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Torkildsen G, Abelson MB, Gomes PJ, McLaurin E, Potts SL, Mah FS. Vehicle-Controlled, Phase 2 Clinical Trial of a Sustained-Release Dexamethasone Intracanalicular Insert in a Chronic Allergen Challenge Model. J Ocul Pharmacol Ther 2017;33(2):79-90.Abstract

PURPOSE: To evaluate the efficacy and safety of a sustained-release dexamethasone intracanalicular insert (Dextenza™) in a model of allergic conjunctivitis. METHODS: This was a randomized, double-masked, vehicle-controlled, Phase 2 study. Subjects had to have a positive conjunctival allergen challenge (CAC) reaction to allergen (bilateral +2 itching and redness on 5-point, 0-4 scales) at Visit 1, and for 2 of 3 time points on subsequent visits. Subjects who met entry criteria were randomized to receive Dextenza or PV (vehicle insert). Challenges occurred over 42 days, with efficacy assessed at 14 (primary endpoint visit), 28, and 40 days postinsertion. Outcome measures included the evaluation of ocular itching, redness, tearing, chemosis, eyelid swelling, rhinorrhea, and congestion. RESULTS: Twenty-eight subjects completed the study in the Dextenza group and 31 in the vehicle group. At 14 days postinsertion, Dextenza was statistically superior to PV, with least square mean differences for ocular itching of -0.76, -0.97, and -0.87 at 3, 5, and 7 min post-CAC, and for conjunctival redness of -0.46, -0.66, and -0.68 at 7, 15, and 20 min post-CAC. Clinical significance, defined as a 1-U decrease from PV, was not met for primary efficacy. Secondary endpoints, including number of subjects reporting itching and conjunctival redness, indicated superior performance of Dextenza compared with vehicle. Eleven Dextenza-treated (35.5%) and 10 vehicle-treated (30.3%) subjects each experienced a single adverse event. CONCLUSION: This Phase 2 study demonstrated preliminary efficacy and safety data of Dextenza for treatment of allergic conjunctivitis.

Witkin AJ, Chang DF, Jumper MJ, Charles S, Eliott D, Hoffman RS, Mamalis N, Miller KM, Wykoff CC. Vancomycin-Associated Hemorrhagic Occlusive Retinal Vasculitis: Clinical Characteristics of 36 Eyes. Ophthalmology 2017;124(5):583-595.Abstract

PURPOSE: To expand understanding of presentation, diagnosis, and outcomes of hemorrhagic occlusive retinal vasculitis (HORV). DESIGN: Retrospective case series. PARTICIPANTS: Thirty-six eyes of 23 patients. METHODS: The American Society of Cataract and Refractive Surgery (ASCRS) and the American Society of Retina Specialists (ASRS) formed a joint task force to define clinical characteristics of HORV and to study its prevalence, cause, treatment, and outcomes. An online registry was established on both societies' web sites. Surveys were e-mailed to members of both societies soliciting cases of suspected HORV. A literature search was performed to uncover additional cases. MAIN OUTCOME MEASURES: Historical data including intraoperative characteristics, images, treatment regimens, and visual and anatomic outcomes. RESULTS: Characteristic findings of HORV included unremarkable postoperative day 1 undilated examination, delayed-onset painless vision loss, mild anterior chamber and vitreous inflammation, sectoral retinal hemorrhages in areas of ischemia, and predilection for venules and peripheral involvement. Based on predetermined diagnostic criteria, 36 eyes of 23 patients were diagnosed with HORV. All eyes received intraocular vancomycin via intracameral bolus (33/36), via intravitreal injection (1/36), or through the irrigation bottle (2/36). Patients sought treatment with HORV 1 to 21 days after surgery or intravitreal injection. Visual results usually were poor: 22 of 36 eyes (61%) had 20/200 or worse visual acuity and 8 of 36 eyes (22%) had no light perception (NLP). Neovascular glaucoma developed in 20 of 36 eyes (56%). Seven eyes received additional intravitreal vancomycin after surgery; 5 of these 7 eyes had NLP visual acuity at the most recent examination. Three eyes received intravitreal corticosteroids and had final visual acuities of 20/40, 20/70, and hand movements. CONCLUSIONS: Hemorrhagic occlusive retinal vasculitis is a rare, potentially devastating condition that can develop after cataract surgery or intraocular injection. All cases in this series were associated with intraocular vancomycin. Disease course and findings suggest that HORV is caused by a delayed hypersensitivity reaction to vancomycin. Early treatment with corticosteroids likely is beneficial. Subsequently, anti-vascular endothelial growth factor injections and panretinal photocoagulation are important to prevent neovascular glaucoma, a common complication. Avoidance of additional intravitreal vancomycin is recommended if HORV is suspected.

