2017

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Khoueir Z, Jassim F, Poon LY-C, Tsikata E, Ben-David GS, Liu Y, Shieh E, Lee R, Guo R, Papadogeorgou G, Braaf B, Simavli H, Que C, Vakoc BJ, Bouma BE, de Boer JF, Chen TC. Diagnostic Capability of Peripapillary Three-dimensional Retinal Nerve Fiber Layer Volume for Glaucoma Using Optical Coherence Tomography Volume Scans. Am J Ophthalmol 2017;182:180-193.Abstract
PURPOSE: To determine the diagnostic capability of peripapillary 3-dimensional (3D) retinal nerve fiber layer (RNFL) volume measurements from spectral-domain optical coherence tomography (OCT) volume scans for open-angle glaucoma (OAG). DESIGN: Assessment of diagnostic accuracy. METHODS: Setting: Academic clinical setting. STUDY POPULATION: Total of 180 patients (113 OAG and 67 normal subjects). OBSERVATION PROCEDURES: One eye per subject was included. Peripapillary 3D RNFL volumes were calculated for global, quadrant, and sector regions, using 4 different-size annuli. Peripapillary 2D RNFL thickness circle scans were also obtained. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUROC) values, sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios. RESULTS: Among all 2D and 3D RNFL parameters, best diagnostic capability was associated with inferior quadrant 3D RNFL volume of the smallest annulus (AUROC value 0.977). Otherwise, global 3D RNFL volume AUROC values were comparable to global 2D RNFL thickness AUROC values for all 4 annulus sizes (P values: .0593 to .6866). When comparing the 4 annulus sizes for global RNFL volume, the smallest annulus had the best AUROC values (P values: .0317 to .0380). The smallest-size annulus may have the best diagnostic potential, partly owing to having no areas excluded for being larger than the 6 × 6 mm(2) scanned region. CONCLUSION: Peripapillary 3D RNFL volume showed excellent diagnostic performance for detecting glaucoma. Peripapillary 3D RNFL volume parameters have the same or better diagnostic capability compared to peripapillary 2D RNFL thickness measurements, although differences were not statistically significant.
Kim EC, Toyono T, Berlinicke CA, Zack DJ, Jurkunas U, Usui T, Jun AS. Screening and Characterization of Drugs That Protect Corneal Endothelial Cells Against Unfolded Protein Response and Oxidative Stress. Invest Ophthalmol Vis Sci 2017;58(2):892-900.Abstract

Purpose: To screen for and characterize compounds that protect corneal endothelial cells against unfolded protein response (UPR) and oxidative stress. Methods: Bovine corneal endothelial cells (BCECs) were treated for 48 hours with 640 compounds from a Food and Drug Administration (FDA)-approved drug library and then challenged with thapsigargin or H2O2 to induce UPR or oxidative stress, respectively. Cell viability was measured using the CellTiter-Glo survival assay. Selected "hits" were subjected to further dose-response testing, and their ability to modulate expression of UPR and oxidative stress markers was assessed by RT-PCR, Western blot, and measurement of protein carbonyl and 8-hydroxydeoxyguanosine (8-OHdG) adducts in immortalized human corneal endothelial cells (iHCECs). Results: Forty-one drugs at 20 μM and 55 drugs at 100 μM increased survival of H2O2-challenged cells, and 8 drugs at 20 μM and 2 drugs at 100 μM increased survival of thapsigargin-challenged cells, compared with untreated control cells. Nicergoline, ergothioneine, nimesulide, oxotremorine, and mefenamic acid increased survival of both H2O2- and thapsigargin-challenged cells. Oxotremorine altered DNA damage inducible 3 (CHOP) gene expression, glucose-regulated protein 78 kDa (GRP78) and activating transcription factor 4 (ATF4) protein expression, and protein carbonyl and 8-OHdG levels. Mefenamic acid altered GRP78 protein expression and protein carbonyl and 8-OHdG levels. Conclusions: Oxotremorine and mefenamic acid are potential survival factors for corneal endothelial cells under UPR and oxidative stress. The described assay can be further expanded to screen additional drugs for potential therapeutic effect in corneal endothelial diseases such as Fuchs' endothelial corneal dystrophy.

