Reactive microglia and infiltrating peripheral monocytes have been implicated in many neurodegenerative diseases of the retina and CNS. However, their specific contribution in retinal degeneration remains unclear. We recently showed that peripheral monocytes that infiltrate the retina after ocular injury in mice become permanently engrafted into the tissue, establishing a proinflammatory phenotype that promotes neurodegeneration. In this study, we show that microglia regulate the process of neuroglia remodeling during ocular injury, and their depletion results in marked upregulation of inflammatory markers, such as , , and in the retina, and abnormal engraftment of peripheral CCR2 CX3CR1 monocytes into the retina, which is associated with increased retinal ganglion cell loss, retinal nerve fiber layer thinning, and pigmentation onto the retinal surface. Furthermore, we show that other types of ocular injuries, such as penetrating corneal trauma and ocular hypertension also cause similar changes. However, optic nerve crush injury-mediated retinal ganglion cell loss evokes neither peripheral monocyte response in the retina nor pigmentation, although peripheral CX3CR1 and CCR2 monocytes infiltrate the optic nerve injury site and remain present for months. Our study suggests that microglia are key regulators of peripheral monocyte infiltration and retinal pigment epithelium migration, and their depletion results in abnormal neuroglia remodeling that exacerbates neuroretinal tissue damage. This mechanism of retinal damage through neuroglia remodeling may be clinically important for the treatment of patients with ocular injuries, including surgical traumas.

Although there are many anecdotal reports of children with developmental dyslexia complaining of vision symptoms when reading, empirical studies are lacking. The primary aim of the present study was to document self-reported vision-related symptoms in children with developmental dyslexia and typically reading peers. We also explored whether vision symptoms were correlated with sensorimotor measures of vergence, accommodation and ocular motor tracking skills. Using a prospective group comparison observational design, we assessed 28 children with developmental dyslexia (DD) and 33 typically reading children (TR) 7-11 years of age. Participants completed psychoeducational testing, a comprehensive sensorimotor eye examination, and the Convergence Insufficiency Symptom Survey (CISS), which includes 9 items pertaining to vision-related symptoms (CISS-V) and 6 that could have cognitive influence (CISS-C). CISS-V were significantly greater in DD than TR children. Ocular motor tracking, assessed by an infra-red limbal eye tracker while reading text, was most clearly associated with the visual symptoms, but only within the DD group. Vision-related symptom surveys followed by a comprehensive eye examination with detailed evaluation of sensorimotor functioning for those who report a high prevalence of symptoms may be clinically relevant for children with DD.

PURPOSE: To compare the rates of infectious endophthalmitis following intravitreal injection of ranibizumab using prefilled syringes vs conventional preparation. DESIGN: Multicenter retrospective cohort study. METHODS: All eyes receiving intravitreal injection of 0.5 mg ranibizumab for retinal vascular diseases at 10 retina practices across the United States (2016 to 2017) and Japan (2009 to 2017) were included. The total numbers of eyes and injections were determined from billing codes. Endophthalmitis cases were determined from billing records and evaluated with chart review. Primary outcome was the rate of postinjection acute endophthalmitis. Secondary outcomes were visual acuity and microbial spectrum. RESULTS: A total of 243 754 intravitreal 0.5 mg ranibizumab injections (165 347 conventional and 78 407 prefilled) were administered to 43 132 unique patients during the study period. In the conventional ranibizumab group, a total of 43 cases of suspected endophthalmitis occurred (0.026%; 1 in 3845 injections) and 22 cases of culture-positive endophthalmitis occurred (0.013%; 1 in 7516 injections). In the prefilled ranibizumab group, 12 cases of suspected endophthalmitis occurred (0.015%; 1 in 6534 injections) and 2 cases of culture-positive endophthalmitis occurred (0.0026%; 1 in 39 204 injections). Prefilled syringes were associated with a trend toward decreased risk of suspected endophthalmitis (odds ratio 0.59; 95% confidence interval 0.31-1.12; P = .10) and a statistically significant decreased risk of culture-positive endophthalmitis (odds ratio 0.19; 95% confidence interval 0.045-0.82; P = .025). Average logMAR vision loss at final follow-up was significantly worse for eyes that developed endophthalmitis from the conventional ranibizumab preparation compared to the prefilled syringe group (4.45 lines lost from baseline acuity vs 0.38 lines lost; P = .0062). Oral-associated flora was found in 27.3% (6/22) of conventional ranibizumab culture-positive endophthalmitis cases (3 cases of Streptococcus viridans, 3 cases of Enterococcus faecalis) compared to 0 cases in the prefilled ranibizumab group. CONCLUSION: In a large, multicenter, retrospective study the use of prefilled syringes during intravitreal injection of ranibizumab was associated with a reduced rate of culture-positive endophthalmitis, including from oral flora, as well as with improved visual acuity outcomes.

