January 2019

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Martínez-Carrasco R, Sánchez-Abarca LI, Nieto-Gómez C, García EM, Sánchez-Guijo F, Argüeso P, Aijón J, Hernández-Galilea E, Velasco A. Subconjunctival injection of mesenchymal stromal cells protects the cornea in an experimental model of GVHD. Ocul Surf 2019;Abstract
PURPOSE: To evaluate the therapeutic effect of subconjunctival injection of human mesenchymal stromal cells (hMSCs) in the cornea of mice with graft versus host disease (GVHD). METHODS: GVHD was induced in mice after hematopoietic stem cell transplantation (HSCT) between MHC-mismatched mouse strains. Subconjunctival injection of hMSCs was applied at day 10 post-HSCT. Infiltration of CD3 cells in the cornea and epithelial alterations were analyzed by immunofluorescence. Tear was assessed using the PRT test and TearLab Osmolarity System. qPCR was used to evaluate changes in cytokines, Pax6 and Sprr1b expression. To evaluate the effect of irradiation, we analyzed the expression of these genes in TBI mice. RESULTS: Immune cell invasion occurs in mice with GVHD, as shown by the presence of CD3 cells in the cornea. Interestingly, eyes treated with hMSC did not present CD3 cells. Tear osmolarity was increased in GVHD eyes, but not in treated eyes. TNFa expression was highly increased in all corneas except in Control and treated eyes. Pax6 in corneal epithelium showed a similar pattern in GVHD and Control mice, and its gene expression was enhanced in GVHD corneas. In contrast, Pax6 was reduced in GVHD + MSC corneas. We also found an increase in SPRR1B staining in GVHD eyes that was lower in GVHD + MSC mice, demonstrating that corneal keratinization is less frequent after treatment with hMSC. CONCLUSIONS: The treatment with hMSCs by subconjunctival injection is effective in reducing corneal inflammation and squamous metaplasia in ocular GVHD (oGVHD). Local treatment with hMSCs is a promising strategy for oGVHD.
Mukai R, Park DH, Okunuki Y, Hasegawa E, Klokman G, Kim CB, Krishnan A, Gregory-Ksander M, Husain D, Miller JW, Connor KM. Mouse model of ocular hypertension with retinal ganglion cell degeneration. PLoS One 2019;14(1):e0208713.Abstract
OBJECTIVES: Ocular hypertension is a primary risk factor for glaucoma and results in retinal ganglion cell (RGC) degeneration. Current animal models of glaucoma lack severe RGC cell death as seen in glaucoma, making assessment of physiological mediators of cell death difficult. We developed a modified mouse model of ocular hypertension whereby long-lasting elevation of intraocular pressure (IOP) is achieved, resulting in significant reproducible damage to RGCs. RESULTS: In this model, microbeads are mixed with hyaluronic acid and injected into the anterior chamber of C57BL/6J mice. The hyaluronic acid allows for a gradual release of microbeads, resulting in sustained blockage of Schlemm's canal. IOP elevation was bimodal during the course of the model's progression. The first peak occurred 1 hours after beads injection, with an IOP value of 44.69 ± 6.00 mmHg, and the second peak occurred 6-12 days post-induction, with an IOP value of 34.91 ± 5.21 mmHg. RGC damage was most severe in the peripheral retina, with a loss of 64.1% compared to that of untreated eyes, while the midperiphery exhibited a 32.4% loss, 4 weeks following disease induction. CONCLUSIONS: These results suggest that sustained IOP elevation causes more RGC damage in the periphery than in the midperiphery of the retina. This model yields significant and reproducible RGC degeneration.
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Nanji KC, Fain B, Morley MG, Bayes J. In Response. Anesth Analg 2019;128(1):e11-e12.
