Direct Ophthalmic Healthcare Resource Use among Geographic Atrophy Patients in a Large Cohort from the United Kingdom

Objective To estimate the direct ophthalmic health care resource use in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Design Retrospective analysis of anonymized data derived from electronic medical records acquired at 10 clinical sites in the United Kingdom. Participants Patients aged ≥50 years with ≥1 eye with a clinical record of GA or, for comparison, bilateral early/intermediate AMD. Four subgroups were identified: GA in both eyes (GA : GA); GA in 1 eye, choroidal neovascularization (CNV) in the fellow eye (GA : CNV); GA in 1 eye with early or intermediate AMD in the fellow eye (GA : E); and early/intermediate AMD in both eyes (E : E). Methods Electronic medical records were analyzed to derive the median number of visits over the first 2 years following diagnosis of GA or early/intermediate AMD. Clinical tests recorded at visits were used to calculate estimated costs (payer perspective) of monitoring. Analyses were restricted to patients with an initial diagnosis on or after January 1, 2011 to represent present day monitoring and costs associated with AMD. Main Outcome Measures Median number of visits and estimated monitoring costs per patient (in £) over the first 2 years among patients with ≥2 years of follow-up and in the individual subgroups. Intravitreal treatment costs in the GA : CNV group were excluded. Results For all 3 GA subgroups (n = 1080), the median number of visits over the first 2 years was 5 and monitoring costs were £460.80 per patient. The GA : CNV subgroup (n = 355) had the highest number of visits (median, 15), with a cost of £1581, compared with the GA : E subgroup (n = 283; median 4 visits; cost ∼£369) and the GA : GA subgroup (n = 442; median 3 visits; cost ∼£277). Ophthalmic tests were conducted most frequently in the GA : CNV subgroup. Visits and costs in the E : E subgroup (n = 6079) were lower. Conclusions Resource use in patients with GA varies considerably and is strongly influenced by the concomitant presence of CNV and lack of monitoring strategies for GA

Ophthalmology research in the UK’s National Health Service: the structure and performance of the NIHR’s Ophthalmology research portfolio

Purpose- To report on the composition and performance of the portfolio of Ophthalmology research studies in the United Kingdom’s National Institute for Health Research (NIHR) Clinical Research Network (UK CRN). Methods- Ophthalmology studies open to recruitment between 1 April 2010 and 31 March 2018 were classified by: sub-specialty, participant age, gender of Chief Investigator, involvement of genetic investigations, commercial/ non-commercial, interventional/observational design. Frequency distributions for each covariate and temporal variation in recruitment to time and target were analysed. Results- Over 8 years, 137,377 participants were recruited (average of 15,457 participants/year; range: 5485–32,573) with growth by year in proportion of commercial studies and hospital participation in England (76% in 2017/18). Fourteen percent of studies had a genetic component and most studies (82%) included only adults. The majority of studies (41%) enrolled patients with retinal diseases, followed by glaucoma (17%), anterior segment and cataract (13%), and ocular inflammation (6%). Overall, 68% of non-commercial studies and 55% of commercial studies recruited within the anticipated time set by the study and also recruited to or exceeded the target number of participants. Conclusions- High levels of clinical research activity, growth and improved performance have been observed in Ophthalmology in UK over the past 8 years. Some sub-specialties that carry substantial morbidity and a very high burden on NHS services are underrepresented and deserve more patient-centred research. Yet the NIHR and its CRN Ophthalmology National Specialty Group has enabled key steps in achieving the goal of embedding research into every day clinical care

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters.

Funder: All funders per study are acknowledged in the Supplementary FileA new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Abstract: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia

Osteoblast CFTR inactivation reduces differentiation and osteoprotegerin expression in a mouse model of cystic fibrosis-related bone disease.

