Whole-Exome Sequencing of Patients with Posterior Segment Uveitis.
American journal of ophthalmology
OBJECTIVE: To elucidate molecular risk factors for posterior segment uveitis using a functional genomics approach.DESIGN: Genetic Association Cohort Study.METHODS: SETTING: Single-center study at an academic referral center.STUDY POPULATION: 164 patients with clinically diagnosed uveitis of the posterior segment.MAIN OUTCOME MEASURES: Exome sequencing was used to detect variants identified in 164 patients with posterior segment uveitis. A phenotype-driven analysis, protein structural modeling and in silico calculations were then used to rank and predict the functional consequences of key variants.RESULTS: A total of 203 single nucleotide variants, in 23 genes across 164 patients, were included in this study. Both known and novel variants were identified in genes previously implicated in specific types of syndromic uveitis - such as NOD2 (Blau Syndrome) and CAPN5 NIV (Neovascular Inflammatory Vitreoretinopathy) - as well as variants in genes not previously linked to posterior segment uveitis. Based on a ranked list and protein-protein-interaction network, missense variants in NOD-like receptor family genes (NOD2, NLRC4, NLRP3, and NLRP1), CAPN5, and TYK2 were characterized via structural modeling and in silico calculations to predict how specific variants might alter protein structure and function. The majority of analyzed variants were notably different from wild type.CONCLUSIONS: This study implicates new pathways and immune signaling proteins that may be associated with posterior segment uveitis susceptibility. A larger cohort and functional studies will help validate the pathogenicity of the mutations identified. In specific cases, whole exome sequencing can help diagnose non-syndromic uveitis patients harboring known variants for syndromic inflammatory diseases.
View details for DOI 10.1016/j.ajo.2020.07.021
View details for PubMedID 32707200
Assessment of Online Sites Reliability, Accountability, Readability, Accessibility and Translation for Intravitreal Injections.
Patients increasingly use the internet to access health-related information to further understand their treatments and conditions. This study compares the quality, accountability, readability, accessibility and presence of translation between private and academic online source material available to the public regarding intravitreal injections.Cross-sectional analysis PARTICIPANTS: Top 20 websites on a Google search for the terms 'eye injections', 'intravitreal injections' and 'anti-VEGF injections'.Websites were classified as private or academic. Quality and accountability were assessed using the internationally recognized DISCERN criteria and the Health on the Net (HONcode). All 20 sites were independently graded by 2 retinal physicians and differences were adjudicated by a third experienced retinal physician. Readability was evaluated using an online tool that provides a consensus readability grade level. The presence of and languages available for translation were recorded. The top 5 ranked websites' content quality, accountability and readability was also compared with the other 15 websites.Primary outcome measure is comparing the DISCERN and HONcode quality and accountability scores between academic and private websites. Secondary outcome measures include evaluating readability, accessibility and presence of translation (in particular, Spanish).Eleven academic and 9 private websites were included. The overall mean score using DISCERN criteria for the academic websites (3.11±0.46) was significantly higher than that of private websites (2.23±0.61; p<0.007). Similarly, out of a possible total 14 points for the HONcode, the average quality score for academic websites (10.91±2.66) was higher compared to private websites (6.44±3.36; p<0.009). The mean consensus reading grade level was similar between academic (11.73±1.68) and private websites (11.78±1.48; p=0.94). Spanish translation was offered by only 7 of the 20 websites (5 academic and 2 private websites).The overall quality and accountability of online content for academic sites was significantly higher compared to private websites. Translation was rarely provided and the readability grade level was significantly higher for both groups than recommended. Improving the quality, accountability, readability, accessibility and incorporating translation in websites can help improve patients' health literacy regarding intravitreal injections, potentially leading to increased adherence to therapy plans and improved treatment outcomes.
View details for DOI 10.1016/j.oret.2020.05.019
View details for PubMedID 32497854
Proteomic analysis of intermediate uveitis suggests myeloid cell recruitment and implicates IL-23 as a therapeutic target.
American journal of ophthalmology case reports
2020; 18: 100646
To profile vitreous protein expression of intermediate uveitis (IU) patients.We identified a mean of 363 ± 41 unique proteins (mean ± SD) in IU vitreous and 393 ± 69 unique proteins in control samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of liquid vitreous biopsies collected during pars plana vitrectomy. A total of 233 proteins were differentially expressed among control and IU samples, suggesting a protein signature that could distinguish the two groups. Pathway analysis identified 22 inflammatory mediators of the interleukin-12 (IL-12) signaling pathway in IU vitreous. Upstream regulator analysis identified downstream mediators of IL-23 and myeloid differentiation primary response protein (MYD88), both of which are involved in the recruitment and differentiation of myeloid cells. Taken together, our results suggest the recruitment of myeloid cells as an upstream pathway in the pathogenesis of IU.This study provides insights into proteins that will serve as biomarkers and therapeutic targets for IU. These biomarkers will help design future clinical trials using rational molecular therapeutics.
