2020

Age-related macular degeneration (AMD) is the most common cause of irreversible blindness and visual impairment in individuals over the age of 50 years in western societies. More than 25 million people currently suffer from this illness in the world, with an additional 500 000 every year, approximately. It is a multifactorial ocular disease that affects the maculae due to a late-onset progressive neurodegeneration and dysfunction of photoreceptors and retinal pigment epithelium (RPE). There are many subtypes of AMD but basically two broad forms: the nonneovascular (dry, nonexudative) and neovascular (wet, exudative). Exudative AMD is the less common form (about 15%) but tends to progress more rapidly. At the moment, wet AMD is treated primarily on the basis of anti-vascular endothelial growth factor (VEGF) agents, which have led to massive improvement in the prognosis of the disease since they were first introduced. This article focuses on the latest treatment approaches to neovascular AMD. An extensive literature review was performed in order to illustrate the effectiveness of current and future anti-VEGF agents as well as the landmark clinical studies that have been carried out to establish these drugs as a gold standard in the therapy of wet AMD.

Telemedicine is the provision of healthcare-related services from a distance and is poised to move healthcare from the physician's office back into the patient's home. The field of ophthalmology is often at the forefront of technological advances in medicine including telemedicine and the use of artificial intelligence. Multiple studies have demonstrated the reliability of tele-ophthalmology for use in screening and diagnostics and have demonstrated benefits to patients, physicians, as well as payors. There remain obstacles to widespread implementation, but recent legislation and regulation passed due to the devastating COVID-19 pandemic have helped to reduce some of these barriers. This review describes the current status of tele-ophthalmology in the United States including benefits, hurdles, current programs, technology, and developments in artificial intelligence. With ongoing advances patients may benefit from improved detection and earlier treatment of eye diseases, resulting in better care and improved visual outcomes.

PURPOSE: To characterize surgical confusions in ophthalmology to determine their incidence, root causes, and impact on patients and physicians. DESIGN: Retrospective cohort study of errors in ophthalmic surgical procedures between January 1, 2006, and December 31, 2017. PARTICIPANTS: One hundred forty-three cases involving surgical confusions. METHODS: Cases were identified by the Ophthalmic Mutual Insurance Company from closed case files and by the New York State Health Department from the New York Patient Occurrence Reporting and Tracking program that identified the surgical confusions. MAIN OUTCOME MEASURES: Incidence and impact by intended surgery, error type, and root cause as well as preventability by the Universal Protocol. RESULTS: Of the 143 cases of surgical confusions identified, 92 cases (64.3%) were deemed preventable by the Universal Protocol. Approximately two thirds, 95 cases (66.4%), were cases of incorrect implants being used during cataract surgery (cataract extraction and intraocular lens implantation), of which 33 cases (34.7%) were not preventable by the Universal Protocol. Wrong eye blocks or anesthesia accounted for 20 cases (14.0%), incorrect eye procedures accounted for 10 cases (7.00%), incorrect refractive surgery measurements accounted for 6 cases (4.20%), incorrect patient or procedure accounted for 5 cases (3.50%), incorrect intraocular gas concentration accounted for 4 cases (2.80%), and incorrect medication in surgery accounted for 3 cases (2.10%). The most common root cause of confusion was an inadequately performed time out, which was responsible for nearly one third of all surgical confusions, 46 cases (32.2%). Incorrect lens orders or calculations before surgery (so-called upstream errors) were the second most common cause of surgical confusion, involving 31 cases (21.7%). The average legal indemnity for incorrect implant during cataract surgery was $57 514 (United States dollars). The average indemnity for incorrect refractive surgery measurement was $123 125, that for incorrect eye procedure was $50 000, and that for incorrect gas concentration was $220 844. CONCLUSIONS: Most surgical confusions could have been prevented by following the Universal Protocol properly. However, upstream errors, originating in the clinic or office before surgery, and ineffective communication during time outs suggest a need for modification of the Universal Protocol.

