Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis.

Although mutations in mitochondrial-associated genes are linked to inflammation and susceptibility to infection, their mechanistic contributions to immune outcomes remain ill-defined. We discovered that the disease-associated gain-of-function allele Lrrk2G2019S (leucine-rich repeat kinase 2) perturbs mitochondrial homeostasis and reprograms cell death pathways in macrophages. When the inflammasome is activated in Lrrk2G2019S macrophages, elevated mitochondrial ROS (mtROS) directs association of the pore-forming protein gasdermin D (GSDMD) to mitochondrial membranes. Mitochondrial GSDMD pore formation then releases mtROS, promoting a switch to RIPK1/RIPK3/MLKL-dependent necroptosis. Consistent with enhanced necroptosis, infection of Lrrk2G2019S mice with Mycobacterium tuberculosis elicits hyperinflammation and severe immunopathology. Our findings suggest a pivotal role for GSDMD as an executer of multiple cell death pathways and demonstrate that mitochondrial dysfunction can direct immune outcomes via cell death modality switching. This work provides insights into how LRRK2 mutations manifest or exacerbate human diseases and identifies GSDMD-dependent necroptosis as a potential target to limit Lrrk2G2019S-mediated immunopathology.

An Mtb-Human Protein-Protein Interaction Map Identifies a Switch between Host Antiviral and Antibacterial Responses.

Although macrophages are armed with potent antibacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage intrinsic bacterial control, and the Mtb strategies to overcome them, are poorly understood. To further study these processes, we used an affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two factors involved in Mtb pathogenesis-the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl-/- macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between antibacterial and antiviral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map for developing a deeper understanding of the intricate interactions between Mtb and its host.

Deficiency in Galectin-3, -8, and -9 impairs immunity to chronic Mycobacterium tuberculosis infection but not acute infection with multiple intracellular pathogens.

Macrophages employ an array of pattern recognition receptors to detect and eliminate intracellular pathogens that access the cytosol. The cytosolic carbohydrate sensors Galectin-3, -8, and -9 (Gal-3, Gal-8, and Gal-9) recognize damaged pathogen-containing phagosomes, and Gal-3 and Gal-8 are reported to restrict bacterial growth via autophagy in cultured cells. However, the contribution of these galectins to host resistance during bacterial infection in vivo remains unclear. We found that Gal-9 binds directly to Mycobacterium tuberculosis (Mtb) and Salmonella enterica serovar Typhimurium (Stm) and localizes to Mtb in macrophages. To determine the combined contribution of membrane damage-sensing galectins to immunity, we generated Gal-3, -8, and -9 triple knockout (TKO) mice. Mtb infection of primary macrophages from TKO mice resulted in defective autophagic flux but normal bacterial replication. Surprisingly, these mice had no discernable defect in resistance to acute infection with Mtb, Stm or Listeria monocytogenes, and had only modest impairments in bacterial growth restriction and CD4 T cell activation during chronic Mtb infection. Collectively, these findings indicate that while Gal-3, -8, and -9 respond to an array of intracellular pathogens, together these membrane damage-sensing galectins play a limited role in host resistance to bacterial infection.

A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1.

Nucleic acids from bacteria or viruses induce potent immune responses in infected cells1-4. The detection of pathogen-derived nucleic acids is a central strategy by which the host senses infection and initiates protective immune responses5,6. Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor7,8. It catalyses the synthesis of cyclic GMP-AMP (cGAMP)9-12, which stimulates the induction of type I interferons through the STING-TBK1-IRF-3 signalling axis13-15. STING oligomerizes after binding of cGAMP, leading to the recruitment and activation of the TBK1 kinase8,16. The IRF-3 transcription factor is then recruited to the signalling complex and activated by TBK18,17-20. Phosphorylated IRF-3 translocates to the nucleus and initiates the expression of type I interferons21. However, the precise mechanisms that govern activation of STING by cGAMP and subsequent activation of TBK1 by STING remain unclear. Here we show that a conserved PLPLRT/SD motif within the C-terminal tail of STING mediates the recruitment and activation of TBK1. Crystal structures of TBK1 bound to STING reveal that the PLPLRT/SD motif binds to the dimer interface of TBK1. Cell-based studies confirm that the direct interaction between TBK1 and STING is essential for induction of IFNß after cGAMP stimulation. Moreover, we show that full-length STING oligomerizes after it binds cGAMP, and highlight this as an essential step in the activation of STING-mediated signalling. These findings provide a structural basis for the development of STING agonists and antagonists for the treatment of cancer and autoimmune disorders.

