Demonstration of an online tool to assist managed care formulary evidence-based decision making: meta-analysis of topical prostaglandin analog efficacy

BACKGROUND: The purpose of this paper was to demonstrate the use of an online service for conducting a systematic review and meta-analysis of the efficacy of topical prostaglandin analogs in reducing intraocular pressure (IOP) in glaucoma and ocular hypertension. METHODS: An online service provider (Doctor Evidence) reviewed and extracted data from the peer-reviewed literature through September 2009. Randomized controlled studies of at least three months’ duration assessing at least two prostaglandin analogs in patients with primary open-angle glaucoma, ocular hypertension, or normal-tension glaucoma were included. The primary endpoint was mean IOP. Summary estimates were created using random-effects models. The Q Chi-square test was used to assess statistical heterogeneity. RESULTS: Sixteen studies satisfied the inclusion criteria and were analyzed. On average, greater IOP-lowering was seen with bimatoprost relative to latanoprost (1 mmHg, P = 0.025) and travoprost (0.8 mmHg, P = 0.033) based on mean IOP after 12–26 weeks of treatment. No statistical difference was observed in IOP-lowering between latanoprost and travoprost (P = 0.841). Findings were similar to previously published meta-analyses of topical prostaglandin analogs. CONCLUSION: Systematic reviews relying on meta-analytic techniques to create summary statistics are considered to be the “gold standard” for synthesizing evidence to support clinical decision-making. However, the process is time-consuming, labor-intensive, and outside the capability of most formulary managers. We have demonstrated the effectiveness of a commercial service that facilitates the process of conducting such reviews

A multicenter evaluation of the efficacy and duration of action of alcaftadine 0.25% and olopatadine 0.2% in the conjunctival allergen challenge model

Background: The purpose of this study was to evaluate the efficacy and duration of action of once-daily dosing with alcaftadine 0.25% ophthalmic solution and olopatadine 0.2% ophthalmic solution as compared with placebo in the prevention of ocular itching, and to directly compare the efficacy of alcaftadine 0.25% with olopatadine 0.2% in the prevention of ocular itching associated with allergic conjunctivitis using the conjunctival allergen challenge model. Methods: Subjects with allergic conjunctivitis (n = 127) were enrolled in a multicenter, double-masked, randomized, active-controlled and placebo-controlled clinical trial. Using the conjunctival allergen challenge model, this study was conducted over the course of approximately 5 weeks. Subjects were randomized into one of three treatment arms: alcaftadine 0.25% ophthalmic solution, olopatadine 0.2% ophthalmic solution, or placebo. Study medications were administered twice over the course of the trial. The primary efficacy measure for the study was ocular itching evaluated by the subject at 3, 5, and 7 minutes post challenge. Secondary endpoints, measured at 7, 15, and 20 minutes post challenge, included conjunctival, ciliary, and episcleral redness, lid swelling, chemosis, and tearing. Duration of action was measured at 16 and 24 hours post-instillation of the study medication at visits 3 and 4, respectively. Results: For the primary measure of ocular itching, both actives, alcaftadine 0.25% and olopatadine 0.2%, were statistically superior to placebo at all three measured time points for both the 16-hour and 24-hour measures (P < 0.0001). Eyes treated with alcaftadine 0.25% had numerically lower mean ocular itching scores than eyes treated with olopatadine 0.2% at every time point, and this difference was statistically significant at the 3-minute time point 16 hours post instillation (P = 0.026). Eyes treated with alcaftadine 0.25% and with olopatadine 0.2% displayed significantly less lid swelling relative to placebo at every time point for the 16-hour and 24-hour post-instillation visits (P < 0.005). Alcaftadine 0.25% was the only active treatment that provided statistically significant relief of chemosis at every time point of the 24-hour post-instillation visit. Conclusion: Both the alcaftadine 0.25% and olopatadine 0.2% ophthalmic solutions provided highly effective relief of ocular itching at both 16 and 24 hours post-instillation. Treatment differences between the actives were most pronounced at the earliest time point (3 minutes post-challenge) following conjunctival allergen challenge (16 hours), when alcaftadine 0.25% ophthalmic solution was statistically superior to olopatadine 0.2% ophthalmic solution. Alcaftadine 0.25% was the only treatment to provide significant relief from chemosis at both 16 and 24 hours post-instillation. Both active treatments and placebo were generally safe and well tolerated