Springelkamp H, Iglesias AI, Mishra A, Höhn R, Wojciechowski R, Khawaja AP, Nag A, Wang YX, Wang JJ, Cuellar-Partida G, Gibson J, Cooke Bailey JN, Vithana EN, Gharahkhani P, Boutin T, Ramdas WD, Zeller T, Luben RN, Yonova-Doing E, Viswanathan AC, Yazar S, Cree AJ, Haines JL, Koh JY, Souzeau E, Wilson JF, Amin N, Müller C, Venturini C, Kearns LS, Kang JH, Kang JH, Tham YC, Zhou T, van Leeuwen EM, Nickels S, Sanfilippo P, Liao J, van der Linde H, Zhao W, van Koolwijk LME, Zheng L, Rivadeneira F, Baskaran M, van der Lee SJ, Perera S, de Jong PTVM, Oostra BA, Uitterlinden AG, Fan Q, Hofman A, Tai E-S, Vingerling JR, Sim X, Wolfs RCW, Teo YY, Lemij HG, Khor CC, Willemsen R, Lackner KJ, Aung T, Jansonius NM, Montgomery G, Wild PS, Young TL, Burdon KP, Hysi PG, Pasquale LR, Wong TY, Klaver CCW, Hewitt AW, Jonas JB, Mitchell P, Lotery AJ, Foster PJ, Vitart V, Pfeiffer N, Craig JE, Mackey DA, Hammond CJ, Wiggs JL, Cheng C-Y, van Duijn CM, Macgregor S. New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics. Hum Mol Genet 2017;Abstract

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Woods SE, Lieberman MT, Lebreton F, Trowel E, de la Fuente-Núñez C, Dzink-Fox J, Gilmore MS, Fox JG. Characterization of Multi-Drug Resistant Enterococcus faecalis Isolated from Cephalic Recording Chambers in Research Macaques (Macaca spp.). PLoS One 2017;12(1):e0169293.Abstract

Nonhuman primates are commonly used for cognitive neuroscience research and often surgically implanted with cephalic recording chambers for electrophysiological recording. Aerobic bacterial cultures from 25 macaques identified 72 bacterial isolates, including 15 Enterococcus faecalis isolates. The E. faecalis isolates displayed multi-drug resistant phenotypes, with resistance to ciprofloxacin, enrofloxacin, trimethoprim-sulfamethoxazole, tetracycline, chloramphenicol, bacitracin, and erythromycin, as well as high-level aminoglycoside resistance. Multi-locus sequence typing showed that most belonged to two E. faecalis sequence types (ST): ST 4 and ST 55. The genomes of three representative isolates were sequenced to identify genes encoding antimicrobial resistances and other traits. Antimicrobial resistance genes identified included aac(6')-aph(2"), aph(3')-III, str, ant(6)-Ia, tetM, tetS, tetL, ermB, bcrABR, cat, and dfrG, and polymorphisms in parC (S80I) and gyrA (S83I) were observed. These isolates also harbored virulence factors including the cytolysin toxin genes in ST 4 isolates, as well as multiple biofilm-associated genes (esp, agg, ace, SrtA, gelE, ebpABC), hyaluronidases (hylA, hylB), and other survival genes (ElrA, tpx). Crystal violet biofilm assays confirmed that ST 4 isolates produced more biofilm than ST 55 isolates. The abundance of antimicrobial resistance and virulence factor genes in the ST 4 isolates likely relates to the loss of CRISPR-cas. This macaque colony represents a unique model for studying E. faecalis infection associated with indwelling devices, and provides an opportunity to understand the basis of persistence of this pathogen in a healthcare setting.