The opportunistic intracellular bacterial pathogen Rhodococcus equi elicits type I interferon by engaging cytosolic DNA sensing in macrophages.

Rhodococcus equi is a major cause of foal pneumonia and an opportunistic pathogen in immunocompromised humans. While alveolar macrophages constitute the primary replicative niche for R. equi, little is known about how intracellular R. equi is sensed by macrophages. Here, we discovered that in addition to previously characterized pro-inflammatory cytokines (e.g., Tnfa, Il6, Il1b), macrophages infected with R. equi induce a robust type I IFN response, including Ifnb and interferon-stimulated genes (ISGs), similar to the evolutionarily related pathogen, Mycobacterium tuberculosis. Follow up studies using a combination of mammalian and bacterial genetics demonstrated that induction of this type I IFN expression program is largely dependent on the cGAS/STING/TBK1 axis of the cytosolic DNA sensing pathway, suggesting that R. equi perturbs the phagosomal membrane and causes DNA release into the cytosol following phagocytosis. Consistent with this, we found that a population of ~12% of R. equi phagosomes recruits the galectin-3,-8 and -9 danger receptors. Interestingly, neither phagosomal damage nor induction of type I IFN require the R. equi's virulence-associated plasmid. Importantly, R. equi infection of both mice and foals stimulates ISG expression, in organs (mice) and circulating monocytes (foals). By demonstrating that R. equi activates cytosolic DNA sensing in macrophages and elicits type I IFN responses in animal models, our work provides novel insights into how R. equi engages the innate immune system and furthers our understanding how this zoonotic pathogen causes inflammation and disease.

Management of macular oedema due to retinal vein occlusion: An evidence-based systematic review and meta-analysis.

BACKGROUND: Central retinal vein occlusion and branch retinal vein occlusion are common causes of visual loss due to associated macular oedema. The aim of this review was to assess the effectiveness of interventions improving vision and treating macular oedema in central retinal vein occlusion and branch retinal vein occlusion. METHODS: Medical search engines and clinical trial registries were systematically searched. Randomised clinical trials with ≥90 eyes and real-world outcome studies with ≥100 eyes each with ≥6 months follow-up were included. RESULTS: There were 11 randomised controlled trials evaluating treatments for central retinal vein occlusion which met the inclusion criteria and 10 for branch retinal vein occlusion. There were 10 real world outcome studies of central retinal vein occlusion and 5 real world outcome studies of branch retinal vein occlusion. Meta-analysis was performed on studies that met the defined inclusion criteria. Main outcomes were change in visual acuity at 6-, 12-, 24- and 36 months by treatment. CONCLUSIONS: Intravitreal anti-vascular endothelial derived growth factor is recommended as first line treatment over intravitreal corticosteroid due to its effectiveness and lower rate of ocular adverse events. Best outcomes are achieved when intravitreal treatment is started early. Macular laser may have an adjunctive role in branch retina vein occlusion but not central retinal vein occlusion.

Story Memory Impairment Rates and Association with Hippocampal Volumes in a Memory Clinic Population.

OBJECTIVE: Story memory tasks are among the most commonly used memory tests; however, research suggests they may be less sensitive to memory decline and have a weaker association with hippocampal volumes than list learning tasks. To examine its utility, we compared story memory to other memory tests on impairment rates and association with hippocampal volumes. METHOD: Archival records from 1617 older adults (Mage = 74.41, range = 65-93) who completed the Wechsler Memory Scale - 4th edition (WMS-IV) Logical Memory (LM), Hopkins Verbal Learning Test - Revised (HVLT-R), and Brief Visuospatial Memory Test - Revised (BVMT-R) as part of a clinical neuropsychological evaluation were reviewed. Scores >1.5 SD below age-adjusted means were considered impaired, and frequency distributions were used to examine impairment rates. A subset of participants (n = 179) had magnetic resonance imaging (MRI) data that underwent image quality assessment. Partial correlations and linear regression analyses, accounting for age, education, and total intracranial volume (TIV), examined associations between memory raw scores and hippocampal volumes. RESULTS: For delayed recall, nearly half of the sample was impaired on HVLT-R (48.8%) and BVMT-R (46.1%), whereas a little more than a third was impaired on LM (35.7%). Better performance on all three measures was related to larger hippocampal volumes (r's =. 26-.43, p's < .001). Individually adding memory scores to regression models predicting hippocampal volumes improved the model fit for all measures. CONCLUSIONS: Despite findings suggesting that story memory is less sensitive to memory dysfunction, it was not differentially associated with hippocampal volumes compared to other memory measures. Results support assessing memory using different formats and modalities in older adults.