Regulation of ABCA1 by AMD-Associated Genetic Variants and Hypoxia in iPSC-RPE

Age-related macular degeneration (AMD) is a progressive disease of the macula characterized by atrophy of the retinal pigment epithelium (RPE) and photoreceptor degeneration, leading to severe vision loss at advanced stages in the elderly population. Impaired reverse cholesterol transport (RCT) as well as intracellular lipid accumulation in the RPE are implicated in AMD pathogenesis. Here, we focus on ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transport protein in the RPE, and analyze conditions that lead to ABCA1 dysregulation in induced pluripotent stem cell (iPSC)-derived RPE cells (iRPEs). Our results indicate that the risk-conferring alleles rs1883025 (C) and rs2740488 (A) in ABCA1 are associated with increased ABCA1 mRNA and protein levels and reduced efficiency of cholesterol efflux from the RPE. Hypoxia, an environmental risk factor for AMD, reduced expression of ABCA1 and increased intracellular lipid accumulation. Treatment with a liver X receptor (LXR) agonist led to an increase in ABCA1 expression and reduced lipid accumulation. Our data strengthen the homeostatic role of cholesterol efflux in the RPE and suggest that increasing cellular cholesterol export by stimulating ABCA1 expression might lessen lipid load, improving RPE survival and reducing the risk of developing AMD

Ocular Itch Relief with Alcaftadine 0.25% Versus Olopatadine 0.2% in Allergic Conjunctivitis: Pooled Analysis of Two Multicenter Randomized Clinical Trials

Introduction: The efficacy and safety of the once-daily topical ophthalmic solutions, alcaftadine 0.25% and olopatadine 0.2%, in preventing ocular itching associated with allergic conjunctivitis were evaluated. Methods: Pooled analysis was conducted of two double-masked, multicenter, active- and placebo-controlled studies using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis. Subjects were randomized 1:1:1 to receive alcaftadine 0.25%, olopatadine 0.2%, or placebo. The primary efficacy measure was subject-evaluated mean ocular itching at 3 min post-CAC and 16 h after treatment instillation. Secondary measures included ocular itching at 5 and 7 min post-CAC. Ocular itch was determined over all time points measured (3, 5, and 7 min) post-CAC and the proportion of subjects with minimal itch (itch score <1) and zero itch (itch score = 0) was also assessed. Results: A total of 284 subjects were enrolled in the two studies. At 3 min post-CAC and 16 h after treatment instillation, alcaftadine 0.25% achieved a significantly lower mean itch score compared with olopatadine 0.2% (0.50 vs. 0.87, respectively; P = 0.0006). Alcaftadine demonstrated a significantly lower mean itch score over all time points compared with olopatadine (0.68 vs. 0.92, respectively; P = 0.0390); both alcaftadine- and olopatadine-treated subjects achieved significantly lower overall mean ocular itching scores compared with placebo (2.10; P < 0.0001 for both actives). Minimal itch over all time points was reported by 76.1% of alcaftadine-treated subjects compared with 58.1% of olopatadine-treated subjects (P = 0.0121). Treatment with alcaftadine 0.25% and olopatadine 0.2% was safe and well tolerated; no serious adverse events were reported. Conclusion: Once-daily alcaftadine 0.25% ophthalmic solution demonstrated greater efficacy in prevention of ocular itching compared with olopatadine 0.2% at 3 min post-CAC (primary endpoint), and over all time points, 16 h post-treatment instillation. Alcaftadine and olopatadine both provided effective relief compared with placebo and were generally well tolerated. Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0155-3) contains supplementary material, which is available to authorized users

Long‐term surveillance biopsy: Is it necessary after pediatric heart transplant?