Kim JS, Kanjlia S, Merabet LB, Bedny M. Development of the Visual Word Form Area Requires Visual Experience: Evidence from Blind Braille Readers. J Neurosci 2017;37(47):11495-11504.Abstract
Learning to read causes the development of a letter- and word-selective region known as the visual word form area (VWFA) within the human ventral visual object stream. Why does a reading-selective region develop at this anatomical location? According to one hypothesis, the VWFA develops at the nexus of visual inputs from retinotopic cortices and linguistic input from the frontotemporal language network because reading involves extracting linguistic information from visual symbols. Surprisingly, the anatomical location of the VWFA is also active when blind individuals read Braille by touch, suggesting that vision is not required for the development of the VWFA. In this study, we tested the alternative prediction that VWFA development is in fact influenced by visual experience. We predicted that in the absence of vision, the "VWFA" is incorporated into the frontotemporal language network and participates in high-level language processing. Congenitally blind (n = 10, 9 female, 1 male) and sighted control (n = 15, 9 female, 6 male), male and female participants each took part in two functional magnetic resonance imaging experiments: (1) word reading (Braille for blind and print for sighted participants), and (2) listening to spoken sentences of different grammatical complexity (both groups). We find that in blind, but not sighted participants, the anatomical location of the VWFA responds both to written words and to the grammatical complexity of spoken sentences. This suggests that in blindness, this region takes on high-level linguistic functions, becoming less selective for reading. More generally, the current findings suggest that experience during development has a major effect on functional specialization in the human cortex.SIGNIFICANCE STATEMENT The visual word form area (VWFA) is a region in the human cortex that becomes specialized for the recognition of written letters and words. Why does this particular brain region become specialized for reading? We tested the hypothesis that the VWFA develops within the ventral visual stream because reading involves extracting linguistic information from visual symbols. Consistent with this hypothesis, we find that in congenitally blind Braille readers, but not sighted readers of print, the VWFA region is active during grammatical processing of spoken sentences. These results suggest that visual experience contributes to VWFA specialization, and that different neural implementations of reading are possible.
Knezevic A, Yoon MK. Differences in Wait Times for Cosmetic Blepharoplasty by ASOPRS Members. Ophthalmic Plast Reconstr Surg 2018;34(3):222-224.Abstract
PURPOSE: Adequate access to subspecialty care is of concern to patients and physicians alike. One measure of availability is the wait time for cosmetic procedures. The authors investigated geographical differences in wait times for cosmetic upper eyelid blepharoplasty of American Society of Ophthalmic Plastic and Reconstructive Surgery members across the country. METHODS: This study surveyed all 533 American Society of Ophthalmic Plastic and Reconstructive Surgery members' practices in the United States based on the publically available contact information (www.asoprs.org). Scripted telephone calls were made requesting self-referred cosmetic upper eyelid blepharoplasty. Wait times until the first available appointment and time until the first available surgery date were collected. RESULTS: Of the membership, 387 (72.6% response rate) respondents offered appointments for cosmetic upper eyelid blepharoplasty. Overall, 84.2% of respondents were male. Practice breakdown was 83.4% in private practice and 16.5% in academic practice. Median wait time until the next available appointment was 14 days (mean 21.2 days, 0-205 days; p = 0.145). Private practice wait time was shorter than academic (median 14 vs. 18 days, mean 19.7 vs. 28.9 days; p =0.004). However, there was wide variability based on region. CONCLUSIONS: Patients seeking cosmetic upper eyelid blepharoplasty have good access to care by American Society of Ophthalmic Plastic and Reconstructive Surgery members. There are variabilities based on academic versus private practice. Further study can evaluate whether similar findings exist for medically necessary functional procedures. This information may help assess the need for additional practitioners.
Kobashi H, Kamiya K, Shimizu K. Dry Eye After Small Incision Lenticule Extraction and Femtosecond Laser-Assisted LASIK: Meta-Analysis. Cornea 2017;36(1):85-91.Abstract

