July 2015

Aggarwal S, Kheirkhah A, Cavalcanti BM, Cruzat A, Colon C, Brown E, Borsook D, Prüss H, Hamrah P. Autologous Serum Tears for Treatment of Photoallodynia in Patients with Corneal Neuropathy: Efficacy and Evaluation with InVivo Confocal Microscopy. Ocul Surf 2015;13(3):250-62.Abstract

OBJECTIVE: Patients suffering from corneal neuropathy may present with photoallodynia; i.e., increased light sensitivity, frequently with a normal slit-lamp examination. This study aimed to evaluate the efficacy of autologous serum tears (AST) for treatment of severe photoallodynia in corneal neuropathy and to correlate clinical findings with corneal subbasal nerve alterations by in vivo confocal microscopy (IVCM). METHODS: Retrospective case control study with 16 patients with neuropathy-induced severe photoallodynia compared to 16 normal controls. Symptom severity, clinical examination and bilateral corneal IVCM scans were recorded. RESULTS: All patients suffered from extreme photoallodynia (8.8±1.1) with no concurrent ocular surface disease. Subbasal nerves were significantly decreased at baseline in patients compared to controls; total nerve length (9208±1264 vs 24714±1056 μm/mm(2); P<.0001) and total nerve number (9.6±1.4 vs 28.6±2.0; P<.0001), respectively. Morphologically, significantly increased reflectivity (2.9±0.2 vs 1.8±0.1; P<.0001), beading (in 93.7%), and neuromas (in 62.5%) were seen. AST (3.6±2.1 months) resulted in significantly decreased symptom severity (1.6±1.7; P=.02). IVCM demonstrated significantly improved nerve parameters (P<.005), total nerve length (15451±1595 μm/mm(2)), number (13.9±2.1), and reflectivity (1.9±0.1). Beading and neuromas were seen in only 56.2% and 7.6% of patients. CONCLUSION: Patients with corneal neuropathy-induced photoallodynia show profound alterations in corneal nerves. AST restores nerve topography through nerve regeneration, and this correlated with improvement in patient-reported photoallodynia. The data support the notion that corneal nerve damage results in alterations in afferent trigeminal pathways to produce photoallodynia.

Amparo F, Schaumberg DA, Dana R. Comparison of Two Questionnaires for Dry Eye Symptom Assessment: The Ocular Surface Disease Index and the Symptom Assessment in Dry Eye. Ophthalmology 2015;122(7):1498-503.Abstract

PURPOSE: The aim of this study was to compare patient-reported symptoms of dry eye disease (DED) as assessed by the Ocular Surface Disease Index (OSDI), a 12-item symptom frequency-based questionnaire, and the Symptom Assessment iN Dry Eye (SANDE), a 2-item frequency- and severity-based visual analog scale. DESIGN: Clinic-based evaluation of a diagnostic test. PARTICIPANTS: A total of 114 patients with DED. METHODS: Patients were administered the OSDI and SANDE questionnaires at baseline and follow-up visits to evaluate DED-related symptoms. The correlations between both questionnaires' scores were evaluated using the Spearman coefficient, and their clinical differences were assessed using Bland-Altman analysis. MAIN OUTCOME MEASURES: Baseline and follow-up visit OSDI and SANDE dry eye symptom scores. RESULTS: At the baseline visit, the OSDI and SANDE questionnaire scores were significantly correlated (R = 0.64; P < 0.001). Moreover, a significant correlation was found between changes in the OSDI and SANDE scores from baseline to follow-up visits (R = 0.47; P < 0.001). A Bland-Altman analysis, after score normalization, revealed a difference (bias) of less than 2 centesimal units between the scores of the 2 questionnaires. CONCLUSIONS: Data collected from the SANDE questionnaire showed a significant correlation and negligible score differences with those from the OSDI, suggesting that the SANDE visual analog scale-based questionnaire has the potential to provide clinicians with a short, quick, and reliable measure for DED symptoms.

Boynton GE, Raoof D, Niziol LM, Hussain M, Mian SI. Prospective Randomized Trial Comparing Efficacy of Topical Loteprednol Etabonate 0.5% Versus Cyclosporine-A 0.05% for Treatment of Dry Eye Syndrome Following Hematopoietic Stem Cell Transplantation. Cornea 2015;34(7):725-32.Abstract

PURPOSE: To evaluate the safety and efficacy of topical loteprednol etabonate (LE) 0.5% compared with cyclosporine A (CsA) 0.05% for the prophylaxis and treatment of dry eye syndrome (DES) after hematopoietic stem cell transplantation (HSCT). METHODS: Seventy-five patients were randomized to LE (n = 76 eyes of 38 patients) or CsA (n = 74 eyes of 37 patients) pre-HSCT. Lissamine green and fluorescein staining, tear break-up time, tear osmolarity (Osm), Schirmer score (Sch), intraocular pressure, visual acuity, and Ocular Surface Disease Index were assessed pre-HSCT, 3, 6, 9, and 12 months post-HSCT. RESULTS: There were no differences in DES incidence (P = 0.22; log-rank test) or progression (P = 0.41; log-rank test) between the 2 treatment arms during the course of the study. Among eyes with no DES at enrollment, the Kaplan-Meier analysis yielded a 90% rate of DES development in cyclosporine-treated eyes and a 79% rate of DES development in LE-treated eyes by 12 months post-HSCT. The Kaplan-Meier analysis of eyes with DES at enrollment demonstrated a 38% rate of disease progression among cyclosporine-treated eyes and a 26% rate of disease progression among loteprednol-treated eyes by 12 months. No patient in either group had an elevation of 10 mm Hg or greater from baseline at any study visit, and no patients had their treatment discontinued for elevation in intraocular pressure. CONCLUSIONS: Pre-HSCT initiation of LE 0.5% appears to be safe and may be as effective as CsA 0.5% for the treatment and prophylaxis of DES following HSCT.