TRIM14 Is a Key Regulator of the Type I IFN Response during Mycobacterium tuberculosis Infection.

Tripartite motif-containing proteins (TRIMs) play a variety of recently described roles in innate immunity. Although many TRIMs regulate type I IFN expression following cytosolic nucleic acid sensing of viruses, their contribution to innate immune signaling and gene expression during bacterial infection remains largely unknown. Because Mycobacterium tuberculosis is an activator of cGAS-dependent cytosolic DNA sensing, we set out to investigate a role for TRIM proteins in regulating macrophage responses to M. tuberculosis In this study, we demonstrate that TRIM14, a noncanonical TRIM that lacks an E3 ubiquitin ligase RING domain, is a critical negative regulator of the type I IFN response in Mus musculus macrophages. We show that TRIM14 interacts with both cGAS and TBK1 and that macrophages lacking TRIM14 dramatically hyperinduce IFN stimulated gene (ISG) expression following M. tuberculosis infection, cytosolic nucleic acid transfection, and IFN-ß treatment. Consistent with a defect in resolution of the type I IFN response, Trim14 knockout macrophages have more phospho-Ser754 STAT3 relative to phospho-Ser727 and fail to upregulate the STAT3 target Socs3, which is required to turn off IFNAR signaling. These data support a model whereby TRIM14 acts as a scaffold between TBK1 and STAT3 to promote phosphorylation of STAT3 at Ser727 and resolve ISG expression. Remarkably, Trim14 knockout macrophages hyperinduce expression of antimicrobial genes like Nos2 and are significantly better than control cells at limiting M. tuberculosis replication. Collectively, these data reveal an unappreciated role for TRIM14 in resolving type I IFN responses and controlling M. tuberculosis infection.

One-year real-world outcomes of bevacizumab for the treatment of macular oedema secondary to retinal vein occlusion.

BACKGROUND: Bevacizumab is the only agent that many people can afford, yet there are only limited data on whether it improves macular oedema (MO) secondary to retinal vein occlusion (RVO) in real-world clinical practice. Here we studied 12-month real-world treatment outcomes of bevacizumab for RVO-related MO. METHODS: This was a multicentre, observational study analysing 12-month data from the Fight Retinal Blindness! (FRB) database. We studied treatment-naïve eyes with MO secondary to RVO commencing bevacizumab therapy between June 2009 and June 2019. Visual acuity (VA) and central subfield thickness (CST) were measured at baseline, 6 and 12 months. The primary outcome was a change in VA from baseline to 12 months. RESULTS: Two hundred and twenty treatment naive eyes were analyzed. The baseline VA for BRVO was better than CRVO (55.8 vs. 42.6 LogMAR letters) and this gap widened over the 12-month period, with a 12-month VA change of +14.0 (95% CI 11.1, 16.8) letters for BRVO and + 11.9 (95% CI 6.4, 17.4) for CRVO. The mean CST at baseline was 511 µm for BRVO and 627 µm for CRVO, falling at 12 months by -155 µm (-190, -121) in BRVO and -198 µm (-252, -145) in CRVO. The median number of injections for BRVO and CRVO completers was 7 (5, 9). CONCLUSIONS: Bevacizumab can be an effective treatment of RVO-MO in a real-world setting with outcomes approaching those reported by the seminal clinical trials. The functional and anatomical outcomes of intravitreal therapy were better for BRVO than CRVO.

Using Lean Six Sigma techniques to improve efficiency in outpatient ophthalmology clinics.

