Purpose: To report the safety and efficacy of a novel cell injection therapy using cultured human corneal endothelial cells (hCECs) for endothelial failure conditions via the report of the long-term 5-year postoperative clinical data from a first-in-humans clinical trial group.Design: Prospective observational study.Participants: This study involved 11 eyes of 11 patients with pseudophakic endothelial failure conditions who underwent hCEC injection therapy between December 2013 and December 2014.Methods: All patients underwent follow-up examinations at 1 week, 4 weeks, 12 weeks, and 24 weeks and 1 year, 2 years, 3 years, 4 years, and 5 years after surgery. Specific corneal endothelial cell parameters (i.e., corneal endothelial cell density [ECD], coefficient of variation of area, and percentage of hexagonal cells) and central corneal thickness, best-corrected visual acuity (BCVA) on a Landolt C eye chart, and intraocular pressure (IOP) were recorded.Main Outcome Measures: The primary outcome was the change in central ECD after cell injection therapy, and the secondary outcome was corneal thickness, BCVA, and IOP during the 5-year-postoperative follow-up period.Results: At 5 years after surgery, normal corneal endothelial function was restored in 10 of the 11 eyes, the mean AE standard deviation central corneal ECD was 1257 AE 467 cells/mm 2 (range, 601e2067 cells/mm 2 ), BCVA improved significantly in 10 treated eyes, the mean visual acuity changed from 0.876 logarithm of the minimum angle of resolution before surgery to 0.046 logarithm of the minimum angle of resolution after surgery, and no major adverse reactions directly related to the hCEC injection therapy were observed.Conclusions: The findings in this study confirmed the safety and efficacy of cultured hCEC injection therapy for up to 5 years after surgery.

This systematic review aimed to determine currently reported clinical and prodromal ocular symptoms in patients with coronavirus disease 2019 (COVID-19). METHODS. An online article search was performed in PubMed and EMBASE. Altogether 15 studies (retrospective, prospective, or case studies) involving 1533 patients with COVID-19, reporting on ocular symptoms, and with outcome data available were identified. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were followed. Study-specific estimates (incidence rates of ocular symptoms in patients with COVID-19) of cases were combined using one-group meta-analysis in a random-effects model. RESULTS. Of all included studies, 11.2% (95% confidence interval, 5.5-16.9; 78/1526 cases) reported ocular symptoms. The most common ocular finding was conjunctivitis. Prodromal ocular symptoms occurred in 12.5% (13/104 cases) of patients with COVID-19. Positive real-time polymerase chain reaction results were obtained for 16.7% (10/60 cases) of conjunctival samples and 0% (0/17 cases) of tear samples. Twelve ocular conjunctival swab samples tested positive for SARS-CoV-2. Ten cases were from subjects showing ocular symptoms (16.7%, 10/60 cases), and the remaining two cases were from subjects without ocular manifestation (1.8%, 2/113 cases). Limitations included the short study period, small sample size, findings were limited to the Asian population, only seven articles included ophthalmologic examination details, and there is currently no consensus on COVID-19 management. CONCLUSIONS. Ocular symptoms may occur in the presymptomatic phase as a prodromal symptom (12.5%, 13/104 cases), suggesting the possibility of viral transmission from the conjunctiva.

This study investigated the pathophysiological features of pachychoroid neovasculopathy (PNV) and neovascular age-related macular degeneration (nAMD) by analysing and comparing cytokine profiles in aqueous humour (AH) collected from 18 PNV, 18 nAMD and 11 control patients. Responses to intravitreal injection of aflibercept were also analysed in the PNV and nAMD groups. In the PNV group, vascular endothelial growth factor (VEGF)-A was significantly lower than in the nAMD group (p = 0.03) but was almost identical to that in the control group (p = 0.86). The nAMD group showed positive correlations between interleukin (IL)-6 and IL-8 (r = 0.78, p < 0.001), IL-6 and monocyte chemoattractant protein (MCP)-1 (r = 0.68, p = 0.002) and IL-8 and MCP-1 (r = 0.68, p = 0.002). In the nAMD group, eyes with dry maculae one month after the first aflibercept injection showed significantly lower VEGF-A and placental growth factor (PlGF) at baseline than those with wet maculae (p = 0.02 for both). However, there was no significant difference between dry and wet maculae in the PNV group. The results suggest that angiogenic factors and proinflammatory cytokines may play the distinct roles in the pathogenesis of PNV and nAMD.