PURPOSE: To compare postoperative ocular surface integrity and innervation between small incision lenticule extraction (SMILE) and femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK). METHODS: The Cochrane Central Register of Controlled Trials, PubMED, and EMBASE were searched for prospective comparative studies. Trials meeting the selection criteria were quality appraised, and the data were extracted by 2 independent authors. The weighted mean differences (WMDs) and 95% confidence intervals (CIs) were used to compare dry eye examinations and corneal subbasal nerve density (SMILE-FS-LASIK). RESULTS: The study covered 5 trials. No significant difference was found in the Schirmer test score between both groups (WMD = -1.91 and 0.27; 95% CI, -5.02 to 1.20 and -0.99 to 1.54; P = 0.23 and 0.67 at 1- and 6-month follow-ups, respectively). Tear breakup time in the SMILE group significantly exceeded that in the FS-LASIK group (WMD = 0.65 and 1.14; 95% CI, 0.20-1.10 and 0.18-2.10; P = 0.004 and 0.02, at 1- and 6-month follow-ups, respectively). Ocular surface disease index scores were significantly better in the SMILE group 6 months postoperatively (WMD = -10.12, 95% CI, -16.07 to -4.18, P = 0.0008). No significant difference was found in tear osmolarity between both groups (WMD = -5.19 and -6.37; 95% CI, -17.15 to 6.76 and -22.74 to 10.00; P = 0.39 and 0.45 at 1- and 6-month follow-ups, respectively). Higher corneal sensitivity was observed in the SMILE group 1 and 6 months postoperatively (WMD = 11.35 and 3.49; 95% CI, 7.29-15.40 and 1.76-5.21; P < 0.00001 and <0.0001, at 1- and 6-month follow-ups, respectively). Corneal subbasal nerve density was also significantly higher in SMILE-treated eyes than it was in FS-LASIK-treated eyes 1 month postoperatively (WMD = 4.72, 95% CI, 1.10-8.34, P = 0.01). CONCLUSIONS: According to this meta-analysis, the SMILE procedure has fewer negative impacts on the ocular surface and corneal innervation than does FS-LASIK. Furthermore, SMILE shows superiority over FS-LASIK by a exhibiting a lower risk of postoperative dry eye.

Kobashi H, Kamiya K, Shimizu K. Randomized Comparison Between Rebamipide Ophthalmic Suspension and Diquafosol Ophthalmic Solution for Dry Eye After Penetrating Keratoplasty. J Ocul Pharmacol Ther 2017;33(1):13-18.Abstract

PURPOSE: To compare the ocular surfaces of patients treated with rebamipide (REB) ophthalmic suspension or diquafosol (DQS) ophthalmic solution for dry eye syndrome after penetrating keratoplasty (PK). METHODS: A total of 40 eyes of 40 patients who had dry eyes after undergoing PK were enrolled and randomly divided into an REB group and a DQS group. Both REB and DQS groups used each eye drop four times. The tear breakup time (TBUT), corneal fluorescein staining scores, and dry eye-related quality-of-life score (DEQS) were evaluated before treatment, 2 weeks after start of treatment and 4 weeks after start of treatment. RESULTS: We found a significant improvement in TBUT (P < 0.001, Dunnett's test) and fluorescein scores (P < 0.001) 4 weeks after treatment in the REB group. Similar results were obtained in the DQS group (P < 0.001 and P = 0.01, respectively). No significant improvements in DEQS were found 4 weeks after treatment in each group (P = 0.15 and P = 0.63, analysis of variance, respectively). No significant differences were seen in these variables and in the changes between the groups after treatment. CONCLUSIONS: REB and DQS may be effective for the management of dry eye syndrome after PK in terms of ocular surface findings. In our study, effects of REB appear to be equivalent to those of DQS in the patients.

