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To assess the 52-week efficacy and safety of brolucizumab 6 mg administered every 4 weeks compared with aflibercept 2 mg dosed every 4 weeks in eyes with neovascular age-related macular degeneration (nAMD) and persistent retinal fluid.Multicenter, randomized, double-masked phase 3a study.Participants with recalcitrant nAMD (persistent residual retinal fluid despite previous frequent anti-vascular endothelial growth factor treatment).Eyes were randomized (2:1) to intravitreal brolucizumab 6 mg or aflibercept 2 mg every 4 weeks up to and including week 100.The primary end point was analysis of noninferiority in mean best-corrected visual acuity (BCVA) change from baseline to week 52 (margin, 4 letters). Other key end points included change in central subfield thickness (CST) from baseline to week 52, fluid-free status (no intraretinal fluid and no subretinal fluid), and safety.At week 52, brolucizumab was noninferior to aflibercept in BCVA change from baseline (least squares mean difference, -0.6 Early Treatment Diabetic Retinopathy Study letters; 95% confidence interval [CI], -2.1 to 0.9; P0.001). A total of 4.8% and 1.7% of participants reported a 15-letter or more BCVA loss from baseline at week 52 in the brolucizumab and aflibercept groups, respectively. In eyes treated with brolucizumab compared with those treated with aflibercept, the CST was reduced significantly (P0.001), and a significantly greater proportion of eyes were fluid free at week 52 (40.4% brolucizumab vs. 19.0% aflibercept; 95% CI, 13.9-29.0; P0.001). Incidence of intraocular inflammation (IOI), including retinal vasculitis and retinal vascular occlusion, were 9.3% (0.8% and 2.0%) for brolucizumab versus 4.5% (0% and 0%) for aflibercept, respectively.Visual acuity outcomes in previously treated participants with nAMD and persistent retinal fluid receiving brolucizumab 6 mg dosed every 4 weeks were noninferior to aflibercept 2 mg dosed every 4 weeks, with superior anatomic outcomes. However, incidences of IOI, including retinal vasculitis and retinal vascular occlusion, also were higher, leading to study termination.

PURPOSE: To evaluate the outcomes of primary topography-guided laser in situ keratomileusis (LASIK) in eyes with subjective refractive astigmatism of 2.00 diopters (D) or greater. METHODS: This was a prospective study in consecutive eyes with cylinder of 2.00 D or greater that had LASIK using the Alcon WaveLight EX500 excimer laser and T-CAT/Contoura software (Alcon Laboratories, Inc., Fort Worth, TX). The accuracy, efficacy, safety, cylinder vector analysis, higher order aberrations, and patients' subjective quality of vision were assessed. Eyes with naturally occurring topographic irregular astigmatism were not excluded. RESULTS: The mean cylinder was −2.55 D preoperatively and −0.34 D postoperatively; 81% and 95% of eyes were within ±0.50 and ±0.75 D of intended cylinder after LASIK, respectively. The correction index and index of success were 1.00 and 0.13, respectively. The efficacy and safety indexes were 0.98 and 1.04, respectively. The preoperative corneal topography irregularity index, anterior corneal higher order aberrations, and refractive astigmatism magnitude were mildly correlated to postoperative residual astigmatism. Mean ocular and corneal coma were not increased postoperatively. Patients had significant improvements after LASIK in both subjective uncorrected quality of vision and night vision disturbances compared to spectacle- and contact lens–corrected vision before LASIK. CONCLUSIONS: Topography-guided ablation using the Alcon WaveLight EX500 excimer laser and T-CAT/Contoura software results in excellent accuracy, efficacy, and safety, with improved postoperative subjective quality of vision and reduced night vision disturbances in virgin eyes with refractive astigmatism of 2.00 D or greater, including eyes with topographic naturally occurring irregular astigmatism. [ J Refract Surg. 2019;35(2):78–86.]

Purpose To describe the incidence, risk factors, and outcomes before and after irrigation of clinically significant laser in situ keratomileusis (LASIK) flap striae. Setting Multisurgeon multicenter standardized protocol practice. Design Retrospective case-control series. Methods Eyes with striae necessitating flap relift and irrigation were identified. Preoperative, intraoperative, and postoperative variables were collected. Incidence, risk factors, and outcomes were assessed. Results Of the 109 403 eyes that had LASIK, the incidence of striae-treated eyes was 0.79% (n = 875), with 8.7% irrigated the first hour after surgery. The preoperative spherical equivalent (SE) and ablation depth exponentially increased the striae risk (R2 = 0.9674; P .05) after the relift. A laser refractive enhancement was performed in 6.28% of relifted striae eyes versus 3.04% in nonstriae control eyes. Conclusions Flap striae requiring surgeon intervention occurred in 0.79% of eyes. Higher preoperative SE values were associated with an exponential increase risk for striae. Treatment by lifting and irrigation significantly improved the accuracy, efficacy, and safety to a level close to that of contralateral control eyes, although striae-treated eyes were more likely to need excimer laser retreatment.

