Vitreoretinal lymphoma (VRL) is a rare ocular pathology that is notorious for mimicking chronic uveitis, which is a seemingly benign condition in comparison. The most common form of VRL is the diffuse large B-cell type, and there has been a high mortality rate. This dismal prognosis can be improved significantly if the disease is diagnosed early, but until now there is no consensus on an appropriate diagnostic algorithm. We conducted a retrospective search of PubMed Central^® and analyzed results from thirty-three studies that were published between 2011–2021. The chosen studies incorporated some popular testing tools for VRL, and our analyses focused on comparing the average sensitivity of five diagnostic methods. The methods included cytology including ancillary immunohistochemistry, Myeloid Differentiation Factor 88 (MyD88) mutation analysis, polymerase chain reaction (PCR) for monoclonal rearrangements of immunoglobulin heavy chain (IgH) and T-cell Receptor (TCR) genes, flow cytometry, and IL10 and IL6 analysis. Across the varied diagnostic methods employed in thirty-three studies explored in this analysis, MyD88 mutation assay emerged as a strong contender given its sensitivity and low coefficient of variation. There is an imminent need for the introduction of newer assays that can further improve the sensitivity of identifying MyD88 mutation in cancer cells seen in the vitreous.

Purpose: This study aimed to describe the choroidal features of ocular amyloidosis using multimodal imaging, to correlate these findings with systemic involvement, and to propose a choroidal grading system. Methods: Eleven patients with systemic amyloidosis were reviewed retrospectively. Each case was assigned a grade according to the severity of choroidal findings as determined by both enhanced depth imaging optical coherence tomography and indocyanine green angiography. The severity of systemic amyloidosis was then correlated with the choroidal involvement. Results: On indocyanine green angiography, all patients exhibited hyperfluorescent spots in the late stage and were classified according to preexisting criteria. On enhanced depth imaging optical coherence tomography, hyperreflective foci were seen in the choriocapillaris and Sattler's layer in Grade 1, partial loss of Sattler's layer was additionally seen in Grade 2, and a dense hyperreflective Haller's layer was seen in Grade 3. Choroidal grading scores were significantly correlated with the systemic severity score (P = 0.0014, Pearson's correlation coefficient; ρ = 0.83). Conclusion: With ocular amyloidosis, evaluation of choroidal characteristics using multimodal imaging may serve as a biomarker for systemic involvement.

To investigate potential biomarkers and biological processes associated with diabetic retinopathy (DR) using transcriptomic and proteomic data. The OmicsPred PheWAS application was interrogated to identify genes and proteins associated with DR and diabetes mellitus (DM) at a false discovery rate (FDR)-adjusted p-value of <0.05 and also <0.005. Gene Ontology PANTHER analysis and STRING database analysis were conducted to explore the biological processes and protein interactions related to the identified biomarkers. The interrogation identified 49 genes and 22 proteins associated with DR and/or DM; these were divided into those uniquely associated with diabetic retinopathy, uniquely associated with diabetes mellitus, and the ones seen in both conditions. The Gene Ontology PANTHER and STRING database analyses highlighted associations of several genes and proteins associated with diabetic retinopathy with adaptive immune response, valyl-TRNA aminoacylation, complement activation, and immune system processes. Our analyses highlight potential transcriptomic and proteomic biomarkers for DR and emphasize the association of known aspects of immune response, the complement system, advanced glycosylation end-product formation, and specific receptor and mitochondrial function with DR pathophysiology. These findings may suggest pathways for future research into novel diagnostic and therapeutic strategies for DR.

Purpose: To develop an algorithm and scripts to combine disparate multimodal imaging modalities and show its use by overlaying en-face optical coherence tomography angiography (OCTA) images and Optos ultra-widefield (UWF) retinal images using the Fiji (ImageJ) plugin BigWarp. Methods: Optos UWF images and Heidelberg en-face OCTA images were collected from various patients as part of their routine care. En-face OCTA images were generated and ten (10) images at varying retinal depths were exported. The Fiji plugin BigWarp was used to transform the Optos UWF image onto the en-face OCTA image using matching reference points in the retinal vasculature surrounding the macula. The images were then overlayed and stacked to create a series of ten combined Optos UWF and en-face OCTA images of increasing retinal depths. The first algorithm was modified to include two scripts that automatically aligned all the en-face OCTA images. Results: The Optos UWF image could easily be transformed to the en-face OCTA images using BigWarp with common vessel branch point landmarks in the vasculature. The resulting warped Optos image was then successfully superimposed onto the ten Optos UWF images. The scripts more easily allowed for automatic overlay of the images. Conclusions: Optos UWF images can be successfully superimposed onto en-face OCTA images using freely available software that has been applied to ocular use. This synthesis of multimodal imaging may increase their potential diagnostic value. Script A is publicly available at https://doi.org/10.6084/m9.figshare.16879591.v1 and Script B is available at https://doi.org/10.6084/m9.figshare.17330048.

Background/purpose: A comprehensive review of the degree of disorder in all genes in the Retinal Information Network (RetNet) Database is implicated in inherited retinal diseases (IRDs). Their association with a missense variation was evaluated. Methods: IRD genes from RetNet were included in this study. Publicly available data on the genome aggregation database (gnomAD) were used to analyze the number of total and pathogenic missense variants. Metapredict, an accurate and high-performance predictor that reproduces consensus disorder scores, was used to calculate disorder. Main outcome measures: The main outcome measures were percent disorder, percent pathogenicity, number of total missense variants, and percent total missense variation. Results: We included 287 RetNet genes with relevant data available from gnomAD. Mean percent disorder was 26.3% ± 26.0%, mean percent pathogenicity was 5.2% ± 11.0%, mean number of total missense variants was 424.4 ± 450.0, and mean percent total missense was 50.0% ± 13.4%. The percent disorder followed a bimodal distribution with the highest number of occurrences in the 0 to 10th disorder decile. The five outlier proteins in the first disorder decile with a higher-than-expected number of total missense variation were identified (HMCN1, ADGRV, USH2A, DYNC2H1, LAMA1, and SLC38A8). When excluded, % total missense was significantly associated with percent disorder (R = 0.238 and p = 0.0240). Conclusions: This novel study examining all genes implicated in IRDs found that the majority genes had a disorder in the 0 to 10th decile and were relatively intolerant to missense variation. This may have future utility when interpreting variants of undetermined significance and missense variants.

Intrinsically disordered regions (IDRs) are protein regions that are unable to fold into stable tertiary structures, enabling their involvement in key signaling and regulatory functions via dynamic interactions with diverse binding partners. An understanding of IDRs and their association with biological function may help elucidate the pathogenesis of inherited retinal diseases (IRDs). The main focus of this work was to investigate the degree of disorder in 14 proteins implicated in IRDs and their relationship with the number of pathogenic missense variants. Metapredict, an accurate, high-performance predictor that reproduces consensus disorder scores, was used to probe the degree of disorder as a function of the amino acid sequence. Publicly available data on gnomAD and ClinVar was used to analyze the number of pathogenic missense variants. We show that proteins with an over-representation of missense variation exhibit a high degree of disorder, and proteins with a high amount of disorder tolerate a higher degree of missense variation. These proteins also exhibit a lower amount of pathogenic missense variants with respect to total missense variants. These data suggest that protein function may be related to the overall level of disorder and could be used to refine variant interpretation in IRDs.