In development, embryonic ectoderm differentiates into neuroectoderm and surface ectoderm using poorly understood mechanisms. Here, we show that the transcription factor OVOL2 maintains the transcriptional program of human corneal epithelium cells (CECs), a derivative of the surface ectoderm, and that OVOL2 may regulate the differential transcriptional programs of the two lineages. A functional screen identified OVOL2 as a repressor of mesenchymal genes to maintain CECs. Transduction of OVOL2 with several other transcription factors induced the transcriptional program of CECs in fibroblasts. Moreover, neuroectoderm derivatives were found to express mesenchymal genes, and OVOL2 alone could induce the transcriptional program of CECs in neural progenitors by repressing these genes while activating epithelial genes. Our data suggest that the difference between the transcriptional programs of some neuroectoderm- and surface ectoderm-derivative cells may be regulated in part by a reciprocally repressive mechanism between epithelial and mesenchymal genes, as seen in epithelial-to-mesenchymal transition.

The optical and biomechanical properties of the cornea are largely governed by the collagen-rich stroma, a layer that represents approximately 90% of the total thickness. Within the stroma, the specific arrangement of superimposed lamellae provides the tissue with tensile strength, whilst the spatial arrangement of individual collagen fibrils within the lamellae confers transparency. In keratoconus, this precise stromal arrangement is lost, resulting in ectasia and visual impairment. In the normal cornea, we previously characterised the three-dimensional arrangement of an elastic fiber network spanning the posterior stroma from limbus-to-limbus. In the peripheral cornea/limbus there are elastin-containing sheets or broad fibers, most of which become microfibril bundles (MBs) with little or no elastin component when reaching the central cornea. The purpose of the current study was to compare this network with the elastic fiber distribution in post-surgical keratoconic corneal buttons, using serial block face scanning electron microscopy and transmission electron microscopy.We have demonstrated that the MB distribution is very different in keratoconus. MBs are absent from a region of stroma anterior to Descemet's membrane, an area that is densely populated in normal cornea, whilst being concentrated below the epithelium, an area in which they are absent in normal cornea. We contend that these latter microfibrils are produced as a biomechanical response to provide additional strength to the anterior stroma in order to prevent tissue rupture at the apex of the cone. A lack of MBs anterior to Descemet's membrane in keratoconus would alter the biomechanical properties of the tissue, potentially contributing to the pathogenesis of the disease.

PURPOSE. To clarify the distinct molecular pathogenesis of central serous chorioretinopathy (CSC) and pachychoroid neovasculopathy (PNV). METHODS. Aqueous humor (AH) was collected from 18 acute CSC, 20 chronic CSC, and 20 PNV patients. Concentrations of 30 cytokines in the AH were analyzed using a multiplex bead immunoassay, and the cytokine profiles were compared among these three groups of patients. The areas of choroidal vascular hyperpermeability (CVH) and choroidal thickness (CT), including measurement of the vascular layers, were investigated to analyze the features of choroidal abnormality in acute CSC, chronic CSC, and PNV. Additionally, associations between cytokine profiles and choroidal abnormalities were analyzed. RESULTS. Proinflammatory cytokines, IL-6 and IL-8 were significantly upregulated in the chronic CSC group compared with the acute CSC or PNV groups. Angiogenic cytokines and VEGF-A were upregulated at levels that almost reached significance along with disease progression from acute to chronic CSC, whereas the upregulation was not significant from chronic CSC to PNV. In the chronic CSC group, strong positive correlations were confirmed between VEGF-A and placental growth factor (PlGF) (r ¼ 0.75, P < 0.001) and IL-6 and VEGF-A (r ¼ 0.74, P < 0.001), and angiogenesis-related cytokines were positively correlated with the typical choroidal abnormalities, areas of CVH, mean CT, and mean large choroidal vessel layer thickness. However, there was no association between these choroidal abnormality parameters and AH cytokines in the PNV group. CONCLUSIONS. The results suggest that choroidal abnormalities in chronic CSC may be associated with upregulated angiogenesis.

