Levels of the HtrA1 Protein in Serum and Vitreous Humor Are Independent of Genetic Risk for Age-Related Macular Degeneration at the 10q26 Locus.

Purpose: The purpose of this study was to determine if levels of the HtrA1 protein in serum or vitreous humor are influenced by genetic risk for age-related macular degeneration (AMD) at the 10q26 locus, age, sex, AMD status, and/or AMD disease severity, and, therefore, to determine the contribution of systemic and ocular HtrA1 to the AMD disease process. Methods: A custom-made sandwich ELISA assay (SCTM ELISA) for detection of the HtrA1 protein was designed and compared with three commercial assays (R&D Systems, MyBiosource 1 and MyBiosource 2) using 65 serum samples. Concentrations of HtrA1 were thereafter determined in serum and vitreous samples collected from 248 individuals and 145 human donor eyes, respectively. Results: The SCTM ELISA demonstrated high specificity, good recovery, and parallelism within its linear detection range and performed comparably to the R&D Systems assay. In contrast, we were unable to demonstrate the specificity of the two assays from MyBioSource using either recombinant or native HtrA1. Analyses of concentrations obtained using the validated SCTM assay revealed that genetic risk at the 10q26 locus, age, sex, or AMD status are not significantly associated with altered levels of the HtrA1 protein in serum or in vitreous humor (P > 0.05). Conclusions: HtrA1 levels in serum and vitreous do not reflect the risk for AMD associated with the 10q26 locus or disease status. Localized alteration in HTRA1 expression in the retinal pigment epithelium, rather than systemic changes in HtrA1, is the most likely driver of elevated risk for developing AMD among individuals with risk variants at the 10q26 locus.

Vitreomacular interface abnormalities in the Ghanaian African.

BACKGROUND/OBJECTIVE: Describe vitreomacular interface abnormalities (VMIA) using spectral-domain optical coherence tomography (SD-OCT), and correlations with age-related macular degeneration (AMD) grade in Ghanaian Africans. SUBJECTS/METHODS: Prospective, cross-sectional study of adults aged ≥50 years recruited in Ghana AMD Study. Participant demographics, medical histories, ophthalmic examination, digital colour fundus photography (CFP) were obtained. High-resolution five-line raster OCT, Macular Cube 512 × 128 scans, and additional line scans in areas of clinical abnormality, were acquired. SD-OCT VMI features classified by International Vitreomacular Traction Study Group system and relationships to AMD grade were evaluated. OUTCOMES: VMIA prevalence, posterior vitreous detachment (PVD), vitreomacular adhesions (VMA), vitreomacular traction (VMT), epiretinal membranes (ERM), correlations with AMD grade. RESULTS: The full Ghana AMD cohort included 718 participants; 624 participants (1248 eyes) aged ≥50 years (range = 50-101, mean = 68.8), 68.9% female were included in this analysis. CFP with OCT scans were available for 776 eyes (397 participants); 707 (91.1%) had gradable CFP and OCT scans for both AMD and VMI grading forming the dataset for this report. PVD was absent in 504 (71.3%); partial and complete PVD occurred in 16.7% and 12.0% respectively. PVD did not increase with age (p = 0.720). VMIA without traction and macular holes were observed in 12.2% of eyes; 87.8% had no abnormalities. VMIA was not significantly correlated with AMD grade (p = 0.819). CONCLUSIONS: This provides the first assessment of VMIA in Ghanaian Africans. VMIA are common in Africans; PVD may be less common than in Caucasians. There was no significant association of AMD grade with VMIA.

Characterization of West African Crystalline Macular Dystrophy in the Ghanaian Population.