Nilsson AK, Löfqvist C, Najm S, Hellgren G, Sävman K, Andersson MX, Smith LEH, Hellström A. Influence of Human Milk and Parenteral Lipid Emulsions on Serum Fatty Acid Profiles in Extremely Preterm Infants. JPEN J Parenter Enteral Nutr 2019;43(1):152-161.Abstract
BACKGROUND: Infants born prematurely are at risk of a deficiency in ω-6 and ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs) arachidonic acid (AA) and docosahexaenoic acid (DHA). We investigated how fatty acids from breast milk and parenteral lipid emulsions shape serum LC-PUFA profiles in extremely preterm infants during early perinatal life. METHODS: Ninety infants born < 28 weeks gestational age were randomized to receive parenteral lipids with or without the ω-3 LC-PUFAs eicosapentaenoic acid (EPA) and DHA (SMOFlipid: Fresenius Kabi, Uppsala, Sweden, or Clinoleic: Baxter Medical AB, Kista, Sweden, respectively). The fatty acid composition of infant serum phospholipids was determined from birth to postmenstrual age 40 weeks, and in mother's milk total lipids on postnatal day 7. Enteral and parenteral intake of LC-PUFAs was correlated with levels in infant serum. RESULTS: Infants administered parenteral ω-3 LC-PUFAs received 4.4 and 19.3 times more DHA and EPA, respectively, over the first 2 weeks of life. Parenteral EPA but not DHA correlated with levels in infant serum. We found linear relationships between dietary EPA and DHA and infant serum levels in the Clinoleic (Baxter Medical AB) group. The volume of administered SMOFlipid (Fresenius Kabi) was inversely correlated with serum AA, whereas Clinoleic (Baxter Medical AB) inversely correlated with serum EPA and DHA. CONCLUSIONS: There appears to be no or low correlation between the amount of DHA administered parenterally and levels measured in serum. Whether this observation reflects serum phospholipid fraction only or truly represents the amount of accreted DHA needs to be investigated. None of the parenteral lipid emulsions satisfactorily maintained high levels of both ω-6 and ω-3 LC-PUFAs in infant serum.
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Pan BX, Margeta MA. Elevated Intraocular Pressure in a Young Man With a History of Laser-Assisted In Situ Keratomileusis. JAMA Ophthalmol 2019;
Parikh R, Feng PW, Tainsh L, Sakurada Y, Balaratnasingam C, Khurana RN, Hemmati H, Modi YS. Comparison of Ophthalmic Medication Prices Between the United States and Australia. JAMA Ophthalmol 2019;Abstract
Importance: Health care prices may drive differences in health care costs across high-income nations. Adalimumab, ranibizumab, and aflibercept are high-cost medications in the United States and Australia. A comparison of their prices over time may elucidate how ophthalmic medication prices contribute to health care costs. Objective: To compare changes in the prices of adalimumab, ranibizumab, and aflibercept in the United States and Australia, the highest and lowest spenders on health care, respectively, among high-income nations. Design, Setting, and Participants: This retrospective price comparison study examined prices paid by government entities in the United States (Medicare) and Australia (Pharmaceuticals and Benefits Scheme). The analysis and data collection were conducted from March 28 to May 4, 2018, in accordance with guidelines set by the International Society for Pharmacoeconomics and Outcomes Research Task Force on Good Research Practices and prior published studies. No human participants or related data were included in this study. Exposures: The change in mean prices of adalimumab, ranibizumab, and aflibercept in the United States and Australia. Main Outcomes and Measures: Initial, final, and change in medication price annually from 2013 to 2017 in inflation-adjusted 2017 US dollars. Results: The mean prices (US dollar prices unadjusted for inflation) in 2013 and 2017 in the United States were $1114 ($1053) and $1818 ($1818), respectively, for adalimumab; $2102 ($1988) and $1904 ($1904), respectively, for ranibizumab; and $2074 ($1961) and $1956 ($1956), respectively, for aflibercept. The mean (Australian dollar prices unadjusted for inflation) 2013 and 2017 prices in Australia were $1854 (A $1797) and $1206 (A $1574), respectively, for adalimumab; $2157 (A $2090) and $972 (A $1268), respectively, for ranibizumab; and $2030 ($1967) and $996 ($1300), respectively, for aflibercept. The estimated annual change in price for adalimumab was +12.8% (95% CI, 9.1%-16.5%) in the United States compared with -11.1% (95% CI, -15.0% to -7.1%) in Australia, a difference of 23.9% per year (95% CI, 19.7%-28.0%; P < .001). The annual change in price for ranibizumab was -2.6% (95% CI, -3.9% to -1.3%) in the United States compared with -18.5% (95% CI, -29.3% to -7.8%) in Australia, a difference of 15.9% per year (95% CI, 7.6%-24.2%; P = .003). The annual change in price for aflibercept was -1.5% (95% CI, -2.2% to -0.7%) in the United States compared with -16.9% (95% CI, -25.1% to -8.6%) in Australia, a difference of 15.4% (95% CI, 9.1%-21.8%; P = .001). Conclusions and Relevance: Results of this study indicate that the prices of adalimumab, ranibizumab, and aflibercept significantly decreased during the past 5 years in Australia compared with the United States. These data do not indicate why these differences are noted or what actions might affect future pricing in either country.