Konstantinou EK, Notomi S, Kosmidou C, Brodowska K, Al-Moujahed A, Nicolaou F, Tsoka P, Gragoudas E, Miller JW, Young LH, Vavvas DG. Verteporfin-induced formation of protein cross-linked oligomers and high molecular weight complexes is mediated by light and leads to cell toxicity. Sci Rep 2017;7:46581.Abstract

Verteporfin (VP) was first used in Photodynamic therapy, where a non-thermal laser light (689 nm) in the presence of oxygen activates the drug to produce highly reactive oxygen radicals, resulting in local cell and tissue damage. However, it has also been shown that Verteporfin can have non-photoactivated effects such as interference with the YAP-TEAD complex of the HIPPO pathway, resulting in growth inhibition of several neoplasias. More recently, it was proposed that, another non-light mediated effect of VP is the formation of cross-linked oligomers and high molecular weight protein complexes (HMWC) that are hypothesized to interfere with autophagy and cell growth. Here, in a series of experiments, using human uveal melanoma cells (MEL 270), human embryonic kidney cells (HEK) and breast cancer cells (MCF7) we showed that Verteporfin-induced HMWC require the presence of light. Furthermore, we showed that the mechanism of this cross-linking, which involves both singlet oxygen and radical generation, can occur very efficiently even after lysis of the cells, if the lysate is not protected from ambient light. This work offers a better understanding regarding VP's mechanisms of action and suggests caution when one studies the non-light mediated actions of this drug.