Low bone mass and increased fracture risk are recognized complications of cystic fibrosis (CF). CF-related bone disease (CFBD) is characterized by uncoupled bone turnover--impaired osteoblastic bone formation and enhanced osteoclastic bone resorption. Intestinal malabsorption, vitamin D deficiency and inflammatory cytokines contribute to CFBD. However, epidemiological investigations and animal models also support a direct causal link between inactivation of skeletal cystic fibrosis transmembrane regulator (CFTR), the gene that when mutated causes CF, and CFBD. The objective of this study was to examine the direct actions of CFTR on bone. Expression analyses revealed that CFTR mRNA and protein were expressed in murine osteoblasts, but not in osteoclasts. Functional studies were then performed to investigate the direct actions of CFTR on osteoblasts using a CFTR knockout (Cftr-/-) mouse model. In the murine calvarial organ culture assay, Cftr-/- calvariae displayed significantly less bone formation and osteoblast numbers than calvariae harvested from wildtype (Cftr+/+) littermates. CFTR inactivation also reduced alkaline phosphatase expression in cultured murine calvarial osteoblasts. Although CFTR was not expressed in murine osteoclasts, significantly more osteoclasts formed in Cftr-/- compared to Cftr+/+ bone marrow cultures. Indirect regulation of osteoclastogenesis by the osteoblast through RANK/RANKL/OPG signaling was next examined. Although no difference in receptor activator of NF-κB ligand (Rankl) mRNA was detected, significantly less osteoprotegerin (Opg) was expressed in Cftr-/- compared to Cftr+/+ osteoblasts. Together, the Rankl:Opg ratio was significantly higher in Cftr-/- murine calvarial osteoblasts contributing to a higher osteoclastogenesis potential. The combined findings of reduced osteoblast differentiation and lower Opg expression suggested a possible defect in canonical Wnt signaling. In fact, Wnt3a and PTH-stimulated canonical Wnt signaling was defective in Cftr-/- murine calvarial osteoblasts. These results support that genetic inactivation of CFTR in osteoblasts contributes to low bone mass and that targeting osteoblasts may represent an effective strategy to treat CFBD

Functional Outcomes of Gastrocnemius Recession for Isolated Gastrocnemius and Gastrocnemius-Soleus Contractures

Category: Ankle Introduction/Purpose: Contracture of the gastrocnemius muscle with or without involvement of the soleus muscle has long been proposed as an etiologic factor in the development of chronic pathology of the foot and ankle including among others plantar fasciitis, hallux valgus, metatarsalgia, and symptomatic pes planovalgus deformity. Very few studies have analyzed the effect on strength and function of the gastrocnemius recession and those that have, are limited by sample size and functional outcome tools utilized. This prospective study reports on strength and functional effect of the gastrocnemius recession utilizing a validated outcome measure on the largest sample size yet reported. Methods: We developed two treatment arms to achieve our aims. Twenty-four patients (25 extremities) underwent a gastrocnemius recession for isolated gastrocnemius and gastrocnemius-soleus contracture. In one arm, eight patients (8 extremities) prospectively underwent range of motion, isokinetic and isometric testing pre-operatively and at 3 and 6 months post-operatively. Validated functional outcomes were also assessed using the Foot Function Index (FFI). In the second arm, an additional sixteen patients (17 extremities) prospectively completed the validated functional outcomes using the FFI. Variables were compared across three time intervals with repeated measure ANOVA with Bonferroni post hoc testing and t testing between control and operative sides was with IBM SPSS Statistics-Version 22. Results: The average age in the 24 patients (25 extremities) was 58.4 ± 15.2 years-old. Treatment for symptomatic pes planovalgus was the most common reason for surgery (10, 40%). Significant improvement in functional outcomes were observed across all three time points (p < 0.001) based on a multivariate repeated measures ANOVA for all 3 subscales (pain, disability, activity limitation) of the FFI. The improvement was significantly greater between pre-operative and 6 months post-operative intervals (p < 0.001) although significant improvements were observed between pre-operative and 3 months post-operative intervals (p=0.001). Range of motion significantly improved between pre-operative and 6 months post-operative intervals (p=0.023) and between 3 and 6 months post-operative intervals (p=0.012). No differences were observed in isokinetic and isometric testing. Conclusion: Analysis of results demonstrates improved range of motion and functional outcomes of the gastrocnemius recession between pre-operative and 6 months post-operative intervals for isolated gastrocnemius and gastrocnemius-soleus contracture