Paschalis EI, Lei F, Zhou C, Chen XN, Kapoulea V, Hui P-C, Dana R, Chodosh J, Vavvas DG, Dohlman CH. Microglia Regulate Neuroglia Remodeling in Various Ocular and Retinal Injuries. J Immunol 2019;202(2):539-549.Abstract
Reactive microglia and infiltrating peripheral monocytes have been implicated in many neurodegenerative diseases of the retina and CNS. However, their specific contribution in retinal degeneration remains unclear. We recently showed that peripheral monocytes that infiltrate the retina after ocular injury in mice become permanently engrafted into the tissue, establishing a proinflammatory phenotype that promotes neurodegeneration. In this study, we show that microglia regulate the process of neuroglia remodeling during ocular injury, and their depletion results in marked upregulation of inflammatory markers, such as , , and in the retina, and abnormal engraftment of peripheral CCR2 CX3CR1 monocytes into the retina, which is associated with increased retinal ganglion cell loss, retinal nerve fiber layer thinning, and pigmentation onto the retinal surface. Furthermore, we show that other types of ocular injuries, such as penetrating corneal trauma and ocular hypertension also cause similar changes. However, optic nerve crush injury-mediated retinal ganglion cell loss evokes neither peripheral monocyte response in the retina nor pigmentation, although peripheral CX3CR1 and CCR2 monocytes infiltrate the optic nerve injury site and remain present for months. Our study suggests that microglia are key regulators of peripheral monocyte infiltration and retinal pigment epithelium migration, and their depletion results in abnormal neuroglia remodeling that exacerbates neuroretinal tissue damage. This mechanism of retinal damage through neuroglia remodeling may be clinically important for the treatment of patients with ocular injuries, including surgical traumas.
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Roelofs KA, Starks V, Yoon MK. Orbital Emphysema: A Case Report and Comprehensive Review of the Literature. Ophthalmic Plast Reconstr Surg 2019;35(1):1-6.Abstract
PURPOSE: The objective of this study was to report a case of persistent and likely self-induced orbital emphysema (OE) following functional endoscopic sinus surgery with dislodgement of a previously placed orbital floor implant and to review the literature surrounding etiologies, pathophysiology, and management of OE. METHODS: Case report and review of the literature. RESULTS AND DISCUSSION: While blunt trauma resulting in disruption of the medial orbital wall is the most common cause of OE, there are an additional 25 underlying etiologies reported in the current literature. Pathophysiology of OE is somewhat dependent on underlying etiology but often involves a 1-way ball valve mechanism such that air may enter the orbit but not exit. When sufficient air enters the orbit, complications secondary to increased intraorbital pressure, including central retinal artery occlusion and compressive optic neuropathy, can occur. Mild cases of OE are typically observed, with most resolving within 7 to 10 days. Moderate cases are often managed by lateral canthotomy and cantholysis with possible needle decompression. Severe cases may require urgent surgical decompression. While the majority of cases of OE are benign and self-limited, there have been 4 reports in the literature documenting significant vision loss. CONCLUSIONS: Although there is often a history of trauma in patients presenting with OE, many other underlying etiologies have been reported with several cases occurring spontaneously. As such, OE should be included on the differential for a patient presenting with a sudden onset of orbital signs.