Chang Y-H, Melvin P, Dagi LR. Goal-determined metrics to assess outcomes ofexotropia surgery. J AAPOS 2015;Abstract

PURPOSE: To present a goal-determined methodology for monitoring outcomes after surgery for exotropia. METHODS: The goal-determined metric required surgeons to rank four possible goals preoperatively: (1) binocular potential, (2) restoration of eye contact, (3) diplopia control; and (4) torticollis management. Potential preoperative risk factors were noted. Goal-specific outcomes criteria were applied to the latest sensory-motor examination, 2-6 months after surgery. The medical records of patients who underwent surgery from 2007 to 2012 were retrospectively reviewed with respect to the goal-directed metric. RESULTS: A total of 852 patients were evaluated in the study period: 411 for restoration of eye contact; 347 for binocular potential; 78 for diplopia resolution; and16 for torticollis management. Excellent (62%) or good (16%) outcomes were achieved in 78%. Procedures to resolve diplopia (OR, 6.56; 95% CI, 3.39-12.68) and to restore eye contact (OR, 3.74; 95% CI, 2.65-5.29) were more likely to result in excellent outcomes than procedures to improve binocular potential. Simultaneous surgery for dissociated vertical deviation (OR, 0.38; 95% CI, 0.16-0.92) and preoperative near deviation ≥50(Δ) (OR, 0.27; 95% CI, 0.17-0.42) limited likelihood of an excellent outcome. Outcomes monitored by simultaneous rather than alternate prism and cover test were more likely graded excellent (OR, 5.16; 95% CI, 3.50-7.62). Applying motor criteria from the binocular potential goal to the entire cohort diminished putative outcomes (P < 0.001). CONCLUSIONS: Goal-determined metric monitoring outcomes of exotropia surgery provides outcomes germane to the reason for intervention, enables analysis of risk factors affecting outcomes, and facilitates reporting on heterogeneous populations.

Chauhan SK, Lee HK, Lee HS, Park EY, Jeong E, Dana R. PTK7+ Mononuclear Cells Express VEGFR2 and Contribute to Vascular Stabilization by Upregulating Angiopoietin-1. Arterioscler Thromb Vasc Biol 2015;35(7):1606-15.Abstract

OBJECTIVE: In angiogenesis, circulating mononuclear cells are recruited to vascular lesions; however, the underlying mechanisms are poorly understood. APPROACH AND RESULTS: Here, we characterize the functional role of protein tyrosine kinase 7 (PTK7)-expressing CD11b(+) mononuclear cells in vitro and in vivo using a mouse model of angiogenesis. Although the frequencies of PTK7(+)CD11b(+) cells in the bone marrow remained similar after vascular endothelial growth factor-A-induced neovascularization, we observed an 11-fold increase in the cornea. Importantly, vascular endothelial growth factor-A-induced chemotaxis of PTK7(+) cells was mediated by vascular endothelial growth factor receptor 2. In a coculture with endothelial cells, PTK7(+)CD11b(+) cells stabilized the vascular network for 2 weeks by expressing high levels of angiopoietin-1. The enhanced vascular stability was abolished by knockdown of angiopoietin-1 in PTK7(+)CD11b(+) cells and could be restored by angiopoietin-1 treatment. CONCLUSIONS: We conclude that PTK7 expression in perivascular mononuclear cells induces vascular endothelial growth factor receptor 2 and angiopoietin-1 expression and thus contributes to vascular stabilization in angiogenesis.

Chen PP, Lin SC, Junk AK, Radhakrishnan S, Singh K, Chen TC. The Effect of Phacoemulsification on Intraocular Pressure in Glaucoma Patients: A Report by the American Academy of Ophthalmology. Ophthalmology 2015;122(7):1294-307.Abstract

OBJECTIVE: To examine effects of phacoemulsification on longer-term intraocular pressure (IOP) in patients with medically treated primary open-angle glaucoma (POAG; including normal-tension glaucoma), pseudoexfoliation glaucoma (PXG), or primary angle-closure glaucoma (PACG), without prior or concurrent incisional glaucoma surgery. METHODS: PubMed and Cochrane database searches, last conducted in December 2014, yielded 541 unique citations. Panel members reviewed titles and abstracts and selected 86 for further review. The panel reviewed these articles and identified 32 studies meeting the inclusion criteria, for which the panel methodologist assigned a level of evidence based on standardized grading adopted by the American Academy of Ophthalmology. One, 15, and 16 studies were rated as providing level I, II, and III evidence, respectively. RESULTS: All follow-up, IOP, and medication data listed are weighted means. In general, the studies reported on patients using few glaucoma medications (1.5-1.9 before surgery among the different diagnoses). For POAG, 9 studies (total, 461 patients; follow-up, 17 months) showed that phacoemulsification reduced IOP by 13% and glaucoma medications by 12%. For PXG, 5 studies (total, 132 patients; follow-up, 34 months) showed phacoemulsification reduced IOP by 20% and glaucoma medications by 35%. For chronic PACG, 12 studies (total, 495 patients; follow-up, 16 months) showed phacoemulsification reduced IOP by 30% and glaucoma medications by 58%. Patients with acute PACG (4 studies; total, 119 patients; follow-up, 24 months) had a 71% reduction from presenting IOP and rarely required long-term glaucoma medications when phacoemulsification was performed soon after medical reduction of IOP. Trabeculectomy after phacoemulsification was uncommon; the median rate reported within 6 to 24 months of follow-up in patients with controlled POAG, PXG, or PACG was 0% and was 7% in patients with uncontrolled chronic PACG. CONCLUSIONS: Phacoemulsification typically results in small, moderate, and marked reductions of IOP and medications for patients with POAG, PXG, and PACG, respectively, and using 1 to 2 medications before surgery. Trabeculectomy within 6 to 24 months after phacoemulsification is rare in such patients. However, reports on its effects in eyes with advanced disease or poor IOP control before surgery are few, particularly for POAG and PXG.

