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Purpose To highlight a case of chorioretinitis sclopetaria, with concomitant macular hole formation and orbital emphysema, caused by a commercial-grade pressure washer. Patient A 19-year-old male presented to the emergency department with a left eye injury, incurred after being sprayed with a commercial-grade pressure washer. He endorsed ipsilateral blurred vision, pain, and linear floaters. Left eye visual acuity was 20/40. Dilated fundus exam showed inferior vitreous hemorrhage, retinal whitening, and pre-, intra-, and sub-retinal hemorrhages, consistent with chorioretinitis sclopetaria. Optical coherence tomography revealed a full-thickness macular hole. Computed tomography scan of the orbits showed subcutaneous and post-septal orbital emphysema. Two months following injury, vitreous and retinal hemorrhages and macular hole resolved. Five months following injury, visual acuity improved to 20/20. Discussion Chorioretinitis sclopetaria is defined as a full-thickness chorioretinal disruption resulting from a high-velocity projectile passing adjacent to or into the orbit without penetrating the globe. Chorioretinal deformation and ocular comorbidities are influenced by the velocity of the missile and its spatial relationship to the orbit. While this pattern of injury is typically associated with indirect trauma to the globe by a BB or a bullet, this is the first report of chorioretinitis sclopetaria precipitated by a high-velocity liquid missile.

Rods and cones are photoreceptor neurons in the retina that are required for visual sensation in vertebrates, wherein the perception of vision is initiated when these neurons respond to photons in the light stimuli. The photoreceptor cell is structurally studied as outer segments (OS) and inner segments (IS) where proper protein sorting, localization, and compartmentalization are critical for phototransduction, visual function, and survival. In human retinal diseases, improper protein transport to the OS or mislocalization of proteins to the IS and other cellular compartments could lead to impaired visual responses and photoreceptor cell degeneration that ultimately cause loss of visual function.Therefore, studying and identifying mechanisms involved in facilitating and maintaining proper protein transport in photoreceptor cells would help our understanding of pathologies involving retinal cell degeneration in inherited retinal dystrophies, age-related macular degeneration, and Usher Syndrome.Our mini-review will discuss mechanisms of protein transport within photoreceptors and introduce a novel role for an unconventional motor protein, MYO1C, in actin-based motor transport of the visual chromophore Rhodopsin to the OS, in support of phototransduction and visual function.

Septo-optic dysplasia (SOD) is a condition that affects the early development of the brain and eyes. It presents with a combination of optic nerve hypoplasia, brain midline structure abnormalities, and pituitary gland hypoplasia.This is a case report of a 4-year-old male who presented with low amplitude horizontal nystagmus and decreased visual acuity 20/60 OU. Further imaging and electrophysiology were conducted to classify the ocular presentation.No iris transillumination was noted, but foveal hypoplasia and disc edema were evident on fundus examination. This prompted neurology consultation and MRI imaging. The MRI was consistent with the diagnosis of SOD showing hypoplasia of the optic nerves, chiasm, and tracts and an absent septum pellucidum, but with normal pituitary development and function. Lumbar puncture and intracranial pressure were normal. Genetic testing identified one pathogenic variant in the SLC45A2, indicating carrier status for oculocutaneous albinism type 4 (OCA4). Flash Visual Evoked Potentials (VEPs) were consistent with chiasm dysfunction or hypoplasia rather than the chiasmal misrouting of OCA.This case report further elaborates the phenotypic variation of SOD, with the finding of blurred disc margins, in the absence of the typical optic nerve double ring sign and with normal intracranial pressure. The findings of fovea hypoplasia and blond fundi lead to the suspicion of OCA either as a separate diagnosis with a second pathogenic variant in SCL45A2 not yet identified or in association with SOD. This case highlights the importance of electrophysiology to help distinguish chiasmal hypoplasia or dysfunction from OCA misrouting.

Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people, with limited treatment options available for most patients. AMD involves the death of retinal pigment epithelium (RPE) and photoreceptor cells, with mitochondria dysfunction being a critical early event. In the current study, we utilized our unique resource of human donor RPE graded for AMD presence and severity to investigate proteome-wide dysregulation involved in early AMD. Organelle-enriched fractions of RPE were isolated from donors with early AMD (n = 45) and healthy age-matched controls (n = 32) and were analyzed by UHR-IonStar, an integrated proteomics platform enabling reliable and in-depth proteomic quantification in large cohorts. A total of 5941 proteins were quantified with excellent analytical reproducibility, and with further informatics analysis, many biological functions and pathways were found to be significantly dysregulated in donor RPE samples with early AMD. Several of these directly pinpointed changes in mitochondrial functions, e.g., translation, ATP metabolic process, lipid homeostasis, and oxidative stress. These novel findings highlighted the value of our proteomics investigation by allowing a better understanding of the molecular mechanisms underlying early AMD onset and facilitating both treatment development and biomarker discovery.