View details for DOI 10.1016/j.ajoc.2020.100646
View details for PubMedID 32274442
View details for PubMedCentralID PMC7132169
- Serous Macular Detachment in Probable Vogt-Koyanagi-Harada Syndrome. JAMA ophthalmology 2020; 138 (5): e191981
Trend in the Utilization of Fluorescein Angiography and Optical Coherence Tomography
ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019
View details for Web of Science ID 000488628103338
Proteomic insight into the pathogenesis of CAPN5-vitreoretinopathy.
2019; 9 (1): 7608
CAPN5 Neovascular Inflammatory Vitreoretinopathy (CAPN5-NIV; OMIM 193235) is a poorly-understood rare, progressive inflammatory intraocular disease with limited therapeutic options. To profile disease effector proteins in CAPN5-NIV patient vitreous, liquid vitreous biopsies were collected from two groups: eyes from control subjects (n = 4) with idiopathic macular holes (IMH) and eyes from test subjects (n = 12) with different stages of CAPN5-NIV. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein expression changes were evaluated by principal component analysis, 1-way ANOVA (significant p-value < 0.05), hierarchical clustering, gene ontology, and pathway representation. There were 216 differentially-expressed proteins (between CAPN5-NIV and control vitreous), including those unique to and abundant in each clinical stage. Gene ontology analysis revealed decreased synaptic signaling proteins in CAPN5-NIV vitreous compared to controls. Pathway analysis revealed that inflammatory mediators of the acute phase response and the complement cascade were highly-represented. The CAPN5-NIV vitreous proteome displayed characteristic enrichment of proteins and pathways previously-associated with non-infectious posterior uveitis, rhegmatogenous retinal detachment (RRD), age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and proliferative vitreoretinopathy (PVR). This study expands our knowledge of affected molecular pathways in CAPN5-NIV using unbiased, shotgun proteomic analysis rather than targeted detection platforms. The high-levels and representation of acute phase response proteins suggests a functional role for the innate immune system in CAPN5-NIV pathogenesis.
View details for DOI 10.1038/s41598-019-44031-7
View details for PubMedID 31110225
- Proteomic Analysis of Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy American Academy of Ophthalmology 2018
Estimation of individual cumulative ultraviolet exposure using a geographically-adjusted, openly-accessible tool.
2016; 16 (1): 1-?
Estimates of an individual's cumulative ultraviolet (UV) radiation exposure can be useful since ultraviolet radiation exposure increases skin cancer risk, but a comprehensive tool that is practical for use in the clinic does not currently exist. The objective of this study is to develop a geographically-adjusted tool to systematically estimate an individual's self-reported cumulative UV radiation exposure, investigate the association of these estimates with skin cancer diagnosis, and assess test reliability.A 12-item online questionnaire from validated survey items for UV exposure and skin cancer was administered to online volunteers across the United States and results cross-referenced with UV radiation indices. Cumulative UV exposure scores (CUES) were calculated and correlated with personal history of skin cancer in a case-control design. Reliability was assessed in a separate convenience sample.1,118 responses were included in the overall sample; the mean age of respondents was 46 (standard deviation 15, range 18 - 81) and 150 (13 %) reported a history of skin cancer. In bivariate analysis of 1:2 age-matched cases (n = 149) and controls (n = 298), skin cancer cases were associated with (1) greater CUES prior to first skin cancer diagnosis than controls without skin cancer history (242,074 vs. 205,379, p = 0.003) and (2) less engagement in UV protective behaviors (p < 0.01). In a multivariate analysis of age-matched data, individuals with CUES in the lowest quartile were less likely to develop skin cancer compared to those in the highest quartile. In reliability testing among 19 volunteers, the 2-week intra-class correlation coefficient for CUES was 0.94. We have provided the programming code for this tool as well as the tool itself via open access.CUES is a useable and comprehensive tool to better estimate lifetime ultraviolet exposure, so that individuals with higher levels of exposure may be identified for counseling on photo-protective measures.
View details for DOI 10.1186/s12895-016-0038-1
View details for PubMedID 26790927
View details for PubMedCentralID PMC4721109
Patient With Gorlin Syndrome and Metastatic Basal Cell Carcinoma Refractory to Smoothened Inhibitors
2014; 150 (8): 877-879
IMPORTANCE Basal cell carcinomas (BCCs) in patients with Gorlin syndrome have been reported to be extremely sensitive to Smoothened (SMO) inhibitors, a novel targeted therapy against the Hedgehog pathway, because of characteristic mutations in these patients. A few cases of disease refractory to oral therapy with SMO inhibitors have been reported in patients with Gorlin syndrome and nonmetastatic BCCs, but refractory disease in distantly metastatic tumors has not been documented in this high-risk group. OBSERVATIONS A man with Gorlin syndrome and innumerable cutaneous BCCs presented with biopsy-proven BCC in his lungs. After SMO inhibitor therapy, almost all of his cutaneous tumors shrank, but his lung metastases did not. These lung metastases remained refractory to treatment despite institution of a second SMO inhibitor. CONCLUSIONS AND RELEVANCE We report a case of Gorlin syndrome in a patient with metastatic BCC refractory to SMO inhibitors. Furthermore, clinical responses in this patient's cutaneous tumors did not parallel the responses in the distant site. However, serial imaging after diagnosis of metastatic disease can be critical to monitor for response to therapy.
View details for DOI 10.1001/jamadermatol.2013.8744
View details for Web of Science ID 000345271000014