BACKGROUND: To assess prevalence and causes of vision loss in Central and South Asia. METHODS: A systematic review of medical literature assessed the prevalence of blindness (presenting visual acuity<3/60 in the better eye), moderate and severe vision impairment (MSVI; presenting visual acuity <6/18 but ≥3/60) and mild vision impairment (MVI; presenting visual acuity <6/12 and ≥6/18) in Central and South Asia for 1990, 2010, 2015 and 2020. RESULTS: In Central and South Asia combined, age-standardised prevalences of blindness, MSVI and MVI in 2015 were for men and women aged 50+years, 3.72% (80% uncertainty interval (UI): 1.39-6.75) and 4.00% (80% UI: 1.41-7.39), 16.33% (80% UI: 8.55-25.47) and 17.65% (80% UI: 9.00-27.62), 11.70% (80% UI: 4.70-20.32) and 12.25% (80% UI:4.86-21.30), respectively, with a significant decrease in the study period for both gender. In South Asia in 2015, 11.76 million individuals (32.65% of the global blindness figure) were blind and 61.19 million individuals (28.3% of the global total) had MSVI. From 1990 to 2015, cataract (accounting for 36.58% of all cases with blindness in 2015) was the most common cause of blindness, followed by undercorrected refractive error (36.43%), glaucoma (5.81%), age-related macular degeneration (2.44%), corneal diseases (2.43%), diabetic retinopathy (0.16%) and trachoma (0.04%). For MSVI in South Asia 2015, most common causes were undercorrected refractive error (accounting for 66.39% of all cases with MSVI), followed by cataract (23.62%), age-related macular degeneration (1.31%) and glaucoma (1.09%). CONCLUSIONS: One-third of the global blind resided in South Asia in 2015, although the age-standardised prevalence of blindness and MSVI decreased significantly between 1990 and 2015.

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts ( = 3,246) and seven African American cohorts ( = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a value <1 × 10 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like () was associated with DR in European discovery cohorts ( = 2.1 × 10), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity ( = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

PURPOSE: To evaluate the durability of diabetic retinopathy (DR) improvements after a change in ranibizumab dosing from monthly to individualized pro re nata (PRN) therapy. DESIGN: Pooled analysis of the open-label extension (OLE) of RIDE and RISE (clinicaltrials.gov identifiers, NCT00473382 and NCT00473330) patients with DR and diabetic macular edema (DME). PARTICIPANTS: Patients who completed 36-month participation in RIDE and RISE and entered the OLE. METHODS: In RIDE and RISE, patients (n = 759) were randomized 1:1:1 to ranibizumab 0.3 mg monthly, 0.5 mg monthly, or monthly sham injections with rescue macular laser available after 6 months, per protocol-specified criteria. After 24 months, sham patients crossed over to ranibizumab 0.5 mg monthly. After 36 months in the core studies, patients in the OLE (n = 500) could receive ranibizumab 0.5 mg PRN based on predefined DME re-treatment criteria. Diabetic retinopathy severity was evaluated photographically using the Early Treatment Diabetic Retinopathy Study DR severity scale. MAIN OUTCOME MEASURES: Change in DR severity from months 36 to 48 by re-treatment status. RESULTS: Among patients who entered the OLE, 121 of 500 (24%) did not require additional ranibizumab injections. Overall, 367 patients had evaluable DR at months 36 and 48. Among patients not requiring ranibizumab re-treatment from months 36 to 48 (88/367), 57% to 78%, 0% to 7%, and 22% to 36% experienced DR severity stability, 2-step or more improvement, and 2-step or more worsening, respectively. Among patients requiring ranibizumab re-treatment (279/367), 84% to 94%, 2%, and 3% to 14% experienced DR severity stability, 2-step or more improvement, and 2-step or more worsening, respectively. On average, vision improvements were maintained during the OLE regardless of change in DR severity. CONCLUSIONS: Diabetic retinopathy severity improvements with ranibizumab were maintained in over 70% of OLE patients after switching from ranibizumab monthly to an individualized ranibizumab 0.5 mg PRN dosing regimen. Because approximately one third of OLE patients experienced DR worsening, careful monitoring should be part of the long-term management of patients with DR.

PURPOSE: To review the published evidence to evaluate the ability of orthokeratology (Ortho-K) treatment to reduce myopic progression in children and adolescents compared with the use of spectacles or daytime contact lenses for standard refractive correction. METHODS: Literature searches of the PubMed database, the Cochrane Library, and the databases of clinical trials were last conducted on August 21, 2018, with no date restrictions but limited to articles published in English. These searches yielded 162 citations, of which 13 were deemed clinically relevant for full-text review and inclusion in this assessment. The panel methodologist then assigned a level of evidence rating to the selected studies. RESULTS: The 13 articles selected for inclusion include 3 prospective, randomized clinical trials; 7 nonrandomized, prospective comparative studies; and 3 retrospective case series. One study provided level I evidence, 11 studies provided level II evidence, and 1 study provided level III evidence. Most studies were performed in populations of Asian ethnicity. Change in axial length was the primary outcome for 10 of 13 studies and change in refraction was the primary outcome for 3 of 13 studies. In these studies, Ortho-K typically reduced axial elongation by approximately 50% over a 2-year study period. This corresponds to average axial length change values of approximately 0.3 mm for Ortho-K patients compared with 0.6 mm for control patients, which corresponds to a typical difference in refraction of approximately 0.5 diopters (D). Younger age groups and individuals with larger than average pupil size may have a greater effect with Ortho-K. Rebound can occur after discontinuation or change to alternative refractive treatment. CONCLUSIONS: Orthokeratology may be effective in slowing myopic progression for children and adolescents, with a potentially greater effect when initiated at an early age (6-8 years). Safety remains a concern because of the risk of potentially blinding microbial keratitis from contact lens wear.