Choi VW, Bigelow CE, McGee TL, Gujar AN, Li H, Hanks SM, Vrouvlianis J, Maker M, Leehy B, Zhang Y, Aranda J, Bounoutas G, Demirs JT, Yang J, Ornberg R, Wang Y, Martin W, Stout KR, Argentieri G, Grosenstein P, Diaz D, Turner O, Jaffee BD, Police SR, Dryja TP. AAV-mediated RLBP1 gene therapy improves the rate of dark adaptation in Rlbp1 knockout mice. Mol Ther Methods Clin Dev 2015;2:15022.Abstract

Recessive mutations in RLBP1 cause a form of retinitis pigmentosa in which the retina, before its degeneration leads to blindness, abnormally slowly recovers sensitivity after exposure to light. To develop a potential gene therapy for this condition, we tested multiple recombinant adeno-associated vectors (rAAVs) composed of different promoters, capsid serotypes, and genome conformations. We generated rAAVs in which sequences from the promoters of the human RLBP1, RPE65, or BEST1 genes drove the expression of a reporter gene (green fluorescent protein). A promoter derived from the RLBP1 gene mediated expression in the retinal pigment epithelium and Müller cells (the intended target cell types) at qualitatively higher levels than in other retinal cell types in wild-type mice and monkeys. With this promoter upstream of the coding sequence of the human RLBP1 gene, we compared the potencies of vectors with an AAV2 versus an AAV8 capsid in transducing mouse retinas, and we compared vectors with a self-complementary versus a single-stranded genome. The optimal vector (scAAV8-pRLBP1-hRLBP1) had serotype 8 capsid and a self-complementary genome. Subretinal injection of scAAV8-pRLBP1-hRLBP1 in Rlbp1 nullizygous mice improved the rate of dark adaptation based on scotopic (rod-plus-cone) and photopic (cone) electroretinograms (ERGs). The effect was still present after 1 year.

Choi HJ, Sun D, Jakobs TC. Astrocytes in the optic nerve head express putative mechanosensitive channels. Mol Vis 2015;21:749-66.Abstract

PURPOSE: To establish whether optic nerve head astrocytes express candidate molecules to sense tissue stretch. METHODS: We used conventional PCR, quantitative PCR, and single-cell reverse transcription PCR (RT-PCR) to assess the expression of various members of the transient receptor potential (TRP) channel family and of the recently characterized mechanosensitive channels Piezo1 and 2 in optic nerve head tissue and in single, isolated astrocytes. RESULTS: Most TRP subfamilies (TRPC, TRPM, TRPV, TRPA, and TRPP) and Piezo1 and 2 were expressed in the optic nerve head of the mouse. Quantitative real-time PCR analysis showed that TRPC1, TRPM7, TRPV2, TRPP2, and Piezo1 are the dominant isoforms in each subfamily. Single-cell RT-PCR revealed that many TRP isoforms, TRPC1-2, TRPC6, TRPV2, TRPV4, TRPM2, TRPM4, TRPM6-7, TRPP1-2, and Piezo1-2, are expressed in astrocytes of the optic nerve head, and that most astrocytes express TRPC1 and TRPP1-2. Comparisons of the TRPP and Piezo expression levels between different tissue regions showed that Piezo2 expression was higher in the optic nerve head and the optic nerve proper than in the brain and the corpus callosum. TRPP2 also showed higher expression in the optic nerve head. CONCLUSIONS: Astrocytes in the optic nerve head express multiple putative mechanosensitive channels, in particular the recently identified channels Piezo1 and 2. The expression of putative mechanosensitive channels in these cells may contribute to their responsiveness to traumatic or glaucomatous injury.

Fay A, Nallasamy N, Bernardini F, Wladis EJ, Durand ML, Devoto MH, Meyer D, Hartstein M, Honavar S, Osaki MH, Osaki TH, Santiago YM, Sales-Sanz M, Vadala G, Verity D. Multinational Comparison of Prophylactic Antibiotic Use for Eyelid Surgery. JAMA Ophthalmol 2015;133(7):778-84.Abstract