BACKGROUND: Increasing patient numbers, complexity of patient management, and healthcare resource limitations have resulted in prolonged patient wait times, decreased quality of service, and decreased patient satisfaction in many outpatient services worldwide. This study investigated the impact of Lean Six Sigma, a service improvement methodology originally from manufacturing, in reducing patient wait times and increasing service capacity in a publicly-funded, tertiary referral outpatient ophthalmology clinic. METHODS: This quality improvement study compared results from two five-months audits of operational data pre- and post-implementation of Lean Six Sigma. A baseline audit was conducted to determine duration and variability of patient in-clinic time and number of patients seen per clinic session. Staff interviews and a time-in-motion study were conducted to identify issues reducing clinic service efficiency. Solutions were developed to address these root causes including: clinic schedule amendments, creation of dedicated postoperative clinics, and clear documentation templates. A post-implementation audit was conducted, and the results compared with baseline audit data. Significant differences in patient in-clinic time pre- and post-solution implementation were assessed using Mann-Whitney test. Differences in variability of patient in-clinic times were assessed using Brown-Forsythe test. Differences in numbers of patients seen per clinic session were assessed using Student's t-test. RESULTS: During the baseline audit period, 19.4 patients were seen per 240-minute clinic session. Median patient in-clinic time was 131 minutes with an interquartile range of 133 minutes (84-217 minutes, quartile 1- quartile 3). Targeted low/negligible cost solutions were implemented to reduce in-clinic times. During the post-implementation audit period, the number of patients seen per session increased 9% to 21.1 (p = 0.016). There was significant reduction in duration (p < 0.001) and variability (p < 0.001) of patient in-clinic time (median 107 minutes, interquartile range 91 minutes [71-162 minutes]). CONCLUSIONS: Lean Six Sigma techniques may be used to reduce duration and variability of patient in-clinic time and increase service capacity in outpatient ophthalmology clinics without additional resource input.

Neovascular age-related macular degeneration at treatment intervals of 14 weeks or greater.

BACKGROUND: We assessed the proportion of eyes with neovascular age-related macular degeneration (nAMD) in routine clinical practice that reach ≥14 week treatment intervals and their outcomes. METHOD: We analysed data from the Fight Retinal Blindness! (FRB!) Project database, a prospectively designed registry of 'real-world' outcomes. Treatment-naive eyes starting vascular endothelial growth factor (VEGF) inhibitors for nAMD from 1st January 2006 were included. Eyes were defined to have reached the ≥14 week treatment interval if they received ≥2 consecutive injections at treatment intervals of ≥14 week but not exceeding 26 weeks. Outcomes were reported in a subgroup of eyes that had 12 months of follow-up from reaching this interval. RESULTS: Of the 3907 treatment-naïve eyes that started treatment during the identified periods on a treat-and-extend regimen and received at least 8 injections over the first 2 years, 402 (10%) eyes received at least 2 consecutive injections at an interval of ≥14 week during their follow-up. Fifty-two percent of these eyes maintained vision to 12 months, however only 40% stayed at this interval and 25% of the lesions reactivated. CONCLUSION: We found that only 10% of eyes with nAMD were extended beyond a 13-week injection interval and that over half had returned to a shorter interval by 12 months. Eyes that stayed at this extended treatment interval maintained stable vision. More data on the outcomes of eyes treated with intervals longer than 3 months are required to establish whether emerging VEGF inhibitors provide a more sustained effect than the currently available drugs.

Preclinical and clinical studies of photobiomodulation therapy for macular oedema.

AIMS/HYPOTHESIS: Diabetic macular oedema (DME) is the leading cause of visual impairment in people with diabetes. Intravitreal injections of vascular endothelial growth factor inhibitors or corticosteroids prevent loss of vision by reducing DME, but the injections must be given frequently and usually for years. Here we report laboratory and clinical studies on the safety and efficacy of 670 nm photobiomodulation (PBM) for treatment of centre-involving DME. METHODS: The therapeutic effect of PBM delivered via a light-emitting diode (LED) device was tested in transgenic mice in which induced Müller cell disruption led to photoreceptor degeneration and retinal vascular leakage. We also developed a purpose-built 670 nm retinal laser for PBM to treat DME in humans. The effect of laser-delivered PBM on improving mitochondrial function and protecting against oxidative stress was studied in cultured rat Müller cells and its safety was studied in pigmented and non-pigmented rat eyes. We then used the retinal laser to perform PBM in an open-label, dose-escalation Phase IIa clinical trial involving 21 patients with centre-involving DME. Patients received 12 sessions of PBM over 5 weeks for 90 s per treatment at a setting of 25, 100 or 200 mW/cm2 for the three sequential cohorts of 6-8 patients each. Patients were recruited from the Sydney Eye Hospital, over the age of 18 and had centre-involving DME with central macular thickness (CMT) of >300 µm with visual acuity of 75-35 Log minimum angle of resolution (logMAR) letters (Snellen visual acuity equivalent of 20/30-20/200). The objective of this trial was to assess the safety and efficacy of laser-delivered PBM at 2 and 6 months. The primary efficacy outcome was change in CMT at 2 and 6 months. RESULTS: LED-delivered PBM enhanced photoreceptor mitochondrial membrane potential, protected Müller cells and photoreceptors from damage and reduced retinal vascular leakage resulting from induced Müller cell disruption in transgenic mice. PBM delivered via the retinal laser enhanced mitochondrial function and protected against oxidative stress in cultured Müller cells. Laser-delivered PBM did not damage the retina in pigmented rat eyes at 100 mW/cm2. The completed clinical trial found a significant reduction in CMT at 2 months by 59 ± 46 µm (p = 0.03 at 200 mW/cm2) and significant reduction at all three settings at 6 months (25 mW/cm2: 53 ± 24 µm, p = 0.04; 100 mW/cm2: 129 ± 51 µm, p < 0.01; 200 mW/cm2: 114 ± 60 µm, p < 0.01). Laser-delivered PBM was well tolerated in humans at settings up to 200 mW/cm2 with no significant side effects. CONCLUSIONS/INTERPRETATION: PBM results in anatomical improvement of DME over 6 months and may represent a safe and non-invasive treatment. Further testing is warranted in randomised clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02181400 Graphical abstract.