Krishnamurthy S, Konstantinou EK, Young LH, Gold DA, Saeij JPJ. The human immune response to Toxoplasma: Autophagy versus cell death. PLoS Pathog 2017;13(3):e1006176.
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Laíns I, Wang J, Providência J, Mach S, Gil P, Gil J, Marques M, Armstrong G, Garas S, Barreto P, Kim IK, Vavvas DG, Miller JW, Husain D, Silva R, Miller JB. Choroidal Changes Associated With Subretinal Drusenoid Deposits in Age-related Macular Degeneration Using Swept-source Optical Coherence Tomography. Am J Ophthalmol 2017;180:55-63.Abstract
PURPOSE: To compare choroidal vascular features of eyes with and without subretinal drusenoid deposits (SDD), using swept-source optical coherence tomography (SS OCT). DESIGN: Multicenter, cross-sectional study. METHODS: We prospectively recruited patients with intermediate age-related macular degeneration (AMD), without other vitreoretinal pathology. All participants underwent complete ophthalmic examination, color fundus photography (used for AMD staging), and spectral-domain OCT (to evaluate the presence of SDD). SS OCT was used to obtain automatic macular choroidal thickness (CT) maps, according to the Early Treatment Diabetic Retinopathy Study (ETDRS) sectors. For data analysis, we considered mean choroidal thickness as the arithmetic mean value of the 9 ETDRS sectors. SS OCT en face images of choroidal vasculature were also captured and converted to binary images. Choroidal vascular density (CVD) was calculated as a percent area occupied by choroidal vessels in a 6-mm-diameter submacular circular. Choroidal vessel volume was calculated by multiplying the average CVD by macular area and CT. Multilevel mixed linear models (to account for the inclusion of 2 eyes of same subject) were performed for analysis. RESULTS: We included 186 eyes (n = 118 subjects), 94 (50.5%) presenting SDD. Multiple regression analysis revealed that, controlling for age, eyes with SDD presented a statistically thinner mean CT (ß = -21.9, P = .006) and CT in all the individual ETDRS fields (ß ≤ -18.79, P ≤ .026). Mean choroidal vessel volume was also significantly reduced in eyes with SDD (ß = -0.003, P = .007). No significant associations were observed with mean CVD. CONCLUSION: In subjects with intermediate AMD, choroidal thickness and vessel volume are reduced in the presence of subretinal drusenoid deposits.
Laíns I, Duarte D, Barros AS, Martins AS, Gil J, Miller JB, Marques M, Mesquita T, Kim IK, da Cachulo ML, Vavvas D, Carreira IM, Murta JN, Silva R, Miller JW, Husain D, Gil AM. Human plasma metabolomics in age-related macular degeneration (AMD) using nuclear magnetic resonance spectroscopy. PLoS One 2017;12(5):e0177749.Abstract
PURPOSE: To differentiate the plasma metabolomic profile of patients with age related macular degeneration (AMD) from that of controls, by Nuclear Magnetic Resonance (NMR) spectroscopy. METHODS: Two cohorts (total of 396 subjects) representative of central Portugal and Boston, USA phenotypes were studied. For each cohort, subjects were grouped according to AMD stage (early, intermediate and late). Multivariate analysis of plasma NMR spectra was performed, followed by signal integration and univariate analysis. RESULTS: Small changes were detected in the levels of some amino acids, organic acids, dimethyl sulfone and specific lipid moieties, thus providing some biochemical information on the disease. The possible confounding effects of gender, smoking history and age were assessed in each cohort and found to be minimal when compared to that of the disease. A similar observation was noted in relation to age-related comorbidities. Furthermore, partially distinct putative AMD metabolite fingerprints were noted for the two cohorts studied, reflecting the importance of nutritional and other lifestyle habits in determining AMD metabolic response and potential biomarker fingerprints. Notably, some of the metabolite changes detected were noted as potentially differentiating controls from patients diagnosed with early AMD. CONCLUSION: For the first time, this study showed metabolite changes in the plasma of patients with AMD as compared to controls, using NMR. Geographical origins were seen to affect AMD patients´ metabolic profile and some metabolites were found to be valuable in potentially differentiating controls from early stage AMD patients. Metabolomics has the potential of identifying biomarkers for AMD, and further work in this area is warranted.
Laíns I, Miller JB, Park DH, Tsikata E, Davoudi S, Rahmani S, Pierce J, Silva R, Chen TC, Kim IK, Vavvas D, Miller JW, Husain D. Structural Changes Associated with Delayed Dark Adaptation in Age-Related Macular Degeneration. Ophthalmology 2017;124(9):1340-1352.Abstract
