Importance: Comparisons of the relative effect of 3 anti-vascular endothelial growth factor agents to treat diabetic macular edema warrant further assessment. Objective: To provide additional outcomes from a randomized trial evaluating 3 anti-vascular endothelial growth factor agents for diabetic macular edema within subgroups based on baseline visual acuity (VA) and central subfield thickness (CST) as evaluated on optical coherence tomography. Design, Setting, and Participants: Post hoc exploratory analyses were conducted of randomized trial data on 660 adults with diabetic macular edema and decreased VA (Snellen equivalent, approximately 20/32 to 20/320). The original study was conducted between August 22, 2012, and August 28, 2013. Analysis was conducted from January 7 to June 2, 2015. Interventions: Repeated 0.05-mL intravitreous injections of 2.0 mg of aflibercept (224 eyes), 1.25 mg of bevacizumab (218 eyes), or 0.3 mg of ranibizumab (218 eyes) as needed per protocol. Main Outcomes and Measures: One-year VA and CST outcomes within prespecified subgroups based on both baseline VA and CST thresholds, defined as worse (20/50 or worse) or better (20/32 to 20/40) VA and thicker (≥400 µm) or thinner (250 to 399 µm) CST. Results: In the subgroup with worse baseline VA (n = 305), irrespective of baseline CST, aflibercept showed greater improvement than bevacizumab or ranibizumab for several VA outcomes. In the subgroup with better VA and thinner CST at baseline (61-73 eyes across 3 treatment groups), VA outcomes showed little difference between groups; mean change was +7.2, +8.4, and +7.6 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively. However, in the subgroup with better VA and thicker CST at baseline (31-43 eyes), there was a suggestion of worse VA outcomes in the bevacizumab group; mean change from baseline to 1 year was +9.5, +5.4, and +9.5 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively, and VA letter score was greater than 84 (approximately 20/20) in 21 of 33 (64%), 7 of 31 (23%), and 21 of 43 (49%) eyes, respectively. The adjusted differences and 95% CIs were 39% (17% to 60%) for aflibercept vs bevacizumab, 25% (5% to 46%) for ranibizumab vs bevacizumab, and 13% (-8% to 35%) for aflibercept vs ranibizumab. Conclusions and Relevance: These post hoc secondary findings suggest that for eyes with better initial VA and thicker CST, some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups. Given the exploratory nature of these analyses and the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients. Trial Registration: clinicaltrials.gov Identifier: NCT01627249.

Tissue decellularization strategies have enabled engineering of scaffolds that preserve native extracellular matrix (ECM) structure and composition. In this study, we developed decellularized retina (decell-retina) thin films. We hypothesized that these films, mimicking the retina niche, would promote human retinal progenitor cell (hRPC) attachment, proliferation and differentiation. Retinas isolated from bovine eyes were decellularized using 1% w/v sodium dodecyl sulfate (SDS) and pepsin digested. The resulting decell-retina was biochemically assayed for composition and cast dried to develop thin films. Attachment, viability, morphology, proliferation and gene expression of hRPC cultured on the films were studied in vitro. Biochemical analyses of decell-retina compared to native retina indicated the bulk of DNA (94%) was removed, while the majority of sulfated GAGs (55%), collagen (83%), hyaluronic acid (87%), and key growth factors were retained. The decell-retina films supported hRPC attachment and growth, with cell number increasing 1.5-fold over a week. RT-PCR analysis revealed hRPC expression of rhodopsin, rod outer membrane, neural retina-specific leucine zipper neural and cone-rod homeobox gene on decell-retina films, indicating photoreceptor development. In conclusion, novel decell-retina films show promise as potential substrates for culture and/or transplantation of retinal progenitor cells to treat retinal degenerative disorders.

Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL-/-), and mFasL-only knock-in (ΔCS) mice. Retinal detachment in FasL-/- mice resulted in a significant reduction of photoreceptor cell death. In contrast, ΔCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss in ΔCS mice was inhibited by a subretinal injection of recombinant sFasL. Thus, Fas/FasL-triggered cell death accounts for a significant amount of photoreceptor cell loss following the retinal detachment. The function of FasL was dependent upon the form of FasL expressed: mFasL triggered photoreceptor cell death, whereas sFasL protected the retina, indicating that enzyme-mediated cleavage of FasL determines, in part, the extent of vision loss following the retinal detachment. Moreover, it also indicates that treatment with sFasL could significantly reduce photoreceptor cell loss in patients with retinal detachment.