Purpose: Suprachoroidal hemorrhage (SCH) is a rare but vision-threatening complication in patients with keratoprosthesis devices (KPro), particularly in the setting of concurrent glaucoma tube shunts. Although there are many approaches to draining an SCH, surgery can be especially challenging in these patients because a crowded anterior chamber, and frequent anterior extension of the SCH. Methods: A case report is discussed. Results: We describe a novel approach to surgical drainage of SCH in a 64-year-old monocular patient with a Type I Boston KPro, an Ahmed valve, and aphakia. Conclusion: Successful repair of appositional SCH in the context of KPro can be safely and effectively achieved by injecting viscoelastic through the backplate holes of the KPro, thereby providing internal tamponade within the vitreous compartment while liquefied hemorrhage is drained by sclerotomy.

Introduction: We compared the print-to-speech properties and human performance characteristics of two artificial intelligence vision aids, Orcam MyEye 1 (a portable device) and Seeing AI (an iPhone and iPad application). Methods: There were seven participants with visual impairments who had no experience with the two reading aids. Four participants had no light perception. Two individuals with measurable acuity and one with light perception were tested while blindfolded. We also tested performance with text of varying appearance in varying viewing conditions. To evaluate human performance, we asked the participants to use the devices to attempt 12 reading tasks similar to activities of daily living. We assessed the ranges of text attributes for which reading was possible, such as print size, contrast, and light level. We also assessed if individuals could complete tasks with the devices and measured accuracy and completion time. Participants also completed a survey concerning the two aids. Results: Both aids achieved greater than 95% accuracy in text recognition for flat, plain word documents and ranged from 13 to 57% accuracy for formatted text on curved surfaces. Both aids could read print sizes as small as 0.8M (20/40 Snellen equivalent, 40 cm viewing distance). Individuals successfully completed 71% and 55% ( p = .114) of tasks while using Orcam MyEye 1 and Seeing AI, respectively. There was no significant difference in time to completion of tasks ( p = .775). Individuals believed both aids would be helpful for daily activities. Discussion: Orcam MyEye 1 and Seeing AI had similar text-reading capability and usability. Both aids were useful to users with severe visual impairments in performing reading tasks. Implications for Practitioners: Selection of a reading device or aid should be based on individual preferences and prior familiarity with the platform, since we found no clear superiority of one solution over the other.

Derivation and differentiation of human induced pluripotent stem cells (hiPSCs) provide the opportunity to generate medically important cell types from individual patients and patient populations for research and the development of potential cell therapies. This technology allows disease modeling and drug screening to be carried out using diverse population cohorts and with more relevant cell phenotypes than can be accommodated using traditional immortalized cell lines. However, technical complexities in the culture and differentiation of hiPSCs, including lack of scale and standardization and prolonged experimental timelines, limit the adoption of this technology for many large-scale studies, including personalized drug screening. The entry of reproducible end-to-end automated workflows for hiPSC culture and differentiation, demonstrated on commercially available platforms, provides enhanced accessibility of this technology for both research laboratories and commercial pharmaceutical testing. Here we have utilized TECAN Fluent automated cell culture workstations to perform hiPSC culture and differentiation in a reproducible and scalable process to generate patient-derived retinal pigment epithelial cells for downstream use, including drug testing. hiPSCs derived from multiple donors with age-related macular degeneration (AMD) were introduced into our automated workflow, and cell lines were cultured and differentiated into retinal pigment epithelium (RPE). Donor hiPSC-RPE lines were subsequently entered in an automated drug testing workflow to measure mitochondrial function after exposure to "mitoactive" compounds. This work demonstrates scalable, reproducible culture and differentiation of hiPSC lines from individuals on the TECAN Fluent platform and illustrates the potential for end-to-end automation of hiPSC-based personalized drug testing.

