SARS-CoV-2 infects cells lining the blood-retinal barrier and induces a hyperinflammatory immune response in the retina via systemic exposure.

SARS-CoV-2 has been shown to cause wide-ranging ocular abnormalities and vision impairment in COVID-19 patients. However, there is limited understanding of SARS-CoV-2 in ocular transmission, tropism, and associated pathologies. The presence of viral RNA in corneal/conjunctival tissue and tears, along with the evidence of viral entry receptors on the ocular surface, has led to speculation that the eye may serve as a potential route of SARS-CoV-2 transmission. Here, we investigated the interaction of SARS-CoV-2 with cells lining the blood-retinal barrier (BRB) and the role of the eye in its transmission and tropism. The results from our study suggest that SARS-CoV-2 ocular exposure does not cause lung infection and moribund illness in K18-hACE2 mice despite the extended presence of viral remnants in various ocular tissues. In contrast, intranasal exposure not only resulted in SARS-CoV-2 spike (S) protein presence in different ocular tissues but also induces a hyperinflammatory immune response in the retina. Additionally, the long-term exposure to viral S-protein caused microaneurysm, retinal pigmented epithelium (RPE) mottling, retinal atrophy, and vein occlusion in mouse eyes. Notably, cells lining the BRB, the outer barrier, RPE, and the inner barrier, retinal vascular endothelium, were highly permissive to SARS-CoV-2 replication. Unexpectedly, primary human corneal epithelial cells were comparatively resistant to SARS-CoV-2 infection. The cells lining the BRB showed induced expression of viral entry receptors and increased susceptibility towards SARS-CoV-2-induced cell death. Furthermore, hyperglycemic conditions enhanced the viral entry receptor expression, infectivity, and susceptibility of SARS-CoV-2-induced cell death in the BRB cells, confirming the reported heightened pathological manifestations in comorbid populations. Collectively, our study provides the first evidence of SARS-CoV-2 ocular tropism via cells lining the BRB and that the virus can infect the retina via systemic permeation and induce retinal inflammation.

MicroPulse Transscleral Laser Therapy Dosimetry Utilizing the Revised P3 Delivery Device: A Randomized Controlled Trial.

PURPOSE: To compare the long-term effectiveness and safety outcomes of 2 treatment dosages of the MicroPulse Transscleral Laser Therapy (MPTLT) procedure on intraocular pressure (IOP) control in patients with primary open-angle glaucoma. DESIGN: Single-blinded randomized controlled trial. SUBJECTS: A total of 19 patients with POAG without prior history of incisional glaucoma surgery. METHODS: Subjects randomized into 2 treatment groups, 100-second (total energy 78.25 joules [J], fluence 109.2 J/cm2) or 120-second (total energy 93.9 J, fluence 131.0 J/cm2) total treatment duration, underwent the MPTLT procedure with the revised P3 delivery probe delivering 2.5 W energy, 31.3% duty cycle, applied in 3 sweeps per hemisphere, avoiding 3 and 9 o'clock. All subjects were followed at 1, 3, 6, 9, and 12 months to compare reduction in IOP and medication. MAIN OUTCOME MEASURES: Absolute and percentage IOP reduction at 6 months. RESULTS: The treatment groups were similar in age, sex, and stage of glaucoma at baseline (all P > 0.05). The 120-second group had significantly better baseline best-corrected visual acuity (BCVA) and a higher percentage of patients with prior MPTLT therapy (ranging from 4-19 months before study). Significantly greater IOP reduction was noted in the 120-second group compared with the 100-second group at 3 months, with mean IOP reduction of 7.3 ± 4.2 mmHg (vs. 0.9 ± 2.5 mmHg, P = 0.006) and percentage IOP reduction of 32.2% ± 18.3% (vs. 4.1% ± 13.7%, P = 0.007). The 120-second group continued to outperform at 6-month follow-up: mean IOP reduction of 9.0 ± 4.8 mmHg (vs. 0.8 ± 2.5 mmHg, P = 0.016) and percentage IOP reduction of 37.8% ± 19.8% (vs. 3.6% ± 13.3%, P = 0.021). At 12 months, 37.5% and 18.2% of the 100- and 120-second groups, respectively, required an additional IOP-lowering procedure (P = 0.35); however, Kaplan-Meier analysis of time to intervention was not significantly different (P = 0.38). There were no vision-threatening complications or changes in BCVA during the study period. CONCLUSIONS: This study demonstrates a dose-response relationship with improved IOP control and excellent safety profile in patients treated with higher treatment total energy and fluence using the revised MPTLT probe. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Mass Spectrometry Defines Lysophospholipids as Ligands for Chicken MHCY Class I Molecules.