Importance: Preservation of vision in patients with diabetes mellitus is critical. Interventions to improve glycemic control through early intensive treatment of diabetes reduce rates of severe retinopathy and preserve visual acuity. Objective: To assess the effects of prior intensive insulin treatment and risk factors on patient-reported visual function in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Design, Setting, and Participants: Cohort study of 1184 participants with type 1 diabetes from the DCCT/EDIC study (randomized clinical trial followed by an observational follow-up study) who completed the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) during EDIC years 17 through 20 (September 1, 2009, through April 30, 2014) in 28 institutions across the United States and Canada. Main Outcomes and Measures: The primary outcome was the composite NEI-VFQ-25 score. Secondary outcomes were visual acuity (measured by the Early Treatment Diabetic Retinopathy Study protocol), retinopathy level (determined by masked grading of stereoscopic color fundus photographs), and NEI-VFQ-25 subscale scores. The composite NEI-VFQ-25 scale and its subscales were scored 0 to 100, corresponding to poor to excellent function, respectively. Results: The overall average NEI-VFQ-25 score for 1184 DCCT/EDIC participants (mean [SD] age, 52.3 [6.9] years; 48% female) with a 30-year duration of diabetes was high (all participants: median, 91.7; interquartile range [IQR], 89.7-96.9; intensive treatment [n = 605]: median, 94.7; IQR, 91.0-97.2; conventional treatment [n = 579]: median, 94.0; IQR, 88.4-96.1; P = .006 for intensive vs conventional). After adjustment for sex, age, hemoglobin A1c level, and retinopathy level at DCCT baseline, the former intensive treatment group had a significant, albeit modest, improvement in overall NEI-VFQ-25 score compared with the former conventional diabetes treatment group (median difference, -1.0; 95% CI, -1.7 to -0.3; P = .006). This beneficial treatment effect was fully attributed to the prior glycemic control in DCCT (explained treatment effect: 100%). Those with visual acuity worse than 20/100 reported the largest decline in visual function (median difference, -21.0; 95% CI, -40.5 to -1.6; P = .03). Conclusions and Relevance: In the DCCT/EDIC cohort, patient-reported visual function remains high in both treatment groups, comparable to previous reports of overall health-related quality of life. Intensive diabetes therapy modestly improved NEI-VFQ-25 score 30 years after the start of the DCCT, the benefit underestimated owing to more nonparticipants from the conventional treatment group. Visual acuity had the greatest effect on patient-reported visual function from among all risk factors. Trial Registration: clinicaltrials.gov Identifiers: NCT00360815 and NCT00360893.

It has been hypothesized that synaptic pruning precedes retinal ganglion cell degeneration in glaucoma, causing early dysfunction to retinal ganglion cells. To begin to assess this, we studied the excitatory synaptic inputs to individual ganglion cells in normal mouse retinas and in retinas with ganglion cell degeneration from glaucoma (DBA/2J), or following an optic nerve crush. Excitatory synapses were labeled by AAV2-mediated transfection of ganglion cells with PSD-95-GFP. After both insults the linear density of synaptic inputs to ganglion cells decreased. In parallel, the dendritic arbors lost complexity. We did not observe any cells that had lost dendritic synaptic input while preserving a normal or near-normal morphology. Within the temporal limits of these observations, dendritic remodeling and synapse pruning thus appear to occur near-simultaneously.

PURPOSE: There is considerable evidence for systemic vascular dysfunction in primary open-angle glaucoma (POAG). We performed nailfold capillary video microscopy to observe directly the nature of nonocular microvasculature abnormalities in POAG. METHODS: We enrolled 199 POAG patients and 124 control subjects from four sites. We used JH-1004 capillaroscopes to perform nailfold capillary video microscopy on the fourth and fifth digits of each subject's nondominant hand. Videos were evaluated for hemorrhages, dilated capillary loops > 50 μm, and avascular zones > 100 μm by graders masked to case status. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) for POAG were obtained by means of logistic regression analyses that were applied to data from all cases and controls. Corresponding estimates of moderate or severe POAG versus mild POAG (based on the Hodapp-Anderson-Parrish scale) were obtained among cases only. RESULTS: After controlling for demographic factors, family history of glaucoma, systemic diseases, and use of anticoagulation and antiplatelet therapy, for each 100 nailfold capillaries assessed, all types of microvascular abnormalities were significantly associated with POAG. Specifically, the presence of any dilated capillaries (OR = 2.9; 95% CI, 1.6-5.6), avascular zones (OR = 4.4; 95% CI, 1.7-11.3) and hemorrhages (OR = 12.2; 95% CI, 5.9-25.1) were associated with POAG. Among cases, the frequency of microvascular abnormalities was not associated with glaucoma severity (P ≥ 0.43). CONCLUSIONS: These data provided support for nonocular capillary bed abnormalities in POAG. Comparable vascular abnormalities in the optic nerve may render it susceptible to glaucomatous damage.

The regulation of myelination and axonal outgrowth in the peripheral nervous system is controlled by a complex signaling network involving various signaling pathways. Members of the A Disintegrin And Metalloproteinase (ADAM) family are membrane-anchored proteinases with both proteolytic and disintegrin characteristics that modulate the function of signaling molecules. One family member, ADAM17, is known to influence myelination by cleaving and thus regulating one of the key signals, neuregulin-1, which controls peripheral nervous system myelination. A similar function for ADAM10 had been suggested by previous in vitro studies. Here, we assessed whether ADAM10 exerts a similar function in vivo and deleted ADAM10 in a cell type-specific manner in either neurons or Schwann cells. We found that ADAM10 is not required in either Schwann cells or neurons for normal myelination during development or for remyelination after injury. Instead, ADAM10 is required specifically in neurons for the outgrowth of myelinated small-fiber axons in vitro and after injury in vivo. Thus, we report for the first time a neuron-intrinsic function of ADAM10 in axonal regeneration that is distinct from that of the related protein family member ADAM17 and that may have implications for targeting ADAM function in nervous system diseases.