Macular Atrophy Incidence and Progression in Eyes with Neovascular Age-Related Macular Degeneration Treated with Vascular Endothelial Growth Factor Inhibitors Using a Treat-and-Extend or a Pro Re Nata Regimen: Four-Year Results of the MANEX Study.

PURPOSE: To compare the incidence and progression of macular atrophy (MA) in eyes with neovascular age-related macular degeneration (nAMD) treated with anti-vascular endothelial growth factor (VEGF) agents using either a treat-and-extend (T&E) or a pro re nata (PRN) regimen over 4 years in a real-world setting. DESIGN: Four-year, multicenter, retrospective comparative study. PARTICIPANTS: Two hundred sixty-four patients with treatment-naive nAMD. METHODS: Consecutive patients with nAMD received anti-VEGF therapy according to a T&E (n = 163) or PRN (n = 101) regimen. Eyes were included if they had received anti-VEGF injections for a period of at least 4 years and had undergone annual fundus autofluorescence (FAF) and OCT imaging using Heidelberg Spectralis. Two masked graders independently delineated areas of MA from serial FAF images using Heidelberg region finder software, and growth rates were calculated. Incident MA was assessed using proportional hazard ratios. MAIN OUTCOMES MEASURES: Macular atrophy incidence and progression over 4 years, association between treatment strategies, and number of injections. RESULTS: At baseline, MA was present in 24% and 20% of study eyes in T&E and PRN groups, respectively (P = 0.45). At year 4, 27% (34/124) and 25% (20/81) of eyes without baseline MA showed detectable MA in the T&E and PRN groups, respectively. In those with MA at baseline, the mean square root area of MA progressed by a rate of 0.4 ± 0.2 mm/year and 0.4 ± 0.1 mm/year in the T&E and PRN groups, respectively (P = 0.23). Multivariate analysis for baseline predictors of MA growth demonstrated that older age, poorer baseline visual acuity, and presence of retinal angiomatous proliferation had a higher risk of greater MA progression (P = 0.03). Regression analysis demonstrated no association between T&E and PRN treatment strategies with the risk of new MA developing during the 4 years of follow-up or the progression of pre-existing MA at year 4 (P = 0.692). CONCLUSIONS: Over 4 years, neither incidence nor progression of MA in eyes with nAMD treated with anti-VEGF injections was influenced by the treatment regimen and injection frequency. Eyes treated with a T&E regimen received more injections and achieved better visual outcomes compared with those treated with a PRN approach.

Ranibizumab or Aflibercept for Diabetic Macular Edema: Comparison of 1-Year Outcomes from the Fight Retinal Blindness! Registry.