OBJECTIVE: West African crystalline maculopathy (WACM) is characterized by the presence of macular hyperrefractile crystal-like deposits. Although the underlying pathophysiology has not been elucidated, a few biologic drivers have been proposed. We analyzed a large WACM case series to gain a more robust understanding of its features and etiology. DESIGN: Prospective, cross-sectional cohort study. SUBJECTS: Participants with WACM were selected from the large cohort recruited in the Ghana Age-Related Macular Degeneration Study. METHODS: Demographic and detailed medical histories, full ophthalmic examinations, digital color fundus photographs, and OCT images were obtained. All cases with WACM were evaluated by 3 retina experts. Crystal numbers, location, and distribution were determined. Associations between WACM and White age-related macular degeneration (AMD) risk variants were assessed using Firth's bias-reduced logistic regression, including age and sex as covariates. MAIN OUTCOME MEASURES: Phenotypic features of, and genetic associations with, WACM. RESULTS: West African crystalline maculopathy was identified in 106 eyes of 53 participants: 22 were bilateral and 24 were unilateral. Grading for AMD was not possible in 1 eye in 7 participants with WACM; therefore, laterality was not assessed in these subjects. Thirty-eight participants were women and were 14 men; sex was unrecorded for 1 participant. The mean age was 68.4 years (range, 45-101 years). Typical WACM crystals were demonstrated on OCT, which were more easily identified at high contrast and predominantly located at the inner limiting membrane. In eyes with copathology, crystals localized deeper in the inner retina, with wider retinal distribution over copathology lesions. There was no association with age or sex. A significant association was observed between the complement factor H (CFH) 402H risk variant and WACM. CONCLUSIONS: This study confirms the localization of crystals adjacent to the inner limiting membrane and distribution over lesions in eyes with copathology. The evaluation of OCT images under high contrast allows improved identification. West African crystalline maculopathy may be associated with the CFH-CFHR5 AMD risk locus identified among Whites; however, it is also possible that the combination of crystals and the CFH 402H allele increases the risk for developing late AMD. Further analyses using larger sample sizes are warranted to identify causalities between genotype and WACM phenotype.

Comparison of the Morphology of the Foveal Pit Between African and Caucasian Populations.

Purpose: The purpose of this study was to characterize foveal pit morphology in an African (Ghanaian) population, to compare it to that of a Caucasian group and to determine if it varied with age in the two populations. Methods: The depth, diameter, slope, and volume of the foveal pit were interpolated from optical coherence tomography volume scans recorded in 84 Ghanaian and 37 Caucasian individuals. Their association with age, sex, and ethnicity was investigated using multilevel regression models. Results: The foveal pit differed significantly in width, slope, and volume between Ghanaian men and women (P < 0.001), but only in width and volume between Caucasian men and women (P < 0.01). In Ghanaians, age was associated with a narrowing of the foveal depression and a reduction of its volume. Overall, these changes were more pronounced in women as compared to men and were largely absent from the Caucasian group. When controlled for age, the foveal pit of Ghanaians was significantly wider and larger in volume as compared to the Caucasian group (P < 0.001). Conclusions: The morphology of the foveal pit differs between African and Caucasian individuals. These anatomic differences should be considered when examining differences in prevalence and clinical features of vitreoretinal disorders involving the fovea between the two populations. Translational Relevance: Differences in retinal anatomy may partly explain variations in the prevalence and clinical features of retinal diseases between Africans and Caucasians. Such differences should be adequately considered in diagnoses and monitoring of ocular diseases in patients with African ancestry.

Firearm-related injury and death in the United States: a call to action from 8 health professional organizations and the American Bar Association.

Deaths and injuries related to firearms constitute a major public health problem in the United States. In response to firearm violence and other firearm-related injuries and deaths, an interdisciplinary, interprofessional group of leaders of 8 national health professional organizations and the American Bar Association, representing the official policy positions of their organizations, advocate a series of measures aimed at reducing the health and public health consequences of firearms. The specific recommendations include universal background checks of gun purchasers, elimination of physician "gag laws," restricting the manufacture and sale of military-style assault weapons and large-capacity magazines for civilian use, and research to support strategies for reducing firearm-related injuries and deaths. The health professional organizations also advocate for improved access to mental health services and avoidance of stigmatization of persons with mental and substance use disorders through blanket reporting laws. The American Bar Association, acting through its Standing Committee on Gun Violence, confirms that none of these recommendations conflict with the Second Amendment or previous rulings of the U.S. Supreme Court.

Fundus autofluorescence characteristics of nascent geographic atrophy in age-related macular degeneration.