PURPOSE: To examine the relationship between dark adaptation (DA) and optical coherence tomography (OCT)-based macular morphology in age-related macular degeneration (AMD). DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients with AMD and a comparison group (>50 years) without any vitreoretinal disease. METHODS: All participants were imaged with spectral-domain OCT and color fundus photographs, and then staged for AMD (Age-related Eye Disease Study system). Both eyes were tested with the AdaptDx (MacuLogix, Middletown, PA) DA extended protocol (20 minutes). A software program was developed to map the DA testing spot (2° circle, 5° superior to the fovea) to the OCT B-scans. Two independent graders evaluated the B-scans within this testing spot, as well as the entire macula, recording the presence of several AMD-associated abnormalities. Multilevel mixed-effects models (accounting for correlated outcomes between 2 eyes) were used for analyses. MAIN OUTCOME MEASURES: The primary outcome was rod-intercept time (RIT), defined in minutes, as a continuous variable. For subjects unable to reach RIT within the 20 minutes of testing, the value of 20 was assigned. RESULTS: We included 137 eyes (n = 77 subjects), 72.3% (n = 99 eyes) with AMD and the remainder belonging to the comparison group. Multivariable analysis revealed that even after adjusting for age and AMD stage, the presence of any abnormalities within the DA testing spot (ß = 4.8, P < 0.001), as well as any abnormalities in the macula (ß = 2.4, P = 0.047), were significantly associated with delayed RITs and therefore impaired DA. In eyes with no structural changes within the DA testing spot (n = 76, 55.5%), the presence of any abnormalities in the remaining macula was still associated with delayed RITs (ß = 2.00, P = 0.046). Presence of subretinal drusenoid deposits and ellipsoid zone disruption were a consistent predictor of RIT, whether located within the DA testing spot (P = 0.001 for both) or anywhere in the macula (P < 0.001 for both). Within the testing spot, the presence of classic drusen or serous pigment epithelium detachment was also significantly associated with impairments in DA (P ≤ 0.018). CONCLUSIONS: Our results suggest a significant association between macular morphology evaluated by OCT and time to dark-adapt. Subretinal drusenoid deposits and ellipsoid zone changes seem to be strongly associated with impaired dark adaptation.
Laíns I, Miller JB, Mukai R, Mach S, Vavvas D, Kim IK, Miller JW, Husain D. HEALTH CONDITIONS LINKED TO AGE-RELATED MACULAR DEGENERATION ASSOCIATED WITH DARK ADAPTATION. Retina 2018;38(6):1145-1155.Abstract
PURPOSE: To determine the association between dark adaption (DA) and different health conditions linked with age-related macular degeneration (AMD). METHODS: Cross-sectional study, including patients with AMD and a control group. Age-related macular degeneration was graded according to the Age-Related Eye Disease Study (AREDS) classification. We obtained data on medical history, medications, and lifestyle. Dark adaption was assessed with the extended protocol (20 minutes) of AdaptDx (MacuLogix). For analyses, the right eye or the eye with more advanced AMD was selected. Multivariate linear and logistic regressions were performed, accounting for age and AMD stage. RESULTS: Seventy-eight subjects (75.6% AMD; 24.4% controls) were included. Multivariate assessments revealed that body mass index (BMI; β = 0.30, P = 0.045), taking AREDS vitamins (β = 5.51, P < 0.001), and family history of AMD (β = 2.68, P = 0.039) were significantly associated with worse rod intercept times. Abnormal DA (rod intercept time ≥ 6.5 minutes) was significantly associated with family history of AMD (β = 1.84, P = 0.006), taking AREDS supplements (β = 1.67, P = 0.021) and alcohol intake (β = 0.07, P = 0.017). CONCLUSION: Besides age and AMD stage, a higher body mass index, higher alcohol intake, and a family history of AMD seem to impair DA. In this cohort, the use of AREDS vitamins was also statistically linked with impaired DA, most likely because of an increased severity of disease in subjects taking them.
Lam JD, Oh DJ, Wong LL, Amarnani D, Park-Windhol C, Sanchez AV, Cardona-Velez J, McGuone D, Stemmer-Rachamimov AO, Eliott D, Bielenberg DR, van Zyl T, Shen L, Gai X, D'Amore PA, Kim LA, Arboleda-Velasquez JF. Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis. Diabetes 2017;66(7):1950-1956.Abstract
Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world's working adult population and affects those with type 1 and type 2 diabetes. We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31(+) vascular endothelial cells obtained from human PDR fibrovascular membranes (FVMs) via transcriptomic analysis. In vitro studies using human retinal microvascular endothelial cells (HRMECs) showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation. Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVMs and angiogenic tufts in the retina of mice with oxygen-induced retinopathy, suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis. Inhibition of RUNX1 activity with the Ro5-3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy, supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.
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.

