Increased H3K4me3 methylation and decreased miR-7113-5p expression lead to enhanced Wnt/ß-catenin signaling in immune cells from PTSD patients leading to inflammatory phenotype.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a psychiatric disorder accompanied by chronic peripheral inflammation. What triggers inflammation in PTSD is currently unclear. In the present study, we identified potential defects in signaling pathways in peripheral blood mononuclear cells (PBMCs) from individuals with PTSD. METHODS: RNAseq (5 samples each for controls and PTSD), ChIPseq (5 samples each) and miRNA array (6 samples each) were used in combination with bioinformatics tools to identify dysregulated genes in PBMCs. Real time qRT-PCR (24 samples each) and in vitro assays were employed to validate our primary findings and hypothesis. RESULTS: By RNA-seq analysis of PBMCs, we found that Wnt signaling pathway was upregulated in PTSD when compared to normal controls. Specifically, we found increased expression of WNT10B in the PTSD group when compared to controls. Our findings were confirmed using NCBI's GEO database involving a larger sample size. Additionally, in vitro activation studies revealed that activated but not naïve PBMCs from control individuals expressed more IFNγ in the presence of recombinant WNT10B suggesting that Wnt signaling played a crucial role in exacerbating inflammation. Next, we investigated the mechanism of induction of WNT10B and found that increased expression of WNT10B may result from epigenetic modulation involving downregulation of hsa-miR-7113-5p which targeted WNT10B. Furthermore, we also observed that WNT10B overexpression was linked to higher expression of H3K4me3 histone modification around the promotor of WNT10B. Additionally, knockdown of histone demethylase specific to H3K4me3, using siRNA, led to increased expression of WNT10B providing conclusive evidence that H3K4me3 indeed controlled WNT10B expression. CONCLUSIONS: In summary, our data demonstrate for the first time that Wnt signaling pathway is upregulated in PBMCs of PTSD patients resulting from epigenetic changes involving microRNA dysregulation and histone modifications, which in turn may promote the inflammatory phenotype in such cells.

CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice.

Dysbiosis in gut microbiome has been shown to be associated with inflammatory and autoimmune diseases. Previous studies from our laboratory demonstrated the pivotal role played by CD44 in the regulation of EAE, a murine model of multiple sclerosis. In the current study, we determined whether these effects resulted from an alteration in gut microbiota and the short-chain fatty acid (SCFA) production in CD44 knockout (CD44KO) mice. Fecal transfer from naïve CD44KO but not C57BL/6 wild type (CD44WT) mice, into EAE-induced CD44WT mice, led to significant amelioration of EAE. High-throughput bacterial 16S rRNA gene sequencing, followed by clustering sequences into operational taxonomic units (OTUs) and biochemical analysis, revealed that EAE-induced CD44KO mice showed significant diversity, richness, and evenness when compared to EAE-induced CD44WT mice at the phylum level, with dominant Bacteroidetes (68.5%) and low Firmicutes (26.8%). Further, data showed a significant change in the abundance of SCFAs, propionic acid, and i-butyric acid in EAE-CD44KO compared to EAE-CD44WT mice. In conclusion, our results demonstrate that the attenuation of EAE seen following CD44 gene deletion in mice may result from alterations in the gut microbiota and SCFAs. Furthermore, our studies also demonstrate that the phenotype of gene knock-out animals may be shaped by gut microbiota.

Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.