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Saban DR, Hodges RR, Mathew R, Reyes NJ, Yu C, Kaye R, Swift W, Botten N, Serhan CN, Dartt DA. Resolvin D1 treatment on goblet cell mucin and immune responses in the chronic allergic eye disease (AED) model. Mucosal Immunol 2019;12(1):145-153.Abstract
Severe, chronic eye allergy is an understudied, vision-threatening condition. Treatments remain limited. We used a mouse model of severe allergic eye disease (AED) to determine whether topical application of the pro-resolution mediator Resolvin D1 (RvD1) terminates the response. AED was induced by injection of ovalbumin (OVA) followed by topical challenge of OVA daily. RvD1 was applied topically prior to OVA. Clinical symptoms were scored. Eye washes were assayed for MUC5AC. After 7 days, eyes were removed and the number of goblet cells, T helper cell responses and presence of immune cells in draining lymph nodes and conjunctiva determined. Topical RvD1 treatment significantly reduced symptoms of AED. RvD1 did not alter the systemic type 2 immune response in the lymph nodes. AED increased the total amount of goblet cell mucin secretion, but not the number of goblet cells. RvD1 prevented this increase, but did not alter goblet cell number. Absolute numbers of CD4 + T cells, total CD11b + myeloid cells, eosinophils, neutrophils, and monocytes, but not macrophages increased in AED versus RvD1-treated mice. We conclude that topical application of RvD1 reduced the ocular allergic response by local actions in conjunctival immune response and a decrease in goblet cell mucin secretion.
Savage SW, Spano LP, Bowers AR. The effects of age and cognitive load on peripheral-detection performance. J Vis 2019;19(1):15.Abstract
Age-related declines in both peripheral vision and cognitive resources could contribute to the increased crash risk of older drivers. However, it is unclear whether increases in age and cognitive load result in equal detriments to detection rates across all peripheral target eccentricities (general interference effect) or whether these detriments become greater with increasing eccentricity (tunnel effect). In the current study we investigated the effects of age and cognitive load on the detection of peripheral motorcycle targets (at 5°-30° eccentricity) in static images of intersections. We used a dual-task paradigm in which cognitive load was manipulated without changing the complexity of the central (foveal) visual stimulus. Each image was displayed briefly (250 ms) to prevent eye movements. When no cognitive load was present, age resulted in a tunnel effect; however, when cognitive load was high, age resulted in a general interference effect. These findings suggest that tunnel and general interference effects can co-occur and that the predominant effect varies with the level of demand placed on participants' resources. High cognitive load had a general interference effect in both age groups, but the effect attenuated at large target eccentricities (opposite of a tunnel effect). Low cognitive load had a general interference effect in the older but not the younger group, impairing detection of motorcycle targets even at 5° eccentricity, which could present an imminent collision risk in real driving.
Shao C, Chen Y, Nakao T, Amouzegar A, Yin J, Tahvildari M, Lužnik Z, Chauhan SK, Dana R. Local Delivery of Regulatory T Cells Promotes Corneal Allograft Survival. Transplantation 2019;103(1):182-190.Abstract
BACKGROUND: Regulatory T (Treg) cell-based immunotherapies have been studied as potential cell-based modalities for promoting transplant survival. However, the efficacy of local delivery of Treg cells in corneal transplantation has not been fully elucidated. Herein, we investigated the kinetics of migration of subconjunctivally injected Treg cells and their role in promoting corneal allograft survival. METHODS: GFPCD4CD25Foxp3 Treg cells were isolated from draining lymph nodes (DLNs) of GFP transgenic mice and were subconjunctivally injected to corneal allograft recipients. Next, Treg cells, conventional T cells (Tconv) or a combination of both was locally injected to graft recipients, and graft survival was determined by evaluating opacity scores for 10 weeks. Transplanted mice without treatment served as controls. The frequencies of major histocompatibility complex-IICD11b antigen-presenting cells, IFNγCD4 Th1 cells, and CD45 cells in the DLNs and cornea were evaluated at week 2 posttransplantation using flow cytometry. Expressions of IFNγ, IL-10 and TGF-β in the grafts were assessed using reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: GFP Treg cells were detected in the ipsilateral cornea and DLNs of recipients 6 hours after injection. Subconjunctival injection of Treg cells significantly decreased the frequencies of mature antigen-presenting cells in the graft and DLNs, suppressed Th1 frequencies in DLNs, and inhibited CD45 cell infiltration to the graft. Finally, locally delivered Treg cells significantly reduced the expression of IFN-γ, enhanced the levels of IL-10 and TGF-β in the graft, and promoted long-term allograft survival. CONCLUSIONS: Our study elucidates the kinetics of migration of locally delivered Treg cells and shows their role in suppressing host immune response against the allograft.