James Kohler,* Tu M Tran,* Susan Sun, Sandra R Montezuma Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA*These authors contributed equally to this workCorrespondence: Sandra R MontezumaDepartment of Ophthalmology and Visual Neurosciences, University of Minnesota, 420 Delaware St SE, MMC 493, Minneapolis, MN, 55455, USATel +1 612 626 2452Fax +1 612 626 3119Email smontezu@umn.eduPurpose: To assess attitudes of pre-clinical undergraduate medical students toward learning smartphone funduscopy (SF) and its appropriateness as a teaching tool.Patients and Methods: Second year medical students received instruction on direct ophthalmoscopy (DO) and SF; they were then paired with a peer and randomly assigned to perform DO or SF first. The SF technique involved freehand alignment of the axes of the smartphone camera with a condenser lens. Both techniques were done through a maximally dilated pupil. A questionnaire was completed to acquire data on baseline experience, performance of both examination techniques, attitudes, and appropriateness. Statistical significance testing and Bland-Altman analysis were used to determine differences between DO and SF, and a multivariable mixed regression model was fitted to identify any predictors for positive attitudes toward DO or SF.Results: One hundred thirty-seven (137) individuals completed the study. A similar proportion of students could identify the optic nerve, macula, and vessels using DO and SF. However, self-reported quality scores were higher for DO for the optic nerve (p = 0.006) and macula (p = 0.08). The mean (standard deviation) attempts to identify these major structures were 2.7 (SD 2.3) for DO and 4.5 (SD 2.9) for SF (p < 0.001). Attitudes of students were consistently more positive toward DO across the five questions assessed. A small subset of students had equally positive attitudes toward DO and SF. Improved quality scores were predictive of positive attitudes for both DO and SF. Ultimately, 24% of students preferred SF over DO.Conclusion: Among inexperienced examiners of the fundus through a dilated pupil, SF is a non-inferior technique to DO in identifying structures. Despite overall favorable attitudes towards the more familiar DO, those students who quickly learned the SF technique had similar satisfaction scores. Teaching SF should be considered in undergraduate medical education.Keywords: direct, fundus, imaging, medical student, ophthalmoscope, smartphone

An 84-year-old female presented with bilateral scotomas and progressive nyctalopia over 1 year. Best-corrected visual acuity was 20/50 in both eyes with reduced color vision. Goldmann visual field showed bilateral cecocentral scotomas and generalized constriction of the visual fields. This led to an electroretinogram showing an electronegative pattern consistent with autoimmune retinopathies. Infectious workup was negative. Anti-retinal antibodies were positive, leading to a presumed diagnosis of cancer-associated retinopathy (CAR). Imaging showed a previously unknown left renal lower pole mass, and she underwent a radical nephrectomy. Biopsy showed nuclear grade-3 clear cell renal carcinoma staged T1. The patient was treated with oral prednisone with no ocular improvement. We report on a rare case of clear cell renal carcinoma causing CAR. CAR is an important paraneoplastic syndrome to diagnose since the majority of ocular cases precede other manifestations of malignancy. Therefore, a timely diagnosis of CAR can be lifesaving or at least life-extending.

Purpose: This work describes the characteristics and unique features of ocular syphilis. Methods: Ten serologically proven cases of ocular syphilis were retrospectively analyzed. Results: Eighteen eyes of 10 patients were affected. Nine of 10 patients were male and the mean age was 58 years (range, 36-81 years). HIV antibody testing was positive in 3 patients (30%). Five cases were first diagnosed by an ophthalmologist. One patient presented with a syphilitic rash. The most common ocular findings were panuveitis (n = 6) and cystoid macular edema (n = 4). Ocular involvement was unilateral in 2 cases and bilateral in 8. Best-corrected visual acuity improved in 13 of 18 eyes (72%) after treatment. Three cases developed recurrent retinal detachments that required repair with silicone oil. Conclusions: Most cases were HIV negative. Syphilitic uveitis can be the initial presentation of syphilis without classic systemic manifestation. Ophthalmologists play an important role in the diagnosis and treatment of syphilis.

AimTo demonstrate the potential clinically meaningful benefits of a thermal camera integrated with the Argus II, an artificial vision therapy system, for assisting Argus II users in localising and discriminating heat-emitting objects.MethodsSeven blind patients implanted with Argus II retinal prosthesis participated in the study. Two tasks were investigated: (1) localising up to three heat-emitting objects by indicating the location of the objects and (2) discriminating a specific heated object out of three presented on a table. Heat-emitting objects placed on a table included a toaster, a flat iron, an electric kettle, a heating pad and a mug of hot water. Subjects completed the two tasks using the unmodified Argus II system with a visible-light camera and the thermal camera-integrated Argus II.ResultsSubjects more accurately localised heated objects displayed on a table (p=0.011) and discriminated a specific type of object (p=0.005) presented with the thermal camera integrated with the Argus II versus the unmodified Argus II camera.ConclusionsThe thermal camera integrated with the artificial vision therapy system helps users to locate and differentiate heat-emitting objects more precisely than a visible light sensor. The integration of the thermal camera with the Argus II may have significant benefits in patients’ daily life.

Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to age-related macular degeneration (AMD)1–3. We generated transcriptional profiles of postmortem retina from 453 controls and cases at distinct stages of AMD and integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 non-coding genes, with genotypes at over 9 million common single nucleotide polymorphisms (SNPs) for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets4, 5. Cis-eQTL analysis identified 10,474 genes under genetic regulation, including 4,541 eQTLs detected only in the retina. Integrated analysis of AMD-GWAS with eQTLs ascertained likely target genes at six reported loci. Using transcriptome-wide association analysis (TWAS), we identified three additional genes, RLBP1, HIC1 and PARP12, after Bonferroni correction. Our studies expand the genetic landscape of AMD and establish the Eye Genotype Expression (EyeGEx) database as a resource for post-GWAS interpretation of multifactorial ocular traits.

Unconventional myosins, linked to deafness, are also proposed to play a role in retinal cell physiology. However, their direct role in photoreceptor function remains unclear. We demonstrate that systemic loss of the unconventional myosin MYO1C in mice, specifically causes rhodopsin mislocalization, leading to impaired visual function. Electroretinogram analysis of Myo1c knockout (Myo1c-KO) mice showed a progressive loss of photoreceptor function. Immunohistochemistry and binding assays demonstrated MYO1C localization to photoreceptor inner and outer segments (OS) and identified a direct interaction of rhodopsin with MYO1C. In Myo1c-KO retinas, rhodopsin mislocalized to rod inner segments (IS) and cell bodies, while cone opsins in OS showed punctate staining. In aged mice, the histological and ultrastructural examination of the phenotype of Myo1c-KO retinas showed progressively shorter photoreceptor OS. These results demonstrate that MYO1C is important for rhodopsin localization to the photoreceptor OS, and for normal visual function.

Purpose: This work reports a case of retinal and vitreous hemorrhage after a dexamethasone (Ozurdex, Allergan) intravitreal implant injection to treat clinically significant macular edema (ME) in a patient with moderate nonproliferative diabetic retinopathy. Methods: A 61-year-old woman who had a vitrectomy 3 years prior in the right eye underwent intravitreal dexamethasone implant injection in the right eye. Immediately after the injection, the patient noted numerous floaters, with visual acuity decline from 20/30 before injection, to counting fingers at 3 feet after injection. Dilated examination revealed the dexamethasone implant resting against the retina, just inferior to the inferior arcade. On 360° fundus examination, the retina was found to be flat and attached. Optical coherence tomography of the macula demonstrated that the dexamethasone implant was preretinal, possibly having lifted the internal limiting membrane. Results: Thirty minutes after the injection, the patient reported that her vision was starting to clear. The patient was informed about what had transpired and warned about signs and symptoms of retinal detachment. She canceled her 1-week follow-up appointment because her vision returned to baseline. By 4 weeks post injection, her vision was 20/20 without macular edema. Conclusions: This case represents the first reported instance in which retinal impact by an Ozurdex implant was observed without treatment and vision recovered to baseline.

Purpose To report a case of Nocardia cyriacigeorgica endophthalmitis. Methods Case report. Results A 71-year-old man on long-term steroid therapy for poor respiratory function from lung carcinoma and presumed recent liver metastases presented with a four week history of blurry vision in the left eye. Ophthalmic examination revealed a white elevated mass in the macula with hemorrhage, concerning for metastasis. The patient was treated for presumed ocular metastases but had poor response to radiotherapy and was diagnosed four weeks later with N. cyriacigeorgica by retinal biopsy. Despite intravitreal and systemic antibiotics, the patient had progression of disease and died of respiratory involvement. Conclusion Nocardia endogenous endophthalmitis can present as a mass retinal lesion in immunosuppressed patients with metastatic disease. Early vitreous and retinal biopsy may be required for definitive diagnosis and treatment. A pulmonary source of infection should be suspected and monitored closely.