Thanos A, Todorich B, Hypes SM, Yonekawa Y, Thomas B, Randhawa S, Drenser KA, Trese MT. RETINAL VASCULAR TORTUOSITY AND EXUDATIVE RETINOPATHY IN A FAMILY WITH DYSKERATOSIS CONGENITA MASQUERADING AS FAMILIAL EXUDATIVE VITREORETINOPATHY. Retin Cases Brief Rep 2017;11 Suppl 1:S187-S190.Abstract

PURPOSE: To report a novel presentation of dyskeratosis congenita masquerading as familial exudative vitreoretinopathy. METHODS: Observational case series involving single family and literature review. RESULTS: A brother and sister were diagnosed with familial exudative vitreoretinopathy at ages 4 and 2, respectively. Both patients were managed with laser photocoagulation. Eight years after the initial presentation, both siblings developed pancytopenia secondary to bone marrow failure. Laboratory work-up revealed severely shortened telomere length in both patients, and genetic testing revealed a missense mutation in the gene that encodes the reverse transcriptase component of telomerase, confirming the diagnosis of dyskeratosis congenita. The father of both children was a carrier of the same mutation, who exhibited marked retinal vascular tortuosity of the second-order vessels. CONCLUSION: Dyskeratosis congenita is a severe multisystem disorder, which should be considered in cases of pediatric exudative retinopathies with concurrent signs and/or symptoms of bone marrow failure.

Wan MJ, Mantagos IS, Shah AS, Kazlas M, Hunter DG. Comparison of Botulinum Toxin With Surgery for the Treatment of Acute-Onset Comitant Esotropia in Children. Am J Ophthalmol 2017;176:33-39.Abstract

PURPOSE: To determine whether botulinum toxin is as effective as strabismus surgery in the treatment of acute-onset comitant esotropia in children. DESIGN: Retrospective, nonrandomized, comparative clinical study. METHODS: Setting: Tertiary care pediatric hospital. STUDY POPULATION: Forty-nine children with acute-onset comitant esotropia. INTERVENTION: Treatment with either botulinum toxin ("chemodenervation group") or standard incisional strabismus surgery ("surgery group"). MAIN OUTCOME MEASURE: Success rate at 6 months (total horizontal deviation of 10 prism diopters or less and evidence of binocular single vision). RESULTS: There were 16 patients in the chemodenervation group and 33 patients in the surgery group. The success rate was not significantly different at 6 months (81% vs 61%, P = .20) or at 18 months (67% vs 58%, P = .74). The median angle of deviation and median stereoacuity were not significantly different at 6 or 18 months. The chemodenervation procedure was not inferior to incisional strabismus surgery at 6 months. The duration of general anesthesia (5 vs 71 min, P < .001) and time in the post-anesthesia care unit (37 vs 93 min, P < .001) were significantly shorter in the chemodenervation group. Botulinum toxin injection payment averaged $874 per procedure compared with $2783 for strabismus surgery. CONCLUSIONS: Botulinum toxin is at least as effective as surgery in the treatment of acute-onset comitant esotropia at 6 months while reducing the duration of general anesthesia and healthcare costs.

Phadikar P, Saxena S, Ruia S, Lai TYY, Meyer CH, Eliott D. The potential of spectral domain optical coherence tomography imaging based retinal biomarkers. Int J Retina Vitreous 2017;3:1.Abstract

BACKGROUND: Biomarker", a merged word of "biological marker", refers to a broad subcategory of medical signs that objectively indicate the state of health, and well-being of an individual. Biomarkers hold great promise for personalized medicine as information gained from diagnostic or progression markers can be used to tailor treatment to the individual for highly effective intervention in the disease process. Optical coherence tomography (OCT) has proved useful in identifying various biomarkers in ocular and systemic diseases. MAIN BODY: Spectral domain optical coherence tomography imaging-based biomarkers provide a valuable tool for detecting the earlier stages of the disease, tracking progression, and monitoring treatment response. The aim of this review article is to analyze various OCT based imaging biomarkers and their potential to be considered as surrogate endpoints for diabetic retinopathy, age related macular degeneration, retinitis pigmentosa and vitreomacular interface disorder. These OCT based surrogate markers have been classified as retinal structural alterations (macular central subfield thickness and cube average thickness); retinal ultrastructural alterations (disruption of external limiting membrane and ellipsoid zone, thinning of retinal nerve fiber layer and ganglion cell layer); intraretinal microangiopathic changes; choroidal surrogate endpoints; and vitreoretinal interface endpoints. CONCLUSION: OCT technology is changing very quickly and throughout this review there are some of the multiple possibilities that OCT based imaging biomarkers will be more useful in the near future for diagnosis, prognosticating disease progression and as endpoint in clinical trials.