Smith JR, Pe'er J, Belfort RN, Cardoso F, Carvajal RD, Carvalho C, Coupland SE, Desjardins L, Francis JH, Gallie BL, Gombos DS, Grossniklaus HE, Heegaard S, Jager MJ, Kaliki S, Ksander BR, Maeurer M, Moreno E, Pulido JS, Ryll B, Singh AD, Zhao J, Parreira A, Wilson DJ, O'Brien JM. Proceedings of the Association for Research in Vision and Ophthalmology and Champalimaud Foundation Ocular Oncogenesis and Oncology Conference. Transl Vis Sci Technol 2019;8(1):9.Abstract
The 2018 Ocular Oncogenesis and Oncology Conference was held through a partnership of the Association for Research in Vision and Ophthalmology (ARVO) and the Champalimaud Foundation. Twenty-one experts from international ocular oncology centers, from the Champalimaud Clinical Centre and the Champalimaud Foundation Cancer Research Program, and from patient advocacy organizations, delivered lectures on subjects that ranged from global ocular oncology, to basic research in mechanisms of ocular malignancy, to clinical research in ocular cancers, and to anticipated future developments in the area. The scientific program of the conference covered a broad range of ocular tumors-including uveal melanoma, retinoblastoma, ocular surface tumors, and adnexal and intraocular lymphomas-and pathogenesis and management were deliberated in the context of the broader systemic cancer discipline. In considering the latest basic and clinical research developments in ocular oncogenesis and oncology, and providing the opportunity for cross-talk between ocular cancer biologists, systemic cancer biologists, ocular oncologists, systemic oncologists, patients, and patient advocates, the forum generated new knowledge and novel insights for the field. This report summarizes the content of the invited talks at the 2018 ARVO-Champalimaud Foundation Ocular Oncogenesis and Oncology Conference.
Strauss RW, Kong X, Bittencourt MG, Ho A, Jha A, Schönbach EM, Ahmed MI, Muñoz B, Ervin A-M, Michaelides M, Birch DG, Sahel J-A, Sunness JS, Zrenner E, Bagheri S, Ip M, Sadda SV, West S, Scholl HPN, Scholl HPN. Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) Study: Design and Baseline Characteristics (Report No. 1). Ophthalmic Res 2019;61(1):36-43.Abstract
PURPOSE: To describe the study design and characteristics at first visit of participants in the longitudinal Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) study. METHODS: Scotopic microperimetry (sMP) was performed in one designated study eye in a subset of participants with molecularly proven ABCA4-associated Stargardt disease (STGD1) enrolled in a multicenter natural history study (ProgStar). Study visits were every 6 months over a period ranging from 6 to 24 months, and also included fundus autofluorescence (FAF). RESULTS: SMART enrolled 118 participants (118 eyes). At the first visit of SMART, the mean sensitivity in mesopic microperimetry was 11.48 (±5.05; range 0.00-19.88) dB and in sMP 11.25 (±5.26; 0-19.25) dB. For FAF, all eyes had a lesion of decreased autofluorescence (mean lesion size 3.62 [±3.48; 0.10-21.46] mm2), and a total of 76 eyes (65.5%) had a lesion of definitely decreased autofluorescence with a mean lesion size of 3.46 (±3.60; 0.21-21.46) mm2. CONCLUSIONS: Rod function is impaired in STGD1 and can be assessed by sMP. Testing rod function may serve as a potential outcome measure for future clinical treatment trials. This is evaluated in the SMART study.
Sullivan DA. How to choose and conduct a research project: some advice for young investigators. Arq Bras Oftalmol 2019;82(1):1.
