The Comparison of Retinal Microvascular Findings in Acute COVID-19 and 1-Year after Hospital Discharge Assessed with Multimodal Imaging-A Prospective Longitudinal Cohort Study.

This study aimed to quantify possible long-term impairment of the retinal microcirculation and microvasculature by reassessing a cohort of patients with acute COVID-19 without other known comorbidities one year after their discharge from the hospital. Thirty patients in the acute phase of COVID-19 without known systemic comorbidities were enrolled in this prospective longitudinal cohort study. Fundus photography, SS-OCT, and SS-OCTA using swept-source OCT (SS-OCT, Topcon DRI OCT Triton; Topcon Corp., Tokyo, Japan) were performed in the COVID-19 unit and 1-year after hospital discharge. The cohort's median age was 60 years (range 28-65) and 18 (60%) were male. Mean vein diameter (MVD) significantly decreased over time, from 134.8 µm in the acute phase to 112.4 µm at a 1-year follow-up (p < 0.001). A significantly reduced retinal nerve fiber layer (RNFL) thickness was observed at follow-up in the inferior quadrant of the inner ring (mean diff. 0.80 95% CI 0.01-1.60, p = 0.047) and inferior (mean diff. 1.56 95% CI 0.50-2.61, p < 0.001), nasal (mean diff. 2.21 95% CI 1.16-3.27, p < 0.001), and superior (mean diff. 1.69 95% CI 0.63-2.74, p < 0.001) quadrants of the outer ring. There were no statistically significant differences between the groups regarding vessel density of the superior and deep capillary plexuses. The transient dilatation of the retinal vessels in the acute phase of COVID-19, as well as RNFL thickness changes, could become a biomarker of angiopathy in patients with severe COVID-19.

The impact of acute COVID-19 on the retinal microvasculature assessed with multimodal imaging.

PURPOSE: To quantify retinal microvascular findings in the acute phase of COVID-19 using multimodal imaging and compare them with healthy, age-matched controls. METHODS: Hospitalized patients in the acute phase of COVID-19 without known systemic comorbidities (n = 75) and healthy controls (n = 101) aged 18-65 were enrolled in this prospective cross-sectional study. The retinal microcirculation and microvasculature impairments were assessed using fundus photography, swept-source optical coherence tomography, and swept-source optical coherence tomography angiography in the COVID-19 unit and compared with healthy, age-matched controls. RESULTS: Retinal findings were predominately observed in patients with severe disease (P = 0.006). Patients with severe disease were shown to have increased both mean vein diameter (Coef. = 19.28, 95% CI: 7.34-31.23, P = 0.002) and mean artery diameter (Coef. = 11.07, 95% CI: 0.84-21.67, P = 0.044). Neither blood vessel diameters were correlated with any confounding variables (age, sex, treatment with oxygen, LDH, or ferritin). Patients with severe COVID-19 were shown to have significantly increased retinal nerve fiber layer thickness in the superior and inferior quadrants both in the inner (S: P = 0.046; I: P = 0.016) and outer (S: P = 0.026; I: P = 0.014) ring and significantly increased GCL thickness in the outer temporal quadrant (P = 0.038). There were no statistically significant differences in vessel density or the foveal avascular zone area between the groups. CONCLUSION: The severity of COVID-19 was significantly correlated with the presence of retinal microangiopathy, which could become a biomarker of angiopathy in patients with COVID-19.

The Relative Preservation of the Central Retinal Layers in Leber Hereditary Optic Neuropathy.

