Jiangxia Wang

Replication of the TCF4 Intronic variant in Late-onset fuchs corneal dystrophy and evidence of independence from the FCD2 locus

PURPOSE Fuchs corneal dystrophy (FCD) is an autosomal dominant disease of the corneal endothelium with variable penetrance and expressivity. Recently, rs613872, an intronic variation of TCF4 associated with late-onset FCD, was reported. The present study was undertaken to examine this association in our cohort of FCD patients, to assess the significance of this finding, and to investigate the candidacy of TCF4 in the context of the mapped FCD2 locus. METHODS The authors recruited 170 patients with late-onset FCD and 180 age-matched controls. Blood samples were collected, and genomic DNA was extracted. A panel of nine SNPs spanning the entire TCF4 locus was genotyped both on this cohort and on three previously reported FCD2-linked families. The association of an individual SNP with late-onset FCD was evaluated with the Fisher exact test, and the coding exons and exon-intron boundaries of TCF4 were sequenced in 96 affected persons. RESULTS The risk allele G of rs613872 is associated significantly with late-onset FCD (odds ratio, 4.2; P = 4.28 x 10⁻¹⁵) and was present in male and female affected persons without any sex bias, replicating recent findings, though the authors found no apparent correlation with the severity of the disease phenotype. Moreover, the risk allele did not cosegregate with the disease phenotype in any of the three FCD2-linked families. The authors did not identify any pathogenic variants in the coding region of TCF4. CONCLUSIONS The authors report the first independent replication of rs613872 conferring risk of late-onset FCD. Their data suggest that this risk factor is likely independent of the FCD2 locus, whose causality remains unknown.

Regression of Choroidal Neovascularization Results in Macular Atrophy in Anti-Vascular Endothelial Growth Factor-Treated Eyes

PURPOSE To determine the incidence and progression of macular atrophy in patients with neovascular age-related macular degeneration (AMD) treated with vascular endothelial growth factor (VEGF) antagonists. DESIGN Retrospective interventional case series. METHODS All patients with neovascular AMD treated by the same physician during a 12-month period of ascertainment had all images from their entire follow-up period evaluated, and areas of retina that developed atrophy were compared to the same areas prior to the onset of anti-VEGF treatment. Longitudinal measurements of retinal atrophy were made. RESULTS In 39 patients, 52 eyes with neovascular AMD were identified. We excluded 5 eyes from analysis (4 had retinal pigment epithelium tears, and 1 had a laser scar). Fundus photographs of the remaining eyes showed that 18/47 eyes (38%) contained hypopigmented areas suggestive of atrophy within the macula at some time during follow-up. Spectral-domain optical coherence tomography confirmed that these areas had loss of retinal pigmented epithelium and ellipsoids zones, with or without subretinal material suggestive of subretinal fibrosis. Comparison of fundus photographs with fluorescein angiograms showed that in 13/18 eyes (72%), atrophy developed in areas previously occupied by choroidal neovascularization, and the other 5 eyes had atrophy prior to the onset of anti-VEGF treatment. The mean (± standard deviation) rate of increase in pure atrophic areas (no subretinal material) was 0.7 ± 0.8 mm(2) per year, with a range of 0.01-2.6 mm(2)/year. CONCLUSION Treatment of neovascular AMD with a VEGF-neutralizing protein can result in regression of choroidal neovascularization, which is sometimes associated with atrophy of overlying retina.

