Williams LB, Javed A, Sabri A, Morgan DJ, Huff CD, Grigg JR, Heng XT, Khng AJ, Hollink IHIM, Morrison MA, Owen LA, Anderson K, Kinard K, Greenlees R, Novacic D, Nida Sen H, Zein WM, Rodgers GM, Vitale AT, Haider NB, Hillmer AM, Ng PC, Ng PC, Cheng A, Zheng L, Gillies MC, van Slegtenhorst M, van Hagen MP, Missotten TOAR, Farley GL, Polo M, Malatack J, Curtin J, Martin F, Arbuckle S, Alexander SI, Chircop M, Davila S, Digre KB, Jamieson RV, Deangelis MM. ALPK1 missense pathogenic variant in five families leads to ROSAH syndrome, an ocular multisystem autosomal dominant disorder. Genet Med 2019;21(9):2103-2115.Abstract
PURPOSE: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache. METHODS: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members. RESULTS: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis. CONCLUSION: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.
Van Tyne D, Manson AL, Huycke MM, Karanicolas J, Earl AM, Gilmore MS. Impact of antibiotic treatment and host innate immune pressure on enterococcal adaptation in the human bloodstream. Sci Transl Med 2019;11(487)Abstract
Multidrug-resistant enterococcal strains emerged in the early 1980s and are now among the leading causes of drug-resistant bacterial infection worldwide. We used functional genomics to study an early bacterial outbreak in patients in a Wisconsin hospital between 1984 and 1988 that was caused by multidrug-resistant The goal was to determine how a clonal lineage of became adapted to growth and survival in the human bloodstream. Genome sequence analysis revealed a progression of increasingly fixed mutations and repeated independent occurrences of mutations in a relatively small set of genes. Repeated independent mutations suggested selection within the host during the course of infection in response to pressures such as host immunity and antibiotic treatment. We observed repeated independent mutations in a small number of loci, including a little studied polysaccharide utilization pathway and the locus. Functional studies showed that mutating these loci rendered better able to withstand antibiotic pressure and innate immune defenses in the human bloodstream. We also observed a shift in mutation pattern that corresponded to the introduction of carbapenem antibiotics in 1987. This work identifies pathways that allow enterococci to survive the transition from the human gut into the bloodstream, enabling them to cause severe bacteremia associated with high mortality.
Rong SS, Lee BY, Kuk AK, Yu XT, Li SS, Li J, Guo Y, Yin Y, Osterbur DL, Yam JCS, Cheung CY, Chen LJ, Wong TY, Ng DS-C. Comorbidity of dementia and age-related macular degeneration calls for clinical awareness: a meta-analysis. Br J Ophthalmol 2019;103(12):1777-1783.Abstract
AIM: To determine the association between dementia and age-related macular degeneration (AMD) using meta-analysis. METHODS: We searched in the MEDLINE, EMBASE, Web of Knowledge, PsycInfo and Cochrane database of systematic reviews for studies published from March 1959 to March 2018. We included cross-sectional, case-control and cohort studies that evaluated the association of dementia/Alzheimer's disease (AD) with AMD (as outcome) and the association of AMD with dementia/AD (as outcome). Studies that compared cognitive functions between AMD and controls were also included. The summary outcomes, namely odds ratio (OR), relative risk, mean differences and corresponding 95% CIs, were estimated using random effects models. We performed sensitivity analysis based on study quality and individual study effect to control for potential biases. RESULTS: Among 2159 citation records, we identified 21 studies consisting of 7 876 499 study subjects for meta-analysis. Patients with dementia (p≤0.017, OR≥1.24, I≤9%) or AD (p=0.001, OR=2.22, I=50%) were at risk for AMD, particularly for late AMD (p<0.001, OR=1.37, I=0). AMD was also significantly associated with increased risk of AD/cognitive impairment (p=0.037, OR=2.42, I=38%). Moreover, patients with AMD had poorer cognitive functions when compared with controls, including Mini-Mental State Examination (p<0.001, I≤79%) and Trail Making Test A (p<0.001, I=0). Sensitivity analysis and Egger's test indicated our results were less likely biased. CONCLUSIONS: A significant association between dementia/AD and AMD calls for greater clinical awareness. The cost-effectiveness of routine screening for the other condition in patients with primary diagnosis of dementia/AD or AMD requires further study.