High levels of proinflammatory cytokines have been associated with a loss of tissue function in ocular autoimmune diseases, but the basis for this relationship remains poorly understood. Here we investigate a new role for tumor necrosis factor α in promoting N-glycan-processing deficiency at the surface of the eye through inhibition of N-acetylglucosaminyltransferase expression in the Golgi. Using mass spectrometry, complex-type biantennary oligosaccharides were identified as major N-glycan structures in differentiated human corneal epithelial cells. Remarkably, significant differences were detected between the efficacies of cytokines in regulating the expression of glycogenes involved in the biosynthesis of N-glycans. Tumor necrosis factor α but not IL-1β had a profound effect in suppressing the expression of enzymes involved in the Golgi branching pathway, including N-acetylglucosaminyltransferases 1 and 2, which are required for the formation of biantennary structures. This decrease in gene expression was correlated with a reduction in enzymatic activity and impaired N-glycan branching. Moreover, patients with ocular mucous membrane pemphigoid were characterized by marginal N-acetylglucosaminyltransferase expression and decreased N-glycan branching in the conjunctiva. Together, these data indicate that proinflammatory cytokines differentially influence the expression of N-glycan-processing enzymes in the Golgi and set the stage for future studies to explore the pathophysiology of ocular autoimmune diseases.

PURPOSE: To report the long-term outcome of Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) for delivery of bevacizumab in the treatment of corneal neovascularization (KNV). METHODS: Retrospective, non-comparative, interventional case series of 13 sequential patients treated for KNV at the BostonSight between 2006 and 2017. In all cases, PROSE treatment was initiated for management of ocular surface disease and patients wore PROSE consistently on a daily wear basis prior to bevacizumab treatment. Patients applied a drop of 1% preservative free bevacizumab to the reservoir of PROSE device twice daily. Patients continued with daily wear of the device during treatment and afterwards. RESULTS: 13 patients (8 female and mean age of 45 years) are included with a mean follow-up of 5.1 years (range 6 months-11 years). Underlying ocular diagnoses included Stevens-Johnson syndrome (7), ocular chronic graft-versus-host disease (2), corneal transplant (2), contact lens-related corneal ulcer and limbal stem cell deficiency (1), and familial dysautonomia (1). Median duration of bevacizumab use was 6 months (range 3 months-10 years). Twelve cases (92%) had regression of KNV and 10 cases (77%) had improved best-corrected visual acuity (BCVA) with treatment. Median BCVA improved from -1.1 (LogMAR) at baseline, to -0.66 at end of bevacizumab treatment, and remained -0.63 at last follow-up (P = 0.047). KNV progressed in one eye after discontinuation of bevacizumab. There were no ophthalmic or systemic complications. CONCLUSIONS: Topical bevacizumab used in PROSE is effective in treating KNV and improving vision. Long-term follow-up reveals durable response and no complications.

Lipopeptide daptomycin is a last-line cell-membrane-targeting antibiotic to treat multidrug-resistant Alarmingly, daptomycin-resistant isolates have emerged. The mechanisms underlying daptomycin resistance are diverse and share similarities with resistances to cationic antimicrobial peptides and other lipopeptides, but they remain to be fully elucidated. We selected mutants with increased resistance to daptomycin from a library of transposon insertions in sequent type 8 (ST8) HG003. Insertions conferring increased daptomycin resistance were localized to two genes, one coding for a hypothetical lipoprotein (SAOUHSC_00362, Dsp1), and the other for an alkaline shock protein (SAOUHSC_02441, Asp23). Markerless loss-of-function mutants were then generated for comparison. All transposon mutants and knockout strains exhibited increased daptomycin resistance compared to those of wild-type and complemented strains. Null and transposon insertion mutants also exhibited increased resistance to cationic antimicrobial peptides. Interestingly, the mutant also showed increased resistance to vancomycin, a cell-wall-targeting drug with a different mode of action. Null mutations in both and resulted in increased tolerance as reflected by reduced killing to both daptomycin and vancomycin, as well as an increased tolerance to surfactant (Triton X-100). Neither mutant exhibited increased resistance to lysostaphin, a cell-wall-targeting endopeptidase. These findings identified two genes core to the species that make previously uncharacterized contributions to antimicrobial resistance and tolerance in .