Prevalence and Severity of Fuchs Corneal Dystrophy in Tangier Island

PURPOSE To investigate the clinical and genetic features of late-onset Fuchs corneal dystrophy (FCD) on Tangier, an island in the Chesapeake Bay with an isolated population of approximately 500 individuals. DESIGN Observational, cross-sectional study. METHODS A total of 156 individuals born to inhabitants of Tangier Island volunteered to undergo ophthalmic evaluation. Medical history was ascertained prior to examination. All participants underwent anterior segment examination with slit-lamp biomicroscopy. Retroillumination photographs were acquired from affected individuals and the disease severity was compared with individuals from large families ascertained previously. Genomic DNA samples were investigated for the presence of the recently identified risk allele rs613872, an intronic variant of TCF4. RESULTS Of the 148 examined individuals who were at least 30 years of age, 32 showed the classical symptoms of late-onset FCD (21.6%), providing a minimum prevalence of 11% among individuals over the age of 50 years. Severity was significantly lower compared to 51 cases from unlinked families, among individuals either 50 to 70 or above 70 years of age (P = .05 and P = .01, respectively). Retroillumination photography analyses were suggestive of mild severity when compared with the disease phenotype associated with FCD1- and FCD2-linked families. The rs613872 variant was associated with a higher affectation rate (P = .01), while the wild-type allele was correlated with a higher proportion of subclinical disease (P = .01). CONCLUSIONS In this study population in Tangier, late-onset FCD manifests clinically with a mild phenotype and increased prevalence. The rs613872 variant correlates with increased affectation and a clinical disease phenotype.

Encouraging Influenza Vaccination Among Text4baby Pregnant Women and Mothers

INTRODUCTION Pregnant women, postpartum women, and infants are at high risk for complications from influenza. From October to November 2012, Text4baby, a free national text service for pregnant women and mothers of infants aged <1 year, implemented a module of interactive messages encouraging maternal influenza vaccination. A program evaluation examined whether a text-based reminder or tailored education improved self-reported influenza vaccination or intent to be vaccinated later in the influenza season among Text4baby participants. METHODS Nearly one third (28,609/89,792) of enrollees responded to a text asking about their vaccination plans. Those planning to receive vaccination were randomly assigned to receive an encouragement message or an encouragement message plus the opportunity to schedule a reminder (n=3,021 at follow-up). Those not planning to be vaccinated were randomly assigned to receive general education or education tailored to their reason for non-vaccination (n=3,820 at follow-up). The effect of the enhanced messages was assessed using multinomial logistic regression in 2013-2014. RESULTS A reminder increased the odds of vaccination at follow-up among mothers (AOR=2.0, 95% CI=1.4, 2.9) and of continued intent to be vaccinated later in the season (pregnant, AOR=2.1, 95% CI=1.4, 3.1; mother, AOR=1.7, 95% CI=1.1, 2.5). Among mothers not planning to be vaccinated because of cost, those who received a tailored message about low-cost vaccination had higher odds of vaccination at follow-up (AOR=1.9, 95% CI=1.1, 3.5). Other tailored messages were not effective. CONCLUSIONS Text reminders and tailored education may encourage influenza vaccination among this vulnerable population; both have now been incorporated into Text4baby.

Age-severity relationships in families linked to FCD2 with retroillumination photography

PURPOSE Fuchs corneal dystrophy (FCD) is a progressive disorder of the corneal endothelium and is pathologically defined by the presence of guttae, which are excrescences of the Descemet membrane. The present study was undertaken to investigate the age-severity relationship of the FCD2-linked disease phenotype using retroillumination photography and to compare it with the characteristics of FCD1. METHODS Two large families with multiple affected members were recruited. Exclusion analyses of the known late-onset FCD loci were completed with closely spaced STR markers, whereas genes associated with early- and late-onset FCD were investigated by bidirectional sequencing. Haplotypes were constructed, and two-point LOD scores were calculated. To document age-severity relationships, retroillumination photographs were acquired from members of both families. RESULTS Parametric linkage and haplotype analysis mapped both families to FCD2 with significant two-point LOD scores. A total of 70,249 guttae were counted in 14 persons from both families. A significant increase in guttae density in the inferotemporal region (P = 0.016) was observed, a pattern similarly observed in a family linked to FCD1. Similarly, FCD2-linked families display an exponential trend in severity with age, as was observed in a family linked to FCD1. Finally, comparison of FCD1 and FCD2 exponential models suggested that the FCD1 phenotype is significantly more severe (P = 0.01). CONCLUSIONS A combination of genetic mapping and retroillumination photography was used to quantify the severity of the disease phenotype associated with FCD2 and to compare it to the disease characteristics of FCD1. These data suggest that this approach might have sufficient resolution to discriminate between discrete genetic FCD backgrounds, which will potentially aid in patient management.