Silva RNE, Chiou CA, Wang M, Wang H, Shoji MK, Chou JC, D'Souza EE, Greenstein SH, Brauner SC, Alves MR, Pasquale LR, Shen LQ. Microvasculature of the Optic Nerve Head and Peripapillary Region in Patients With Primary Open-Angle Glaucoma. J Glaucoma 2019;28(4):281-288.Abstract
PURPOSE: To assess optic nerve head (ONH) and peripapillary microvasculature in primary open-angle glaucoma (POAG) of mild to moderate severity using swept-source optical coherence tomography angiography (OCTA). MATERIALS AND METHODS: In a cross-sectional study, swept-source OCTA images were analyzed for 1 eye from each of 30 POAG patients with glaucomatous Humphrey visual field loss and 16 controls. The anatomic boundary of ONH was manually delineated based on Bruch's membrane opening and large vessels were removed from en face angiography images to measure vessel density (VD) and the integrated OCTA by ratio analysis signal (IOS), suggestive of flow, in the ONH and peripapillary region. POAG subgroup analysis was performed based on a history of disc hemorrhage (DH) matched by visual field mean deviation (MD). RESULTS: POAG (mean MD±SD, -3.3±3.0 dB) and control groups had similar demographic characteristics and intraocular pressure on the day of imaging. Groups did not differ in superficial ONH VD or flow indicated by IOS (P≥0.28). POAG eyes showed significantly lower VD (39.4%±4.0%) and flow (38.8%±5.6%) in deep ONH, peripapillary VD (37.9%±2.9%) and flow (43.6%±4.0%) compared with control eyes (44.1%±5.1%, 44.7%±6.9%, 40.7%±1.7%, 47.8%±2.5%, respectively; P≤0.007 for all). In the subgroup analysis, POAG eyes with (n=14) and without DH (n=16) had similar measured OCTA parameters (P>0.99 for all). CONCLUSIONS: The image processing methodology based on the anatomic boundary of ONH demonstrated compromised microvasculature in the deep ONH and peripapillary region in eyes with mild to moderate POAG, regardless of the history of DH.
Jaffe GJ, Foster SC, Pavesio CE, Paggiarino DA, Riedel GE. Effect of an Injectable Fluocinolone Acetonide Insert on Recurrence Rates in Chronic Noninfectious Uveitis Affecting the Posterior Segment: Twelve-Month Results. Ophthalmology 2019;126(4):601-610.Abstract
PURPOSE: To assess the safety and efficacy of an intravitreal fluocinolone acetonide (FA) insert to manage inflammation associated with chronic noninfectious posterior uveitis. DESIGN: Multicenter, randomized, prospective, doubled-masked, sham-controlled, 3-year phase 3 clinical trial. PARTICIPANTS: One hundred twenty-nine participants with recurrent noninfectious posterior uveitis were assigned randomly to FA insert (n = 87) or sham injection (n = 42). The more severely affected eye in participants with bilateral disease was designated as the study eye. METHODS: The insert (FA, 0.18 mg) was injected into the vitreous cavity; sham injection mimicked the insert delivery procedure. Ophthalmic examinations, OCT, and ocular tolerability and discomfort assessments were conducted; study visits were on days 7 and 28 and months 2, 3, 6, 9, and 12. Uveitis recurrence was treated as needed. The 6-month recurrence rate was the primary outcome measure. RESULTS: The 6-month (28% and 91%) and 12-month (38% and 98%) uveitis recurrence rates were significantly lower (P < 0.001) with FA insert vs. sham, respectively. Fewer recurrences per study eye (mean, 0.7 vs. 2.5), lower incidence of 15-letter or more decrease in best-corrected visual acuity (14% vs. 31%), and reduced systemic (19% vs. 40%) and local (7% vs. 62%) uveitis adjunctive treatments were observed with FA insert vs. sham, respectively. The FA insert group showed higher rates of cataract. Intraocular pressure-lowering treatment use was similar between groups. No deaths, treatment-related study discontinuations, or unanticipated safety signals were observed through 12 months. CONCLUSIONS: Chronic noninfectious posterior uveitis was managed successfully in this study population; FA insert eyes experienced fewer uveitis recurrence episodes, required fewer adjunctive treatments, and demonstrated less visual acuity loss compared with sham eyes. The FA insert treatment group showed higher rates of cataract; delivery by injection was not associated with an increase in ocular adverse events or any other safety measures not typically associated with local steroid use, suggesting the procedure is appropriate for an office setting.
