FULL-THICKNESS MACULAR HOLE CLOSURE WITH TOPICAL MEDICAL THERAPY.

PURPOSE: To examine the efficacy and clinical characteristics of successful full-thickness macular hole closure with topical therapy. METHODS: Retrospective case series of full-thickness macular holes managed by a single retinal physician (DS) diagnosed and treated from 2017 to 22. RESULTS: Of 168 patients with full-thickness macular holes, 71 patients were started on steroid, carbonic anhydrase inhibitor, and nonsteroidal antiinflammatory (NSAID) drops. 49 patients (mean 67 years, 59% women) were included in the analysis, and 22 patients were excluded for poor follow-up. In total, 7/49 were secondary post-PPV holes and 42/49 were idiopathic. In addition, 18/49 eyes (36.7%) achieved closure on topical therapy, of which 13 were idiopathic. Hole size was directly correlated with odds of closure: for every 10 µm decrease in size and odds of closure increased by 1.2× ( P = 0.001, CI 1.1-1.4). Average time to closure was 107.2 days (range 20-512 days) and was not correlated with hole size ( P = 0.217, CI -0.478 to +1.938). The presence of VMT was found to be inversely related to successful closure (OR 6.1, P = 0.029, CI 1.2-31.3). There was no significant difference in final best-corrected visual acuity for eyes undergoing primary pars plana vitrectomy versus those trialing drops before undergoing pars plana vitrectomy ( P = 0.318, CI -0.094 to +0.112). CONCLUSION: In the first study to date to report the overall efficacy and clinical characteristics of successful macular hole closure with topical therapy, drops achieved an overall closure rate of 36.7%, with higher efficacy in smaller holes and those without VMT. Rates of MH narrowing and reduction in central foveal thickness acted as predictors of effectiveness of drop therapy.

Use of OCT Angiography to Diagnose and Manage Atypical Presentations of Macular Telangiectasia Type 2.

Macular telangiectasia Type 2 (MacTel) is a bilateral acquired retinal disease characterized by both vascular changes and atrophy of the retina. The purpose of this case series is to highlight the use of optical coherence tomography angiography (OCTA) as a non-invasive imaging modality to distinguish atypical MacTel from other macular conditions with similar presentations. We performed a retrospective review of patients referred to our academic retinal practice with unconfirmed or misdiagnosed MacTel between July 2017 and July 2021. Patients' OCTA imaging findings were reviewed to guide the appropriate diagnosis and management of atypical MacTel. Fifteen eyes from eight patients were included in this study. Six patients were referred with previous diagnoses of either full-thickness macular hole, lamellar hole, vitreomacular traction (VMT), postoperative cystoid macular edema (CME), or diabetic macular edema (DME). Two patients were referred to us to confirm the diagnosis of MacTel. OCTA revealed telangiectatic vessels in the temporal parafovea of all 15 eyes. OCTA also highlighted previously undiagnosed subretinal neovascularization (SRNV) in seven eyes. OCTA imaging is a valuable imaging modality to distinguish MacTel from other macular conditions, whose treatment courses vary substantially. Due to its ease of use, it holds immense potential in the future as treatments for non-proliferative MacTel emerge.

An open-source solution for advanced imaging flow cytometry data analysis using machine learning.

Imaging flow cytometry (IFC) enables the high throughput collection of morphological and spatial information from hundreds of thousands of single cells. This high content, information rich image data can in theory resolve important biological differences among complex, often heterogeneous biological samples. However, data analysis is often performed in a highly manual and subjective manner using very limited image analysis techniques in combination with conventional flow cytometry gating strategies. This approach is not scalable to the hundreds of available image-based features per cell and thus makes use of only a fraction of the spatial and morphometric information. As a result, the quality, reproducibility and rigour of results are limited by the skill, experience and ingenuity of the data analyst. Here, we describe a pipeline using open-source software that leverages the rich information in digital imagery using machine learning algorithms. Compensated and corrected raw image files (.rif) data files from an imaging flow cytometer (the proprietary .cif file format) are imported into the open-source software CellProfiler, where an image processing pipeline identifies cells and subcellular compartments allowing hundreds of morphological features to be measured. This high-dimensional data can then be analysed using cutting-edge machine learning and clustering approaches using "user-friendly" platforms such as CellProfiler Analyst. Researchers can train an automated cell classifier to recognize different cell types, cell cycle phases, drug treatment/control conditions, etc., using supervised machine learning. This workflow should enable the scientific community to leverage the full analytical power of IFC-derived data sets. It will help to reveal otherwise unappreciated populations of cells based on features that may be hidden to the human eye that include subtle measured differences in label free detection channels such as bright-field and dark-field imagery.