IMPORTANCE: Antibiotic stewardship is important in controlling resistance, adverse reactions, and cost. The literature regarding antibiotic use for eyelid surgery is lacking. OBJECTIVES: To determine standard care and assess factors influencing antibiotic prescribing practices for eyelid surgery. DESIGN, SETTING, AND PARTICIPANTS: A survey study was conducted from February 2, 2014, to March 24, 2014. The survey was distributed to 2397 oculoplastic surgeons in private and academic oculoplastic surgery practices in 43 countries. All surgeons were members of ophthalmic plastic and reconstructive surgery societies. Data were analyzed by geographic location. Linear regression was performed to quantify contributions to rates of prescribing postoperative antibiotics for routine eyelid surgical procedures. MAIN OUTCOMES AND MEASURES: Rates of prescribing prophylactic intravenous, oral, and topical antibiotics as well as factors that influence surgeons' prescribing practices. RESULTS: A total of 782 responses were received from 2397 surgeons (average response rate, 36.7%; 2.5% margin of error) from 43 countries. Topical antibiotic use was common in all regions (85.2%). Perioperative intravenous antibiotic use was uncommon in all regions (13.5%). Geographic location was the greatest predictor of antibiotic prescribing practices (range, 2.9% in the United Kingdom to 86.7% in India; mean, 24%). Within Europe, Italy had the highest rate of antibiotic prescriptions for eyelid surgery (41.7%) and the United Kingdom had the lowest rate (2.9%.) In South America, Venezuela had the highest rate of antibiotic prescriptions for eyelid surgery (83.3%) and Chile had the lowest rate (0%). The practice locations that were associated with routinely prescribing postoperative oral antibiotics were India (odds ratio [OR], 15.83; 95% CI, 4.85-51.68; P < .001), Venezuela (OR, 13.47; 95% CI, 1.43-127.19; P = .02), and Southeast Asia (OR, 2.80; 95% CI, 1.15-6.84; P = .02). Conversely, practice location in the United Kingdom (OR, 0.048; 95% CI, 0.0063-0.37; P = .004), Australia and New Zealand (OR, 0.15; 95% CI, 0.033-0.67; P = .01), and the United States and Canada (OR, 0.41; 95% CI, 0.23-0.72; P = .002) were associated with decreased rates of postoperative oral antibiotic use. Surgeons' concern for allergic reactions was associated with decreased rates of prescribing antibiotics (OR, 0.34; 95% CI, 0.23-0.49; P < .001), while surgeons' concern for infection was associated with increased rates of prescribing antibiotics (OR 1.80; 95% CI, 1.45-2.23; P < .001). CONCLUSIONS AND RELEVANCE: These results from members of ophthalmic plastic and reconstructive surgery societies confirm that antibiotic prescribing practices for routine eyelid surgical procedures vary widely throughout the world. No standard of care has been established that would require the routine use of postoperative prophylactic antibiotics following eyelid surgery.

Goldstein JE, Jackson ML, Fox SM, Deremeik JT, Massof RW, Massof RW. Clinically Meaningful Rehabilitation Outcomes of Low Vision Patients Served by Outpatient Clinical Centers. JAMA Ophthalmol 2015;133(7):762-9.Abstract

IMPORTANCE: To facilitate comparative clinical outcome research in low vision rehabilitation, we must use patient-centered measurements that reflect clinically meaningful changes in visual ability. OBJECTIVE: To quantify the effects of currently provided low vision rehabilitation (LVR) on patients who present for outpatient LVR services in the United States. DESIGN, SETTING, AND PARTICIPANTS: Prospective, observational study of new patients seeking outpatient LVR services. From April 2008 through May 2011, 779 patients from 28 clinical centers in the United States were enrolled in the Low Vision Rehabilitation Outcomes Study. The Activity Inventory, a visual function questionnaire, was administered to measure overall visual ability and visual ability in 4 functional domains (reading, mobility, visual motor function, and visual information processing) at baseline and 6 to 9 months after usual LVR care. The Geriatric Depression Scale, Telephone Interview for Cognitive Status, and Medical Outcomes Study 36-Item Short-Form Health Survey physical functioning questionnaires were also administered to measure patients' psychological, cognitive, and physical health states, respectively, and clinical findings of patients were provided by study centers. MAIN OUTCOMES AND MEASURES: Mean changes in the study population and minimum clinically important differences in the individual in overall visual ability and in visual ability in 4 functional domains as measured by the Activity Inventory. RESULTS: Baseline and post-rehabilitation measures were obtained for 468 patients. Minimum clinically important differences (95% CIs) were observed in nearly half (47% [95% CI, 44%-50%]) of patients in overall visual ability. The prevalence rates of patients with minimum clinically important differences in visual ability in functional domains were reading (44% [95% CI, 42%-48%]), visual motor function (38% [95% CI, 36%-42%]), visual information processing (33% [95% CI, 31%-37%]), and mobility (27% [95% CI, 25%-31%]). The largest average effect size (Cohen d = 0.87) for the population was observed in overall visual ability. Age (P = .006) was an independent predictor of changes in overall visual ability, and logMAR visual acuity (P = .002) was predictive of changes in visual information processing. CONCLUSIONS AND RELEVANCE: Forty-four to fifty percent of patients presenting for outpatient LVR show clinically meaningful differences in overall visual ability after LVR, and the average effect sizes in overall visual ability are large, close to 1 SD.

