PURPOSE: To provide current estimates of the prevalence of diagnosed dry eye disease (DED) and associated demographics among US adults aged ≥18 years. DESIGN: Cross-sectional, population-based survey. METHODS: Data were analyzed from 75,000 participants in the 2013 National Health and Wellness Survey to estimate prevalence/risk of diagnosed DED overall, and by age, sex, insurance, and other demographic factors. We weighted the observed DED prevalence to project estimates to the US adult population and examined associations between demographic factors and DED using multivariable logistic regression. RESULTS: Based on weighted estimates, 6.8% of the US adult population was projected to have diagnosed DED (∼16.4 million people). Prevalence increased with age (18-34 years: 2.7%; ≥75 years: 18.6%) and was higher among women (8.8%; ∼11.1 million) than men (4.5%; ∼5.3 million). After adjustment, there were no substantial differences in prevalence/risk of diagnosed DED by race, education, or US census region. However, there was higher risk of diagnosed DED among those aged 45-54 years (odds ratio [OR]: 1.95; 95% confidence interval [CI]: 1.74-2.20) and ≥75 years (OR: 4.95; 95% CI: 4.26-5.74), vs those aged 18-34 years. Risk was also higher among women vs men (OR: 2.00; 95% CI: 1.88-2.13) and insured vs uninsured participants (OR: 2.12; 95% CI: 1.85-2.43 for those on government and private insurance vs none). CONCLUSIONS: We estimate that >16 million US adults have diagnosed DED. Prevalence is higher among women than men, increases with age, and is notable among those aged 18-34 years.

Current treatments for choroidal neovascularization, a major cause of blindness for patients with age-related macular degeneration, treat symptoms but not the underlying causes of the disease. Inflammation has been strongly implicated in the pathogenesis of choroidal neovascularization. We examined the inflammatory role of Toll-like receptor 2 (TLR2) in age-related macular degeneration. TLR2 was robustly expressed by the retinal pigment epithelium in mouse and human eyes, both normal and with macular degeneration/choroidal neovascularization. Nuclear localization of NF-κB, a major downstream target of TLR2 signaling, was detected in the retinal pigment epithelium of human eyes, particularly in eyes with advanced stages of age-related macular degeneration. TLR2 antagonism effectively suppressed initiation and growth of spontaneous choroidal neovascularization in a mouse model, and the combination of anti-TLR2 and antivascular endothelial growth factor receptor 2 yielded an additive therapeutic effect on both area and number of spontaneous choroidal neovascularization lesions. Finally, in primary human fetal retinal pigment epithelium cells, ligand binding to TLR2 induced robust expression of proinflammatory cytokines, and end products of lipid oxidation had a synergistic effect on TLR2 activation. Our data illustrate a functional role for TLR2 in the pathogenesis of choroidal neovascularization, likely by promoting inflammation of the retinal pigment epithelium, and validate TLR2 as a novel therapeutic target for reducing choroidal neovascularization.

OBJECTIVE: Emotion processing is known to be mediated by a complex network of cortical and subcortical regions with evidence of specialized hemispheric lateralization within the brain. In light of prior evidence indicating that lateralization of cognitive functions (such as language) may depend on normal visual development, we investigated whether the lack of prior visual experience would have an impact on the development of specialized hemispheric lateralization in emotional processing. METHOD: We addressed this issue by comparing performance in early blind and sighted controls on a dichotic listening task requiring the detection of specific emotional vocalizations (i.e., suggestive of happiness or sadness) presented independently to either ear. RESULTS: Consistent with previous studies, we found that sighted individuals showed enhanced detection of positive vocalizations when presented in the right ear (i.e., processed within the left hemisphere) and negative vocalizations when presented in the left ear (i.e., right hemisphere). It is interesting to note that although blind individuals were as accurate as sighted controls in detecting the valance of the vocalization, performance was not consistent with any pattern of specialized hemispheric lateralization. CONCLUSIONS: Overall, these results suggest that although the lack of prior visual experience may not lead to impaired emotion processing performance, the underlying neurophysiological substrate (i.e., degree of special hemispheric lateralization) may depend on normal visual development. (PsycINFO Database Record