Collagens in the atherosclerotic plaque signal regulation of cell behavior and provide tensile strength to the fibrous cap. Type VIII collagen, a short-chain collagen, is up-regulated in atherosclerosis; however, little is known about its functions in vivo. We studied the response to arterial injury and the development of atherosclerosis in type VIII collagen knockout mice (Col8(-/-) mice). After wire injury of the femoral artery, Col8(-/-) mice had decreased vessel wall thickening and outward remodeling when compared with Col8(+/+) mice. We discovered that apolipoprotein E (ApoE) is an endogenous repressor of the Col8a1 chain, and, therefore, in ApoE knockout mice, type VIII collagen was up-regulated. Deficiency of type VIII collagen in ApoE(-/-) mice (Col8(-/-);ApoE(-/-)) resulted in development of plaques with thin fibrous caps because of decreased smooth muscle cell migration and proliferation and reduced accumulation of fibrillar type I collagen. In contrast, macrophage accumulation was not affected, and the plaques had large lipid-rich necrotic cores. We conclude that in atherosclerosis, type VIII collagen is up-regulated in the absence of ApoE and functions to increase smooth muscle cell proliferation and migration. This is an important mechanism for formation of a thick fibrous cap to protect the atherosclerotic plaque from rupture.

Avi Wallerstein,1,2 Eser Adiguzel,2 Mathieu Gauvin,1,2 Nima Mohammad-Shahi,1 Mark Cohen2,3 1Department of Ophthalmology, Faculty of Medicine, McGill University, 2LASIK MD, Montreal, 3Department of Surgery, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada Purpose: Collagen cross-linking (CXL) for post-laser-assisted in situ keratomileusis (LASIK) ectasia (PLE) is traditionally performed either epi-on or epi-off on the corneal surface. This study describes a novel technique in treating early PLE with under-flap CXL (ufCXL) to the stromal bed and reports on 6-month outcomes.Patients and methods: Case series of seven patients (eight eyes) with topography-diagnosed early PLE treated with ufCXL. Inclusion criteria were early, mild PLE defined as new-onset postoperative manifest refraction cylinder ≤1.50 D, with new topographic inferior steepening consistent with ectasia, uncorrected distance visual acuity (UDVA) of 20/40 or better, and corrected distance visual acuity (CDVA) of 20/25 or better. Existing LASIK flap was lifted, riboflavin was applied directly to the stromal bed, flap was repositioned, and 18 mW/cm2 ultraviolet light was applied for 3 minutes to the corneal surface. Post-ufCXL manifest refraction, UDVA and CDVA, corneal cylinder, Kmax, and corneal irregularity index were compared with pre-ufCXL measurements.Results: Patients had a pre-ufCXL sphere of 0.09±0.48 D and cylinder of −0.78±0.49 D. At6months, post-ufCXL sphere (0.06±0.8 D; P=0.89) and cylinder (−1.09±0.76 D, P=0.26) were unchanged. Cumulative post-ufCXL UDVA was unchanged, achieving 20/20, 20/30, and 20/40 in 25%, 88%, and 88%, respectively, compared with 13%, 63%, and 88% pre-ufCXL (P=0.68). Post-ufCXL CDVA was unchanged (P=0.93) with a gain of one line in two eyes, a loss of one line in one eye, and five eyes unchanged. The efficacy index (P=0.76), safety index (P=0.89), Kmax (P=0.94), and corneal irregularity index (P=0.73) were also unchanged.Conclusion: Preliminary results with ufCXL for early PLE are promising, demonstrating maintenance of visual accuracy, efficacy, safety, Kmax, and cylinder, with much quicker recovery times than surface CXL. Keywords: CXL, LASIK, ufCXL, post-LASIK ectasia, cross-linking, LASIK complications, stromal bed

Collagens constitute a major portion of the extracellular matrix in the atherosclerotic plaque, where they contribute to the strength and integrity of the fibrous cap, and also modulate cellular responses via specific receptors and signaling pathways. This review focuses on the diverse roles that collagens play in atherosclerosis; regulating the infiltration and differentiation of smooth muscle cells and macrophages; controlling matrix remodeling through feedback signaling to proteinases; and influencing the development of atherosclerotic complications such as plaque rupture, aneurysm formation and calcification. Expanding our understanding of the pathways involved in cell–matrix interactions will provide new therapeutic targets and strategies for the diagnosis and treatment of atherosclerosis.

Objective— Type VIII collagen is upregulated after vascular injury and in atherosclerosis. However, the role of type VIII collagen endogenously expressed by smooth muscle cells (SMCs) and in the context of the vascular matrix microenvironment, which is rich in type I collagen, is not known. To address this, we have compared aortic SMCs from wild-type (WT) mice to SMCs from type VIII collagen-deficient (KO) mice when plated on type I collagen. Methods and Results— Type VIII collagen was upregulated after wounding of WT SMCs. KO SMCs exhibited greater adhesion to type I collagen than WT SMCs (optical density [OD 595 ]=0.458±0.044 versus 0.193±0.071). By contrast, the WT SMCs spread more (389±75% versus 108±14% increase in cell area), migrated further (total distance 80.6±6.2 μm versus 64.2±4.4 μm), and exhibited increased [ 3 H]-thymidine uptake (160 000±22 300 versus 63 100±12 100 counts per minute) when compared with KO SMCs. Gelatin zymograms showed that WT SMCs expressed latent matrix metalloproteinase 2, whereas KO SMCs did not. Addition of exogenous type VIII collagen returned levels of KO SMC adhesion (OD 595 =0.316±0.038), migration (79.5±5.8 μm), and latent matrix metalloproteinase 2 expression to levels comparable to WT SMCs. Conclusions— This study suggests that SMCs can modify the matrix microenvironment by producing type VIII collagen, using it to overlay type I collagen, and generating a substrate favorable for migration.