PURPOSE: To assess the retinal anatomy and array position in the Argus II Retinal Prosthesis recipients. DESIGN: Prospective, non-comparative cohort study METHODS: Setting: international multicenter study Patients: Argus II recipients enrolled in the Post-Market Surveillance Studies. Procedures: Spectral-domain Optical Coherence Tomography images collected for the Surveillance Studies (NCT01860092 and NCT01490827) were reviewed. Baseline and postoperative macular thickness, electrode-retina distance (gap), optic disc-array overlap, and preretinal membrane presence were recorded at 1, 3, 6, and 12 months. Main Outcome Measures: Axial retinal thickness and axial gap along the array’s long axis (a line between the tack and handle), maximal retinal thickness and maximal gap along a B-scan near the tack, midline, and handle. RESULTS: Thirty-three patients from 16 surgical sites in the United States and Germany were included. Mean axial retinal thickness increased from month 1 through month 12 at each location, but reached statistical significance only at the array midline (p- value=0.007). The rate of maximal thickness increase was highest near the array midline (slope=6.02, p=0.004), compared to the tack (slope=3.60, p

Inherited retinopathies are a group of genetic disorders that lead to blindness and/or vision impairment. Until now, treatment options for inherited retinopathies largely remained limited to supportive therapy. Gene therapy is an attractive therapeutic technique that allows repair of diseased genes, and it has shown success in vision improvement for patients affected by retinal disorders caused by genetic mutations. The US Food and Drug Administration approved the first gene therapy treatment for the eye, indicated for biallelic RPE65 mutation associated Leber congenital amaurosis (LCA), in December of 2017. Additionally, results from other ongoing clinical trials could further establish gene therapy as the milestone treatment that plays a role in disease process reversal for inherited retinopathies. This review article provides an update on the status of gene therapy for treatment of a variety of retinopathies, including LCA, choroideremia, achromatopsia, Stargardt disease, X-linked retinitis pigmentosa, and X-linked retinoschisis. Furthermore, this article explores transport methods of the genetic material, as well as therapy-delivery approaches used in the clinical setting.

Purpose: To report the association of optic nerve head (ONH) drusen with Best vitelliform macular dystrophy (BVMD). Methods: Chart review. Patients: Five patients from 3 families. Results: Multimodal imaging and ophthalmic examination demonstrated findings consistent with ONH drusen, in association with BVMD, in 5 patients. Conclusion: We report the association of BVMD with ONH drusen in 5 patients. This combination has previously been reported only once. We recommend that patients with a diagnosis of BVMD undergo autofluorescence and ultrasound imaging of the optic nerve to help facilitate this diagnosis, as some ONH drusen can be buried.

PurposeTo determine whether age-related macular degeneration (AMD) severity or the frequency of retinal pigment epithelium mitochondrial DNA lesions differ in human donor eyes that have undergone cataract surgery compared to phakic eyes.MethodsEyes from human donors aged ≥ 55 years were obtained from the Minnesota Lions Eye Bank. Cataract surgery status was obtained from history provided to Eye Bank personnel by family members at the time of tissue procurement. Donor eyes were graded for AMD severity using the Minnesota Grading System. Quantitative PCR was performed on DNA isolated from macular punches of retinal pigment epithelium to quantitate the frequency of mitochondrial DNA lesions in the donor tissue. Univariable and multivariable analyses were performed to evaluate for associations between (1) cataract surgery and AMD severity and (2) cataract surgery and mitochondrial DNA lesion frequency.ResultsA total of 157 subjects qualified for study inclusion. Multivariable analysis with age, sex, smoking status, and cataract surgery status showed that only age was associated with AMD grade. Multivariable analysis with age, sex, smoking status, and cataract surgery status showed that none of these factors were associated with retinal pigment epithelium mitochondrial DNA lesion frequency.ConclusionsIn this study of human donor eyes, neither retinal pigment epithelium mitochondrial DNA damage nor the stage of AMD severity are independently associated with cataract surgery after adjusting for other AMD risk factors. These new pathologic and molecular findings provide evidence against a relationship between cataract surgery and AMD progression and support the idea that cataract surgery is safe in the setting of AMD.

