan­fotocoagulação isolada. Métodos: Sessenta olhos de 30 pa­cientes foram randomizados em dois grupos: um submetido a panfotocoagulação com injeções de ranibizumabe (grupo estudo), e o outro submetimedo a panfotocoagulação isolada (grupo controle). Todos olhos foram tratados em 3 sessões de laser, seguindo recomendação do Early Treatment Diabetic Retinopathy Study (ETDRS). Avaliação da sensibilidade ao contraste foi realizada sob condições fotópicas (85 cd/m2) com tabela Visual Contrast Test Sensitivity 6500, permitindo avaliação de cinco frequências espaciais medidas com redes senoidais: 1.5, 3.0, 6.0, 12.0 e 18.0 ciclos por grau de ângulo visual (cpd). Foram realizadas medidas dos limiares de sensibilidade ao contraste intra e entre grupos na visita inicial, no 1º, 3º, e 6º mês de seguimento. Resultados: Cinquenta e oito olhos, 28 do grupo estudo e 30 do grupo controle, atingiram o término do estudo. Análise comparativa da SC entre os grupos mostrou diferença estatisticamente significante, nas baixas frequências espaciais, no 1º mês em 1.5 cpd (p=0,001) e 3.0 cpd (p=0,04), no 3º mês em 1.5 cpd (p=0,016) e no 6º mês em 3.0 cpd (p=0,026) a favor do grupo estudo. Conclusão: O tratamento com panfotocoagulação associada a injeção de ranibizumabe parece causar menos danos a sensibilidade ao contraste quando comparada com panfotocoagulação isolada em olhos com retinopatia diabética proliferativa de não alto risco. Dessa forma, os resultados apresentados podem justificar a associação do ranibizumabe à panfotocoagulação nestes pacientes.

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Injections are widely performed in the healthcare practice. Silicone has long been thought to be an inert and harmless material. Although used for decades in medical implants, including heart valves, breast implants, and as a tamponade for retinal detachment surgery, silicone oil might have deleterious effects. Agitation of the syringe to expel air at the moment of drug preparation not only leads to silicone oil release but also to therapeutic protein aggregation. Lab studies have shown that silicone oil microdroplets can act as an adjuvant to promote a break in immunological tolerance and induce antibody response. Similarly, recent studies have suggested a causal link between agitation of siliconized syringes and ocular inflammation after intravitreal injection. Systemically, silicone oil has been reported in association with autoimmune diseases and skin granuloma after either direct injection of dermal fillers or secondary leakage from silicone breast implant. However, it has not been established yet a potential link between the silicone oil released by the syringes and such relevant systemic adverse events. Few professionals are aware that agitation of a siliconized syringe might lead to silicone oil release, which, in turn, acts an adjuvant to an increased immunogenicity. We strongly recommend that every healthcare professional be aware of the use of silicone oil in the syringe manufacturing process, the factors that promote its release and the potential complications to the organism. Ultimately, we recommend that safer syringes be widely available.

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PURPOSE: To assess the variability of silicone oil (SO) particles released across syringes from the same lot and the role of different needle gauges. MATERIALS AND METHODS: Four syringe models and six needle models were assessed for SO release. About 50 microliters of a buffer solution were loaded into the syringe, needle or syringe/needle setup. The data were analyzed by imaging flow cytometry with fluorescently labeling for SO. RESULTS: All syringe models had a high coefficient of variation in SO release across syringes from the same lot. The amount of SO was significantly greater in the syringe when the needle was attached. SO particles with the BD 30G needle attached to the syringe were statistically greater than the 27G counterpart (p = 0.005). None of the other comparisons was statistically different. Finally, the number of SO particles was higher in the syringe/needle setup than in needles only (p = 0.0024). CONCLUSION: We found a high variability in SO content across syringes from the same lot. Additionally, there was no clear association between needle gauge and the number of SO particles, as well as their coefficient of variation. Finally, the needles accounted for a small number of SO particles in comparison to the combined syringe-needle setup.

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PURPOSE: Assessment of the anti-angiogenic activity and the safety of ophthalmic use of four pentacyclic triterpenes (friedelin, friedelinol, lupenone, and lupeol). METHODS: Triterpenes cytotoxicity (5-640 µmol L-1) was examined in ARPE-19 cells by sulforhodamine B colorimetric method, and the anti-angiogenic activity (50-1000 µmol L-1) was evaluated in the chorioallantoic membrane model. Full-field electroretinography and histological analysis were performed to evaluate intraocular effects of these four triterpenes (at 100 or 500 µmol L-1) in eyes of Wistar rats, for 15 days. RESULTS: In the cytotoxicity assay, friedelin and friedelinol were not able to drastically reduce cell growth. A dose-dependent response was observed in groups exposed to lupeol or lupenone. During the chorioallantoic membrane assay, friedelinol at 500 µmol L-1 reduced the vascularity in 26%; lupeol and lupenone showed promising anti-angiogenic activity, reducing three parameters: vascularized area (> 30%), number of junctions (> 20%), and vessel length (> 15%). According to the electroretinographic and histologic findings, triterpenes at 100 µmol L-1 or lupenone at 500 µmol L-1 did not induce any transient or permanent disturbance in retinal structure or functioning. CONCLUSIONS: Triterpenes at 100 µmol L-1 or lupenone at 500 µmol L-1 were considered safe for potential ophthalmic use.

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