OBJECTIVE: To evaluate the 24-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly or as needed (pro re nata [PRN]) in patients with neovascular age-related macular degeneration (wet AMD). DESIGN: Twenty-four-month, multicenter, randomized, double-masked, active treatment-controlled phase 3 trial. PARTICIPANTS: Patients (n = 1098) ≥ 50 years of age with treatment-naïve subfoveal wet AMD. METHODS: Patients were randomized to receive intravitreal injections of ranibizumab 0.5 mg or 2.0 mg monthly or PRN after 3 monthly loading doses. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean change in best-corrected visual acuity (BCVA) from baseline at month 12. Key secondary end points included mean change in BCVA from baseline at month 24, proportion of patients who gained ≥ 15 letters in BCVA, mean number of ranibizumab injections, and mean change in central foveal thickness from baseline over time by spectral-domain optical coherence tomography. Ocular and systemic safety events also were evaluated through month 24. RESULTS: At month 24, the mean change from baseline in BCVA was (letters) +9.1 (0.5 mg monthly), +7.9 (0.5 mg PRN), +8.0 (2.0 mg monthly), and +7.6 (2.0 mg PRN). The change in mean BCVA from month 12 to 24 was (letters) -1.0, -0.3, -1.2, and -1.0, respectively. The proportion of patients who gained ≥ 15 letters from baseline in BCVA at month 24 was 34.5%, 33.1%, 37.6%, and 34.8%, respectively. The mean number of ranibizumab injections through month 24 was 21.4, 13.3, 21.6, and 11.2, respectively; 5.6 and 4.3 mean injections were required in year 2 in the 0.5 mg and 2.0 mg PRN groups, respectively. The average treatment interval in the 0.5 mg PRN group was 9.9 weeks after 3 monthly loading doses, and 93% of these patients did not require monthly dosing. Ocular and systemic safety profiles over 2 years were similar among all 4 treatment groups and were consistent with previous ranibizumab trials in AMD. CONCLUSIONS: At month 24, mean BCVA improvements were clinically meaningful and similar among all 4 ranibizumab treatment groups. The 0.5 mg PRN group achieved a mean gain of 7.9 letters at month 24 with an average of 13.3 injections (5.6 injections in year 2). No new safety events were identified over 24 months.

Safety and efficacy of ixoberogene soroparvovec in neovascular age-related macular degeneration in the United States (OPTIC): a prospective, two-year, multicentre phase 1 study.

Background: Gene therapy, successfully used in rare, monogenetic disorders, may prove to be a durable management approach for common, polygenetic conditions, including neovascular age-related macular degeneration (nAMD). Repeated injections, oftentimes monthly, and possibly for decades, of vascular endothelial growth factor antagonists (anti-VEGF), is the standard for nAMD. We hypothesised that an in-office, intravitreal administration of ixoberogene soroparvovec (ixo-vec, formerly ADVM-022), a single-dose gene therapy encoding for the proven anti-VEGF protein, aflibercept, would transform retinal cells to continually produce aflibercept to minimise treatment burden in nAMD. Methods: In this two-year, open-label, prospective, multicentre phase 1 study, patients with nAMD responding to anti-VEGF were assigned to four cohorts differing by ixo-vec dose (2 × 1011 vs 6 × 1011 vector genomes (vg/eye)) and prophylactic steroids (oral prednisone vs topical difluprednate). The primary outcome was the type, severity, and incidence of ocular and systemic adverse events (AEs); secondary endpoints included vision, central subfield thickness (CST), and the number of supplemental injections. This study was registered with ClinicalTrials.gov, NCT03748784. Findings: Thirty patients with nAMD were enrolled between November 14, 2018 and June 30, 2020 at nine study sites in the United States. No systemic ixo-vec related AEs were noted. Across both dose groups the most common adverse event was anterior chamber cell, which was reported in 11 participants in the 6 × 1011 dose group and in 7 participants in the 2 × 1011 dose group; intraocular inflammation was responsive to topical corticosteroids, with no anterior chamber cells or vitreous cells observed in 2 × 1011 vg/eye patients at the end of the study. Vision and CST remained stable throughout two years with annualised anti-VEGF injections reduced by 80% (10.0 mean annualised anti-VEGF injections to 1.9) in 2 × 1011 vg/eye and 98% (9.8 mean annualised anti-VEGF injections to 0.2) in 6 × 1011 vg/eye cohorts. Interpretation: Ixo-vec was generally well-tolerated, maintained vision, and improved anatomical outcomes in nAMD, with a substantial reduction in anti-VEGF injections. A single administration of an in-office gene therapy, with vectorised protein with an already established clinical benefit, has the potential to revolutionise the management of common ocular disorders requiring ongoing, frequent therapeutic interventions. Funding: Adverum Biotechnologies.