PURPOSE: We examined the fundus autofluorescence (FAF) characteristics of nascent geographic atrophy (nGA), pathological features preceding the development of drusen-associated atrophy in eyes with age-related macular degeneration (AMD) that can be visualized using high-resolution optical coherence tomography (OCT). METHODS: Spectral-domain OCT (SD-OCT) and FAF imaging were performed longitudinally in 221 eyes with intermediate AMD (having at least drusen >125 µm), and seven areas that developed drusen-associated atrophy in five eyes were examined and categorized with respect to FAF characteristics. These categories then were used to characterize 49 areas of nGA or drusen-associated atrophy on SD-OCT identified in a cross-sectional study with 230 participants with bilateral intermediate AMD. RESULTS: Sequential imaging revealed that FAF characteristics in the atrophic areas could be grouped into three categories: predominantly hyperautofluorescent (hyperAF), presence of both hyper- and hypoautofluorescence (mixed AF), or predominantly hypoautofluorescent (hypoAF). In the cross-sectional study, the FAF characteristics were significantly dependent on the type of atrophic area (P = 0.002), where areas of nGA appeared most commonly as being mixed AF (63%), while areas of drusen-associated atrophy most commonly as hypoAF (86%). CONCLUSIONS: Fundus autofluorescence imaging revealed that areas of nGA were most commonly characterized by both hyper- and hypoautofluorescent changes, which differs from areas of drusen-associated atrophy that most often appeared hypoautofluorescent. These findings provide important insights into the FAF characteristics of areas undergoing atrophic changes in eyes still considered to be in the early stages of AMD by current methods, and thus assist in the characterization of disease severity in these early stages.

Optical coherence tomography-defined changes preceding the development of drusen-associated atrophy in age-related macular degeneration.

PURPOSE: To characterize the pathological changes preceding the development of drusen-associated atrophy in eyes with age-related macular degeneration (AMD) using spectral-domain optical coherence tomography (SD-OCT). DESIGN: Longitudinal and cross-sectional retrospective observational study. PARTICIPANTS: A total of 181 participants with intermediate AMD in at least 1 eye (141 unilateral, 40 bilateral) were assessed longitudinally. A total of 230 participants with bilateral intermediate AMD (40 longitudinal participants with an additional 190 participants) were analyzed cross-sectionally. METHODS: Spectral-domain OCT, color fundus photography (CFP), near-infrared reflectance, and fundus autofluorescence imaging were performed in all participants at cross-section and every 3 months for up to 30 months in the longitudinal study. Spectral-domain OCT volume scans were examined for features that portend the development of drusen-associated atrophy, and the topography, prevalence, and risk factors of these features were determined through cross-sectional analysis. MAIN OUTCOME MEASURES: The pathological features on SD-OCT preceding the development of drusen-associated atrophy and the characteristics of these features. RESULTS: Twenty areas from 16 eyes of 16 participants developed drusen-associated atrophy after an average of 20 months (range, 8-30 months). Spectral-domain OCT features unique in these areas included: subsidence of the outer plexiform layer (OPL) and inner nuclear layer (INL), and development of a hyporeflective wedge-shaped band within the limits of the OPL. These characteristics were termed "nascent geographic atrophy" (nGA), describing features that portend the development of drusen-associated atrophy. Cross-sectional examination of participants with bilateral intermediate AMD revealed that independent risk factors for the presence of nGA included the presence of pigmentary changes (odds ratio [OR], 16.84; 95% confidence interval [CI], 2.42-117.24) and nGA in the fellow eye (OR, 4.15; 95% CI, 1.12-15.34); nGA was present in 21.9% of participants with drusen >125 µm and pigmentary changes in both eyes. CONCLUSIONS: This study identified pathological changes occurring before the development of drusen-associated atrophy using SD-OCT, which we defined as nGA. Although nGA is undetectable on CFP, it is important for determining the risk of future vision loss in AMD and could be used as an earlier surrogate end point in interventional trials targeting the early stages of AMD.

Reticular pseudodrusen: a risk factor for geographic atrophy in fellow eyes of individuals with unilateral choroidal neovascularization.