PURPOSE: Both ranibizumab and aflibercept improved vision and decreased macular thickness in eyes with diabetic macular edema (DME) in clinical trials. This study compared the 12-month treatment outcomes of each drug in routine clinical practice. DESIGN: Retrospective analysis of data from the prospectively designed observational Fight Retinal Blindness! registry. PARTICIPANTS: Treatment-naive eyes tracked in the registry that initiated treatment with either ranibizumab (0.5 mg) or aflibercept (2 mg) for DME from December 1, 2013, through June 1, 2018. METHODS: Visual acuity (VA) was analyzed at 12 months in all eyes (completers, noncompleters, and eyes that switched treatment). MAIN OUTCOME MEASURES: The primary outcome was the mean change in VA from baseline to 12 months. RESULTS: We identified 383 eyes (ranibizumab, n = 166 eyes; aflibercept, n = 217 eyes) of 291 patients. Eyes receiving aflibercept showed a lower mean VA (mean difference, -3.1 letters) and a thicker maculae (mean difference, +26 µm) at baseline than those receiving ranibizumab, which were not significantly different. Patients receiving ranibizumab were older (mean difference, +2.7 years). The adjusted mean difference in VA change and central subfield thickness (CST) reduction were, respectively, +1 letter (1.4 letters for aflibercept vs. 0.4 letter for ranibizumab; P = 0.4) and -30 µm (-85 vs. -55 µm; P < 0.01) in eyes with initial VA of 20/40 or better and +3 letters (10.6 vs. 7.6 letters; P < 0.01) and -46 µm (-148 vs. -102 µm; P < 0.02) in those with VA of 20/50 or worse. Eyes in the aflibercept group received more median injections over 12 months than the ranibizumab group although this difference was not significant (8 vs. 6 injections; P = 0.13). Treatment switches, albeit low, were more frequent from ranibizumab to aflibercept than vice versa. Significantly more eyes in the aflibercept group were lost to follow-up within 12 months (21% vs. 9% ranibizumab; P < 0.01). CONCLUSIONS: Both drugs were beneficial for DME. Aflibercept-treated eyes, which had borderline worse vision and thicker maculae at baseline, showed larger CST reductions after 12 months of treatment. Larger VA gains were observed with aflibercept treatment when the initial VA was 20/50 or worse.

Emerging corticosteroid delivery platforms for treatment of diabetic macular edema.

INTRODUCTION: Diabetic macular edema (DME) is a leading cause of vision impairment. Low-grade inflammation is thought to play a critical role in its pathogenesis. Although vascular endothelial growth factor inhibitors are used first-line, not all eyes with DME respond optimally and may respond better to corticosteroids. Currently corticosteroids for DME are given intravitreally and require regular monitoring. There is an unmet need for longer lasting therapies and/or effective noninvasive therapies such as those given via oral or topical routes. AREAS COVERED: This review discusses emerging corticosteroid delivery platforms for DME treatment. A literature search of investigational novel therapeutic steroid delivery platform in DME was conducted. Results are presented from preclinical, phase 1,2 & 3 clinical trials of various drug delivery systems using new technologies such as Solubilizing Nanoparticle technology, Mucus Penetrating Particles technology and Particle Replication In Non-wetting Templates. These new platforms aim to deliver corticosteroids effectively via topical, episcleral, subtenon, oral, and intravitreal routes. EXPERT OPINION: These novel drug delivery platforms have the potential to lead to noninvasive or minimally invasive therapies and may overcome the shortcomings of current pharmacotherapy. However, larger comparative trials are needed for these agents to be added to the current armamentarium in DME management.

Multicolor imaging in macular telangiectasia-a comparison with fundus autofluorescence.

PURPOSE: To describe various clinical features of idiopathic juxtafoveal retinal telangiectasis group 2A or idiopathic macular telangiectasia type 2 (MacTel) on multicolor imaging (MCI) and compare imaging findings of MacTel on MCI with fundus autofluorescence (FAF). METHODS: Patients with a clinical diagnosis of MacTel based on Gass and Blodi's classification were included. FAF and MCI images were graded qualitatively for stage of disease, margins of involvement, hyperautofluorescence on FAF (corresponding retinal atrophy on MCI), and detection of crystals. FAF and MCI were graded quantitatively for the area and number of quadrants involved, hypoautofluorescene on FAF (corresponding intraretinal pigment hyperplasia or retinal pigment epithelium [RPE] atrophy on MCI), and foci of right-angled venules. RESULTS: Seventy-eight eyes of forty five patients were included with both imaging modalities showing no difference with respect to staging of non-proliferative MacTel. Retinal crystals were recognized on MCI but not on FAF. Neurosensory retinal atrophy and  subretinal neovascular membranes were detected using MCI with 92.3 and 83.3% sensitivity, respectively. Intraretinal pigmented hyperplasia was more accurately detected (70.1 vs 58.4%) compared with RPE atrophy on MCI. MCI showed larger area of involvement, higher number of quadrants involved (p < 0.001), and better delineation of margins (p = 0.002) compared with FAF. A higher mean number of vessel dipping foci was noted on MCI in comparison with FAF (3.34 vs 3.1). CONCLUSION: Various parameters were more easily defined using MCI compared with FAF which qualifies MCI as an enface depth-resolved imaging adjunct to conventional multimodal imaging in MacTel. The ability to detect enface as well as cross-sectional imaging features makes MCI a valuable tool in MacTel.