Cataract surgery cost utility revisited in 2012: a new economic paradigm.

OBJECTIVE: To assess the 2012 cost utility of cataract surgery in the United States and to compare 2012 cost-utility data with those from 2000. DESIGN: Value-Based Medicine (Flourtown, PA), patient preference-based, comparative effectiveness analysis and cost-utility analysis using 2012 real United States dollars. PARTICIPANTS: Previously published Patient Outcomes Research Team Study data and time tradeoff utilities obtained from patients with vision loss. Visual acuity measurements from patients wtih untreated cataract were used as controls. INTERVENTION: Thirteen-year, average, first-eye and second-eye cataract surgery cost-utility analysis using the societal and third-party insurer cost perspectives. MAIN OUTCOME MEASURES: Patient value gain in quality-adjusted life years (QALYs) and percent gain in quality of life as well as the cost-utility ratio using the dollars expended per QALY gained. Patient and financial value outcomes were discounted at 3% annually with net present value analysis. RESULTS: First-eye cataract surgery conferred 1.6212 QALYs over the 13-year model, a 20.8% quality-of-life gain. Bilateral cataract surgery conferred 2.8152 QALYs over 13 years, a 36.2% improvement in quality of life. The direct ophthalmic medical cost for unilateral cataract surgery in 2012 United States nominal dollars was $2653, an inflation-adjusted 34.2% less than in 2000 and 85% less than in 1985. The 2012 inflation-adjusted physician fee was 10.1% of that in 1985. The 13-year societal cost perspective, financial return on investment (ROI) for first-eye cataract surgery was $121,198, a 4567% gain. The third-party insurer cost perspective average cost-utility ratio was $2653/1.6212 = $1636/QALY for unilateral cataract surgery, whereas the societal cost perspective average cost-utility ratio was -$121,198/1.6212 = -$74,759/QALY. The net 13-year $123.4-billion financial ROI from a 1-year cohort of cataract surgery patients was accrued: Medicare, $36.4 billion; Medicaid, $3.3 billion; other insurers, $9.6 billion; patients, $48.6 billion; and increased United States national productivity, $25.4 billion. CONCLUSIONS: Cataract surgery in 2012 greatly improved quality of life and was highly cost effective. It was 34.4% less expensive than in 2000 and 85% less expensive than in 1985. Initial cataract surgery yielded an extraordinary 4567% financial ROI to society over the 13-year model.

Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration.

OBJECTIVE: To evaluate the 12-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly and on an as-needed (PRN) basis in treatment-naïve patients with subfoveal neovascular age-related macular degeneration (wet AMD). DESIGN: A 24-month, phase III, randomized, multicenter, double-masked, dose-response study. PARTICIPANTS: Patients aged ≥ 50 years with subfoveal wet AMD. METHODS: Patients (n = 1098) were randomized to receive ranibizumab 0.5 mg or 2.0 mg intravitreal injections administered monthly or on a PRN basis after 3 monthly loading doses. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean change from baseline in best-corrected visual acuity (BCVA) at month 12. Key secondary end points included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained ≥ 15 letters of BCVA. Unless otherwise specified, end point analyses were performed using the last-observation-carried-forward method to impute missing data. RESULTS: At month 12, the mean change from baseline in BCVA for the 4 groups was +10.1 letters (0.5 mg monthly), +8.2 letters (0.5 mg PRN), +9.2 letters (2.0 mg monthly), and +8.6 letters (2.0 mg PRN). The proportion of patients who gained ≥ 15 letters from baseline at month 12 in the 4 groups was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. The mean change from baseline in CFT at month 12 in the 4 groups was -172.0 µm, -161.2 µm, -163.3 µm, and -172.4 µm, respectively. The mean number of injections was 7.7 and 6.9 for the 0.5-mg PRN and 2.0-mg PRN groups, respectively. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and comparable between groups. CONCLUSIONS: At month 12, the ranibizumab 2.0 mg monthly group did not meet the prespecified superiority comparison and the ranibizumab 0.5 mg and 2.0 mg PRN groups did not meet the prespecified noninferiority (NI) comparison. However, all treatment groups demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes, with the PRN groups requiring approximately 4 fewer injections (6.9-7.7) than the monthly groups (11.2-11.3). No new safety events were observed despite a 4-fold dose escalation in the study. The pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) study confirmed that ranibizumab 0.5 mg dosed monthly provides optimum results in patients with wet AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Overview of ocular anesthesia: past and present.