Purpose:The objective of this study is to perform a systematic review and provide an update on the diagnosis and management of retinopathy associated with incontinentia pigmenti (IP).Design:This is a systematic review.Methods:A literature search was performed for articles related to IP-associated retinopathy on PubMed, Embase, and ScienceDirect with no date limitations. Articles published on ophthalmology journals were screened and original human studies pertaining to the diagnosis and management of IP retinopathy were included for data analysis. The clinical and imaging findings, treatment, follow-up frequency and duration, and final visual outcomes were recorded.Results:The literature search retrieved 388 articles across the databases. Forty-two full-text peer-reviewed original human studies, containing 100 eyes of 60 unique patients of IP retinopathy, met our inclusion criteria. The majority of patients (68%) presented with IP retinopathy during the first 2 years of life, and 12 eyes of 8 patients who progressed from mild to severe IP retinopathy were all presented before the age of 4 months. Thirty-one (31%) eyes developed retinal detachment, 24 (24%) eyes had a final visual acuity of light perception or no light perception, and 14 (14%) eyes had a visual acuity of 20/50 or better.Conclusion:The results of this systematic review suggest that early detection and early frequent reevaluation of retinopathy in patients with IP in the first 2 years of life are key in obtaining optimal visual outcomes. Therefore, we propose an updated IP retinopathy management algorithm.

A 61-year-old white man was referred to the University of Minnesota Department of Ophthalmology with a diagnosis of cystoid macular edema (CME) following bilateral cataract surgery 2 months prior. Chorioretinal folds and CME were present on fundus examination and optical coherence tomography (OCT). His past medical history included diabetes mellitus for 18 years, hypertension for 5 years, and heart disease with bypass surgery. His most recent glycosylated hemoglobin test (HbA1C) was 8.3 (normal

Age-related macular degeneration (AMD) is a complex and progressive degenerative eye disease resulting in severe loss of central vision. Recent evidence indicates that immune system dysregulation could contribute to the development of AMD. We hypothesize that defective lysosome-mediated clearance causes accumulation of waste products in the retinal pigmented epithelium (RPE), activating the immune system and leading to retinal tissue injury and AMD. We have generated unique genetically engineered mice in which lysosome-mediated clearance (both by phagocytosis and autophagy) in RPE cells is compromised, causing the development of features of early AMD. Our recent data indicate a link between lipocalin-2 (LCN-2) and the inflammatory responses induced in this mouse model. We show that nuclear factor-κB (NF-κB) and STAT-1 may function as a complex in our animal model system, together controlling the upregulation of LCN-2 expression in the retina and stimulating an inflammatory response. This study revealed increased infiltration of LCN-2-positive neutrophils in the choroid and retina of early AMD patients as compared with age-matched controls. Our results demonstrate that, both in our animal model and in human AMD, the AKT2-NF-κB-LCN-2 signalling axis is involved in activating the inflammatory response, making this pathway a potential target for AMD treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Purpose To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. Methods This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. Results Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. Conclusion Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

Purpose To investigate the effect of a wider field-of-view (FOV) of a retinal prosthesis on the users' performance in locating objects. Methods One female and four male subjects who were blind due to end-stage retinitis pigmentosa and had been implanted with the Argus II retinal prosthesis participated (aged 63.4 ± 15.4). Thermal imaging was captured by an external sensor and converted to electrical stimulation to the retina. Subjects were asked to localize and to reach for heat-emitting objects using two different FOV mappings: a normal 1:1 mapping (no zoom) that provided 18° × 11° FOV and a 3:1 mapping (zoom out) that provided 49° × 35° FOV. Their accuracy and response time were recorded. Results Subjects were less accurate and took longer to complete the tasks with zoom out compared to no zoom. Localization accuracy decreased from 83% (95% confidence interval, 75%, 90%) with no zoom to 76% (67%, 83%) with zoom out (P = 0.07). Reaching accuracy differed between the two mappings only in one subject. Response time increased by 43% for the localization task (24%, 66%; P < 0.001) and by 20% for the reaching task (0%, 45%; P = 0.055). Conclusions Argus II wearers can efficiently find heat-emitting objects with the default 18° × 11° FOV of the current Argus II. For spatial localization, a higher spatial resolution may be preferred over a wider FOV. Translational Relevance Understanding the trade-off between FOV and spatial resolution in retinal prosthesis users can guide device optimization.