Due to limited and conflicting data in pediatric patients, long‐term routine surveillance endomyocardial biopsy (RSB) in pediatric heart transplant (HT) remains controversial. We sought to characterize the rate of positive RSB and determine factors associated with RSB‐detected rejection. Records of patients transplanted at a single institution from 1995 to 2015 with >2 year of post‐HT biopsy data were reviewed for RSB‐detected rejections occurring >2 year post‐HT. We illustrated the trajectory of significant rejections (ISHLT Grade ≥3A/2R) among total RSB performed over time and used multivariable logistic regression to model the association between time and risk of rejection. We estimated Kaplan‐Meier freedom from rejection rates by patient characteristics and used the log‐rank test to assess differences in rejection probabilities. We identified the best‐fitting Cox proportional hazards regression model. In 140 patients, 86% did not have any episodes of significant RSB‐detected rejection >2 year post‐HT. The overall empirical rate of RSB‐detected rejection >2 year post‐HT was 2.9/100 patient‐years. The percentage of rejection among 815 RSB was 2.6% and remained stable over time. Years since transplant remained unassociated with rejection risk after adjusting for patient characteristics (OR = 0.98; 95% CI 0.78‐1.23; P = 0.86). Older age at HT was the only factor that remained significantly associated with risk of RSB‐detected rejection under multivariable Cox analysis (P = 0.008). Most pediatric patients did not have RSB‐detected rejection beyond 2 years post‐HT, and the majority of those who did were older at time of HT. Indiscriminate long‐term RSB in pediatric heart transplant should be reconsidered given the low rate of detected rejection.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147767/1/petr13330_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147767/2/petr13330.pd

Effects of preservation methods of muscle tissue from upper-trophic level reef fishes on stable isotope values (δ13C and δ15N)

© The Author(s), 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PeerJ 3 (2015): e874, doi:10.7717/peerj.874.Research that uses stable isotope analysis often involves a delay between sample collection in the field and laboratory processing, therefore requiring preservation to prevent or reduce tissue degradation and associated isotopic compositions. Although there is a growing literature describing the effects of various preservation techniques, the results are often contextual, unpredictable and vary among taxa, suggesting the need to treat each species individually. We conducted a controlled experiment to test the effects of four preservation methods of muscle tissue from four species of upper trophic-level reef fish collected from the eastern Gulf of Mexico (Red Grouper Epinephelus morio, Gag Mycteroperca microlepis, Scamp Mycteroperca phenax, and Red Snapper Lutjanus campechanus). We used a paired design to measure the effects on isotopic values for carbon and nitrogen after storage using ice, 95% ethanol, and sodium chloride (table salt), against that in a liquid nitrogen control. Mean offsets for both δ13C and δ15N values from controls were lowest for samples preserved on ice, intermediate for those preserved with salt, and highest with ethanol. Within species, both salt and ethanol significantly enriched the δ15N values in nearly all comparisons. Ethanol also had strong effects on the δ13C values in all three groupers. Conversely, for samples preserved on ice, we did not detect a significant offset in either isotopic ratio for any of the focal species. Previous studies have addressed preservation-induced offsets in isotope values using a mass balance correction that accounts for changes in the isotope value to that in the C/N ratio. We tested the application of standard mass balance corrections for isotope values that were significantly affected by the preservation methods and found generally poor agreement between corrected and control values. The poor performance by the correction may have been due to preferential loss of lighter isotopes and corresponding low levels of mass loss with a substantial change in the isotope value of the sample. Regardless of mechanism, it was evident that accounting for offsets caused by different preservation methods was not possible using the standard correction. Caution is warranted when interpreting the results from specimens stored in either ethanol or salt, especially when using those from multiple preservation techniques. We suggest the use of ice as the preferred preservation technique for muscle tissue when conducting stable isotope analysis as it is widely available, inexpensive, easy to transport and did not impart a significant offset in measured isotopic values. Our results provide additional evidence that preservation effects on stable isotope analysis can be highly contextual, thus requiring their effects to be measured and understood for each species and isotopic ratio of interest before addressing research questions.Funding was provided by a grant to CD Stallings and TS Switzer from the National Oceanic and Atmospheric Administration, Cooperative Research Program (NA12NMF4540081)