Gong Y, Li J, Sun Y, Fu Z, Liu C-H, Evans L, Tian K, Saba N, Fredrick T, Morss P, Chen J, Smith LEH. Optimization of an Image-Guided Laser-Induced Choroidal Neovascularization Model in Mice. PLoS One 2015;10(7):e0132643.Abstract

The mouse model of laser-induced choroidal neovascularization (CNV) has been used in studies of the exudative form of age-related macular degeneration using both the conventional slit lamp and a new image-guided laser system. A standardized protocol is needed for consistent results using this model, which has been lacking. We optimized details of laser-induced CNV using the image-guided laser photocoagulation system. Four lesions with similar size were consistently applied per eye at approximately double the disc diameter away from the optic nerve, using different laser power levels, and mice of various ages and genders. After 7 days, the mice were sacrificed and retinal pigment epithelium/choroid/sclera was flat-mounted, stained with Isolectin B4, and imaged. Quantification of the area of the laser-induced lesions was performed using an established and constant threshold. Exclusion criteria are described that were necessary for reliable data analysis of the laser-induced CNV lesions. The CNV lesion area was proportional to the laser power levels. Mice at 12-16 weeks of age developed more severe CNV than those at 6-8 weeks of age, and the gender difference was only significant in mice at 12-16 weeks of age, but not in those at 6-8 weeks of age. Dietary intake of omega-3 long-chain polyunsaturated fatty acid reduced laser-induced CNV in mice. Taken together, laser-induced CNV lesions can be easily and consistently applied using the image-guided laser platform. Mice at 6-8 weeks of age are ideal for the laser-induced CNV model.

Haun AM, Peli E. Similar Sensitivity to Ladder Contours in Macular Degeneration Patients and Controls. PLoS One 2015;10(7):e0128119.Abstract

PURPOSE: To determine whether people with central field loss (CFL) from macular degeneration have improved ability to recognize a particularly difficult spatial configuration embedded in noise, the peripherally-viewed 'ladder contour'. The visibility of these configuration has been linked to general contour integration ability and crowding limitations in peripheral vision. METHODS: We used a trial-based yes-no task. CFL patients and normally-sighted controls performed the task, looking for ladder contours embedded in a field of randomly oriented Gabor patches, at a range of stimulus presentation times (varying stimulus difficulty). Viewing eccentricity in CFL patients was set by their preferred retinal loci (PRLs) and matched artificially in the control group. The contours were presented so as to be tangent to the CFL region, given a patient's PRL location. RESULTS: CFL and normally-sighted groups performed similarly on the task. The only significant determinant of performance was the viewing eccentricity. CONCLUSIONS: CFL patients do not seem to develop any improved ability to recognize ladder contours with their parafoveal retina, which suggests that there is no underlying improvement in contour integration or reduction in crowding limitations in the region of the PRL despite extended daily use.

Hong J, Shi W, Liu Z, Pineda R, Cui X, Sun X, Xu J. Limitations of Keratoplasty in China: A Survey Analysis. PLoS One 2015;10(7):e0132268.Abstract

PURPOSE: Each year, over 8,000 corneal transplantation surgeries are performed in China. Unlike developed countries, which have established standard requirements for operative experience for corneal specialists, little information exists on surgical training for keratoplasty in China. The aim of this study was to assess the keratoplasty experience of Chinese corneal specialists and to characterize their surgical patterns. METHODS: One hundred and twenty-one corneal specialists in 16 provinces (65 cities) in China were invited to complete an anonymous survey at the 2014 Chinese Corneal Society annual meeting, which consisted of questions with single or multiple-choice answers. Demographics, the number and type of keratoplasties performed, and the perceived limiting factors for performing keratoplasties were analyzed. RESULTS: An overwhelming 89% response rate was achieved. Of the 108 respondents, 76% worked in tertiary centers, and only 23% held a medical doctorate degree. Furthermore, 69% of the participants had received corneal fellowship training of less than one year. Only 71% were capable of keratoplasties. Among those doing keratoplasty, 68% performed less than 50 keratoplasties each year. Of the same group of keratoplasty surgeons, 88% of corneal specialists capable of keratoplasties had performed penetrating keratoplasties, 87% had performed lamellar keratoplasties, 12% had performed deep anterior lamellar keratoplasties, and 5% had performed Descemet's stripping endothelial keratoplasties. When questioned on the reasons for the low number of keratoplasties performed in China, the respondents deemed the following factors most important: lack of surgical training (71%), a shortage of donor supply (52%), and a lack of curricula (42%). A multivariate logistic regression analysis showed that corneal transplantation capabilities are significantly associated with responders' education levels and training time. CONCLUSION: Keratoplasty surgery experience is suboptimal for Chinese corneal specialists. Penetrating and lamellar keratoplasties are the preferred surgical patterns. Our findings raise concerns about the adequacy of keratoplasty training in China.

Hoshi S, Okamoto F, Arai M, Hirose T, Sugiura Y, Kaji Y, Oshika T. In Vivo and In Vitro Feasibility Studies of Intraocular Use of Polyethylene Glycol-Based Synthetic Sealant to Close Retinal Breaks in Porcine and Rabbit Eyes. Invest Ophthalmol Vis Sci 2015;56(8):4705-11.Abstract