Purpose: To compare the rates of clinically significant artifacts for two-dimensional peripapillary retinal nerve fiber layer (RNFL) thickness versus three-dimensional (3D) neuroretinal rim thickness using spectral-domain optical coherence tomography (SD-OCT). Methods: Only one eye per patient was used for analysis of 120 glaucoma patients and 114 normal patients. For RNFL scans and optic nerve scans, 15 artifact types were calculated per B-scan and per eye. Neuroretinal rim tissue was quantified by the minimum distance band (MDB). Global MDB neuroretinal rim thicknesses were calculated before and after manual deletion of B-scans with artifacts and subsequent automated interpolation. A clinically significant artifact was defined as one requiring manual correction or repeat scanning. Results: Among glaucomatous eyes, artifact rates per B-scan were significantly more common in RNFL scans (61.7%, 74 of 120) compared to B-scans in neuroretinal rim volume scans (20.9%, 1423 of 6820) (95% confidence interval [CI], 31.6-50.0; < 0.0001). For clinically significant artifact rates per eye, optic nerve scans had significantly fewer artifacts (15.8% of glaucomatous eyes, 13.2% of normal eyes) compared to RNFL scans (61.7% of glaucomatous eyes, 25.4% of normal eyes) (glaucoma group: 95% CI, 34.1-57.5, < 0.0001; normal group: 95% CI, 1.3-23.3, = 0.03). Conclusions: Compared to the most commonly used RNFL thickness scans, optic nerve volume scans less frequently require manual correction or repeat scanning to obtain accurate measurements. Translational Relevance: This paper illustrates the potential for 3D OCT algorithms to improve in vivo imaging in glaucoma.

On the occasion of being awarded the Prentice Medal, I was asked to summarize my translational journey. Here I describe the process of becoming a low-vision rehabilitation clinician and researcher, frustrated by the unavailability of effective treatments for some conditions. This led to decades of working to understand patients' needs and the complexities and subtleties of their visual systems and conditions. It was followed by many iterations of developing vision aids and the techniques needed to objectively evaluate their benefit. I specifically address one path: the invention and development of peripheral prisms to expand the visual fields of patients with homonymous hemianopia, leading to our latest multiperiscopic prism (mirror-based design) with its clear 45° field-of-view image shift.

Identification of cell type-specific regulatory elements (CREs) is crucial for understanding development and disease, although identification of functional regulatory elements remains challenging. We hypothesized that context-specific CREs could be identified by context-specific non-coding RNA (ncRNA) profiling, based on the observation that active CREs produce ncRNAs. We applied ncRNA profiling to identify rod and cone photoreceptor CREs from wild-type and mutant mouse retinas, defined by presence or absence, respectively, of the rod-specific transcription factor (TF) -dependent ncRNA expression strongly correlated with epigenetic profiles of rod and cone photoreceptors, identified thousands of candidate rod- and cone-specific CREs, and identified motifs for rod- and cone-specific TFs. Colocalization of NRL and the retinal TF CRX correlated with rod-specific ncRNA expression, whereas CRX alone favored cone-specific ncRNA expression, providing quantitative evidence that heterotypic TF interactions distinguish cell type-specific CRE activity. We validated the activity of novel -dependent ncRNA-defined CREs in developing cones. This work supports differential ncRNA profiling as a platform for the identification of cell type-specific CREs and the discovery of molecular mechanisms underlying TF-dependent CRE activity.