Landegger LD, Pan B, Askew C, Wassmer SJ, Gluck SD, Galvin A, Taylor R, Forge A, Stankovic KM, Holt JR, Vandenberghe LH. A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat Biotechnol 2017;35(3):280-284.Abstract

Efforts to develop gene therapies for hearing loss have been hampered by the lack of safe, efficient, and clinically relevant delivery modalities. Here we demonstrate the safety and efficiency of Anc80L65, a rationally designed synthetic vector, for transgene delivery to the mouse cochlea. Ex vivo transduction of mouse organotypic explants identified Anc80L65 from a set of other adeno-associated virus (AAV) vectors as a potent vector for the cochlear cell targets. Round window membrane injection resulted in highly efficient transduction of inner and outer hair cells in mice, a substantial improvement over conventional AAV vectors. Anc80L65 round window injection was well tolerated, as indicated by sensory cell function, hearing and vestibular function, and immunologic parameters. The ability of Anc80L65 to target outer hair cells at high rates, a requirement for restoration of complex auditory function, may enable future gene therapies for hearing and balance disorders.

Learned D, Eliott D. Management of Delayed Suprachoroidal Hemorrhage after Glaucoma Surgery. Semin Ophthalmol 2017;:1-5.Abstract
PURPOSE: To review the most current treatment recommendations and outcomes for delayed suprachoroidal hemorrhages. METHODS: Article review of management and outcomes of suprachoroidal hemorrhages, with emphasis on delayed suprachoroidal hemorrhages in the setting of glaucoma surgery. CONCLUSION: Time of drainage of suprachoroidal hemorrhages remains controversial. Earlier drainage should be considered with high intraocular pressure, expulsion of intraocular content, or retinal detachment. In clinically stable eyes with suprachoroidal hemorrhage, recommendations range from observation to immediate drainage. Clot lysis occurs at roughly 14 days.
Lebreton F, Manson AL, Saavedra JT, Straub TJ, Earl AM, Gilmore MS. Tracing the Enterococci from Paleozoic Origins to the Hospital. Cell 2017;169(5):849-861.e13.Abstract
We examined the evolutionary history of leading multidrug resistant hospital pathogens, the enterococci, to their origin hundreds of millions of years ago. Our goal was to understand why, among the vast diversity of gut flora, enterococci are so well adapted to the modern hospital environment. Molecular clock estimation, together with analysis of their environmental distribution, phenotypic diversity, and concordance with host fossil records, place the origins of the enterococci around the time of animal terrestrialization, 425-500 mya. Speciation appears to parallel the diversification of hosts, including the rapid emergence of new enterococcal species following the End Permian Extinction. Major drivers of speciation include changing carbohydrate availability in the host gut. Life on land would have selected for the precise traits that now allow pathogenic enterococci to survive desiccation, starvation, and disinfection in the modern hospital, foreordaining their emergence as leading hospital pathogens.
Lee JK, Shin SR, Desalvo A, Lee G, Lee JY, Polini A, Chae S, Jeong H, Kim J, Choi H, Lee HY. Nonmediated, Label-Free Based Detection of Cardiovascular Biomarker in a Biological Sample. Adv Healthc Mater 2017;6(17)Abstract
Direct electrochemical (EC) monitoring in a cell culture medium without electron transporter as called mediator is attractive topic in vitro organoid based on chip with frequently and long-time monitoring since it can avoid to its disadvantage as stability, toxicity. Here, direct monitoring with nonmediator is demonstrated based on impedance spectroscopy under the culture medium in order to overcome the limitation of mediator. The applicability of EC monitoring is shown by detecting alpha-1-anti trypsin (A1AT) which is known as biomarkers for cardiac damage and is widely chosen in organoid cardiac cell-based chip. The validity of presented EC monitoring is proved by observing signal processing and transduction in medium, mediator, medium-mediator complex. After the observation of electron behavior, A1AT as target analyte is immobilized on the electrode and detected using antibody-antigen interaction. As a result, the result indicates limit of detection is 10 ng mL(-1) and linearity for the 10-1000 ng mL(-1) range, with a sensitivity of 3980 nF (log [g mL])(-1) retaining specificity. This EC monitoring is based on label-free and reagentless detection, will pave the way to use for continuous and simple monitoring of in vitro organoid platform.
Lee R, Khoueir Z, Tsikata E, Chodosh J, Dohlman CH, Chen TC. Long-term Visual Outcomes and Complications of Boston Keratoprosthesis Type II Implantation. Ophthalmology 2017;124(1):27-35.Abstract