The blood retinal barrier (BRB) closely regulates the retinal microenvironment. Its compromise leads to the accumulation of retinal fluid containing potentially harmful plasma components. While eyes with non-exudative age-related macular degeneration (AMD) were previously felt to have an intact BRB, we propose that the BRB in non-exudative AMD eyes may be subclinically compromised, allowing entry of retina-toxic plasma proteins. We test this hypothesis by measuring retinal levels of abundant plasma proteins that should not cross the intact BRB. Two cohorts of frozen, post mortem neurosensory retinas were studied by Western analysis. One cohort from Alabama had 4 normal controls and 4 eyes with various forms of AMD. Another cohort from Minnesota had 5 intermediate AMD eyes and 5 normals. Both cohorts were age/post mortem interval (PMI) matched. The non-exudative AMD retinas in the Alabama cohort had significantly higher levels of albumin and complement component 9 (C9) than normal controls. The positive control exudative AMD donor retina had higher levels of all but one serum protein. In both macular and peripheral neurosensory retina samples, intermediate AMD retinas in the Minnesota cohort had significantly higher levels of albumin, fibrinogen, IgG, and C9 than controls. Our results suggest that there may be moderate subclinical BRB leakage in non-exudative AMD. Potentially harmful plasma components including complement or iron could enter the neurosensory retina in AMD patients prior to advanced disease. Thus, therapies aiming to stabilize the BRB might have a role in the management of non-exudative AMD.

Introduction To assess the anatomical changes taking place in the choroid after a scleral buckle (SB) procedure for retinal detachment repair. Methods This cross-sectional study looked at 23 adults with a history of unilateral retinal detachment repaired with a SB or other encircling element. The subjects underwent bilateral Enhanced Depth Spectral Domain Optical Coherence Tomography to image the choroid. The choroidal thickness (CT) was measured, and the non-operative eye was used as an internal control. Results CT was measured to be 170.8 ± 60.9 µm (mean ± SD) in eyes with SBs compared to 175.1 ± 61.9 µm in non-operative eyes. There was no statistically significant difference between the two groups (mean 4.3 µm, 95% CI −8.7, 17.3, p value 0.4973, paired t test). Conclusion Placement of an SB as part of a surgery to repair retinal detachment did not significantly alter CT at the macula.

OBJECTIVE To evaluate the benefit of integrating thermal imaging into an artificial vision therapy system, the Argus II retinal prosthesis, in simplifying a complex scene and improving mobility performance in the presence of other persons. APPROACH Four Argus II retinal implant users were evaluated on two tasks: to locate and approach target persons in a booth, and to navigate a hallway while avoiding people. They completed the tasks using both the original Argus II system (the 'Argus II camera') and a thermal-integrated Argus II system (the 'thermal camera'). The safety and efficiency of their navigation were evaluated by their walking speed, navigation errors, and the number of collisions. MAIN RESULTS Navigation performance was significantly superior when using the thermal camera compared to using the Argus II camera, including 75% smaller angle of deviation (p < 0.001), 48% smaller error of distance (p < 0.05), and 30% fewer collisions (p < 0.05). The thermal camera also brought the additional benefit of allowing the participants to perform the task in the dark as efficiently as in the light. More importantly, these benefits did not come at a cost of reduced walking speed. SIGNIFICANCE Using the thermal camera in the Argus II system, compared to a visible-light camera, could improve the wearers' navigation performance by helping them better approach or avoid other persons. Adding the thermal camera to future artificial vision therapy systems may complement the visible-light camera and improve the users' mobility safety and efficiency, enhancing their quality of life.

Age-related macular degeneration (AMD) involves the loss of retinal pigment epithelium (RPE) and photoreceptors and is one of the leading causes of blindness in the elderly. Oxidative damage to proteins, lipids, and DNA has been associated with RPE dysfunction and AMD. In this study, we evaluated oxidative stress in AMD and the efficacy of antioxidant, N-acetyl-L-cysteine (NAC), in protecting RPE from oxidative damage. To test this idea, primary cultures of RPE from human donors with AMD (n=32) or without AMD (No AMD, n=21) were examined for expression of NADPH oxidase (NOX) genes, a source of reactive oxygen species (ROS). Additionally, the cells were pretreated with NAC for 2 hours and then treated with either hydrogen peroxide (H2O2) or tert-butyl hydroperoxide (t-BHP) to induce cellular oxidation. Twenty-four hours after treatment, ROS production, cell survival, the content of glutathione (GSH) and adenosine triphosphate (ATP), and cellular bioenergetics were measured. We found increased expression of p22phox, a NOX regulator, in AMD cells compared to No AMD cells (p=0.02). In both AMD and No AMD cells, NAC pretreatment reduced t-BHP-induced ROS production and protected from H2O2-induced cell death and ATP depletion. In the absence of oxidation, NAC treatment improved mitochondrial function in both groups (p<0.01). Conversely, the protective response exhibited by NAC was disease-dependent for some parameters. In the absence of oxidation, NAC significantly reduced ROS production (p<0.001) and increased GSH content (p=0.02) only in RPE from AMD donors. Additionally, NAC-mediated protection from H2O2-induced GSH depletion (p=0.04) and mitochondrial dysfunction (p<0.05) was more pronounced in AMD cells compared with No AMD cells. These results demonstrate the therapeutic benefit of NAC by mitigating oxidative damage in RPE. Additionally, the favorable outcomes observed for AMD RPE support NAC’s relevance and the potential therapeutic value in treating AMD.