Prospective study of aflibercept for the treatment of persistent macular oedema secondary to retinal vein occlusions in eyes not responsive to long-term treatment with bevacizumab or ranibizumab.

IMPORTANCE: To examine the effect of switching from intravitreal bevacizumab or ranibizumab to aflibercept in eyes with persistent macular oedema due to retinal vein occlusion (RVO). BACKGROUND: We report the results of a prospective interventional study on the effect of aflibercept 2 mg in eyes with persistent macular oedema after long-term treatment with bevacizumab or ranibizumab. DESIGN: Non-randomized, prospective clinical trial. PARTICIPANTS: Eighteen eyes of eighteen patients were included. METHODS: Eyes with persistent macular oedema despite a minimum of four previous intravitreal bevacizumab/ranibizumab injections were recruited into this 48-week trial. Three loading doses of intravitreal aflibercept were administered every 4-weeks, thereafter every 8-weeks until week 48. MAIN OUTCOME MEASURES: Mean change from baseline in best corrected visual acuity (BCVA) as measured by early treatment diabetic retinopathy score (ETDRS) and central macular thickness (CMT) as measured by spectral domain optical coherence tomography (SD-OCT) at 48 weeks. RESULTS: Patients had received a mean of 40.0 ± 17.8 bevacizumab/ranibizumab intravitreal injections prior to switching to aflibercept. The mean number of previous injections administered in the 12-months preceding entry into the study was 10.2 ± 2.4. Mean vision change at week 48 was +21.1 ± 5.1 ETDRS letters in the BRVO group and +18.8 ± 5.9 letters at in the CRVO group (P < .001 for both groups). Mean decrease in CMT was 87.6 ± 48.8 µm and 191.0 ± 128.3 µm, in the BRVO and CRVO groups, respectively (P < .001). Using linear regression analyses, a higher number of previous intravitreal ranibizumab/bevacizumab injections and thicker pre-switch CMT were correlated with greater visual gains. CONCLUSION AND RELEVANCE: Switching to aflibercept from bevacizumab or ranibizumab in eyes with persistent macular oedema due to RVO can lead to functional and anatomical improvement. This effect was more obvious in eyes with a greater CMT prior to the switch.

Changes in real-world treatment patterns for diabetic macular oedema from 2009 to 2019 and 5-year outcomes: Data from the Fight Retinal Blindness! Registry.

IMPORTANCE: Evaluating the treatment outcomes of diabetic macular oedema (DMO) in routine clinical practice provides data for comparison with those of clinical trials. BACKGROUND: Phase 3 clinical trials of vascular endothelial growth factor (VEGF) inhibitors for DMO have reported significant improvements in visual acuity (VA) not previously reported with laser and steroid treatments. DESIGN: Retrospective analysis of observational data from routine clinical practice. PARTICIPANTS: Eyes receiving treatments for DMO tracked in the Fight Retinal Blindness! Registry. METHODS: We analysed 510 eyes (347 patients) that started DMO treatment between 2009 and 2014. MAIN OUTCOME MEASURES: Changes in DMO treatment patterns and mean change in VA (letters logMAR) and central subfield thickness (CST) 5 years after starting treatment. RESULTS: Treatment choice for DMO changed to predominantly VEGF inhibitors from 2009 to 2014. A total of 238 eyes (47%) were followed for at least 5 years. The mean VA at the start of treatment improved from 2009 (58 letters) to 2014 (68 letters) while mean VA change at 5 years were + 4.5 and + 5.3 letters for eyes starting treatment in 2009 and 2014, respectively. The mean CST dropped from 401 µm at baseline to 314 µm at 5 years. Eyes received a median of four injections in the first, two in the second, third and fourth and three in the fifth years. CONCLUSIONS AND RELEVANCE: Changing the treatment of DMO from macular laser and intravitreal triamcinolone to VEGF inhibitors from 2011 onwards was associated with better VA outcomes, part of which were due to better VA at the start of treatment. The outcomes of treatment in eyes in real-world practice were, however, worse than those reported by clinical trials, likely because they were undertreated.