Di Zazzo A, Micera A, Coassin M, Varacalli G, Foulsham W, De Piano M, Bonini S. InflammAging at Ocular Surface: Clinical and Biomolecular Analyses in Healthy Volunteers. Invest Ophthalmol Vis Sci 2019;60(5):1769-1775.Abstract
Purpose: To assess the ocular surface in volunteers who consider themselves as healthy, in order to evaluate how para-inflammatory mechanisms fail with age, and thus investigate the phenomenon of "InflammAging." Methods: In this observational prospective cohort study, volunteers were categorized into three groups according to age: young (19-40 years), middle-aged (41-60 years), and older adults (61-93 years). Clinical assessments included tear breakup time (T-BUT) and Schirmer test type I. Dry eye symptoms were evaluated by the Ocular Surface Disease Index (OSDI) questionnaire. Conjunctival mRNA and protein expression of intercellular adhesion molecule-1 (ICAM-1), MUC5AC, and IL-8 were measured by real-time PCR and immunofluorescence. Results: A total of 82 volunteers (38 males and 44 females) were enrolled. T-BUT decreased significantly with increasing age (young: 11.13 ± 0.18 seconds; middle-aged: 10.83 ± 0.56 seconds; older: 9.00 ± 1.00 seconds, P < 0.05). Schirmer test values decreased significantly with age (young: 20.6 ± 1.0 mm; middle-aged: 19.2 ± 1.2 mm; older: 16.0 ± 1.1 mm, P < 0.05). OSDI scores increased with age in both groups, but they were substantially higher in women. Conjunctival expression of inflammatory markers ICAM-1, IL-8, and MUC5AC increased with age. Conclusions: Clinical signs, symptoms, and biomarkers of chronic inflammation increased with age in a cohort of volunteers who considered themselves healthy, indicating an age-related progressive impairment of ocular surface system function.
Yazdani M, Chen X, Tashbayev B, Utheim ØA, Ræder S, Hua Y, Eidet JR, Stojanovic A, Dartt DA, Utheim TP. Evaluation of the Ocular Surface Disease Index Questionnaire as a Discriminative Test for Clinical Findings in Dry Eye Disease Patients. Curr Eye Res 2019;44(9):941-947.Abstract
: To investigate to what extent the OSDI can be utilized as a discriminative test for clinical findings. : One thousand and ninety patients with dry eye disease (DED) were consecutively included and examined for osmolarity, tear film break-up time (TFBUT), ocular protection index (OPI), ocular surface staining (OSS), Schirmer I test (ST), meibum expressibility (ME), meibum quality (MQ), and diagnosis of meibomian gland dysfunction (MGD). Receiver-operating characteristic curve (ROC) analysis considering optimum balanced sensitivity and specificity (close to 50%) was used for assessment. : The present study on more than 1,000 patients indicates that the OSDI in the ROC curve analysis is a poor discriminator of pathological scores for TFBUT ≤ 5 (AUC = 0.553; = .012) and ≤10 s (AUC = 0.608; = .002), OSS ≥ 3 (AUC = 0.54; = .043), ST ≤ 5 (AUC = 0.550; = .032) and ≤10 mm/5 min (AUC = 0.544; = .016), and ME ≥ 1 (AUC = 0.594; = <0.001). Pathological scores for osmolarity >308 and >316 mOsm/L, OPI, OSS > 1, MQ, and MGD could not be discriminated by OSDI ( > .05). : Cut-off values for the OSDI can be defined to discriminate pathological TFBUT (≤5 and ≤10), OSS (≥3), ST (≤5 and ≤10) and ME, however, the discriminability was low. Our comprehensive study emphasises the importance of taking both symptoms and signs into account in DED management.
