3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with pleiotropic cytoprotective properties albeit without the bleeding risks. The anti-inflammatory activities of 3K3A-APC were demonstrated in multiple preclinical injury models, including various neurological disorders. We determined the ability of 3K3A-APC to inhibit ocular inflammation in a murine model of lipopolysaccharide (LPS)-induced uveitis. Leukocyte recruitment, microglia activation, NLRP3 inflammasome and IL-1β levels were assessed using flow cytometry, retinal cryosection histology, retinal flatmount immunohistochemistry and vascular imaging, with and without 3K3A-APC treatment. LPS triggered robust inflammatory cell recruitment in the posterior chamber. The 3K3A-APC treatment significantly decreased leukocyte numbers and inhibited leukocyte extravasation from blood vessels into the retinal parenchyma to a level similar to controls. Resident microglia, which underwent an inflammatory transition following LPS injection, remained quiescent in eyes treated with 3K3A-APC. An inflammation-associated increase in retinal thickness, observed in LPS-injected eyes, was diminished by 3K3A-APC treatment, suggesting its clinical relevancy. Finally, 3K3A-APC treatment inhibited inflammasome activation, determined by lower levels of NLRP3 and its downstream effector IL-1β. Our results highlight the anti-inflammatory properties of 3K3A-APC in ocular inflammation and suggest its potential use as a novel treatment for retinal diseases associated with inflammation.

Purpose: To characterize ocular surface temperature (OST) in healthy eyes and its association with systemic risk factors of cardiovascular and ischemic heart disease. Methods: This prospective cross-sectional study included consenting subjects who were examined at the Institute for Medical Screening in Sheba Medical Center. A Therm-App™ thermal imaging camera (Opgal LTD, Israel) was used for OST acquisition, and the mean OST of the medial canthal, lateral canthal, and central cornea regions were measured. Room and body temperatures were also recorded. Past medical and ocular history as well as data from various clinical examinations performed at the same visit were obtained. Results: Thermographic images were obtained from 186 subjects, 150 of which were included in the final analysis. OST was significantly higher in the medial canthal, central cornea, and lateral canthal regions in people with a history of ischemic heart disease (p = 0.02, p = 0.02, and p = 0.03, respectively). There were no significant OST differences (ANOVA test) associated with the presence of hypertension, diabetes mellitus, or active smoking status. Conclusions: OST correlated positively with the presence of ischemic heart disease. This correlation, its pathophysiological base, and its clinical application warrants further investigation.

The activated protein C (APC) ability to inhibit choroidal neovascularization (CNV) growth and leakage was recently shown in a murine model. A modified APC, 3K3A-APC, was designed to reduce anticoagulant activity while maintaining full cytoprotective properties, thus diminishing bleeding risk. We aimed to study the ability of 3K3A-APC to induce regression of CNV and evaluate vascular endothelial growth factor (VEGF) role in APC’s activities in the retina. CNV was induced by laser photocoagulation on C57BL/6J mice. APC and 3K3A-APC were injected intravitreally after verification of CNV presence. CNV volume and vascular penetration were evaluated on retinal pigmented epithelium (RPE)-choroid flatmount by fluorescein isothiocyanate (FITC)-dextran imaging. VEGF levels were measured using immunofluorescence anti-VEGF staining. We found that 3K3A-APC induced regression of pre-existing CNV. VEGF levels, measured in the CNV lesion sites, significantly decreased upon APC and 3K3A-APC treatment. Reduction in VEGF was sustained 14 days post a single APC injection. As 3K3A-APC retained APCs’ activities, we conclude that the anticoagulant properties of APC are not mandatory for APC activities in the retina and that VEGF reduction may contribute to the protective effects of APC and 3K3A-APC. Our results highlight the potential use of 3K3A-APC as a novel treatment for CNV and other ocular pathologies.

3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with cytoprotective properties and reduced bleeding risks. We studied the potential use of 3K3A-APC as a multi-target therapeutic option for choroidal neovascularization (CNV), a common cause of vision loss in age-related macular degeneration. CNV was induced by laser photocoagulation in a murine model, and 3K3A-APC was intravitreally injected. The impact of 3K3A-APC treatment on myeloid and microglia cell activation and recruitment and on NLRP3 inflammasome, IL-1β, and VEGF levels was assessed using cryosection, retinal flat-mount immunohistochemistry and vascular imaging. Additionally, we evaluated the use of fluorescein angiography as a surrogate marker for in vivo evaluation of the efficacy of 3K3A-APC treatment against leaking CNV lesions. Our results demonstrated that 3K3A-APC treatment significantly reduced the accumulation and activation of myeloid cells and microglia in the CNV area and decreased the NLRP3 and IL-1β levels at the CNV site and the surrounding retina. Furthermore, 3K3A-APC treatment resulted in leakage regression and CNV growth suppression. These findings indicate that the anti-inflammatory activities of 3K3A-APC contribute to CNV inhibition. Our study suggests the potential use of 3K3A-APC as a novel multi-target treatment for CNV.

Expeditious publication is an important factor when considering publishing ophthalmic research. We investigated the factors associated with shorter publication times in pediatric ophthalmology and strabismus (POS). We analyzed 2487 POS articles from 8 ophthalmology journals publishing POS articles. Time from submission to acceptance, from acceptance to publication, and from submission to publication were calculated for each article. We compared trends over time of factors affecting the publication times from 2002 to 2007 and those from 2014 to 2018. Median peer review durations were 156 days from submission to acceptance; 79 days from acceptance to publication, and 244 days from submission to publication. The American Journal of Ophthalmology, JAMA Ophthalmology, and Strabismus had the shortest submission to publication time. Authors from Africa, East Europe, Central and South America received the fastest processing time in all time categories, although most authors were based in North America and UK. All-time intervals decreased annually, significantly more during the first decade. In the study's second period, more co-authors and affiliated departments correlated with shorter review times. Manuscripts in higher Impact Factor (IF) journals had faster publication times in the first decade. Female senior authors faced longer submission-to-acceptance times in the first decade. This gender gap disappeared in the second period. A general improvement occurred with most journals, specifically those journals with a higher number of co-authors and affiliated departments, indicating an efficient collaborative authorship. Low-income regions benefited from comparatively shorter time intervals. The gender gap in senior authorship diminished over time.