Chicken (Gallus gallus) MHCY class I molecules are highly polymorphic yet substantially different from polymorphic MHC class I molecules that bind peptide Ags. The binding grooves in MHCY class I molecules are hydrophobic and too narrow to accommodate peptides. An earlier structural study suggested that ligands for MHCY class I might be lipids, but the contents of the groove were not clearly identified. In this study, lysophospholipids have been identified by mass spectrometry as bound in two MHCY class I isoforms that differ substantially in sequence. The two isoforms, YF1*7.1 and YF1*RJF34, differ by 35 aa in the α1 and α2 domains that form the MHC class I ligand binding groove. Lyso-phosphatidylethanolamine (lyso-PE) 18:1 was the dominant lipid identified in YF1*7.1 and YF1*RJF34 expressed as recombinant molecules and renatured with ß2-microglobulin in the presence of a total lipid extract from Escherichia coli. Less frequently detected were lyso-PE 17:1, lyso-PE 16:1, and lysophosphatidylglycerols 17:1 and 16:0. These data provide evidence that lysophospholipids are candidate ligands for MHCY class I molecules. Finding that MHCY class I isoforms differing substantially in sequence bind the same array of lysophospholipids indicates that the amino acid polymorphism that distinguishes MHCY class I molecules is not key in defining ligand specificity. The polymorphic positions lie mostly away from the binding groove and might define specificity in interactions of MHCY class I molecules with receptors that are presently unidentified. MHCY class I molecules are distinctive in bound ligand and in display of polymorphic residues.

Uveal and capsular biocompatibility of a new hydrophobic acrylic microincision intraocular lens.

PURPOSE: To evaluate uveal biocompatibility and capsular bag opacification of a new hydrophobic acrylic microincision intraocular lens (IOL) in comparison with a commercially available 1-piece hydrophobic acrylic IOL. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Eight New Zealand rabbits underwent bilateral phacoemulsification and implantation of the preloaded Nanex multiSert IOL in one eye and a commercially available preloaded lens (AcrySof IQ in UltraSert, model AU00T0) in the contralateral eye. A slitlamp examination was performed weekly for 4 weeks. The rabbits were then killed humanely and their globes enucleated. Capsular bag opacification was assessed from the Miyake-Apple view, and the eyes were subjected to histopathologic evaluation. RESULTS: Postoperative inflammatory reactions were similar between the test and control eyes in the 8 New Zealand rabbits. The mean postmortem central posterior capsule opacification (PCO) was 0.93 ± 0.73 in the test group and 1.19 ± 0.53 in the control group. The mean postmortem peripheral PCO was 1.75 ± 0.92 in the test group and 2.06 ± 0.77 in the control group. Central and peripheral PCO scores were not statistically different between the test and control groups (P = .41 and P = .35, respectively, 2-tailed t test: paired 2-sample for means). CONCLUSIONS: A new 1-piece hydrophobic acrylic microincision IOL incorporating an ultraviolet-ozone treatment on the posterior surface performed similarly to a commercially available 1-piece hydrophobic acrylic IOL in terms of uveal and capsular biocompatibility in the rabbit model. To our knowledge, this is the first hydrophobic acrylic microincision IOL to demonstrate similar PCO performance when compared with a conventional, commercially available IOL.

Posterior capsule opacification prevention by an intraocular lens incorporating a micropatterned membrane on the posterior surface.