: Overview of the evolving epidemiology of human immunodeficiency virus (HIV)-related ocular disease over time. : Narrative review. : HIV enhances susceptibility to opportunistic eye infections, has direct pathogenic effects, and places patients at risk of immune recovery inflammatory syndromes in previously infected eyes after starting highly-active antiretroviral therapy (HAART). Widespread availability of HAART has resulted in a decrease of infectious ocular conditions such as cytomegalovirus retinitis, toxoplasmic retinitis, squamous cell carcinoma of the conjunctiva, and microvascular retinopathy. However, large coexisting burdens of tuberculosis, herpesvirus infection and syphilis (among others) continue to contribute to the burden of ocular disease, especially in low-resource settings. Growing risks of cataract, retinopathy and retinal nerve fiber thinning can affect patients with chronic HIV on HAART; thought due to chronic inflammation and immune activation. : The changing epidemic of ocular disease in HIV-infected patients warrants close monitoring and identification of interventions that can help reduce the imminent burden of disease.

PURPOSE: To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy. DESIGN: Multicenter, randomized, double-masked, vehicle-controlled trial. PARTICIPANTS: Patients with neurotrophic persistent epithelial defect with or without stromal thinning. METHODS: The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 μg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat. MAIN OUTCOME MEASURES: The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally (<0.5 mm of fluorescein staining in the greatest dimension of the lesion area) and conservatively (0-mm lesion staining and no other residual staining). Secondary variables included corneal healing at 4 weeks of masked treatment (key secondary end point), overall changes in lesion size, rates of disease progression, and changes in visual acuity and corneal sensitivity from baseline to week 8. RESULTS: Conventional assessment of corneal healing showed statistically significant differences at week 8: compared to 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) achieved less than 0.5 mm of lesion staining (+40.4%; 95% confidence interval [CI], 14.2%-66.6%; P = 0.006). Conservative assessment of corneal healing also reached statistical significance at week 8: compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0 mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%-73.1%; P < 0.001). Moreover, the conservative measure of corneal healing showed statistical significance at week 4 (key secondary end point). Compared to vehicle, cenegermin-treated patients showed statistically significant reductions in lesion size and disease progression rates during masked treatment. Cenegermin was well tolerated; adverse effects were mostly local, mild, and transient. CONCLUSIONS: Cenegermin treatment showed higher rates of corneal healing than vehicle in neurotrophic keratopathy associated with nonhealing corneal defects.

PURPOSE: To review the published literature assessing the efficacy of binocular therapy for the treatment of amblyopia compared with standard treatments. METHODS: Literature searches with no date restrictions and limited to the English language were conducted in January 2018 and updated in April 2019 in the PubMed database and the Cochrane Library database with no restrictions. The search yielded 286 citations, and the full text of 50 articles was reviewed. Twenty articles met the inclusion criteria for this assessment and were assigned a level of evidence rating by the panel methodologist. Six studies were rated level I, 1 study was rated level II, and 13 studies were rated level III because of the impact on the development and popularization of this technology. RESULTS: Two of the level I and II studies reviewed described a significant improvement in visual acuity in the binocular group versus standard patching standard treatment (the total number of patients in these 2 studies was 147). However, the 5 studies that failed to show a visual improvement from binocular therapy compared with standard treatments were larger and more rigorously designed (the total number of patients in these 5 studies was 813). Level I and II studies also failed to show a significant improvement over baseline in sensory status, including depth of suppression and stereopsis of those treated with binocular therapy. Several smaller level III case series (total number of patients in these 13 studies was 163) revealed more promising results than the binocular treatments studied in the level I and II studies, especially using treatments that are more engaging and are associated with better compliance. CONCLUSIONS: There is no level I evidence to support the use of binocular treatment as a substitute for current therapies for amblyopia (including patching and optical treatment). Furthermore, 2 large randomized controlled trials showed inferior performance compared with standard patching treatment. On the basis of this review of the published literature, binocular therapy cannot be recommended as a replacement for standard amblyopia therapy. However, more research is needed to determine the potential benefits of proposed binocular treatments in the future.