Geospatial Distribution and Clustering of Chlamydia trachomatis in Communities Undergoing Mass Azithromycin Treatment

PURPOSE We detected spatial clustering of households with Chlamydia trachomatis infection (CI) and active trachoma (AT) in villages undergoing mass treatment with azithromycin (MDA) over time. METHODS We obtained global positioning system (GPS) coordinates for all households in four villages in Kongwa District, Tanzania. Every 6 months for a period of 42 months, our team examined all children under 10 for AT, and tested for CI with ocular swabbing and Amplicor. Villages underwent four rounds of annual MDA. We classified households as having ≥1 child with CI (or AT) or having 0 children with CI (or AT). We calculated the difference in the K function between households with and without CI or AT to detect clustering at each time point. RESULTS Between 918 and 991 households were included over the 42 months of this analysis. At baseline, 306 households (32.59%) had ≥1 child with CI, which declined to 73 households (7.50%) at 42 months. We observed borderline clustering of households with CI at 12 months after one round of MDA and statistically significant clustering with growing cluster sizes between 18 and 24 months after two rounds of MDA. Clusters diminished in size at 30 months after 3 rounds of MDA. Active trachoma did not cluster at any time point. CONCLUSIONS This study demonstrates that CI clusters after multiple rounds of MDA. Clusters of infection may increase in size if the annual antibiotic pressure is removed. The absence of growth after the three rounds suggests the start of control of transmission.

CTG18.1 Expansion in TCF4 Increases Likelihood of Transplantation in Fuchs Corneal Dystrophy.

Purpose: Fuchs dystrophy is the leading indication of corneal transplantation in the United States. A CTG18.1 trinucleotide repeat in TCF4 correlates with increased severity in Fuchs dystrophy; however, quantitative estimates of increased transplantation risk, including effects of age and sex, are unclear. Methods: In a tertiary institution clinical practice, 574 participants were enrolled in a longitudinal study of Fuchs dystrophy after slit-lamp biomicroscopy confirmed significant central guttae and/or corneal transplantation in both eyes. We documented clinical history, examination findings, and demographic information. We acquired blood samples, extracted DNA, and sequenced the CTG18.1 trinucleotide repeat in TCF4. In this retrospective case–control study, the number of participants with triplet expansion, defined as greater than 40 CTG repeats, and transplantation status were assessed. Kaplan–Meier estimates of timing and transplantation events were produced. The Cox proportional hazard regression model was used to assess the relationship between age, sex, triplet expansion, and surgery. Results: A total of 106 participants (18.5%) previously underwent corneal transplantation in at least 1 eye at the time of initial evaluation. A higher proportion of individuals harboring allele expansion had undergone transplantation (78/357, 21.8%) compared with those without the expanded allele (28/217, 12.9%), a significant association (P = 0.007). The log-rank test demonstrates a significant difference in survival function over time (P = 0.027), with a hazard ratio of 1.64 (95% confidence interval, 1.05–2.55). Conclusions: Expansion of the TCF4 CTG trinucleotide repeat was associated with 1.64 times higher likelihood of corneal transplantation at a given age in patients with Fuchs dystrophy.