PURPOSE: Absorbable polyethylene glycol-based synthetic sealant (PEG sealant) polymerizes under xenon illumination and forms a clear, flexible, and firmly adherent hydrogel. The intraocular biocompatibility of PEG sealant and efficacy for closing retinal breaks were evaluated. METHODS: In an in vitro study, retinal detachment with a tear was created in porcine eyecups after vitreous gel removal. Polyethylene glycol-based synthetic sealant was applied to cover the tear and polymerized with a 40-second application of xenon light. Retinal adhesion strength was tested by forcefully squirting balanced salt solution (BSS) onto the retinal tear. Polyethylene glycol-based synthetic sealant was soaked in the BSS, incubated at 37°C, and the pH measured periodically over 72 hours. In an in vivo study, PEG sealant was injected into the vitreous cavity of the left eyes of rabbits. Ophthalmologic examinations were performed and bilateral ERGs were recorded simultaneously before and 28 days after injection. The eyes were enucleated for histological evaluation. RESULTS: Adhesion of PEG sealant to the retina was good in BSS. A forceful squirt of BSS onto the retinal tear covered with PEG sealant did not detach the retina; the retinal tear without PEG sealant detached immediately. The pH of the BSS containing PEG sealant was between 7.2 and 8.2. No inflammatory reaction was observed in the eyes throughout 28 days of follow-up. The ERGs recorded before and after injection showed typical patterns. Histological examinations did not reveal any abnormality or inflammation. CONCLUSIONS: Polyethylene glycol-based synthetic sealant appeared to effectively seal retinal breaks and was not toxic to the eye.

Jakobiec FA, Stagner AM, Raizman MB, Hatton MP. Histopathologic Clues in Diagnosing Oral Mucosal Grafts to the Conjunctiva. Ophthal Plast Reconstr Surg 2015;Abstract

Excised redundant, forniceal "conjunctival" tissue from a 67-year-old man who experienced a chemical injury to his OS 25 years earlier was evaluated histopathologically with the hematoxylin-eosin, periodic acid Schiff (PAS) with and without diastase, mucicarmine, and Alcian blue methods. Additional immunoperoxidase testing for gross cystic disease fluid protein-15 (GCDFP-15) was undertaken. Non-keratinizing squamous epithelium composed of 8 to 10 layers of swollen keratinocytes without goblet cells surmounted a variably dense and well-vascularized collagenized lamina propria deep to which, in submucosal fibroadipose tissue, was embedded an accessory gland. The acini of the gland were composed of both GCDFP-15-positive serous cells and mucicarmine-positive goblet cells, indicating they were seromucinous rather than entirely serous, as is characteristic of normal lacrimal glandular tissue. Different features of the surface epithelium, the lamina propria, and the submucosa can separate the conjunctival and oral mucous membranes. A close analysis of the cytologic composition of associated accessory glands can reinforce the correct diagnosis of an oral mucous membrane graft when the past surgical history is unclear, because only serous cells but not mucocytes comprise the lacrimal glandular units.

Joshi PK, Esko T, Mattsson H, Eklund N, Gandin I, Nutile T, Jackson AU, Schurmann C, Smith AV, Zhang W, Okada Y, Stančáková A, Faul JD, Zhao W, Bartz TM, Concas MP, Franceschini N, Enroth S, Vitart V, Trompet S, Guo X, Chasman DI, O'Connel JR, Corre T, Nongmaithem SS, Chen Y, Mangino M, Ruggiero D, Traglia M, Farmaki A-E, Kacprowski T, Bjonnes A, van der Spek A, Wu Y, Giri AK, Yanek LR, Wang L, Hofer E, Rietveld CA, McLeod O, Cornelis MC, Pattaro C, Verweij N, Baumbach C, Abdellaoui A, Warren HR, Vuckovic D, Mei H, Bouchard C, Perry JRB, Cappellani S, Mirza SS, Benton MC, Broeckel U, Medland SE, Lind PA, Malerba G, Drong A, Yengo L, Bielak LF, Zhi D, van der Most PJ, Shriner D, Mägi R, Hemani G, Karaderi T, Wang Z, Liu T, Demuth I, Zhao JH, Meng W, Lataniotis L, van der Laan SW, Bradfield JP, Wood AR, Bonnefond A, Ahluwalia TS, Hall LM, Salvi E, Yazar S, Carstensen L, de Haan HG, Abney M, Afzal U, Allison MA, Amin N, Asselbergs FW, Bakker SJL, Barr GR, Baumeister SE, Benjamin DJ, Bergmann S, Boerwinkle E, Bottinger EP, Campbell A, Chakravarti A, Chan Y, Chanock SJ, Chen C, Chen IY-D, Collins FS, Connell J, Correa A, Cupples AL, Smith GD, Davies G, Dörr M, Ehret G, Ellis SB, Feenstra B, Feitosa MF, Ford I, Fox CS, Frayling TM, Friedrich N, Geller F, Scotland G, Gillham-Nasenya I, Gottesman O, Graff M, Grodstein F, Gu C, Haley C, Hammond CJ, Harris SE, Harris TB, Hastie ND, Heard-Costa NL, Heikkilä K, Hocking LJ, Homuth G, Hottenga J-J, Huang J, Huffman JE, Hysi PG, Ikram AM, Ingelsson E, Joensuu A, Johansson Å, Jousilahti P, Jukema WJ, Kähönen M, Kamatani Y, Kanoni S, Kerr SM, Khan NM, Koellinger P, Koistinen HA, Kooner MK, Kubo M, Kuusisto J, Lahti J, Launer LJ, Lea RA, Lehne B, Lehtimäki T, Liewald DCM, Lind L, Loh M, Lokki M-L, London SJ, Loomis SJ, Loukola A, Lu Y, Lumley T, Lundqvist A, Männistö S, Marques-Vidal P, Masciullo C, Matchan A, Mathias RA, Matsuda K, Meigs JB, Meisinger C, Meitinger T, Menni C, Mentch FD, Mihailov E, Milani L, Montasser ME, Montgomery GW, Morrison A, Myers RH, Nadukuru R, Navarro P, Nelis M, Nieminen MS, Nolte IM, O'Connor GT, Ogunniyi A, Padmanabhan S, Palmas WR, Pankow JS, Patarcic I, Pavani F, Peyser PA, Pietilainen K, Poulter N, Prokopenko I, Ralhan S, Redmond P, Rich SS, Rissanen H, Robino A, Rose LM, Rose R, Sala C, Salako B, Salomaa V, Sarin A-P, Saxena R, Schmidt H, Scott LJ, Scott WR, Sennblad B, Seshadri S, Sever P, Shrestha S, Smith BH, Smith JA, Soranzo N, Sotoodehnia N, Southam L, Stanton AV, Stathopoulou MG, Strauch K, Strawbridge RJ, Suderman MJ, Tandon N, Tang S-T, Taylor KD, Tayo BO, Töglhofer AM, Tomaszewski M, Tšernikova N, Tuomilehto J, Uitterlinden AG, Vaidya D, van Hylckama Vlieg A, van Setten J, Vasankari T, Vedantam S, Vlachopoulou E, Vozzi D, Vuoksimaa E, Waldenberger M, Ware EB, Wentworth-Shields W, Whitfield JB, Wild S, Willemsen G, Yajnik CS, Yao J, Zaza G, Zhu X, Zhu X, Salem RM, Melbye M, Bisgaard H, Samani NJ, Cusi D, Mackey DA, Cooper RS, Froguel P, Pasterkamp G, Grant SFA, Hakonarson H, Ferrucci L, Scott RA, Morris AD, Palmer CNA, Dedoussis G, Deloukas P, Bertram L, Lindenberger U, Berndt SI, Lindgren CM, Timpson NJ, Tönjes A, Munroe PB, Sørensen TIA, Rotimi CN, Arnett DK, Oldehinkel AJ, Kardia SLR, Balkau B, Gambaro G, Morris AP, Eriksson JG, Wright MJ, Martin NG, Hunt SC, Starr JM, Deary IJ, Griffiths LR, Tiemeier H, Pirastu N, Kaprio J, Wareham NJ, Pérusse L, Wilson JG, Girotto G, Caulfield MJ, Raitakari O, Boomsma DI, Gieger C, van der Harst P, Hicks AA, Kraft P, Sinisalo J, Knekt P, Johannesson M, Magnusson PKE, Hamsten A, Schmidt R, Borecki IB, Vartiainen E, Becker DM, Bharadwaj D, Mohlke KL, Boehnke M, van Duijn CM, Sanghera DK, Teumer A, Zeggini E, Metspalu A, Gasparini P, Ulivi S, Ober C, Toniolo D, Rudan I, Porteous DJ, Ciullo M, Spector TD, Hayward C, Dupuis J, Loos RJF, Wright AF, Chandak GR, Vollenweider P, Shuldiner AR, Ridker PM, Rotter JI, Sattar N, Gyllensten U, North KE, Pirastu M, Psaty BM, Weir DR, Laakso M, Gudnason V, Takahashi A, Chambers JC, Kooner JS, Strachan DP, Campbell H, Hirschhorn JN, Perola M, Polašek O, Wilson JF. Directional dominance on stature and cognition indiverse human populations. Nature 2015;523(7561):459-62.Abstract