BACKGROUND/AIMS: Although being a more objective tool for assessment and follow-up of angle closure, reliability studies have reported a moderate diagnostic performance for anterior segment optical coherence tomography (OCT) technologies when comparing with gonioscopy as the reference standard. We aim to determine factors associated with diagnostic disagreement in angle closure when assessed by anterior segment swept source OCT (SS-OCT, CASIA SS-1000; Tomey, Nagoya, Japan) and gonioscopy. METHODS: Cross-sectional study. A total of 2027 phakic subjects aged ≥50 years, with no relevant previous ophthalmic history, were consecutively recruited from a community polyclinic in Singapore. Gonioscopy and SS-OCT (128 radial scans) for the entire circumference of the angle were performed for each subject. A two-quadrant closed gonioscopic definition was used. On SS-OCT images, angle closure was defined as iridotrabecular contact (ITC) to the extent of ≥35%, ≥50% and ≥75% of the circumferential angle. Diagnostic disagreements between both methods, that is, false positives or overcalls and false negatives or undercalls were defined, respectively, as gonioscopic open/closed angles inversely assessed as closed/open by SS-OCT. RESULTS: Two hundred and seventy-two (14.7%) resulted in overcall results (false positives) when ≥50% of the angle circumference was closed using SS-OCT. These eyes had significantly wider (anterior chamber width, 11.7 vs 11.6 mm, p<0.001) and deeper (anterior chamber depth (ACD), 2.4 vs 2.2 mm, p<0.001) anterior chambers than eyes assessed by both methods as closed (true positives). Deeper ACD (OR 9.31) and lower lens vault (LV) (OR 0.04) were significantly associated with a false positive diagnosis in the multivariate analysis. Most of these cases had short (52.6%) or irregular (39%) ITC in SS-OCT images. CONCLUSIONS: We found that anterior chamber dimensions, determined by ACD and LV, were factors significantly associated with diagnostic disagreement between anterior segment SS-OCT and gonioscopy in angle closure assessment.

As the general population ages, more people are affected by eye diseases, such as retinopathies. It is therefore critical to improve imaging of eye disease mouse models. Here, we demonstrate that 1) rapid, quantitative 3D and 4D (time lapse) imaging of cellular and subcellular processes in the mouse eye is feasible, with and without tissue clearing, using light-sheet fluorescent microscopy (LSFM); 2) flat-mounting retinas for confocal microscopy significantly distorts tissue morphology, confirmed by quantitative correlative LSFM-Confocal imaging of vessels; 3) LSFM readily reveals new features of even well-studied eye disease mouse models, such as the oxygen-induced retinopathy (OIR) model, including a previously unappreciated 'knotted' morphology to pathological vascular tufts, abnormal cell motility and altered filopodia dynamics when live-imaged. We conclude that quantitative 3D/4D LSFM imaging and analysis has the potential to advance our understanding of the eye, in particular pathological, neuro-vascular, degenerative processes.

Enterococci are commensals that proliferated as animals crawled ashore hundreds of millions of years ago. They are also leading causes of multidrug-resistant hospital-acquired infections. While most studies are driven by clinical interest, comparatively little is known about enterococci in the wild or the effect of human activity on them. Pharmaceutical pollution and runoff from other human activities are encroaching widely into natural habitats. To assess their reach into remote habitats, we investigated the identity, genetic relatedness, and presence of specific traits among 172 enterococcal isolates from wild Magellanic penguins. Four enterococcal species, 18 lineage groups, and different colonization patterns were identified. One lineage, sequence type 475 (ST475), was isolated from three different penguins, making it of special interest. Its genome was compared to those of other sequence types (ST116 and ST242) recovered from Magellanic penguins, as well as to an existing phylogeny of isolated from diverse origins over the past 100 years. No penguin-derived strains were closely related to dominant clinical lineages. Most possessed intact CRISPR defenses, few mobile elements, and antibiotic resistances limited to those intrinsic to the species and lacked pathogenic features conveyed by mobile elements. Interestingly, plasmids were identified in penguin isolates that also had been reported for other marine mammals. Enterococci isolated from penguins showed limited anthropogenic impact, indicating that they are likely representative of those naturally circulating in the ecosystem inhabited by the penguins. These findings establish an important baseline for detecting the encroachment of human activity into remote planetary environments. Enterococci are host-associated microbes that have an unusually broad range, from the built hospital environment to the guts of insects and other animals in remote locations. Despite their occurrence in the guts of animals for hundreds of millions of years, we know little about the properties that confer this range or how anthropogenic activities may be introducing new selective forces. Magellanic penguins live at the periphery of human habitation. It was of interest to examine enterococci from these animals for the presence of antibiotic resistance and other markers reflective of anthropogenic selection. Diverse enterococcal lineages found discount the existence of a single well-adapted intrinsic penguin-specific species. Instead, they appear to be influenced by a carnivorous lifestyle and enterococci present in the coastal sea life consumed. These results indicate that currently, the penguin habitat remains relatively free of pollutants that select for adaptation to human-derived stressors.