Collagens in the extracellular matrix play important roles modulating the vascular response to injury during the progression of atherosclerosis and restenosis. Collagen can regulate smooth muscle cell (SMC) proliferation, and SMC and macrophage migration and proteinase production. The discoidin domain receptors, DDR1 and DDR2, are novel transmembrane collagen receptors with tyrosine kinase activity, and signal to upregulate matrix metalloproteinase (MMP) expression. Research in our laboratory has been focused on the expression and functions of DDR1 in the cardiovascular system. DDR1 expression is increased following vascular injury. We have shown that DDR1−/− SMCs have a reduced capacity to proliferate and migrate, and have reduced MMP expression compared with DDR1+/+ cells. We injured the carotid arteries of DDR1−/− mice and found a dramatic reduction in neointimal thickening. These studies suggest that DDR1 plays a role in arterial wound repair and helps to elucidate the roles of collagen and the DDRs in atherosclerosis and restenosis.

The extracellular matrix signals and regulates the behavior of vascular cells during the pathogenesis of atherosclerosis. Type VIII collagen, a short chain collagen, is scarcely present in normal arteries, but is dramatically upregulated in atherosclerosis and after other types of vascular injury. Cell culture studies have revealed that this protein supports smooth muscle cell (SMC) adhesion and stimulates migration, however little is known about the signaling or the mechanisms by which this occurs. SMCs isolated from wild-type C57BL/6 and type VIII collagen deficient mice were studied using assays to measure chemotactic and haptotactic migration, and remodeling and contraction of 3-dimensional type I collagen gels. Col8 −/− SMCs exhibited impairments in migration, and a strongly adhesive phenotype with prominent stress fibers, stable microtubules and pronounced central basal focal adhesions. The addition of exogenous type VIII collagen to the Col8 −/− SMCs rescued the impairments in migration, and restored cytoskeletal architecture so that it was similar to Col8 +/+ cells. We measured elevated levels of active GTP-RhoA in the Col8 −/− cells, and this too was reversed by treatment with exogenous type VIII collagen. We showed that type VIII collagen normally suppresses RhoA activation through a beta-1 integrin dependent mechanism. MMP-2 levels were reduced in the Col8 −/− SMCs, and knockdown of MMP-2 in Col8 +/+ SMCs partially recapitulated the decreases in migration and 3D gel contraction seen in Col8 −/− cells, showing that type VIII collagen-stimulated migration was dependent on MMP-2. Inhibition of Rho restored MMP-2 activity in the Col8 −/− cells, and partially rescued migration, demonstrating that the elevations in RhoA activity were responsible for the suppression of migration of these cells. In conclusion, we have shown that type VIII collagen signals through beta-1 integrin receptors to suppress RhoA, allowing optimal configuration of the cytoskeleton, and the stimulation of MMP-2-dependent cell migration.

Phenotypic switching of vascular smooth muscle cells (VSMCs) is known to play a critical role in the development of atherosclerosis. However, the factors present within lesions that mediate VSMC phenotypic switching are unclear. Oxidized phospholipids (OxPLs), including 1-palmitoyl-2-(5-oxovaleroyl)- sn -glycero-3-phosphorylcholine (POVPC), are active components of minimally modified low density lipoprotein and have been previously shown to induce multiple proatherogenic events in endothelial cells and macrophages, but their effects on VSMCs have been largely unexplored until recently. We previously showed that OxPLs induced phenotypic switching of VSMCs, including suppression of SMC differentiation marker genes. The goal of the present studies was to test the hypothesis that OxPLs alter extracellular matrix production and VSMC migration. Results showed that POVPC activated expression of several extracellular matrix proteins in VSMC. POVPC increased expression of type VIII collagen α1 chain ( Col8a1 ) mRNA in cultured VSMCs and in vivo in rat carotid arteries by 9-fold and 4-fold, respectively. POVPC-induced activation of Col8a1 gene expression was reduced by small interfering RNA–mediated suppression of Krüppel-like factor 4 (Klf4) and Sp1, and was abolished in Klf4- knockout VSMCs. POVPC increased Klf4 binding to the Col8a1 gene promoter both in vivo in rat carotid arteries and in cultured VSMCs based on chromatin immunoprecipitation assays. Moreover, POVPC-induced VSMC migration was markedly reduced in Klf4 - or type VIII collagen–knockout VSMCs. Given evidence that OxPLs are present within atherosclerotic lesions, it is interesting to suggest that OxPL-induced changes in VSMC phenotype may contribute to the pathogenesis of atherosclerosis at least in part through changes in extracellular matrix composition.