Barrett AM, Houston KE. Update on the Clinical Approach to Spatial Neglect. Curr Neurol Neurosci Rep 2019;19(5):25.Abstract
PURPOSE OF REVIEW: Spatial neglect is asymmetric orienting and action after a brain lesion, causing functional disability. It is common after a stroke; however, it is vastly underdocumented and undertreated. This article addresses the implementation gap in identifying and treating spatial neglect, to reduce disability and improve healthcare costs and burden. RECENT FINDINGS: Professional organizations published recommendations to implement spatial neglect care. Physicians can lead an interdisciplinary team: functionally relevant spatial neglect assessment, evidence-based spatial retraining, and integrated spatial and vision interventions can optimize outcomes. Research also strongly suggests spatial neglect adversely affects motor systems. Spatial neglect therapy might thus "kick-start" rehabilitation and improve paralysis recovery. Clinicians can implement new techniques to detect spatial neglect and lead interdisciplinary teams to promote better, integrated spatial neglect care. Future studies of brain imaging biomarkers to detect spatial neglect, and real-world applicability of prism adaptation treatment, are needed.
Wan A, Place E, Pierce EA, Comander J. Characterizing variants of unknown significance in rhodopsin: A functional genomics approach. Hum Mutat 2019;40(8):1127-1144.Abstract
Characterizing the pathogenicity of DNA sequence variants of unknown significance (VUS) is a major bottleneck in human genetics, and is increasingly important in determining which patients with inherited retinal diseases could benefit from gene therapy. A library of 210 rhodopsin (RHO) variants from literature and in-house genetic diagnostic testing were created to efficiently detect pathogenic RHO variants that fail to express on the cell surface. This study, while focused on RHO, demonstrates a streamlined, generalizable method for detecting pathogenic VUS. A relatively simple next-generation sequencing-based readout was developed so that a flow cytometry-based assay could be performed simultaneously on all variants in a pooled format, without the need for barcodes or viral transduction. The resulting dataset characterized the surface expression of every RHO library variant with a high degree of reproducibility (r  = 0.92-0.95), recategorizing 37 variants. For example, three retinitis pigmentosa pedigrees were solved by identifying VUS which showed low expression levels (p.G18D, p.G101V, and p.P180T). Results were validated across multiple assays and correlated with clinical disease severity. This study presents a parallelized, higher-throughput cell-based assay for the functional characterization of VUS in RHO, and can be applied more broadly to other inherited retinal disease genes and other disorders.
Nocera AL, Mueller SK, Stephan JR, Hing L, Seifert P, Han X, Lin DT, Amiji MM, Libermann T, Bleier BS. Exosome swarms eliminate airway pathogens and provide passive epithelial immunoprotection through nitric oxide. J Allergy Clin Immunol 2019;143(4):1525-1535.e1.Abstract
BACKGROUND: Nasal mucosa-derived exosomes (NMDEs) harbor immunodefensive proteins and are capable of rapid interepithelial protein transfer. OBJECTIVES: We sought to determine whether mucosal exposure to inhaled pathogens stimulates a defensive swarm of microbiocidal exosomes, which also donate their antimicrobial cargo to adjacent epithelial cells. METHODS: We performed an institutional review board-approved study of healthy NMDE secretion after Toll-like receptor (TLR) 4 stimulation by LPS (12.5 μg/mL) in the presence of TLR4 inhibitors. Interepithelial transfer of exosomal nitric oxide (NO) synthase and nitric oxide was measured by using ELISAs and NO activity assays. Exosomal antimicrobial assays were performed with Pseudomonas aeruginosa. Proteomic analyses were performed by using SOMAscan. RESULTS: In vivo and in vitro LPS exposure induced a 2-fold increase in NMDE secretion along with a 2-fold increase in exosomal inducible nitric oxide synthase expression and function through TLR4 and inhibitor of nuclear factor κB kinase activation. LPS stimulation increased exosomal microbiocidal activity against P aeruginosa by almost 2 orders of magnitude. LPS-stimulated exosomes induced a 4-fold increase in NO production within autologous epithelial cells with protein transfer within 5 minutes of contact. Pathway analysis of the NMDE proteome revealed 44 additional proteins associated with NO signaling and innate immune function. CONCLUSIONS: We provide direct in vivo evidence for a novel exosome-mediated innate immunosurveillance and defense mechanism of the human upper airway. These findings have implications for lower airway innate immunity, delivery of airway therapeutics, and host microbiome regulation.