PURPOSE OF REVIEW: Many choices of ocular anesthetic techniques are available to the ophthalmologist. This study reviews currently used techniques of topical, subconjunctival and regional block anesthesia used in ophthalmic procedures. RECENT FINDINGS: The choices of anesthetics that are available are considered and a new ocular anesthetic gel is described that provides sustained ocular surface anesthesia, minimal side-effects and may also have antimicrobial properties. SUMMARY: Consideration of ocular anesthetic techniques and anesthetic choice plays a critical role for the success and safety of ophthalmic surgery.

Vitreous nonsteroidal antiinflammatory drug concentrations and prostaglandin E2 levels in vitrectomy patients treated with ketorolac 0.4%, bromfenac 0.09%, and nepafenac 0.1%.

PURPOSE: To assess vitreous concentrations of nonsteroidal antiinflammatory drugs (NSAIDs) and prostaglandin E(2) in patients treated with NSAIDs before vitrectomy. METHODS: This was an investigator-masked, randomized, multicenter study. Patients received ketorolac 0.4% 4 times a day, bromfenac 0.09% 2 times a day, nepafenac 0.1% 3 times a day, or no NSAID for 3 days before surgery. Nonsteroidal antiinflammatory drugs and prostaglandin E(2) levels were determined in vitreous samples collected at the beginning of surgery. RESULTS: Thirty-one patients were included in the analyses. The mean (SD) vitreous concentrations were as follows: ketorolac 2.8 (3.2) ng/mL, bromfenac 0.96 (0.31) ng/mL, nepafenac 1.1 (0.6) ng/mL, and amfenac 2.0 (0.8) ng/mL aligned with the initial concentrations of the topical NSAIDs. Mean (SD) vitreous prostaglandin E(2) levels of the control patients and those treated with ketorolac 0.4%, bromfenac 0.09%, or nepafenac 0.1% were 270.6 (91.7) pg/mL, 189.6 (50.2) pg/mL, 247.2 (38.3) pg/mL, and 267.7 (99.7) pg/mL, respectively. Patients treated with ketorolac 0.4% had significantly lower prostaglandin E(2) levels than those treated with no NSAID (P = 0.047) or nepafenac 0.1% (P = 0.028). CONCLUSION: All three NSAIDs penetrated into the vitreous cavity. Topical therapy with ketorolac may lower preoperative vitreous prostaglandin E(2) levels, which may have a clinical impact on the management of prostaglandin-mediated diseases, including cystoid macular edema.

Cost-utility analysis of cataract surgery in the United States for the year 2018.