Sun JK, Glassman AR, Beaulieu WT, Stockdale CR, Bressler NM, Flaxel C, Gross JG, Shami M, Jampol LM, Jampol LM. Rationale and Application of the Protocol S Anti-Vascular Endothelial Growth Factor Algorithm for Proliferative Diabetic Retinopathy. Ophthalmology 2019;126(1):87-95.Abstract
PURPOSE: To present the rationale, guidelines, and results of ranibizumab treatment for proliferative diabetic retinopathy (PDR) in Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S. DESIGN: Post hoc analyses from a randomized clinical trial. PARTICIPANTS: Three hundred five participants (394 study eyes) having PDR without prior panretinal photocoagulation (PRP). METHODS: Intravitreous ranibizumab (0.5 mg) versus PRP for PDR. Ranbizumab-assigned eyes (n = 191) received monthly injections for 6 months unless resolution was achieved after 4 injections. After 6 months, injections could be deferred if neovascularization was stable over 3 consecutive visits (sustained stability). If neovascularization worsened, monthly treatment resumed. Panretinal photocoagulation could be initiated for failure or futility criteria. MAIN OUTCOME MEASURES: Neovascularization status through 2 years. RESULTS: At 1 month, 19% (35 of 188) of ranibizumab-assigned eyes showed complete neovascularization resolution and an additional 60% (113) showed improvement. At 6 months, 52% (80 of 153) showed neovascularization resolution, 3% (4) were improved, 37% (56) were stable, and 8% (13) had worsened since the last visit. Among eyes with versus without resolved neovascularization at 6 months, the median (interquartile range) number of injections between 6 months and 2 years was 4 (1-7; n = 73) versus 7 (4-11; n = 67; P < 0.001). Injections were deferred in 68 of 73 eyes (93%) meeting sustained stability at least once during the study; 62% (42 of 68) resumed injections within 16 weeks after deferral. At 2 years, 43% (66 of 154) showed neovascularization resolution, 5% (7) showed improvement, 23% (36) were stable, and 27% (42) had worsened since the last visit. Only 3 eyes met criteria for failure or futility through 2 years. CONCLUSIONS: The DRCR.net treatment algorithm for PDR can provide excellent clinical outcomes through 2 years for patients initiating anti-vascular endothelial growth factor (VEGF) therapy for PDR. When choosing between anti-VEGF and PRP as first-line therapy for PDR, treatment decisions should be guided by consideration of the relative advantages of each therapeutic method and anticipated patient compliance with follow-up and treatment recommendations.
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Tang SM, Lau T, Rong SS, Yazar S, Chen LJ, Mackey DA, Lucas RM, Pang CP, Yam JC. Vitamin D and its pathway genes in myopia: systematic review and meta-analysis. Br J Ophthalmol 2019;103(1):8-17.Abstract
OBJECTIVE: To conduct a systematic review and meta-analysis of the association of blood vitamin D (25-hydroxyvitamin D, 25(OH)D) concentration and vitamin D pathway genes with myopia. METHODS: We searched the MEDLINE and EMBASE databases for studies published up to 29 January 2018. Cross-sectional or cohort studies which evaluated the blood 25(OH)D concentration, blood 25(OH)D3 concentration or vitamin D pathway genes, in relation to risk of myopia or refractive errors were included. Standard mean difference (SMD) of blood 25(OH)D concentrations between the myopia and non-myopia groups was calculated. The associations of blood 25(OH)D concentrations and polymorphisms in vitamin D pathway genes with myopia using summary ORs were evaluated. RESULTS: We summarised seven studies involving 25 008 individuals in the meta-analysis. The myopia group had lower 25(OH)D concentration than the non-myopia group (SMD=-0.27 nmol/L, p=0.001). In the full analysis, the risk of myopia was inversely associated with blood 25(OH)D concentration after adjusting for sunlight exposure or time spent outdoors (adjusted odds ratio (AOR)=0.92 per 10 nmol/L, p<0.0001). However, the association was not statistically significant for the <18 years subgroup (AOR=0.91 per 10 nmol/L, p=0.13) and was significant only for 25(OH)D3 (likely to be mainly sunlight derived), but not total 25(OH)D (AOR=0.93 per 10 nmol/L, p=0.00007; AOR=0.91 per 10 nmol/L, p=0.15). We analysed four single nucleotide polymorphisms in the VDR gene from two studies; there was no significant association with myopia. CONCLUSIONS: Lower 25(OH)D is associated with increased risk of myopia; the lack of a genetic association suggests that 25(OH)D level may be acting as a proxy for time outdoors.