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has had an enormous impact on society worldwide, threatening the lives and livelihoods of many. The effects will continue to grow and worsen if economies begin to open without the proper precautions, including expanded diagnostic capabilities. To address this need for increased testing, we have developed a sensitive reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assay compatible with current reagents, which utilizes a colorimetric readout in as little as 30 min. A rapid inactivation protocol capable of inactivating virions, as well as endogenous nucleases, was optimized to increase sensitivity and sample stability. This protocol, combined with the RT-LAMP assay, has a sensitivity of at least 50 viral RNA copies per microliter in a sample. To further increase the sensitivity, a purification protocol compatible with this inactivation method was developed. The inactivation and purification protocol, combined with the RT-LAMP assay, brings the sensitivity to at least 1 viral RNA copy per microliter in a sample. This simple inactivation and purification pipeline is inexpensive and compatible with other downstream RNA detection platforms and uses readily available reagents. It should increase the availability of SARS-CoV-2 testing as well as expand the settings in which this testing can be performed.

Corneal stiffness plays a critical role in shaping the cornea with respect to intraocular pressure and physical interventions. However, it remains difficult to measure the mechanical properties noninvasively. Here, we report the first measurement of shear modulus in human corneas in vivo using optical coherence elastography (OCE) based on surface elastic waves. In a pilot study of 12 healthy subjects aged between 25 and 67, the Rayleigh-wave speed was 7.86 ± 0.75 m/s, corresponding to a shear modulus of 72 ± 14 kPa. Our data reveal two unexpected trends: no correlation was found between the wave speed and IOP between 13-18 mmHg, and shear modulus decreases with age (- 0.32 ± 0.17 m/s per decade). We propose that shear stiffness is governed by the interfibrillar matrix, whereas tensile strength is dominated by collagen fibrils. Rayleigh-wave OCE may prove useful for clinical diagnosis, refractive surgeries, and treatment monitoring.

PURPOSE: To describe the etiology and clinical characteristics of macular edema (ME) in patients with familial exudative vitreoretinopathy. METHODS: Observational, retrospective case series of 30 patients (34 eyes) with ME and familial exudative vitreoretinopathy who underwent spectral-domain optical coherence tomography imaging between 2009 and 2016. Baseline and follow-up optical coherence tomographies were correlated with color fundus photography and fluorescein angiography. RESULTS: The average age was 20.6 years (6.6-68.7). Eighteen eyes exhibited cystoid ME (52.9%), 14 noncystoid ME (41.2%), and 2 eyes (5.9%) with both. Macular edema was foveal in 52.9% (n = 18). Eighteen of 24 eyes (64.3%) with an available fluorescein angiography showed leakage from ME. The most common structural feature was posterior hyaloidal organization/contraction (n = 15). Sixteen eyes were treated with topical or intravitreal steroids (n = 6), intravitreal anti-vascular endothelial growth factor (n = 3), or pars plana vitrectomy with membrane stripping (n = 7). There was no difference between mean preoperative and postoperative LogMAR visual acuity (0.63 [20/85] vs. 0.87 [20/148], P = 0.35) after vitrectomy despite a statistical improvement in the mean central foveal thickness (596 mm vs. 303 mm, P = 0.04). CONCLUSION: Macular edema in familial exudative vitreoretinopathy occurs most commonly because of traction. Vitrectomy is effective for relieving tractional forces with anatomical improvement.