(1) Background: The purpose of this study was to evaluate the thickness of retinal layers in Leber hereditary optic neuropathy (LHON) in the atrophic stage compared with presumably inherited bilateral optic neuropathy of unknown cause with the aim of seeing if any LHON-specific patterns exist. (2) Methods: 14 patients (24 eyes) with genetically confirmed LHON (LHON group) were compared with 13 patients (23 eyes) with negative genetic testing results (mtDNA + WES) and without identified etiology of bilateral optic atrophy (nonLHON group). Segmentation analysis of retinal layers in the macula and peripapillary RNFL (pRNFL) measurements was performed using Heidelberg Engineering Spectralis SD-OCT. (3) Results: In the LHON group, the thickness of ganglion cell complex (GCC) (retinal nerve fiber layer (RNFL)­ganglion cell layer (GCL)­inner plexiform layer (IPL)) in the central ETDRS (Early Treatment Diabetic Retinopathy Study) circle was significantly higher than in the nonLHON group (p < 0.001). In all other ETDRS fields, GCC was thinner in the LHON group. The peripapillary RNFL (pRNFL) was significantly thinner in the LHON group in the temporal superior region (p = 0.001). Longitudinal analysis of our cohort during the follow-up time showed a tendency of thickening of the RNFL, GCL, and IPL in the LHON group in the central circle, as well as a small recovery of the pRNFL in the temporal region, which corresponds to the observed central macular thickening. (4) Conclusions: In LHON, the retinal ganglion cell complex thickness (RNFL-GCL-IPL) appears to be relatively preserved in the central ETDRS circle compared to nonLHON optic neuropathies in the chronic phase. Our findings may represent novel biomarkers as well as a structural basis for possible recovery in some patients with LHON.

TRPV4: Cell type-specific activation, regulation and function in the vertebrate eye.

The architecture of the vertebrate eye is optimized for efficient delivery and transduction of photons and processing of signaling cascades downstream from phototransduction. The cornea, lens, retina, vasculature, ciliary body, ciliary muscle, iris and sclera have specialized functions in ocular protection, transparency, accommodation, fluid regulation, metabolism and inflammatory signaling, which are required to enable function of the retina-light sensitive tissue in the posterior eye that transmits visual signals to relay centers in the midbrain. This process can be profoundly impacted by non-visual stimuli such as mechanical (tension, compression, shear), thermal, nociceptive, immune and chemical stimuli, which target these eye regions to induce pain and precipitate vision loss in glaucoma, diabetic retinopathy, retinal dystrophies, retinal detachment, cataract, corneal dysfunction, ocular trauma and dry eye disease. TRPV4, a polymodal nonselective cation channel, integrate non-visual inputs with homeostatic and signaling functions of the eye. The TRPV4 gene is expressed in most if not all ocular tissues, which vary widely with respect to the mechanisms of TRPV4 channel activation, modulation, oligomerization, and participation in protein- and lipid interactions. Under- and overactivation of TRPV4 may affect intraocular pressure, maintenance of blood-retina barriers, lens accommodation, neuronal function and neuroinflammation. Because TRPV4 dysregulation precipitates many pathologies across the anterior and posterior eye, the channel could be targeted to mitigate vision loss.

The Role of ACE, ACE2, and AGTR2 Polymorphisms in COVID-19 Severity and the Presence of COVID-19-Related Retinopathy.

The proposed SARS-CoV-2-induced dysregulation of the renin-angiotensin-aldosterone (RAAS) system results in endothelial dysfunction and microvascular thrombosis. The retinal plexuses contain terminal vessels without anastomotic connections, making the retina especially susceptible to ischemia. This study aimed to determine the role of selected polymorphisms of genes in the RAAS pathway in COVID-19 severity and their association with the presence of COVID-19 retinopathy. 69 hospitalized patients in the acute phase of COVID-19 without known systemic comorbidities and 96 healthy controls were enrolled in this prospective cross-sectional study. The retina was assessed with fundus photography using a Topcon DRI OCT Triton (Topcon Corp., Tokyo, Japan) in the COVID-19 unit. Genotyping of selected polymorphisms in the genes for ACE (rs4646994), ACE2 (rs2285666), and AGTR2 (rs1403543) was performed. The COVID-19 group was divided into mild (n = 12) and severe (n = 57), and then further divided according to the presence of COVID-19 retinopathy (Yes, n = 50; No, n = 19). The presence of the AGTR2 rs1403543-AA genotype was associated with a 3.8-fold increased risk of COVID-19 retinopathy (p = 0.05). The genotype frequencies of selected gene polymorphisms were not significantly associated with either the presence of COVID-19 or its severity. This is the first study demonstrating a borderline association of the AGTR2 rs1403543-AA genotype with COVID-19 retinopathy in males; hence, the AGTR2 rs 1403543 A allele might represent a genetic risk factor for COVID-19 retinopathy in males.