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Ung C, Laíns I, Silverman RF, Woods R, Lane AM, Papakostas TD, Husain D, Miller JW, Gragoudas ES, Kim IK, Miller JB. Evaluation of choroidal lesions with swept-source optical coherence tomography. Br J Ophthalmol 2019;103(1):88-93.Abstract
AIMS: The aim of our study was to image choroidal lesions with swept-source optical coherence tomography (SS-OCT) and to identify the morphological characteristics associated with optimal visualisation. METHODS: This was a prospective, cross-sectional study. Patients with choroidal melanocytic lesions <3 mm in thickness on B-scan ultrasonography were recruited. All participants underwent SS-OCT. On SS-OCT we evaluated qualitative (eg, lesion outline, detection of scleral-choroidal interface and quality of the image) and quantitative (measurement of maximum lesion thickness and the largest basal diameter) parameters. Probability of optimal image quality was examined using ordered logistic regression models. The main outcome measure was quality of the choroidal lesion images on SS-OCT, defined as: optimal, suboptimal or poor. RESULTS: We included 85 choroidal lesions of 82 patients. There were 24 choroidal lesions (29%) for which image quality was classified as optimal, 31 lesions (37%) as suboptimal and 30 lesions (36%) as poor. The factors associated with optimal image quality were distance closer to the fovea (OR 0.76, p<0.001), posterior pole location (OR 3.87, p=0.05), lower ultrasonography thickness (OR 0.44, p=0.04), lighter lesion pigmentation (OR 0.12, p=0.003) and smaller lesion diameter (OR 0.73, p<0.001). In the multivariable analysis, closer distance to the fovea (OR 0.81, p=0.005), lighter lesion pigmentation (OR 0.11, p=0.01) and smaller lesion diameter (OR 0.76, p=0.006) remained statistically significant. CONCLUSION: SS-OCT is useful in imaging most choroidal melanocytic lesions. Image quality is best when the choroidal lesion is closer to the fovea, has a smaller diameter and a lighter choroidal pigmentation.
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Wang M, Shen LQ, Pasquale LR, Petrakos P, Formica S, Boland MV, Wellik SR, De Moraes CG, Myers JS, Saeedi O, Wang H, Baniasadi N, Li D, Tichelaar J, Bex PJ, Elze T. An Artificial Intelligence Approach to Detect Visual Field Progression in Glaucoma Based on Spatial Pattern Analysis. Invest Ophthalmol Vis Sci 2019;60(1):365-375.Abstract
Purpose: To detect visual field (VF) progression by analyzing spatial pattern changes. Methods: We selected 12,217 eyes from 7360 patients with at least five reliable 24-2 VFs and 5 years of follow-up with an interval of at least 6 months. VFs were decomposed into 16 archetype patterns previously derived by artificial intelligence techniques. Linear regressions were applied to the 16 archetype weights of VF series over time. We defined progression as the decrease rate of the normal archetype or any increase rate of the 15 VF defect archetypes to be outside normal limits. The archetype method was compared with mean deviation (MD) slope, Advanced Glaucoma Intervention Study (AGIS) scoring, Collaborative Initial Glaucoma Treatment Study (CIGTS) scoring, and the permutation of pointwise linear regression (PoPLR), and was validated by a subset of VFs assessed by three glaucoma specialists. Results: In the method development cohort of 11,817 eyes, the archetype method agreed more with MD slope (kappa: 0.37) and PoPLR (0.33) than AGIS (0.12) and CIGTS (0.22). The most frequently progressed patterns included decreased normal pattern (63.7%), and increased nasal steps (16.4%), altitudinal loss (15.9%), superior-peripheral defect (12.1%), paracentral/central defects (10.5%), and near total loss (10.4%). In the clinical validation cohort of 397 eyes with 27.5% of confirmed progression, the agreement (kappa) and accuracy (mean of hit rate and correct rejection rate) of the archetype method (0.51 and 0.77) significantly (P < 0.001 for all) outperformed AGIS (0.06 and 0.52), CIGTS (0.24 and 0.59), MD slope (0.21 and 0.59), and PoPLR (0.26 and 0.60). Conclusions: The archetype method can inform clinicians of VF progression patterns.