PURPOSE: To perform a cost-utility analysis of 2018 United States real dollars for cataract surgery. SETTING: Center for Value-Based Medicine, Hilton Head, South Carolina, USA. DESIGN: Cost-utility analysis. METHODS: A base-case 14-year cost-utility model using the ophthalmic cost perspective was used. Third-party insurer and societal cost perspectives were also analyzed. Patient outcomes and costs were discounted with net present value analysis at 3% a year. RESULTS: First-eye cataract surgery resulted in a 2.523 quality-adjusted life-year (QALY) gain, a 33.3% patient value gain, and 25.5% quality-of-life gain. Bilateral surgery yielded a 44.1% patient value gain, while second-eye cataract surgery alone conferred an 8.1% value gain. First-eye cataract surgery resulted in a gain of 2.52 QALYs, while second-eye surgery added an incremental gain of 0.81 QALYs. The ophthalmic-cost-perspective average cost-utility ratio was $2526/2.523 = $1001/QALY for first-eye cataract surgery. The societal-cost-perspective average cost-utility ratio was -$370 018/2.523 = -$146 629/QALY. The second-eye ophthalmic-cost-perspective cost-utility ratio was $2526/0.814 = $3101/QALY, while the ophthalmic-cost-perspective cost-utility ratio for bilateral cataract surgery was $5052/3.338 = $1514/QALY. The 14-year U.S. 2018 real-dollar societal-cost-perspective net return on investment for first-eye cataract surgery was $370 018 above the $2526 cost expended for cataract surgery. CONCLUSIONS: Cataract surgery in both the first eye and second eye, when analyzed by standard health economic methodologies, is highly cost-effective. Cataract surgery in 2018 was 73.7% more cost-effective than in 2000.

Computational prediction and in vitro validation of VEGFR1 as a novel protein target for 2,3,7,8-tetrachlorodibenzo-p-dioxin.

The toxic manifestations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant, primarily depend on its ability to activate aryl hydrocarbon receptor (AhR), which is a ligand-dependent transcription factor belonging to the superfamily of basic-helix-loop-helix DNA-binding proteins. In the present study, we aimed to identify novel protein receptor targets for TCDD using computational and in vitro validation experiments. Interestingly, results from computational methods predicted that Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) could be one of the potential targets for TCDD in both mouse and humans. Results from molecular docking studies showed that human VEGFR1 (hVEGFR1) has less affinity towards TCDD compared to the mouse VEGFR1 (mVEGFR1). In vitro validation results showed that TCDD can bind and phosphorylate hVEGFR1. Further, results from molecular dynamic simulation studies showed that hVEGFR1 interaction with TCDD is stable throughout the simulation time. Overall, the present study has identified VEGFR1 as a novel target for TCDD, which provides the basis for further elucidating the role of TCDD in angiogenesis.

Lidocaine hydrochloride gel for ocular anesthesia: results of a prospective, randomized study.

BACKGROUND AND OBJECTIVE: This study evaluates the effectiveness of Akten (Akorn, Inc., Buffalo Grove, IL), a novel ophthalmic gel anesthetic agent for complete ocular anesthesia. PATIENTS AND METHODS: This study was conducted as a prospective, randomized, double-blinded, multicenter Phase III clinical trial to evaluate Akten gel. The study had four cohorts of subjects who received sham gel, Akten 1.5%, Akten 2.5%, and Akten 3.5%, respectively. Subjects were assessed for achievement of anesthesia at defined time intervals and questioned for "pain" or "no pain" following pinching of the conjunctiva with 0.3-mm forceps at predetermined intervals. RESULTS: A total of 209 subjects were entered into the study. The percentages of patients achieving the primary endpoint (ie, anesthesia within 5 minutes) were as follows: 22% for sham, 88% for Akten 1.5%, 89% for Akten 2.5%, and 92% for Akten 3.5%, respectively. Safety measures including corneal staining, conjunctival hyperemia, and eye pain with administra-tion were low and comparable in all cohorts. CONCLUSION: Akten gel appears to be an effective and safe ocular anesthetic. All doses were well tolerated and no dose-related corneal toxicity was observed.

Efficacy and Safety of Lampalizumab for Geographic Atrophy Due to Age-Related Macular Degeneration: Chroma and Spectri Phase 3 Randomized Clinical Trials.