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Kruh JN, Kruh-Garcia NA, Foster SC. Evaluation of the Effect of N-Acetylcysteine on Protein Deposition on Contact Lenses in Patients with the Boston Keratoprosthesis Type I. J Ocul Pharmacol Ther 2015;31(6):314-22.Abstract

PURPOSE: To establish the efficacy of topical N-acetylcysteine (NAC) as a treatment to reduce protein deposition on the contact lens surface. METHODS: In this prospective, nonrandomized clinical trial, a total of 10 eyes (9 patients) were enrolled from a single center. All patients had a prior ocular history of either a Boston Keratoprosthesis type I or trichiasis from Stevens-Johnson syndrome, which necessitated full-time contact lens wear. Four visits were required to complete the study. During visit 1, a new contact lens was inserted and a baseline examination was performed. Visit 2 served as the control month, whereas visits 3 and 4 were month 1 and 2 on treatment with 20% NAC. At the end of each visit the contact lens was replaced. The lenses from visit 2 (control month-without NAC) and from visit 3 (treatment month-with NAC) were collected for proteomic analysis. The main outcome measures were to quantify protein deposition, as well as to assess the visual acuity and ocular surface symptoms before and after treatment. RESULTS: Topical NAC resulted in a 20% decrease in protein deposition. This correlated with a trend for improvement in visual acuity and increased subjective improvement in vision at month 1 (P=0.0153) and 2 (P=0.0016). CONCLUSIONS: NAC reduced protein deposition, decreased ocular surface symptoms, and improved contact lens transparency, thereby providing increased optical clarity.