CellProfiler Analyst: interactive data exploration, analysis and classification of large biological image sets.

CellProfiler Analyst allows the exploration and visualization of image-based data, together with the classification of complex biological phenotypes, via an interactive user interface designed for biologists and data scientists. CellProfiler Analyst 2.0, completely rewritten in Python, builds on these features and adds enhanced supervised machine learning capabilities (Classifier), as well as visualization tools to overview an experiment (Plate Viewer and Image Gallery). AVAILABILITY AND IMPLEMENTATION: CellProfiler Analyst 2.0 is free and open source, available at http://www.cellprofiler.org and from GitHub (https://github.com/CellProfiler/CellProfiler-Analyst) under the BSD license. It is available as a packaged application for Mac OS X and Microsoft Windows and can be compiled for Linux. We implemented an automatic build process that supports nightly updates and regular release cycles for the software. CONTACT: anne@broadinstitute.orgSupplementary information: Supplementary data are available at Bioinformatics online.

Piximi - An Images to Discovery web tool for bioimages and beyond.

Deep learning has greatly accelerated research in biological image analysis yet it often requires programming skills and specialized tool installation. Here we present Piximi, a modern, no-programming image analysis tool leveraging deep learning. Implemented as a web application at Piximi.app, Piximi requires no installation and can be accessed by any modern web browser. Its client-only architecture preserves the security of researcher data by running all computation locally. Piximi offers four core modules: a deep learning classifier, an image annotator, measurement modules, and pre-trained deep learning segmentation modules. Piximi is interoperable with existing tools and workflows by supporting import and export of common data and model formats. The intuitive researcher interface and easy access to Piximi allows biological researchers to obtain insights into images within just a few minutes. Piximi aims to bring deep learning-powered image analysis to a broader community by eliminating barriers to entry.

EXUDATIVE MACULAR DETACHMENT FOLLOWING UNCOMPLICATED PARS PLANA VITRECTOMY FOR DIABETIC VITREOUS HEMORRHAGE.

BACKGROUND/PURPOSE: To describe diagnostic characteristics and management of exudative macular detachment, a rare complication of pars plana vitrectomy and endolaser for diabetic vitreous hemorrhage. METHODS: Case report including multimodal imaging. RESULTS: Forty-seven-year-old man with diabetes mellitus Type 2 and proliferative diabetic retinopathy underwent uncomplicated 23-gauge pars plana vitrectomy, Triesence-assisted hyaloid peeling, fill-in endolaser, and intravitreal bevacizumab injection in the left eye for nonclearing visually significant vitreous hemorrhage. On the first postoperative day, patient developed significant macular subretinal fluid. Multimodal imaging revealed numerous pigment epithelial detachments around optic nerve, and subretinal fluid throughout the macula on optical coherence tomography in the absence of retinal breaks on widefield raster, late deep leakage on fluorescein angiography, and corresponding hyperautofluorescence in the same region. Diagnosed with macular exudative retinal detachment, patient was treated with topical and systemic corticosteroids, with gradual resolution of subretinal fluid and visual acuity improvement. DISCUSSION: Exudative retinal detachment following diabetic pars plana vitrectomy with endolaser has been described in as many as 8.78% of cases, however may be missed in the early postoperative period. Multimodal imaging including multiple pigment epithelial detachments on optical coherence tomography, hyperautofluorescence, and late deep leakage on fluorescein angiography can help differentiate this condition from rhegmatogenous retinal detachment and central serous chorioretinopathy, and guide management to include corticosteroids.

Neovascular Glaucoma from Ocular Ischemic Syndrome Treated with Serial Monthly Intravitreal Bevacizumab and Panretinal Photocoagulation: A Case Report.