PURPOSE: To determine whether reticular pseudodrusen (RPD) confer an increased risk of progression to late-stage age-related macular degeneration (AMD) in fellow eyes of those recently diagnosed with unilateral choroidal neovascularization (CNV). DESIGN: Retrospective study. PARTICIPANTS: Two hundred consecutive participants with CNV secondary to AMD in 1 eye and no signs of late-stage AMD in the fellow eye. METHODS: Clinical examination and comprehensive retinal imaging, including spectral-domain optical coherence tomography, near-infrared reflectance (NIR), and color fundus photography, at baseline and every follow-up visit. MAIN OUTCOME MEASURES: Incidence of geographic atrophy (GA) and CNV in the fellow eye. RESULTS: Mean age ± standard deviation was 77±7 years, and 61% of the cohort were female. Fifty-eight percent (n = 116) had RPD, 68% had drusen of 125 µm or more, 36% had pigmentary changes, 10% had both drusen of 125 µm or more and pigmentary changes, and 17% had only RPD in their fellow eyes. After a mean follow-up of 2.3 years, CNV developed in 36% of patients and GA developed in 14% of patients. Those with RPD demonstrated late-stage AMD (61% vs. 33.4%; P <0.001) and GA (22.4% with RPD vs. 2.4% without RPD; P <0.001) more often. The presence of reticular pseudodrusen was an independent risk factor for the development of GA (hazard ratio [HR], 4.93; P = 0.042), but not for CNV (HR, 1.19; P = 0.500), at least within the follow-up of this study. Both drusen of 125 µm or more and pigmentary changes at baseline were significant risk factors for the development of CNV and GA (HR, 1.96-11.73; P ≤0.020). CONCLUSIONS: Reticular pseudodrusen seem to confer an increased risk of progression to GA, in addition to drusen and pigmentary changes. The presence of RPD needs to be taken into account when discussing a patient's prognosis and planning management.

Intraocular pressure response to medication in a clinical setting: the Marshfield Clinic Personalized Medicine Research Project.

PURPOSE: To estimate glaucoma and ocular hypertension prevalence and to describe temporal trends in prescribing patterns and intraocular pressure (IOP) response to topical medications used in glaucoma and ocular hypertension. MATERIALS AND METHODS: The medical records of adult subjects enrolled in the population-based Marshfield Clinic Personalized Medicine Research Project were searched to identify participants who had been diagnosed with ocular hypertension or glaucoma and prescribed agent(s) to lower IOP. All IOPs before and after prescription of the IOP agents were recorded. RESULTS: As of December 31, 2005, 18,773 adults were enrolled in the Personalized Medicine Research Project, 57.1% were female, and their mean age was 50.3 years (range, 18 to 101 y). The overall rate of definite glaucoma in subjects aged 50 years and above was 2.1% (95% confidence interval=1.2, 2.4) and the rate of treated ocular hypertension was 1.4% (95% confidence interval=1.2, 1.7). Topical beta-blockers were the agents prescribed for the majority of subjects until the year 2000, when prostaglandins, first used in 1995, became the primary agent prescribed. In 2005, 75% of subjects used prostaglandin analogs and 46% used topical beta-blockers. The largest relative reduction in IOP in the first 3 months after prescription was observed for prostaglandin analogs (21.4% mean relative reduction), followed by beta-blockers (20.9% mean relative reduction). There has been a significant decrease over time in mean IOP before initiating medical therapy (linear regression beta coefficient=-0.30, P<0.0001, r=0.09). CONCLUSIONS: In this clinic-based setting, we found that treatment of glaucoma has changed over the past 20 years, with ophthalmologists more likely to begin treatment at lower baseline levels of IOP, and prostaglandin analogs the most commonly prescribed and agent to lower IOP.

Porcine sclera: thickness and surface area.

PURPOSE: To assess the thickness and surface area of porcine sclera. METHODS: One hundred twenty-eight porcine globes were sectioned from the center of the cornea to the region of the optic nerve. Photographs of the sectioned sclera including a millimeter scale were taken. Photographic slides were projected onto blank paper, and the scleral silhouette was traced. Perpendicular thickness measurements were taken at 1-mm intervals from the limbus to the optic nerve. The sclera of 18 porcine eyes were cut into small pieces, and the surface area was calculated with computerized digital tracing software. RESULTS: The scleral thickness near the corneal scleral limbus was 0.83 +/- 0.2, 0.91 +/- 0.17, and 1.12 +/- 0.23 mm in the small-, medium-, and large-sized pigs, respectively. Thickness decreased to minimum of 0.31 +/- 0.07, 0.35 +/- 0.1, and 0.43 +/- 0.16 mm at a distance of 5 mm from the limbus in the small- and medium-sized pigs and 6 mm in the large-sized pigs, respectively. The mean scleral surface area was 7.78 +/- 0.66, 9.66 +/- 0.75, and 11.92 +/- 1.57 cm(2) in the small-, medium-, and large-sized pigs, whereas the corneal surface area was 1.09 +/- 0.07, 1.15 +/- 0.09, and 1.40 +/- 0.19 cm(2), respectively. CONCLUSIONS: Porcine scleral thickness is very similar to human scleral thickness. The porcine model is an excellent model for studying transscleral drug delivery.