Li Z, Allingham RR, Nakano M, Jia L, Chen Y, Ikeda Y, Mani B, Chen L-J, Kee C, Garway-Heath DF, Sripriya S, Fuse N, Abu-Amero KK, Huang C, Namburi P, Burdon K, Perera SA, Gharahkhani P, Lin Y, Ueno M, Ozaki M, Mizoguchi T, Krishnadas SR, Osman EA, Lee MC, Chan ASY, Tajudin L-SA, Do T, Goncalves A, Reynier P, Zhang H, Bourne R, Goh D, Broadway D, Husain R, Negi AK, Hsu D, Ho C-L, Blanco AA, Leung CKS, Wong TT, Yakub A, Liu Y, Nongpiur ME, Han JC, Hon DN, Shantha B, Zhao B, Sang J, Zhang N, Sato R, Yoshii K, Panda-Jonas S, Ashley Koch AE, Herndon LW, Moroi SE, Challa P, Foo JN, Bei J-X, Zeng Y-X, Simmons CP, Bich Chau TN, Sharmila PF, Chew M, Lim B, Tam POS, Chua E, Ng XY, Yong VHK, Chong YF, Meah WY, Vijayan S, Seongsoo S, Xu W, Teo YY, Cooke Bailey JN, Kang JH, Haines JL, Cheng CY, Saw S-M, Tai E-S, Tai E-S, Tai E-S, Richards JE, Ritch R, Gaasterland DE, Pasquale LR, Liu J, Jonas JB, Milea D, George R, Al-Obeidan SA, Mori K, Macgregor S, Hewitt AW, Girkin CA, Zhang M, Sundaresan P, Vijaya L, Mackey DA, Wong TY, Craig JE, Sun X, Kinoshita S, Wiggs JL, Khor C-C, Yang Z, Pang CP, Wang N, Hauser MA, Tashiro K, Aung T, Vithana EN. A common variant near TGFBR3 is associated with primary open angle glaucoma. Hum Mol Genet 2015;24(13):3880-92.Abstract

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Morrison MA, Magalhaes TR, Ramke J, Smith SE, Ennis S, Simpson CL, Portas L, Murgia F, Ahn J, Dardenne C, Mayne K, Robinson R, Morgan DJ, Brian G, Lee L, Woo SJ, Zacharaki F, Tsironi EE, Miller JW, Kim IK, Park KH, Bailey-Wilson JE, Farrer LA, Stambolian D, Deangelis MM. Ancestry of the Timorese: age-related macular degeneration associated genotype and allele sharing among human populations from throughout the world. Front Genet 2015;6:238.Abstract

We observed that the third leading cause of blindness in the world, age-related macular degeneration (AMD), occurs at a very low documented frequency in a population-based cohort from Timor-Leste. Thus, we determined a complete catalog of the ancestry of the Timorese by analysis of whole exome chip data and haplogroup analysis of SNP genotypes determined by sequencing the Hypervariable I and II regions of the mitochondrial genome and 17 genotyped YSTR markers obtained from 535 individuals. We genotyped 20 previously reported AMD-associated SNPs in the Timorese to examine their allele frequencies compared to and between previously documented AMD cohorts of varying ethnicities. For those without AMD (average age > 55 years), genotype and allele frequencies were similar for most SNPs with a few exceptions. The major risk allele of HTRA1 rs11200638 (10q26) was at a significantly higher frequency in the Timorese, as well as 3 of the 5 protective CFH (1q32) SNPs (rs800292, rs2284664, and rs12066959). Additionally, the most commonly associated AMD-risk SNP, CFH rs1061170 (Y402H), was also seen at a much lower frequency in the Korean and Timorese populations than in the assessed Caucasian populations (C ~7 vs. ~40%, respectively). The difference in allele frequencies between the Timorese population and the other genotyped populations, along with the haplogroup analysis, also highlight the genetic diversity of the Timorese. Specifically, the most common ancestry groupings were Oceanic (Melanesian and Papuan) and Eastern Asian (specifically Han Chinese). The low prevalence of AMD in the Timorese population (2 of 535 randomly selected participants) may be due to the enrichment of protective alleles in this population at the 1q32 locus.

Müller RT, Pourmirzaie R, Pavan-Langston D, Cavalcanti BM, Aggarwal S, Colón C, Jamali A, Cruzat A, Hamrah P. In Vivo Confocal Microscopy Demonstrates Bilateral Loss of Endothelial Cells in Unilateral Herpes Simplex Keratitis. Invest Ophthalmol Vis Sci 2015;56(8):4899-906.Abstract

PURPOSE: To report bilateral corneal endothelial cell density (ECD), as well as its correlation with subbasal nerve changes, in patients with unilateral herpes simplex keratitis (HSK). METHODS: Thirty-six eyes of 36 patients with corneal scarring caused by HSK, as well as their respective contralateral clinically unaffected eyes, were prospectively studied and compared with 26 eyes of 26 healthy volunteers. In vivo confocal microscopy and corneal sensation of the central cornea were performed bilaterally in all patients and in one random eye of controls. The ECD and subbasal corneal nerve density, including the lengths of total nerves, main trunks, and branches were evaluated and correlated to central corneal sensation. RESULTS: The ECD was significantly lower in eyes affected with HSK than in controls (2304 ± 578 vs. 2940 ± 370 cells/mm2, P < 0.0001). Surprisingly, lower ECD was also detected in contralateral clinically unaffected eyes (2548 ± 423), compared to controls (P = 0.02). Both affected and contralateral eyes showed decrease in total nerve length, compared to controls (10.0 ± 6.3 vs. 17.6 ± 6.3 vs. 21.9 ± 4.3 mm/mm2, respectively; P < 0.05 for all). The ECD correlated positively with total nerve length (r = 0.39, P = 0.0009) and with corneal sensation (r = 0.31, P = 0.009). CONCLUSIONS: In vivo confocal microscopy findings demonstrated alterations in corneal ECD in both affected and clinically unaffected contralateral eyes of patients with unilateral HSK. Moreover, the positive significant correlation between the ECD and the subbasal nerve density may suggest a potential link between corneal innervation and corneal endothelial cell homeostasis.