The Argus II retinal prosthesis (Second Sight Medical Products, Sylmar, CA, USA) is an electronic epiretinal implant designed for use in patients with end-stage retinitis pigmentosa, as well as for other outer retinal degenerative conditions, such as choroideremia, Leber’s congenital amaurosis, Bardet-Biedl syndrome, Usher syndrome and rod–cone disease.1 This device was tested in a clinical trial of 30 subjects in the USA and in Europe to measure the rate of serious adverse events (SAEs) and to assess its effects on functional vision and visual acuity.2–4 Subjects performed better on visual tasks with the device turned on and retained these improvements at 5 years postsurgery.4 Additionally, an acceptable safety profile enabled approval of the device for consumer use by the European regulatory authorities in 2011 (Conformite Europeenne (CE) mark) and by the US Food and Drug Administration (FDA) in 2013 (FDA approval). The implant is composed of an extraocular component, namely, an electronics case and implant coil, as well as an intraocular component involving a 60-electrode array that is tacked over the macula (figure 1). The extraocular and intraocular components are connected by a trans-scleral silicone-coated polyamide electrode cable, and the implantation procedure involves a 5.2 mm pars plana sclerotomy incision to insert the electrode array and the electrode cable into the eye. The sclerotomy is then sutured around the cable and covered by an allograft or autograft material.5 Figure 1 The Argus II retinal prosthesis. Labelled image of the Argus II implant (adapted from Humayun et al 2). As with any system having both intraocular and extraocular components, the trans-scleral electrode cable that traverses the sclerotomy permanently is a high-risk feature of the device, as leakage through the pars plana incision can result in chronic hypotony. The percentages of clinical trial subjects who experienced hypotony were 10.0% at …

Increased fundus autofluorescence is directly related to increased RPE lipofuscin deposition in the retina and has been observed in eyes with age-related macular degeneration (AMD). Smoking is the most significant modifiable risk factor for the development and progression of AMD, in which one of the main mechanisms is oxidative damage from smoking leading to RPE cell toxicity. The relationship between smoking and autofluorescence is not established and could provide insight into pathogenic mechanism of AMD. Therefore, our objective was to compare quantitative fundus autofluorescence (qAF) in the retinae of healthy non-smokers to smokers. We conducted a cross-sectional study at the 2016 Minnesota State Fair. Participants self-reported past medical and ocular history and underwent eye examination as well as qAF imaging with Spectralis confocal scanning laser ophthalmoscope (cSLO) equipped with an internal fluorescent reference. Two sets of images were obtained per eye. Stepwise multiple mixed effects regression model was used to examine the relationship between mean qAF values and smoking status. We enrolled 105 individuals (54 smokers, 61 females, mean age 41 years with range 18–78 years old). Fundus autofluorescence images were analyzable for 85 of 105 individuals contributing 161 eyes (80 right, 81 left). The repeatability coefficients between the first set and second set of images were ±21% of their mean qAF values. Older age and female gender were independently associated with higher qAF. Positive smoking history tended to result in higher qAF values after adjusting for age and gender but was not statistically significant (0.118, 95%CI -0.003, 0.240, P = 0.056). Among smokers, the number of pack-years smoked was not significantly associated with higher qAF. Our study's results are consistent with existing literature in which older age is predictive of intensified autofluorescence, while smoking history does not have as important of an impact on autofluorescence as hypothesized. Several large epidemiological studies have shown that smoking is significantly associated with AMD, and qAF is likely not the appropriate modality to clinically assess smoking's impact on retinae.

Purpose: A 59-year-old man with retinitis pigmentosa, who received an Argus II retinal prosthesis in the left eye 3 years prior, presented with left-sided involuntary facial contractions that occurred only after turning on the Argus II device. Methods: A case report. Results: Given that this patient's reported and visualized lower eyelid twitching corresponds to the location of the external region of the implanted coil, we hypothesize that heat or wirelessly transmitted electrical signals from the external coil to the implanted coil may induce spasm of the facial nerve and thus play a role in hemifacial spasm onset. Conclusions: To our knowledge, this is the first report of hemifacial spasm associated with Argus II use.