Khateb S, Nassisi M, Bujakowska KM, Méjécase C, Condroyer C, Antonio A, Foussard M, Démontant V, Mohand-Saïd S, Sahel J-A, Zeitz C, Audo I. Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations in PDE6A and PDE6B. JAMA Ophthalmol 2019;Abstract
Importance: A precise phenotypic characterization of retinal dystrophies is needed for disease modeling as a basis for future therapeutic interventions. Objective: To compare genotype, phenotype, and structural changes in patients with rod-cone dystrophy (RCD) associated with mutations in PDE6A or PDE6B. Design, Setting, and Participants: In a retrospective cohort study conducted in Paris, France, from January 2007 to September 2017, 54 patients from a cohort of 1095 index patients with RCD underwent clinical examination, including personal and familial history, best-corrected visual acuity (BCVA), color vision, slitlamp examination, full-field electroretinography, kinetic visual fields (VFs), retinophotography, optical coherence tomography, near-infrared fundus autofluorescence, and short-wavelength fundus autofluorescence imaging. Genotyping was performed using microarray analysis, targeted next-generation sequencing, and Sanger sequencing validation with familial segregation when possible. Data were analyzed from September 1, 2017, to February 1, 2018. Clinical variables were subsequently analyzed in 2018. Main Outcomes and Measures: Phenotype and genotype comparison of patients carrying mutations in PDE6A or PDE6B. Results: Of the 54 patients included in the study, 19 patients of 17 families (11 women [58%]; mean [SD] age at diagnosis, 14.83 [10.63] years) carried pathogenic mutations in PDE6A, and 35 patients of 26 families (17 women [49%]; mean [SD] age at diagnosis, 21.10 [11.56] years) had mutations in PDE6B, accounting for prevalences of 1.6% and 2.4%, respectively. Among 49 identified genetic variants, 14 in PDE6A and 15 in PDE6B were novel. Overall, phenotypic analysis revealed no substantial differences between the 2 groups except for night blindness as a presenting symptom that was noted to be more prevalent in the PDE6A than PDE6B group (80% vs 37%, respectively; P = .005). The mean binocular BCVA and VF decrease over time (measured as mean individual slopes coefficients) was comparable between patients with PDE6A and PDE6B mutations: 0.04 (0.12) vs 0.02 (0.05) for BCVA (P = .89) and 14.33 (7.12) vs 13.27 (6.77) for VF (P = .48). Conclusions and Relevance: Mutations in PDE6A and PDE6B accounted for 1.6% and 2.4%, respectively, in a cohort of French patients with RCD. The functional and structural findings reported may constitute the basis of disease modeling that might be used for better prognostic estimation and candidate selection for photoreceptor therapeutic rescue.
Goldstein JM, Tabebordbar M, Zhu K, Wang LD, Messemer KA, Peacker B, Ashrafi Kakhki S, Gonzalez-Celeiro M, Shwartz Y, Cheng JKW, Xiao R, Barungi T, Albright C, Hsu Y-C, Vandenberghe LH, Wagers AJ. In Situ Modification of Tissue Stem and Progenitor Cell Genomes. Cell Rep 2019;27(4):1254-1264.e7.Abstract
In vivo delivery of genome-modifying enzymes holds significant promise for therapeutic applications and functional genetic screening. Delivery to endogenous tissue stem cells, which provide an enduring source of cell replacement during homeostasis and regeneration, is of particular interest. Here, we use a sensitive Cre/lox fluorescent reporter system to test the efficiency of genome modification following in vivo transduction by adeno-associated viruses (AAVs) in tissue stem and progenitor cells. We combine immunophenotypic analyses with in vitro and in vivo assays of stem cell function to reveal effective targeting of skeletal muscle satellite cells, mesenchymal progenitors, hematopoietic stem cells, and dermal cell subsets using multiple AAV serotypes. Genome modification rates achieved through this system reached >60%, and modified cells retained key functional properties. This study establishes a powerful platform to genetically alter tissue progenitors within their physiological niche while preserving their native stem cell properties and regulatory interactions.