Importance: Geographic atrophy (GA) secondary to age-related macular degeneration is a leading cause of visual disability in older individuals. A phase 2 trial suggested that lampalizumab, a selective complement factor D inhibitor, reduced the rate of GA enlargement, warranting phase 3 trials. Objective: To assess the safety and efficacy of lampalizumab vs sham procedure on enlargement of GA. Design, Setting, and Participants: Two identically designed phase 3 double-masked, randomized, sham-controlled clinical trials, Chroma and Spectri, enrolled participants from August 28, 2014, to October 6, 2016, at 275 sites in 23 countries. Participants were aged 50 years or older, with bilateral GA and no prior or active choroidal neovascularization in either eye and GA lesions in the study eye measuring 2.54 to 17.78 mm2 with diffuse or banded fundus autofluorescence patterns. Interventions: Participants were randomized 2:1:2:1 to receive 10 mg of intravitreous lampalizumab every 4 weeks, sham procedure every 4 weeks, 10 mg of lampalizumab every 6 weeks, or sham procedure every 6 weeks, through 96 weeks. Main Outcomes and Measures: Safety and efficacy assessed as mean change from baseline in GA lesion area at week 48 from centrally read fundus autofluorescence images of the lampalizumab arms vs pooled sham arms, in the intent-to-treat population and by complement factor I-profile genetic biomarker. Results: A total of 906 participants (553 women and 353 men; mean [SD] age, 78.1 [8.1] years) were enrolled in Chroma and 975 participants (578 women and 397 men; mean [SD] age, 77.9 [8.1] years) were enrolled in Spectri; 1733 of the 1881 participants (92.1%) completed the studies through 48 weeks. The adjusted mean increases in GA lesion area from baseline at week 48 were 1.93 to 2.09 mm2 across all groups in both studies. Differences in adjusted mean change in GA lesion area (lampalizumab minus sham) were -0.02 mm2 (95% CI, -0.21 to 0.16 mm2; P = .80) for lampalizumab every 4 weeks in Chroma, 0.16 mm2 (95% CI, 0.00-0.31 mm2; P = .048) for lampalizumab every 4 weeks in Spectri, 0.05 mm2 (95% CI, -0.13 to 0.24 mm2; P = .59) for lampalizumab every 6 weeks in Chroma, and 0.09 mm2 (95% CI, -0.07 to 0.24 mm2; P = .27) for lampalizumab every 6 weeks in Spectri. No benefit of lampalizumab was observed across prespecified subgroups, including by complement factor I-profile biomarker. Endophthalmitis occurred after 5 of 12 447 injections (0.04%) or in 5 of 1252 treated participants (0.4%) through week 48. Conclusions and Relevance: In Chroma and Spectri, the largest studies of GA conducted to date, lampalizumab did not reduce GA enlargement vs sham during 48 weeks of treatment. Results highlight the substantial and consistent enlargement of GA, at a mean of approximately 2 mm2 per year. Trial Registration: ClinicalTrials.gov Identifier: NCT02247479 and NCT02247531.

Changing trends in the microbiologic aspects of postcataract endophthalmitis.

OBJECTIVE: To analyze the microbiologic spectrum and in vitro susceptibility profiles over the last 11 years of organisms isolated from the vitreous of patients with endophthalmitis following cataract surgery. METHODS: Records of 497 consecutive patients treated at 1 institution for clinically suspected endophthalmitis following cataract surgery from July 1989 through June 2000 were reviewed. Results of microbiologic culture and in vitro antibiotic susceptibility testing from the periods 1989 to 1994 and 1995 to 2000 were compared. RESULTS: Between the 2 periods, there was a significant increase in the incidence of gram-positive bacteria (92%-97% of bacterial isolates). There was a significant increase in resistance among all bacterial isolates to ciprofloxacin (23%-37%; P = .02). There was increased resistance among coagulase-negative staphylococci to both ciprofloxacin (20%-38%) and cefazolin (19%-40%). Resistance to bacitracin, trimethoprim-sulfamethoxazole, and vancomycin remained unchanged. Vancomycin retained in vitro efficacy against more than 99% of gram-positive bacteria. Ceftazidime was effective against 100% of gram-negative bacteria tested. CONCLUSIONS: The spectrum of pathogens causing postcataract endophthalmitis is changing, and resistance to antibiotics used for its prophylaxis has grown. These findings may affect the empirical treatment of postcataract endophthalmitis, as well as the use and choice of antibiotics in patients undergoing cataract surgery.