Projection of Long-Term Visual Acuity Outcomes Based on Initial Treatment Response in Neovascular Age-Related Macular Degeneration.

PURPOSE: To explore various methods for assessing the early response to vascular endothelial growth factor (VEGF) inhibitors for neovascular age-related macular degeneration and investigate their association with 3-year visual acuity (VA) outcomes. DESIGN: Database study, prospectively designed. PARTICIPANTS: Treatment-naïve eyes in the Fight Retinal Blindness! registry that commenced anti-VEGF therapy between January 1, 2007, and March 1, 2014, that received 3 anti-VEGF injections within the first 3 months. METHODS: The early response was defined as occurring up until the fourth injection. Various early response metrics were explored: (1) achieving good VA (≥70 letters; Snellen equivalent, 20/40), (2) absolute change in VA from baseline, (3) time to first grading of the choroidal neovascular lesion as inactive, and (4) maximum rate of VA change between successive injections. MAIN OUTCOME MEASURES: Proportion of eyes achieving ≥70 letters 3 years. RESULTS: This study included 2051 treatment-naïve eyes from 1828 patients. Achieving good vision at 3 years was associated significantly with (1) having good vision by the fourth injection (VA ≥70 vs. VA <70 letters: odds ratio [OR], 9.8; 95% confidence interval [CI], 6.5-14.7), (2) small (1-5 letters) or large (>5 letters) early VA gains (vs. early VA loss: OR, 1.8; 95% CI, 1.2-2.6; P = 0.002; and OR, 1.8; 95% CI, 1.3-2.5; P < 0.001), (3) fewer injections until first grading of lesion inactivity (≤3 vs. >3 injections: OR, 1.6; 95% CI, 1.2-2.1; P < 0.001), (4) gradual change (between -4 and 4 letters) or rapid gains (≥5 letters) between successive injections (vs. rapid loss: OR, 1.7; 95% CI, 1.1-2.6; P = 0.015; and OR, 1.6; 95% CI, 1.1-2.3; P = 0.018). Eyes that achieved small or large early gains had similar vision at 3 years (65.0 and 64.7 letters, respectively) and had better vision than eyes with early VA loss (57.2 letters). CONCLUSIONS: Attainment of good vision by the fourth injection was associated strongly with 3-year visual outcomes, whereas other early response parameters showed a moderate association. The early response during the initial 3 monthly injections can be a useful guide for subsequent treatment decisions.

DEXAMETHASONE IMPLANT FOR DIABETIC MACULAR EDEMA IN NAIVE COMPARED WITH REFRACTORY EYES: The International Retina Group Real-Life 24-Month Multicenter Study. The IRGREL-DEX Study.

PURPOSE: To investigate efficacy and safety of repeated dexamethasone (DEX) implants over 24 months, in diabetic macular edema (DME) eyes that were treatment naive compared with eyes refractory to anti-vascular endothelial growth factor treatment, in a real-life environment. METHODS: This multicenter international retrospective study assessed best-corrected visual acuity and central subfield thickness (CST) of naive and refractory eyes to anti-vascular endothelial growth factor injections treated with dexamethasone implants. Safety data (intraocular pressure rise and cataract surgery) were recorded. RESULTS: A total of 130 eyes from 125 patients were included. Baseline best-corrected visual acuity and CST were similar for naive (n = 71) and refractory eyes (n = 59). Both groups improved significantly in vision after 24 months (P < 0.001). However, naive eyes gained statistically significantly more vision than refractory eyes (+11.3 ± 10.0 vs. 7.3 ± 2.7 letters, P = 0.01) and were more likely to gain ≥10 letters (OR 3.31, 95% CI 1.19-9.24, P = 0.02). At 6, 12, and 24 months, CST was significantly decreased compared with baseline in both naive and refractory eyes; however, CST was higher in refractory eyes than in naive eyes (CST 279 ± 61 vs. 313 ± 125 µm, P = 0.10). CONCLUSION: Over a follow-up of 24 months, vision improved in diabetic macular edema eyes after treatment with dexamethasone implants, both in eyes that were treatment naive and eyes refractory to anti-vascular endothelial growth factor treatment; however, improvement was greater in naive eyes.