Ocular trauma is a significant cause of blindness worldwide, particularly if associated with glaucoma. Direct damage from blunt or penetrating trauma, bleeding, inflammation, lens-related problems, orbital and brain vascular pathologies related to trauma, and chemical injuries may increase intraocular pressure and lead to traumatic glaucoma. Treatment may be as simple as eliminating the underlying cause in some conditions or management can be challenging, depending on the mechanism of damage. If proper management is not undertaken, visual outcomes can be poor. We discuss a broad spectrum of trauma-related mechanisms of intraocular pressure elevation, as well as their management.

Optic neuritis (ON) is an inflammatory attack of the optic nerve that leads to visual disability. It is the most common optic neuropathy affecting healthy young adults, most commonly women aged 20-45 years. It can be idiopathic and monophasic or as part of a neurologic disease such as multiple sclerosis with recurrence and cumulative damage. Currently, there is no therapy to repair the damage from optic neuritis. Animal models are an essential tool for the understanding of the pathogenesis of optic neuritis and for the development of potential treatment strategies. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental rodent model for human autoimmune inflammatory demyelinating diseases of the central nervous system (CNS). In this review, we discuss the latest rodent models regarding optic neuritis, focusing on EAE model, and on its recent achievements and developments.

The majority of clinical corneal prostheses (KPros) adopt a core-skirt configuration. This configuration is favored owing to the optic core (generally a cylindrical, acrylic-based material, such as PMMA), that not only provides a clear window for the patients' vision, but also confers resistance to biodegradability. The surrounding skirt (typically a biological material, such as corneal tissue) allows for host tissue integration. However, due to poor biointegration between the dissimilar core and skirt materials, it results in a weak adhesion at the interface, giving rise to clinical complications, such as bacterial infections in the tissue-PMMA interface and device extrusion. Here, we physically immobilized nano-hydroxyapatite (nHAp) on a PMMA cylinder via a dip-coating technique, to create a bioactive surface that improved biointegration in vivo. We established that the nHAp coating was safe and stable in the rabbit cornea over five weeks. More importantly, we found that apoptotic, wound healing and inflammatory responses to nHAp-coated PMMA were substantially milder than to non-coated PMMA. More mature collagen, similar to the non-operated cornea, was maintained in the corneal stroma adjacent to the nHAp-coated implant edge. However, around the non-coated cylinder, an abundant new and loose connective tissue formed, similar to bone tissue response to bioinert scaffolds. As a result of superior biointegration, tissue adhesion with nHAp-coated PMMA cylinders was also significantly enhanced compared to non-coated cylinders. This study set a precedent for the future application of the nHAp coating on clinical KPros. STATEMENT OF SIGNIFICANCE: Currently, all clinical corneal prostheses utilize as-manufactured, non-surface modified PMMA optic cylinder. The bioinert cylinder, however, has poor biointegration and adhesion with the surrounding biological tissue, which can give rise to postoperative complications, such as microbial invasion in the tissue-PMMA loose interface and PMMA optic cylinder extrusion. In the current study, we showed that surface modification of the PMMA cylinder with bioactive nano-hydroxyapatite (nHAp) significantly enhanced its biointegration with corneal stromal tissue in vivo. The superior biointegration of the nHAp-coated PMMA was signified by a more attenuated corneal wound healing, inflammatory and fibrotic response, and better tissue apposition, as well as a significantly improved corneal stromal tissue adhesion when compared to the non-coated PMMA.