Baseline Predictors of 12-Month Treatment Response to Ranibizumab in Patients With Wet Age-Related Macular Degeneration.

PURPOSE: To identify baseline characteristics predictive of visual acuity (VA) outcomes at month 12 (M12) and treatment frequency in the first 12 months of the phase III HARBOR study. DESIGN: Retrospective, exploratory analysis of multicenter randomized controlled trial data. METHODS: setting: Randomized, multicenter. STUDY POPULATION: Patients aged ≥50 years with subfoveal wet age-related macular degeneration (AMD) who had best-corrected VA (BCVA) values measured at baseline and M12. INTERVENTION: Intravitreal ranibizumab 0.5 mg administered monthly (n = 249) or as needed (PRN) after 3 monthly loading doses (n = 251). MAIN OUTCOME MEASURES: BCVA change from baseline at M12, percentage of patients who gained ≥15 letters (3 lines) in BCVA from baseline at M12, and percentage of patients who achieved ≥20/40 vision (Snellen) at M12 served as the basis for analyzing baseline predictors of observed VA outcomes in the monthly and PRN groups. Total number of ranibizumab PRN injections in the first 12 months was also evaluated. Only variables that were statistically significant (P < .05) remained in the final statistical models. RESULTS: Baseline predictors of BCVA change from baseline at M12 and/or percentage of 3-line gainers included lower BCVA, younger age, smaller total choroidal neovascularization (CNV) leakage area, smaller area of occult CNV, and presence of subretinal fluid (SRF). Baseline predictors of ≥20/40 vision at M12 included higher BCVA, smaller total CNV leakage area, and presence of SRF. SRF thickness >118.25 µm at baseline predicted requiring more ranibizumab injections in the first 12 months of treatment. CONCLUSIONS: Select baseline characteristics have predictive value for visual prognosis and treatment frequency in ranibizumab-treated patients with wet AMD.

A cost-utility analysis of interventions for severe proliferative vitreoretinopathy.

PURPOSE: The purpose of this study was to report a reference case, patient preference-based, incremental, cost-utility analysis for treatments of retinal detachment associated with severe proliferative vitreoretinopathy (PVR). DESIGN: Computer-based economic model utilizing data from the Medicare health insurance system in the United States. METHODS: A cost-utility analysis compared vitreoretinal surgery using expanding gases and silicone oil therapy to the natural course of retinal detachment associated with severe PVR. The model applies long-term published visual data from the Silicone Study Group, time tradeoff utility analysis, decision analysis with Markov modeling, and discounting of costs and health benefits as per the Panel on Cost-Effectiveness in Health and Medicine. The major outcome measure was in year 2000 United States dollars per quality-adjusted life-year (dollars/QALY) gained. RESULTS: Vitreoretinal surgery for retinal detachment complicated by severe PVR, as compared with no treatment, resulted in a mean gain of 0.128-0.200 discounted (3% annual rate) quality-adjusted life-years per treated patient. Silicone oil (dollars/QALY gained of 40,252 dollars) was slightly more cost-effective than perfluoropropane (C(3)F(8)) gas (dollars/QALY gained of 46,926 dollars) in eyes with PVR without previous vitrectomy, whereas C(3)F(8) gas (dollars/QALY gained of 46,162 dollars) was more cost-effective than silicone oil (dollars/QALY gained of 62,383 dollars) with previous vitrectomy and PVR. Sensitivity analysis resulted in a dollars/QALY gained of 13,347 dollars when 10% of opposite eyes had a severe visual loss to 202,128 dollars when a discount rate of 10% was utilized and opposite eyes initially had good vision. CONCLUSIONS: The incremental expense of interventions for retinal detachment associated with PVR is cost-effective when compared with other widely accepted interventional therapies across diverse medical specialties.

Endophthalmitis after penetrating keratoplasty: microbiologic spectrum and susceptibility of isolates.