PURPOSE: To evaluate posterior capsule opacification (PCO) with a new hydrophobic acrylic intraocular lens (IOL) featuring a new micropatterned membrane, in comparison with a commercially available 1-piece hydrophobic acrylic IOL. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. STUDY DESIGN: Experimental study. METHODS: Twelve New Zealand rabbits had bilateral phacoemulsification and implantation of a ClearSight unpatterned IOL (Group 1), a ClearSight Sharklet-patterned IOL (Group 2), or a control, commercially available IOL (Group 3) (8 IOLs in each group). Slit-lamp examination was performed weekly for 4 weeks. The rabbits were then killed humanely, and their globes enucleated. Capsular bag opacification was assessed from the Miyake-Apple view, and the eyes underwent histopathology. RESULTS: The mean postmortem central PCO was 1.87 ± 1.35 in Group 1, 1.06 ± 1.23 in Group 2, and 3.14 ± 0.89 in Group 3. Peripheral PCO was 2.18 ± 1.36 in Group 1, 1.5 ± 1.03 in Group 2, and 3.57 ± 0.53 in Group 3. When comparing central and peripheral PCO between Groups 1 and 3, the difference was not statistically significant, but it was statistically significant between Groups 2 and 3 (P = .003 and P = .0003, t test with Bonferroni correction). CONCLUSIONS: Unique discontinuous features comprising the micropattern allow for focal adhesions to be precisely guided and therefore controlling cell migration. The patterned membrane incorporated on the posterior surface of the IOL significantly reduced capsular bag opacification compared with a commercially available control IOL.

Localized calcification of hydrophilic acrylic intraocular lenses after posterior segment procedures.

PURPOSE: To describe the clinical and laboratory findings in a series of cases of hydrophilic acrylic intraocular lens (IOL) opacification after posterior segment procedures. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, USA. DESIGN: Experimental study. METHODS: Thirty hydrophilic acrylic IOLs were explanted after various posterior segment procedures (pars plana vitrectomy, intravitreal anti-vascular endothelial growth factor injections) because of localized central anterior surface and subsurface optic opacification associated with decreased visual function. Once received by the laboratory in the dry state or in fixative by the explanting surgeons, microscopic, histochemical (alizarin red), and surface analysis (scanning electron microscopy [SEM], energy-dispersive X-ray spectroscopy [EDS]) evaluations were performed on the IOLs. The surgeons were sent a questionnaire to obtain information pertinent to each case. RESULTS: Of the 30 explanted IOLs, 9 hydrophilic acrylic designs from 7 different manufacturers were identified. Gross microscopy and light microscopy showed granular deposits in a dense round pattern of distribution within the margins of the capsulorhexis or pupil on the anterior surface/subsurface of the IOLs. The granules stained positive for calcium with alizarin red. On SEM coupled with EDS, the granular deposits were found to comprise calcium and phosphate. CONCLUSIONS: A localized pattern of anterior surface/subsurface calcification was seen on hydrophilic acrylic IOLs from various manufacturers. The calcification resembled the pattern seen on calcified IOLs after anterior segment procedures using intracameral injections of air or gas. This calcification of hydrophilic acrylic IOLs is likely the result of blood-aqueous barrier breakdown from repeated intraocular procedures.

Surface deposits mimicking calcification on a hydrophobic acrylic intraocular lens.

We describe the case of a female patient who had 3-piece silicone intraocular lenses (IOLs) bilaterally implanted after uneventful surgeries in 2007. Nine years later, the IOLs were explanted and exchanged with 3-piece hydrophobic acrylic IOLs because of cloudiness on their posterior aspect. Two years later, a similar finding was observed on the hydrophobic acrylic IOLs, and it was more intense in the left eye. The IOL in this eye was explanted and submitted for microscopic evaluation, which demonstrated the presence of multiple deposits irregular in shape and size covering significant areas of anterior and posterior optic surfaces. Elemental analyses ruled out the presence of calcification. The surface deposits stained positive for proteins. To our knowledge, postoperative calcification has not been definitively associated with hydrophobic acrylic IOLs to date.

Characterization of WY 14,643 and its Complex with Aldose Reductase.

The peroxisome proliferator, WY 14,643 exhibits a pure non-competitive inhibition pattern in the aldehyde reduction and in alcohol oxidation activities of human Aldose reductase (hAR). Fluorescence emission measurements of the equilibrium dissociation constants, Kd, of oxidized (hAR•NADP+) and reduced (hAR•NADPH) holoenzyme complexes display a 2-fold difference between them. Kd values for the dissociation of WY 14,643 from the oxidized (hAR•NADP+•WY 14,643) and reduced (hAR•NADPH•WY 14,643) ternary complexes are comparable to each other. The ternary complex structure of hAR•NADP+•WY 14,643 reveals the first structural evidence of a fibrate class drug binding to hAR. These observations demonstrate how fibrate molecules such as WY 14,643, besides being valued as agonists for PPAR, also inhibit hAR.