PURPOSE: To report the long-term visual outcomes and complications after Boston keratoprosthesis type II implantation in the largest single-center case series with the longest average follow-up. DESIGN: Retrospective review of consecutive clinical case series. PARTICIPANTS: Between January 1992 and April 2015 at the Massachusetts Eye and Ear Infirmary, 48 eyes of 44 patients had keratoprosthesis type II implanted by 2 surgeons (C.H.D. and J.C.). METHODS: For each eye, data were collected and analyzed on the preoperative characteristics, intraoperative procedures, and postoperative course. MAIN OUTCOME MEASURES: Visual acuity outcomes, postoperative complications, and device retention. RESULTS: The most common indications for surgery were Stevens-Johnson syndrome in 41.7% (20 of 48 eyes) and mucous membrane pemphigoid in 41.7% (20 of 48 eyes). Mean follow-up duration was 70.2 months (standard deviation, 61.8 months; median, 52 months; range, 6 months to 19.8 years). Almost all patients (95.8%, 46 of 48 eyes) had a preoperative visual acuity of 20/200 or worse. Postoperative visual acuity improved to 20/200 or better in 37.5% (18 of 48 eyes) and to 20/100 or better in 33.3% (16 of 48 eyes) at the last follow-up visit. The most common postoperative complication was retroprosthetic membrane formation in over half (60.4%, 29 of 48 eyes). The most pressing postoperative complication was glaucoma onset or progression in about a third. Preexisting glaucoma was present in 72.9% (35 of 48 eyes). Glaucoma progressed in 27.1% (13 of 48 eyes) and was newly diagnosed in 8.3% (4 of 48 eyes) after surgery. Other postoperative complications were tarsorrhaphy revision in 52.1% (25 of 48 eyes), retinal detachment in 18.8% (9 of 48 eyes), infectious endophthalmitis in 6.3% (3 of 48 eyes), and choroidal detachment or hemorrhage in 8.3% (4 of 48 eyes). Half of eyes retained their initial keratoprosthesis at the last follow-up (50.0%, 24 of 48 eyes). CONCLUSIONS: The Boston keratoprosthesis type II is a viable option to salvage vision in patients with poor prognosis for other corneal procedures. Retroprosthetic membranes, keratoprosthesis retention, and glaucoma are major challenges in the postoperative period; however, the keratoprosthesis can still provide improved vision in a select group of patients.

Levin LA, Miller JW, Zack DJ, Friedlander M, Smith LEH. Special Commentary: Early Clinical Development of Cell Replacement Therapy: Considerations for the National Eye Institute Audacious Goals Initiative. Ophthalmology 2017;124(7):926-934.Abstract
The National Eye Institute launched the Audacious Goals Initiative (AGI) in 2013 with the aim "to restore vision through the regeneration of neurons and neural connections in the eye and visual system." An AGI Town Hall held at the Association for Research in Vision and Ophthalmology Annual Meeting in 2016 brought together basic, translational, and clinical scientists to address the clinical implications of the AGI, with a particular emphasis on diseases amenable to regenerative medicine and strategies to deal with barriers to progess. An example of such a barrier is that replacement of lost neurons may be insufficient because damage to other neurons and non-neuronal cells is common in retinal and optic nerve disease. Reparative processes such as gliosis and fibrosis also can make it difficult to replenish and regenerate neurons. Other issues include choice of animal models, selecting appropriate endpoints, ethics of informed consent, and regulatory issues. Another area critical to next steps in the AGI is the choice of target diseases and the stage at which early development studies should be focused. For example, an advantage of doing clinical trials in patients with early disease is that supporting cellular and structural constituents are still likely to be present. However, regenerative studies in patients with late disease make it easier to detect the effects of replacement therapy against the background of severe visual loss, whereas it may be harder to detect incremental improvement in visual function in those with early disease and considerable remaining visual function. Achieving the goals of the AGI also requires preclinical advances, new imaging techniques, and optimizing translational issues. The work of the AGI is expected to take at least 10 years but should eventually result in therapies to restore some degree of vision to the blind.

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