Web-based internet searches for digital health products in the United Kingdom before and during the COVID-19 pandemic: a time-series analysis using app libraries from the Organisation for the Review of Care and Health Applications (ORCHA).

OBJECTIVES: To explore if consumer interest in digital health products (DHPs), changed following the COVID-19 pandemic and the lockdown measures that ensued. DESIGN: Retrospective time-series analysis of web-based internet searches for DHPs in the UK, split over two periods, pre-COVID-19 lockdown (January 2019-23 March 2020) and post-COVID-19 lockdown (24 March 2020-31 December 2020). SETTING: The UK. PARTICIPANTS: Members of the UK general population using health-app libraries provided by the Organisation for the Review of Care and Health Applications. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was volume of searches for DHPs. Secondary outcomes considered search volumes for 25 different therapeutic areas. Outcomes were assessed for significance using a two-stage Poisson test. RESULTS: There were 126 640 searches for DHPs over the study period. Searches for DHPs increased by 343% from 2446 per month prior to COVID-19 lockdown measures being introduced to 8996 per month in the period following the first COVID-19 lockdown in the UK. In total, 23/25 (92%) of condition areas experienced a significant increase in searches for DHPs, with the greatest increases occurring in the first 2 months following lockdown. Musculoskeletal conditions (2.036%), allergy (1.253%) and healthy living DHPs (1.051%) experienced the greatest increases in searches compared with pre-lockdown. Increased search volumes for DHPs were sustained in the 9 months following the introduction of lockdown measures, with 21/25 (84%) of condition areas experiencing monthly search volumes at least 50% greater than pre-lockdown levels. CONCLUSIONS: The COVID-19 pandemic has profoundly disrupted the routine delivery of healthcare, making face-to-face interaction difficult, and contributing to unmet clinical needs. This study has demonstrated significant increases in internet searches for DHPs by members of the UK population since COVID-19, signifying an increased interest in this potential therapeutic medium. Future research should clarify whether this increased interest has resulted in increased acceptance and utilisation of these technologies also.

Vision training with VEP biofeedback in amblyopia after the critical period.

PURPOSE: The purpose of this study was to investigate the benefits of vision training with visual evoked potentials (VEP) biofeedback in amblyopia after the critical period in 8 to 17-year (11.5 ± 3.1) old children. METHODS: Ten participants with monocular amblyopia after the critical period underwent a 10-week, 20-session vision training program with the Retimax Vision Trainer device. During each session, the participants were instructed to be as focused as possible onto the fixation point in the middle of the screen. The size of the fixation point and the pitch of the background sound were changing according to VEP parameters and thus provided the participants real-time feedback of their visual performance. RESULTS: The mean BCVA improvement across our group was 0.12 LogMAR (p < 0.01). There was also a significant increase in contrast sensitivity to the FACT chart across all spatial frequencies (all p < 0.05). Electrophysiologic data revealed higher steady-state visual evoked potentials (SS-VEP) amplitudes and correspondingly lower fixation point values in the last 2 weeks of training compared to the first 2 weeks (both p < 0.01). Due to unexplainably low VEP amplitude levels in later trainings compared to those in the beginning in two participants, we have not found a significant correlation between the increase in BCVA and the increase in SS-VEP amplitude (p = 0.88). At the follow-up at 2 and 12 months following the end of training, both BCVA and contrast sensitivity remained within the levels achieved at the end of training. In some participants, however, no improvement of BCVA was observed. CONCLUSIONS: The tested vision training approach demonstrates modest but stable improvement of psychophysical parameters as well as objective characteristics in amblyopia after the critical period. Real-time SS-VEP can be used as an objective parameter to monitor participants' attention during vision training stimulation.

