L. Jay Katz

Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤ 0.05 arising from 3,494 novel precursors; 91.5% of these novel miRNAs were identified independently in 10 or more of the processed samples. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons. Of these novel miRNAs, 1,657 (45%) were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stem-loop PCR of a random collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence. Among the newly identified miRNAs are many novel miRNA clusters, new members of known miRNA clusters, previously unreported products from uncharacterized arms of miRNA precursors, and previously unrecognized paralogues of functionally important miRNA families (e.g., miR-15/107). Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7% of the newly discovered miRNAs to be human-specific whereas the majority (94.4%) are primate lineage-specific. Our findings suggest that the repertoire of human miRNAs is far more extensive than currently represented by public repositories and that there is a significant number of lineage- and/or tissue-specific miRNAs that are uncharacterized.

PURPOSE: The purpose of this study was to compare outcomes of subjects with open-angle glaucoma (OAG) not controlled on one medication who underwent either implantation of two iStent inject (®) trabecular micro-bypass devices or received medical therapy consisting of a fixed combination of latanoprost/timolol. PATIENTS AND METHODS: Of 192 subjects who qualified for the study and were enrolled, 94 were randomized to surgery with implantation of two iStent inject(®) devices in the treated eye and 98 to receive medical therapy. RESULTS: At the month 12 visit, 94.7% of eyes (89/94) in the stent group reported an unmedicated intraocular pressure (IOP) reduction of ≥20% versus baseline unmedicated IOP, and 91.8% of eyes (88/98) in the medical therapy group reported an IOP reduction ≥20% versus baseline unmedicated IOP. A 17.5% between-group treatment difference in favor of the iStent inject group was statistically significant (P=0.02) at the ≥50% level of IOP reduction. An IOP ≤18 mmHg was reported in 92.6% of eyes (87/94) in the iStent inject group and 89.8% of eyes (88/98) in the medical therapy group. Mean (standard deviation) IOP decreases from screening of 8.1 (2.6) mmHg and 7.3 (2.2) mmHg were reported in the iStent inject and medical therapy groups, respectively. A high safety profile was also noted in this study in both the iStent inject and medical therapy groups, as measured by stable best corrected visual acuity, cup-to-disc ratio, and adverse events. CONCLUSION: These data show that the use of iStent inject is at least as effective as two medications, with the clinical benefit of reducing medication burden and assuring continuous treatment with full compliance to implant therapy as well as having a highly favorable safety profile.

PURPOSE: To compare the efficacy and safety of brimonidine-Purite (Alphagan; Allergan, Irvine, CA) 0.15% and 0.2% three times daily with brimonidine (Alphagan) 0.2% three times daily in patients with glaucoma or ocular hypertension. PATIENTS AND METHODS: In this 12-month, randomized, multicenter, double-masked, parallel-group study, patients were randomly assigned to receive brimonidine-Purite 0.15% (n = 381), brimonidine-Purite 0.2% (n = 383), or brimonidine 0.2% (n = 383) three times daily. Visits were conducted before the study, at baseline, at weeks 2 and 6, and at months 3, 6, 9, and 12. Diurnal intraocular pressure was measured at 8 am, 10 am, 3 pm, and 5 pm at baseline, week 6, and at months 3, 6, and 12. Intraocular pressure was also measured at 8 and 10 am at week 2 and month 9. Safety was evaluated by adverse events and other ocular and systemic measures. RESULTS: At baseline, mean intraocular pressure was similar in the three treatment groups. During follow-up, there were no statistically significant among-group differences in mean intraocular pressure or mean changes from baseline intraocular pressure (at peak or trough). The difference in mean intraocular pressure between the brimonidine-Purite-0.15% and brimonidine-0.2% treatment group was less than 1 mm Hg at all time points. The relative percent difference in allergic conjunctivitis was 41% lower in the brimonidine-Purite 0.15% group compared with the brimonidine 0.2% group. The comfort and satisfaction rating significantly favored brimonidine-Purite 0.15%. CONCLUSIONS: Over 12-months, brimonidine-Purite 0.15% and 0.2% provided intraocular pressure lowering comparable with brimonidine 0.2% in patients with glaucoma or ocular hypertension. Brimonidine-Purite 0.15% showed the most favorable safety and tolerability profile with a reduced incidence of allergic conjunctivitis and better satisfaction and comfort rating.

PURPOSE: The major objective of this study was to test the reproducibility of a new method of estimating the amount of optic disc damage in patients with glaucoma. METHODS: The Disc Damage Likelihood Scale (DDLS) is based on the appearance of the neuroretinal rim of the optic disc corrected for disc diameter. The eight stages, extending from no damage to far advanced damage, are based on the width of the neuroretinal rim or the circumferential extent of absence of neuroretinal rim. Reproducibility was measured by two masked observers staging 48 optic nerve stereoscopic photographs by two different methods, the cup/disc ratio (c/d) and the DDLS. Also, reproducibility was assessed by three observers examining 34 eyes of 24 patients. RESULTS: With regard to the photographs, the intraobserver and interobserver reproducibility was better using the DDLS than the c/d ratio (98% versus 85% for intraobserver of reproducibility, and 85% versus 74% for interobserver reproducibility). The DDLS correlated better with the Humphrey Visual Field than did any Heidelberg Retina Tomograph parameter. CONCLUSION: In a clinical setting, the DDLS is as reproducible as, or more reproducible than, the c/d ratio system of estimating the amount of disc damage in patients with glaucoma.