PURPOSE: To present pre-papillary vitreous opacity as an uncommon manifestation of inflammation in Behçet's disease that may be specific to this uveitic entity. METHODS: We retrospectively reviewed the charts of 67 patients with Behçet's disease examined at our clinic between 2005 and 2016. Behçet's disease was diagnosed based on established clinical criteria of inflammation involving the eyes, mucocutaneous junctions, and skin. Patients with Behçet's disease who presented with papillitis and a pre-papillary vitreous opacity were identified. Response to anti-inflammatory treatment on examination and optical coherence tomography imaging were evaluated. PubMed searches were performed for (1) other cases with pre-papillary vitreous opacities in uveitic entities and (2) reports of optic nerve involvement specifically in Behçet's disease. RESULTS: We identified three patients with Behçet's disease who presented with unilateral papillitis and a pre-papillary vitreous opacity. The pre-papillary vitreous opacity had a funnel-shaped appearance on optical coherence tomography. All patients were initially treated with steroids, which led to resolution of the opacity clinically and on imaging. We identified one previous report of such a pre-papillary opacity in a patient with Behçet's disease, and no reports of this finding in other uveitic entities. CONCLUSION: This study expands the number of Behçet's disease cases presenting with a pre-papillary vitreous opacity and demonstrates novel optical coherence imaging of this finding. This finding may be specific to Behçet's disease as it was not identified in other uveitic entities in a review of the existing literature.

Angiogenesis, in which vascular endothelial growth factor receptor (VEGFR) 2 plays an essential role, is associated with a variety of human diseases including proliferative diabetic retinopathy and wet age-related macular degeneration. Here we report that a system of adeno-associated virus (AAV)-mediated clustered regularly interspaced short palindromic repeats (CRISPR)-associated endonuclease (Cas)9 from Streptococcus pyogenes (SpCas9) is used to deplete VEGFR2 in vascular endothelial cells (ECs), whereby the expression of SpCas9 is driven by an endothelial-specific promoter of intercellular adhesion molecule 2. We further show that recombinant AAV serotype 1 (rAAV1) transduces ECs of pathologic vessels, and that editing of genomic VEGFR2 locus using rAAV1-mediated CRISPR/Cas9 abrogates angiogenesis in the mouse models of oxygen-induced retinopathy and laser-induced choroid neovascularization. This work establishes a strong foundation for genome editing as a strategy to treat angiogenesis-associated diseases.Abnormal angiogenesis causes many ocular diseases. Here the authors employ CRISPR/Cas9 gene editing technology to silence VEGFR2, a major regulator of angiogenesis, in retinal endothelium and abrogate angiogenesis in the mouse models of oxygen-induced retinopathy and laser-induced choroid neovascularization.

PURPOSE: To evaluate interobserver concordance in measured ocular redness among a group of raters using an objective computer-assisted method (ocular redness index [ORI]) and a group of clinicians using an ordinal comparative scale. METHODS: We conducted a prospective study to evaluate ocular redness in clinical photographs of 12 patients undergoing pterygium surgery. Photographs were acquired preoperatively, and at 1 week and 1 month postoperatively. One group of clinicians graded conjunctival redness in the photographs using an image-based comparative scale. A second group applied the ORI to measure redness in the same photographs. We evaluated redness change between time points, level of agreement among raters, and assessed redness score differences among observers within each group. RESULTS: Interobserver agreement using the image-based redness scale was 0.458 (P < 0.001). Interobserver agreement with the ORI was 0.997 (P < 0.001). We observed statistically significant differences among clinicians' measurements obtained with the image-based redness scale (P < 0.001). There were no significant differences among measurements obtained with the ORI (P = 0.27). We observed a significant change in redness between baseline and follow-up visits with all scoring methods. Detailed analysis of redness change was performed only in the ORI group due to availability of continuous scores. CONCLUSION: Our findings suggest that the ORI scores provide higher consistency among raters than ordinal scales, and can discriminate redness changes that clinical observers often can miss. TRANSLATIONAL RELEVANCE: The ORI may be a reliable alternative to measure ocular redness objectively in the clinic and in clinical trials.