Polymodal Sensory Transduction in Mouse Corneal Epithelial Cells.

Purpose: Contact lenses, osmotic stressors, and chemical burns may trigger severe discomfort and vision loss by damaging the cornea, but the signaling mechanisms used by corneal epithelial cells (CECs) to sense extrinsic stressors are not well understood. We therefore investigated the mechanisms of swelling, temperature, strain, and chemical transduction in mouse CECs. Methods: Intracellular calcium imaging in conjunction with electrophysiology, pharmacology, transcript analysis, immunohistochemistry, and bioluminescence assays of adenosine triphosphate (ATP) release were used to track mechanotransduction in dissociated CECs and epithelial sheets isolated from the mouse cornea. Results: The transient receptor potential vanilloid (TRPV) transcriptome in the mouse corneal epithelium is dominated by Trpv4, followed by Trpv2, Trpv3, and low levels of Trpv1 mRNAs. TRPV4 protein was localized to basal and intermediate epithelial strata, keratocytes, and the endothelium in contrast to the cognate TRPV1, which was confined to intraepithelial afferents and a sparse subset of CECs. The TRPV4 agonist GSK1016790A induced cation influx and calcium elevations, which were abolished by the selective blocker HC067047. Hypotonic solutions, membrane strain, and moderate heat elevated [Ca2+]CEC with swelling- and temperature-, but not strain-evoked signals, sensitive to HC067047. GSK1016790A and swelling evoked calcium-dependent ATP release, which was suppressed by HC067027 and the hemichannel blocker probenecid. Conclusions: These results demonstrate that cation influx via TRPV4 transduces osmotic and thermal but not strain inputs to CECs and promotes hemichannel-dependent ATP release. The TRPV4-hemichannel-ATP signaling axis might modulate corneal pain induced by excessive mechanical, osmotic, and chemical stimulation.

Identification and characterization of dendritic cell subtypes in preserved and cultured cadaveric human corneolimbal tissue on amniotic membrane.

PURPOSE: Rejection is the leading cause of failure of limbal allogafts. Resident dendritic cell (DC) maturation plays a critical role in host allosensitization. There are two lineages: myeloid (mDC) and lymphoid (pDC), with different biological properties. The aim was to analyse the distribution of DC subtypes in limbal explant cultures on amniotic membrane (AM), cultivated on either the epithelial or stromal side and to compare the results with directly isolated cells from cadaveric whole corneoscleral tissue divided into specific areas. METHODS: The expression of CD11c (mDC), CD303/CD123 (pDC) and costimulatory molecules CD80, CD86 and activation markers HLA-DR, CD83 was investigated by flow cytometry. Additionally, the corneal epithelium marker CK12 and ABCB5, a new epithelial stem cell marker, were investigated. RESULTS: Cells positive for pDC and mDC markers were found in all examined areas, with a nonsignificant prevalence of pDC. In limbal explant cultures on AM, the percentage of pDC and mDC was similar, with no statistically significant difference between cultures on epithelial or stromal sides of AM. However, with ex vivo limbal explant cultivation on AM, the pDC content declined significantly (p < 0.05) and the ABCB5 marker was likewise statistically significantly reduced. CONCLUSION: This is the first study to characterize the distribution of pDC and mDC subsets in cultured and noncultured human corneolimbal tissue. Additionally, ABCB5 positive cells were identified. These findings might be important for future strategies, allowing preparation of corneolimbal allografts with optimal stem cell content for a longer lasting therapeutic effect.