Shi Y, Wang H, Yin J, Zhang X, Li M, Xin C, Chen X, Wang N. Outcomes of microcatheter-assisted trabeculotomy following failed angle surgeries in primary congenital glaucoma. Eye (Lond) 2017;31(1):132-139.Abstract

PurposeTo report surgical outcomes of microcatheter-assisted trabeculotomy following failed angle surgeries, and compare those with no previous angle surgery, in primary congenital glaucoma (PCG).MethodsThe early postoperative (12 months) results of 42 eyes of 36 patients who underwent microcatheter-assisted trabeculotomy by single surgeon for PCG were retrospectively analyzed. Group 1, 20 eyes of 16 patients, had no previous angle surgery. Group 2, 22 eyes of 20 patients, had one or two previous failed angle surgeries. Success was defined as an intraocular pressure (IOP) <21 mm Hg with at least a 30% reduction from preoperative IOP with (qualified success) or without (complete success) the use of antiglaucoma medication.ResultsMean IOP decreased from 31.5±7.2 mm Hg on 3 (median, range: 1-5) medications in Group 1 and 34.6±7.3 mm Hg on 3 (median, range: 1-4) medications in Group 2 preoperatively to 15.6±3.1 mm Hg on 0 (median, range: 0-4) medications in Group 1 and 16.0±4.6 mm Hg on 0 (median, range: 0-2) medications in Group 2 postoperatively at 12 months (both P<0.001), respectively. The mean percentage of IOP reduction from preoperative to last postoperative visit was 46.0±20.1% in Group 1 and 45.5±25.0% in Group 2, P=0.947. Qualified and complete successes were comparable between Group 1 and Group 2 (qualified success: 90.0% vs 77.3%, P=0.294; complete success: 78.9% vs 77.3%, P=0.853). Complications were minimal.ConclusionsMicrocatheter-assisted trabeculotomy achieved significant pressure-lowering effects with a reduction in medication use in PCG, and it represents a reasonable choice of initial and repeat surgical treatment for PCG.

Li Y, Andereggen L, Yuki K, Omura K, Yin Y, Gilbert H-Y, Erdogan B, Asdourian MS, Shrock C, de Lima S, Apfel U-P, Zhuo Y, Hershfinkel M, Lippard SJ, Rosenberg PA, Benowitz L. Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration. Proc Natl Acad Sci U S A 2017;114(2):E209-E218.Abstract

Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn(2+)) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn(2+) increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn(2+) accumulation in amacrine cell processes involves the Zn(2+) transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn(2+) chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn(2+) chelation extends for several days after nerve injury. These results show that retinal Zn(2+) dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn(2+) chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.

Simavli H, Poon LY-C, Que CJ, Liu Y, Akduman M, Tsikata E, de Boer JF, Chen TC. Diagnostic Capability of Peripapillary Retinal Volume Measurements in Glaucoma. J Glaucoma 2017;26(6):592-601.Abstract
PURPOSE: To determine the diagnostic capability of spectral domain optical coherence tomography peripapillary retinal volume (RV) measurements. MATERIALS AND METHODS: A total of 156 patients, 89 primary open-angle glaucoma and 67 normal subjects, were recruited. Spectral domain optical coherence tomography peripapillary RV was calculated for 4 quadrants using 3 annuli of varying scan circle diameters: outer circumpapillary annuli of circular grids 1, 2, and 3 (OCA1, OCA2, OCA3). Area under the receiver operating characteristic curves and pairwise comparisons of receiver operating characteristic (ROC) curves were performed to determine which quadrants were best for diagnosing primary open-angle glaucoma. The pairwise comparisons of the best ROC curves for RV and retinal nerve fiber layer (RNFL) were performed. The artifact rates were analyzed. RESULTS: Pairwise comparisons showed that the smaller annuli OCA1 and OCA2 had better diagnostic performance than the largest annulus OCA3 (P<0.05 for all quadrants). OCA1 and OCA2 had similar diagnostic performance, except for the inferior quadrant which was better for OCA1 (P=0.0033). The pairwise comparisons of the best ROC curves for RV and RNFL were not statistically significant. RV measurements had lower rates of artifacts at 7.4% while RNFL measurements had higher rates at 42.9%. CONCLUSIONS: Peripapillary RV measurements have excellent ability for diagnosing not only glaucoma patients but also a subset of early glaucoma patients. The inferior quadrant of peripapillary annulus OCA1 demonstrated the best diagnostic capability for both glaucoma and early glaucoma. The diagnostic ability of RV is comparable with that of RNFL parameters in glaucoma but with lower artifact rates.
Lambiase A, Sullivan BD, Schmidt TA, Sullivan DA, Jay GD, Truitt ER, Bruscolini A, Sacchetti M, Mantelli F. A Two-Week, Randomized, Double-masked Study to Evaluate Safety and Efficacy of Lubricin (150 μg/mL) Eye Drops Versus Sodium Hyaluronate (HA) 0.18% Eye Drops (Vismed®) in Patients with Moderate Dry Eye Disease. Ocul Surf 2017;15(1):77-87.Abstract