PURPOSE: To present the microbial spectrum and susceptibilities of isolates in endophthalmitis following penetrating keratoplasty. DESIGN: Interventional case series. METHODS: The 1,074 consecutive cases of endophthalmitis presenting to Wills Eye Hospital between 1989 and 2000 were reviewed. Fourteen patients with endophthalmitis after penetrating keratoplasty were identified, and vitreous biopsy isolates from these patients were examined. RESULTS: Eleven (78.6%) of 14 vitreous samples were culture-positive, and two others (14.3%) had organisms viewed on pathology specimen, for a total of 13 (92.9%) organism-proven cases of endophthalmitis. Isolates included 10 (76.9%) gram-positive cocci (six Streptococcus sp., three Staphylococcus sp., one identified on pathology specimen only) and three (23.1%) gram-negative organisms (Proteus mirabilis, Serratia marcescens, one identified on pathology specimen only). Susceptibilities to organism-appropriate antibiotic testing are reported, including cefazolin (six of eight, 75.0%), ciprofloxacin (four of seven, 57.1%), nafcillin (four of six, 66.7%), and vancomycin (seven of seven, 100.0%). CONCLUSION: This is the largest series on microbial susceptibilities in postpenetrating keratoplasty endophthalmitis. We report a high percentage of culture-positivity, and a high incidence of gram-positive species, and in particular Streptococcus species, with all tested gram-positive organisms susceptible to vancomycin.

Incremental cost-effectiveness of laser therapy for visual loss secondary to branch retinal vein occlusion.

PURPOSE: To ascertain the incremental cost-effectiveness of therapeutic interventions for improving visual loss associated with branch retinal vein occlusion. METHODS: A cost-utility analysis incorporating data from the Branch Vein Occlusion Study Group was performed using patient-based preferences obtained from time tradeoff utility analysis, decision analysis with Markov modeling, and economic modeling with future value analysis. The cost-effectiveness results are expressed in dollars/QALY (dollars expended per quality-adjusted life-year) gained. This unique model takes into account the visual acuity in the better seeing eye and the recurrent risk for visual loss in the contralateral eye. RESULTS: Laser therapy for macular edema secondary to branch retinal vein occlusion was associated with an incremental dollars/QALY gained of 6118 dollars (in year 2000 U.S. dollars). Two-way sensitivity analysis, varying the discount rate and the proportion of patients developing a vascular occlusion in the contralateral eye, revealed a range of dollars/QALY gained from 3370 dollars to 19,299 dollars. CONCLUSIONS: Laser therapy appears to be a cost-effective intervention for improving visual loss associated with macular edema secondary to branch retinal vein occlusion. Variants of the methodology employed to calculate the incremental cost-effectiveness of this intervention can be widely applied across all specialties in medicine.

Clinically significant corneal astigmatism and pars plana vitrectomy.

PURPOSE: To report a rare and previously unappreciated potential wound-related complication of repeat pars plana vitrectomy (PPV) combined with anterior segment surgery. METHODS: From a total of 135 patients who had undergone PPV over a period of 15 months, 7 patients were identified on the basis of a visually disabling degree of astigmatism persisting at 3 to 4 months following their surgery. These patients were retrospectively studied from the standpoint of the numbers and combination of procedures they had experienced. Videokeratoscopy was employed as an objective method of documenting the astigmatism. RESULTS: The average astigmatism at the corneal plane in these 7 eyes was 4.5 diopters (D). In the 5 patients who required suture lysis for visual rehabilitation, the average corneal astigmatism was slightly greater than 5.0 D. In all cases, the astigmatism was a symmetric "bow-tie" pattern and was in the meridian corresponding to the superonasal and inferotemporal sclerotomies. All 5 of the patients requiring suture lysis had undergone repeat PPV through the same sclerotomies; all had their astigmatism reduced to an average of 1.5 D. CONCLUSION: Visually disabling astigmatism present months after surgery is almost certainly a rare, wound-related complication of PPV, but remains a previously unappreciated possibility in eyes undergoing repeat procedures through the same sclerotomies. Videokeratoscopy provides a reliable and rapid method of detection, while suture lysis in the steep axis represents a simple remedy.