Development and Validation of an Improved Neurological Hemifield Test to Identify Chiasmal and Postchiasmal Lesions by Automated Perimetry

PURPOSE To improve the neurological hemifield test (NHT) using visual field data from both eyes to detect and classify visual field loss caused by chiasmal or postchiasmal lesions. METHODS Visual field and clinical data for 633 patients were divided into a training set (474 cases) and a validation set (159 cases). Each set had equal numbers of neurological, glaucoma, or glaucoma suspect cases, matched for age and for mean deviation between neurological and glaucoma cases. NHT scores as previously described and a new NHT laterality score were calculated. The ability of these scores to distinguish neurological from other fields was assessed with receiver operating characteristic (ROC) analysis. Three machine classifier algorithms were also evaluated: decision tree, random forest, and least absolute shrinkage and selection operator (LASSO). We also evaluated the ability of NHT to identify the type of neurological field defect (homonymous or bitemporal). RESULTS The area under the ROC curve (AUC) for the maximum NHT score was 0.92 (confidence interval [CI]: 0.87, 0.97). Using NHT laterality scores from each eye combined with the sum of NHT scores, the AUC improved to 0.93 (CI: 0.88, 0.98). The largest AUC for machine learning algorithms was for the LASSO method (0.96, CI: 0.92, 0.99). The NHT scores identified the type of neurological defect in 96% (158/164) of patients. CONCLUSIONS The new NHT distinguished neurological field defects from those of glaucoma and glaucoma suspects, providing accurate categorization of defect type. Its implementation may identify unsuspected neurological disease in clinical visual field testing.

Re: Grunwald et al.: risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials (ophthalmology 2014;121:150-61).

Dear Editor: In comparing multifocal to monofocal intraocular lenses implanted to create monovision, Wilkins et al graciously recognized me as the first to publish on the use of full ( 2.75 diopters in the near eye) monovision. However, the statement that only 1 previous study of monovision in cataract surgery has reported overall spectacle independence as an outcome measure misses the point of my report. I found that implanting a lens measured for distance in the dominant eye followed, once the success of the distance correction was confirmed, by a second implantation of a lens measured to create a 2.75-diopter correction in the near eye resulted in 110 of 120 (91%) patients with cataract achieving 20/30 vision in their dominant distance eye, along with J1 or better vision in their near eye. Table 3 in my paper outlines the use of optical aids. Only 7 patients wore any distance correction postoperatively (5.8%), 10 wore near (8.4%), 7 of whom wore both (5.8%), for a spectacle independence rate of 91.6%. Wilkins et al noted a 71.3% rate of spectacle independence using multifocal lenses, after 4 patients had bilateral and 2 patients had unilateral intraocular lens exchanges. No intraocular lens exchange was required in the Wilkins group of monovision patients or in mine. The implantation of monofocal intraocular lenses to create full monovision is a useful operative technique for providing spectacle independence in a safe and cost-effective manner.

Reversible retinal vessel closure from VEGF-induced leukocyte plugging

Clinical trials in patients with macular edema due to diabetic retinopathy or retinal vein occlusion (RVO) have shown that suppression of VEGF not only improves macular edema, but also reopens closed retinal vessels, prevents progression of vessel closure, and improves retinopathy. In this study, we show the molecular basis for those clinical observations. Increased retinal levels of VEGF in mice cause plugging of retinal vessels with leukocytes, vessel closure, and hypoxia. Suppression of VEGF reduces leukocyte plugging, causing reperfusion of closed vessels. Activation of VEGFR1 contributes to leukocyte recruitment, because it is significantly reduced by an anti-VEGFR1-neutralizing antibody. High VEGF increases transcriptional activity of NF-κB and expression of NF-κB target genes, particularly Vcam1. Injection of an anti-VCAM-1-neutralizing antibody reduces VEGF-induced leukocyte plugging. These data explain the broad range of benefits obtained by VEGF suppression in patients with ischemic retinopathies, provide an important insight into the pathogenesis of RVO and diabetic retinopathy, and suggest that sustained suppression of VEGF early in the course of these diseases may prevent vessel closure, worsening ischemia, and disease progression. This study also identifies VEGFR1 and VCAM-1 as molecular targets whose suppression could supplement VEGF neutralization for treatment of RVO and diabetic retinopathy.