PURPOSE. Large-scale protein analysis may bring important insights into molecular changes following branch retinal vein occlusion (BRVO). Using proteomic techniques this study compared aqueous humor samples from patients with BRVO to age-matched controls. METHODS. Aqueous humor samples from treatment naive patients with BRVO complicated by macular edema (n = 19) and age-matched controls (n = 18) were analyzed with labelfree quantification nano liquid chromatography-tandem mass spectrometry (LFQ nLC-MS/MS). The severity of macular edema was measured as central retinal thickness (CRT) with optical coherence tomography. Control samples were obtained prior to cataract surgery. Proteins were filtered by requiring quantification in at least 50% of the samples in each group without imputation of missing values. Significantly changed proteins were identified with a permutation-based calculation with a false discovery rate at 0.05. RESULTS. In BRVO, 52 proteins were differentially expressed. Regulated proteins were involved in cell adhesion, coagulation, and acute-phase response. Apolipoprotein C-III, complement C3, complement C5, complement factor H, fibronectin, and fibrinogen chains were increased in BRVO and correlated with CRT. Fibronectin also correlated with best corrected visual acuity (BCVA) and vascular endothelial growth factor (VEGF). Monocyte differentiation antigen CD14 (CD14) and lipopolysaccharide-binding protein (LBP) were upregulated in BRVO. Contactin-1 and alpha-enolase were downregulated in BRVO and correlated negatively with CRT. CONCLUSIONS. Multiple proteins, including complement factors, fibrinogen chains, and apolipoprotein C-III, correlated with CRT, indicating a multifactorial response. Fibronectin correlated with BCVA, CRT, and VEGF. Fibronectin may reflect the severity of BRVO. The proinflammatory proteins CD14 and LBP were upregulated in BRVO.

ObjectiveTo retrospectively identify epidemiological trends of infection on the ocular surface and investigate trends of resistance to bacterial antibiotics compared with 10-years previous for Staphylococcus aureus, coagulase-negative staphylococci (CNS), and Corynebacterium in Japan.Materials and methodsBacterial isolate samples were collected from the conjunctival sacs of eyes afflicted with conjunctivitis, keratitis, dacryocystitis, and hordeolum from September 2004 through November 2005 (n = 145 isolates) and September 2014 through November 2015 (n = 195 isolates) at the Baptist Eye Institute, Kyoto, Japan. The prevalence of methicillin-resistant S. aureus (MRSA), methicillin-resistant CNS (MR-CNS), and fluoroquinolone-resistant Corynebacterium were examined, and susceptibility of isolated bacteria to levofloxacin (LVFX), cefmenoxime (CMX), chloramphenicol (CP), erythromycin (EM), vancomycin (VCM), and arbekacin (ABK) were compared between both time periods using the disc susceptibility method.ResultsOver the 10-year period from initial to final examination, the prevalence of MRSA and MR-CNS significantly decreased from 52% to 22% (P < 0.05) and from 47% to 25% (P < 0.05), respectively, yet there was no change in the prevalence of fluoroquinolone-resistant Corynebacterium (60% and 54%; P = 0.38). Antibiotic-resistance trend analysis revealed that susceptibility to antibiotics in 2014–2015 was similar to that in 2004–2005. MRSA and MR-CNS were susceptible to CP (88%), VCM (100%), and ABK (100%), while fluoroquinolone-resistant Corynebacterium was susceptible to CMX (100%), VCM (100%), and ABK (96%).ConclusionThe prevalence of MRSA and MR-CNS significantly decreased between the two time periods, yet more than 50% of the Corynebacterium isolates were still resistant to LVFX. Although no increase in bacterial resistance to antibiotics was found, a cautionary use of fluoroquinolone eye drops should be considered.