Wang JC, McKay KM, Sood AB, Laíns I, Sobrin L, Miller JB. Comparison of choroidal neovascularization secondary to white dot syndromes and age-related macular degeneration by using optical coherence tomography angiography. Clin Ophthalmol 2019;13:95-105.Abstract
Purpose: To characterize and compare choroidal neovascularization (CNV) secondary to white dot syndromes (WDS) and age-related macular degeneration (AMD) using optical coherence tomography angiography (OCT-A). Methods: This is a cross-sectional study in which we imaged patients with CNV secondary to WDS and AMD with either the Zeiss Angioplex OCT-A or Optovue AngioVue OCT-A. Relevant demographic and clinical characteristics were collected and analyzed. CNV area and vessel density (VD) were measured by three independent graders, and linear regression analysis was subsequently performed. Results: Three patients with multifocal choroiditis and panuveitis, one patient each with birdshot chorioretinopathy, presumed ocular histoplasmosis syndrome, and persistent placoid maculopathy, and eleven patients with AMD with sufficient image quality were included. CNV associated with WDS was significantly smaller than that secondary to AMD (0.56±0.32 vs 2.79±1.80 mm, =-2.22, =0.01), while no difference in VD was detected (0.46±0.09 vs 0.44±0.09, =0.02, =0.71). Conclusion: CNV networks secondary to WDS appear to be smaller than those secondary to AMD but have similar VD. OCT-A is a powerful tool to investigate properties of CNV from various etiologies. Larger studies are needed for further characterization and understanding of CNV pathogenesis in inflammatory conditions.
Wareham LK, Dordea AC, Schleifer G, Yao V, Batten A, Fei F, Mertz J, Gregory-Ksander M, Pasquale LR, Buys ES, Sappington RM. Increased bioavailability of cyclic guanylate monophosphate prevents retinal ganglion cell degeneration. Neurobiol Dis 2019;121:65-75.Abstract
The nitric oxide - guanylyl cyclase-1 - cyclic guanylate monophosphate (NO-GC-1-cGMP) pathway has emerged as a potential pathogenic mechanism for glaucoma, a common intraocular pressure (IOP)-related optic neuropathy characterized by the degeneration of retinal ganglion cells (RGCs) and their axons in the optic nerve. NO activates GC-1 to increase cGMP levels, which are lowered by cGMP-specific phosphodiesterase (PDE) activity. This pathway appears to play a role in both the regulation of IOP, where reduced cGMP levels in mice leads to elevated IOP and subsequent RGC degeneration. Here, we investigated whether potentiation of cGMP signaling could protect RGCs from glaucomatous degeneration. We administered the PDE5 inhibitor tadalafil orally (10 mg/kg/day) in murine models of two forms of glaucoma - primary open angle glaucoma (POAG; GC-1 mice) and primary angle-closure glaucoma (PACG; Microbead Occlusion Model) - and measured RGC viability at both the soma and axon level. To determine the direct effect of increased cGMP on RGCs in vitro, we treated axotomized whole retina and primary RGC cultures with the cGMP analogue 8-Br-cGMP. Tadalafil treatment increased plasma cGMP levels in both models, but did not alter IOP or mean arterial pressure. Nonetheless, tadalafil treatment prevented degeneration of RGC soma and axons in both disease models. Treatment of whole, axotomized retina and primary RGC cultures with 8-Br-cGMP markedly attenuated both necrotic and apoptotic cell death pathways in RGCs. Our findings suggest that enhancement of the NO-GC-1-cGMP pathway protects the RGC body and axon in murine models of POAG and PACG, and that enhanced signaling through this pathway may serve as a novel glaucoma treatment, acting independently of IOP.

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