PURPOSE: The objective of this clinical trial (NCT02507934) was to assess the efficacy and safety of recombinant human lubricin as compared to a 0.18% sodium hyaluronate (HA) eye drop in subjects with moderate dry eye disease (DED). METHODS: DEWS Grade 2-3 subjects were randomized to use lubricin (N=19, 51.9 ± 11.8 years) or HA (N=20, 61.8 ± 13.3 years). After a saline washout period, subjects administered BID therapy for 7 days, followed by instillation as needed (2-6 drops per eye) for 7 days. Visual analog scale (VAS) including foreign body sensation, burning/stinging, itching, pain, sticky feeling, blurred vision and photophobia were primary outcomes, with secondary endpoints of corneal fluorescein staining, Schirmer test, tear film breakup time (TFBUT), eyelid and conjunctival erythema and number of instillations compared at day 14. RESULTS: The primary endpoint was met. Lubricin supplementation achieved greater than a 72% reduction from baseline in foreign body sensation (P<.013), burning/stinging, pain, sticky feeling (P<.0432), blurred vision (P<.0013), and photophobia (P<.011) in at least one eye. Lubricin also showed significant improvement in fluorescein staining (OD/OS: 43.8%/50.0%, vs. 26.5%/23.3%, P<.0398, P<.0232), TFBUT (P<.010), SANDE frequency (P<.0435), eyelid erythema (P<.004), conjunctival erythema (P<.0013), and instillations (P<.04) as compared to HA. No treatment-related adverse events occurred during the investigation. CONCLUSIONS: Recombinant human lubricin was shown to produce significant improvement in both signs and symptoms of dry eye disease as compared to HA.

Jakobiec FA, Zakka FR, Lorch A. Unsuspected Conjunctival Orbital Dermoid Cyst: Aids in Diagnosis. Ophthal Plast Reconstr Surg 2017;33(5):e123-e126.Abstract
A 25-year-old man with Type 1 diabetes mellitus experienced rapid visual decline and was scheduled for right cataract surgery. At the time of administering an inferotemporal retrobulbar block, a white discharge appeared spontaneously on the surface of the globe. Superotemporally a cyst was found and its contents were subtotally evacuated. Microscopically, eosinophilic, acellular material with chatter artifact and small vacuoles was detected and initially thought to represent a lens choristoma. This material stained moderately with the periodic acid Schiff method and was focally Congo red positive without apple green birefringence; it also stained blue with the Masson trichrome method. Acid-fast staining disclosed the presence of rare vellous hairs. Adherent cells were not epidermal cells (CK5/6) but conjunctival epithelial cells (CK7); CD68-positive histiocytes were also identified. The lesion was diagnosed as a disrupted orbital dermoid cyst of conjunctival origin.
Ji YW, Mittal SK, Hwang HS, Chang E-J, Lee JH, Seo Y, Yeo A, Noh H, Lee HS, Chauhan SK, Lee HK. Lacrimal gland-derived IL-22 regulates IL-17-mediated ocular mucosal inflammation. Mucosal Immunol 2017;10(5):1202-1210.Abstract
Inflammatory damage of mucosal surface of the eye is a hallmark of dry eye disease (DED) and, in severe cases, can lead to significant discomfort, visual impairment, and blindness. DED is a multifactorial autoimmune disorder with a largely unknown pathogenesis. Using a cross-sectional patient study and a well-characterized murine model of DED, herein we investigated the immunoregulatory function of interleukin-22 (IL-22) in the pathogenesis of DED. We found that IL-22 levels were elevated in lacrimal fluids of DED patients and inversely correlated with severity of disease. Acinar cells of the lacrimal glands (LGs), not inflammatory immune cells, are the primary source of IL-22, which suppresses inflammation in ocular surface epithelial cells upon desiccating stress. Moreover, loss of function analyses using IL-22 knockout mice demonstrated that IL-22 is essential for suppression of ocular surface infiltration of Th17 cells and inhibition of DED induction. Our novel findings elucidate immunoregulatory function of LG-derived IL-22 in inhibiting IL-17-mediated ocular surface epitheliopathy in DED thus making IL-22 a new relevant therapeutic target.

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