Botten N, Hodges RR, Li D, Bair JA, Shatos MA, Utheim TP, Serhan CN, Dartt DA. Resolvin D2 elevates cAMP to increase intracellular [Ca] and stimulate secretion from conjunctival goblet cells. FASEB J 2019;33(7):8468-8478.Abstract
Under physiologic conditions, conjunctival goblet cells (CGCs) secrete mucins into the tear film to preserve ocular surface homeostasis. Specialized proresolving mediators (SPMs), like resolvins (Rvs), regulate secretion from CGCs and actively terminate inflammation. The purpose of this study was to determine if RvD2 stimulated mucin secretion and to investigate the cellular signaling components. Goblet cells were cultured from rat conjunctiva. Secretion was measured by an enzyme-linked lectin assay, change in intracellular [Ca] ([Ca]) using Fura-2, and cellular cAMP levels by ELISA. RvD2 (10-10 M) stimulated secretion, increased cellular cAMP levels and the [Ca]. RvD2-stimulated increase in [Ca] and secretion was blocked by Ca chelator 1,2-bis(2-aminophenoxy)ethane-,,','-tetraacetic acid tetrakis and the PKA inhibitor -[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride but not by the cAMP exchange protein inhibitor α-[2-(3-chlorophenyl)hydrazinylidene]-5-(1,1-dimethylethyl)-b-oxo-3-isoxazolepropanenitrile. Forskolin, 3-isobutyl-1-methylxanthine, and 8-bromo-cAMP (8-Br-cAMP) increased [Ca]. Increasing cAMP with 8-Br-cAMP inhibited the increase in [Ca] stimulated by the cAMP-independent agonist cholinergic agonist carbachol. In conclusion, RvD2 uses both cellular cAMP and [Ca] to stimulate glycoconjugate secretion from CGCs, but the interaction of cAMP and [Ca] is context dependent. Thus RvD2 likely assists in the maintenance of the mucous layer of the tear film to sustain ocular surface homeostasis and has potential as a novel treatment for dry eye disease.-Botten, N., Hodges, R. R., Li, D., Bair, J. A., Shatos, M. A., Utheim, T. P., Serhan, C. N., Dartt, D. A. Resolvin D2 elevates cAMP to increase intracellular [Ca] and stimulate secretion from conjunctival goblet cells.
Wang SV, Li N, Rice DS, Grosskreutz CL, Dryja TP, Prasanna G, Lii J, Gagne JJ. Using Healthcare Databases to Refine Understanding of Exploratory Associations Between Drugs and Progression of Open-Angle Glaucoma. Clin Pharmacol Ther 2019;106(4):874-883.Abstract
We sought to refine understanding about associations identified in prior studies between angiotensin-II receptor blockers, metformin, selective serotonin reuptake inhibitors, fibric-acid derivatives, or calcium channel blockers and progression to glaucoma filtration surgery for open-angle glaucoma (OAG). We used new-initiator, active-comparator cohort designs to investigate these drugs in two data sources. We adjusted for confounders using stabilized inverse-probability-of-treatment weights and evaluated results using "intention-to-treat" and "as-treated" follow-up approaches. In both data sources, Kaplan-Meier curves showed trends for more rapid progression to glaucoma filtration surgery in patients taking calcium channel blockers compared with thiazides with as-treated (MarketScan P = 0.15; Medicare P = 0.03) and intention-to-treat follow-up (MarketScan P < 0.01; Medicare P = 0.10). There was suggestion of delayed progression for selective serotonin reuptake inhibitor compared with tricyclic antidepressants in Medicare, which was not observed in MarketScan. Our study provided support for a relationship between calcium channel blockers and OAG progression but not for other investigated drugs.