PURPOSE: To evaluate the associations between optic disc (OD)-related anatomical parameters (interartery angle [IAA] between superior and inferior temporal retinal arteries, OD tilt [TL], rotation [ROT], and torsion [TO], OD surface curvature [CUR], and central retinal vessel trunk entry point location [CRVTL] on OD) and the spherical equivalent of refractive error (SE), and to assess the impact of glaucoma severity on these relationships. METHODS: Cirrus optical coherence tomography (OCT) fundus images and 24-2 visual fields of 438 patients were included. Ellipses were fitted to OD borders. IAA was calculated between marked retinal artery locations on a circle around OD. Blood vessel entry point on OD was marked to locate CRVTL. TL was measured as the angle between the lines fitted to OD clinical boundary and the Bruch's membrane edges on the horizontal B-scans. Ellipse rotation relative to the vertical axis defined ROT. Angle between the long axis of OD and the interartery line defined TO. CUR was determined by the inner limiting membrane on the horizontal B-scans. Linear regression models evaluated by Bayes Factors (BF) were used to determine the covariance structure between the parameters and SE as well as possible impacts of mean deviation (MD). RESULTS: Our results showed that CRVTL had the strongest relationship with SE, followed by ROT, TL, and IAA (BFs: 3.59 × 10(7), 2645, 1126, and 248, respectively). MD did not significantly modulate the relationship between ONH parameters and SE. CONCLUSION: Our results suggest that SE should be considered when interpreting the OD and its circumpapillary region for diagnostic purposes. TRANSLATIONAL RELEVANCE: The reported relationships between OD-related parameters and ametropia may help to decrease false-positive clinical diagnoses of optic neuropathies.

Pain associated with mechanical, chemical, and thermal heat stimulation of the ocular surface is mediated by trigeminal ganglion neurons, while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus. Secretion of the main lacrimal gland is regulated dominantly by autonomic parasympathetic nerves, reflexly activated by eye surface sensory nerves. These also evoke goblet cell secretion through unidentified efferent fibers. Neural pathways involved in the regulation of meibomian gland secretion or mucin release have not been identified. In dry eye disease, reduced tear secretion leads to inflammation and peripheral nerve damage. Inflammation causes sensitization of polymodal and mechano-nociceptor nerve endings and an abnormal increase in cold thermoreceptor activity, altogether evoking dryness sensations and pain. Long-term inflammation and nerve injury alter gene expression of ion channels and receptors at terminals and cell bodies of trigeminal ganglion and brainstem neurons, changing their excitability, connectivity and impulse firing. Perpetuation of molecular, structural and functional disturbances in ocular sensory pathways ultimately leads to dysestesias and neuropathic pain referred to the eye surface. Pain can be assessed with a variety of questionaires while the status of corneal nerves is evaluated with esthesiometry and with in vivo confocal microscopy.

Human corneal endothelial cells (HCEnCs) are terminally differentiated cells that have limited regenerative potential. The large numbers of mitochondria in HCEnCs are critical for pump and barrier function required for corneal hydration and transparency. Fuchs Endothelial Corneal Dystrophy (FECD) is a highly prevalent late-onset oxidative stress disorder characterized by progressive loss of HCEnCs. We previously reported increased mitochondrial fragmentation and reduced ATP and mtDNA copy number in FECD. Herein, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced mitochondrial depolarization decreased mitochondrial mass and Mfn2 levels, which were rescued with mitophagy blocker, bafilomycin, in FECD. Moreover, electron transport chain complex (I, V) decrease in FECD indicated deficient mitochondrial bioenergetics. Transmission electron microscopy of FECD tissues displayed an increased number of autophagic vacuoles containing degenerated and swollen mitochondria with cristolysis. An elevation of LC3-II and LAMP1 and downregulation of Mfn2 in mitochondrial fractions suggested that loss of fusion capacity targets fragmented mitochondria to the pre-autophagic pool and upregulates mitophagy. CCCP-induced mitochondrial fragmentation leads to Mfn2 and LC3 co-localization without activation of proteosome, suggesting a novel Mfn2 degradation pathway via mitophagy. These data indicate constitutive activation of mitophagy results in reduction of mitochondrial mass and abrogates cellular bioenergetics during degeneration of post-mitotic cells of ocular tissue.

The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjögren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.