Purpose: To describe a case of open-angle neovascular glaucoma (NVG) secondary to ocular ischemic syndrome (OIS) treated with a planned series of 6 monthly anti-VEGF injections with interspersed panretinal photocoagulation (PRP) sessions. We term this treatment protocol the Salvaging Conventional Outflow Pathway in Neovascular Glaucoma (SCOPING) Protocol, and this is our (MQ and DS) standard of care for all NVG patients presenting with partially or completely open angles. Case: A 66-year-old man's right eye had a visual acuity of 20/50, intraocular pressure (IOP) of 42 mmHg on 0 IOP-lowering medications, and neovascularization of the iris and angle with no peripheral anterior synechiae. Fundoscopy revealed midperipheral dot-blot hemorrhages without diabetic retinopathy or vein occlusion. Fluorescein angiography revealed peripheral retinal nonperfusion in both eyes. The patient was diagnosed with open-angle NVG secondary to OIS and treated with 6 serial monthly anti-VEGF injections interspersed with 4 PRP sessions, after which his anterior segment neovascularization regressed and IOP normalized on 0 medications. Ten weeks after the last injection, the anterior segment neovascularization and elevated IOP recurred, so he underwent 4 more monthly anti-VEGF injections and 4 PRP sessions, after which his anterior segment neovascularization regressed and his IOP normalized on 0 medications. However, 6 weeks after the last injection, the anterior segment neovascularization and elevated IOP again recurred, so he was resumed on a third course of lifetime monthly anti-VEGF injections, which may be continued in perpetuity. Conclusion: The patient's NVG was quiescent while under the protection of serial anti-VEGF injections with interspersed PRP; however, the disease recurred each time injections were stopped. Therefore, in patients with open-angle NVG secondary to OIS, serial monthly anti-VEGF injections may be necessary combined with PRP to suppress underlying neovascular drive and regress anterior segment neovascularization, maintain physiologic IOP, and prevent synechial angle closure.

Using Advanced Bioinformatics Tools to Identify Novel Therapeutic Candidates for Age-Related Macular Degeneration.

Purpose: Age-related macular degeneration (AMD) is the most common cause of aging-related blindness in the developing world. Although medications can slow progressive wet AMD, currently, no drugs to treat dry-AMD are available. We use a systems or in silico biology analysis to identify chemicals and drugs approved by the Food and Drug Administration for other indications that can be used to treat and prevent AMD. Methods: We queried National Center for Biotechnology Information to identify genes associated with AMD, wet AMD, dry AMD, intermediate AMD, and geographic atrophy to date. We combined genes from various AMD subtypes to reflect distinct stages of disease. Enrichment analysis using the ToppGene platform predicted molecules that can influence AMD genes. Compounds without clinical indications or with deleterious effects were manually filtered. Results: We identified several drug/chemical classes that can affect multiple genes involved in AMD. The drugs predicted from this analysis include antidiabetics, lipid-lowering agents, and antioxidants, which could theoretically be repurposed for AMD. Metformin was identified as the drug with the strongest association with wet AMD genes and is among the top candidates in all dry AMD subtypes. Curcumin, statins, and antioxidants are also among the top drugs correlating with AMD-risk genes. Conclusions: We use a systematic computational process to discover potential therapeutic targets for AMD. Our systematic and unbiased approach can be used to guide targeted preclinical/clinical studies for AMD and other ocular diseases. Translational Relevance: Advanced bioinformatics models identify novel chemicals and approved drug candidates that can be efficacious for different subtypes of AMD.

High-Fat Diet Alters the Retinal Pigment Epithelium and Choroidal Transcriptome in the Absence of Gut Microbiota.

Relationships between retinal disease, diet, and the gut microbiome have started to emerge. In particular, high-fat diets (HFDs) are associated with the prevalence and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy (DR). These effects are thought to be partly mediated by the gut microbiome, which modulates interactions between diet and host homeostasis. Nevertheless, the effects of HFDs on the retina and adjacent retinal pigment epithelium (RPE) and choroid at the transcriptional level, independent of gut microbiota, are not well-understood. In this study, we performed the high-throughput RNA-sequencing of germ-free (GF) mice to explore the transcriptional changes induced by HFD in the RPE/choroid. After filtering and cleaning the data, 649 differentially expressed genes (DEGs) were identified, with 616 genes transcriptionally upregulated and 33 genes downregulated by HFD compared to a normal diet (ND). Enrichment analysis for gene ontology (GO) using the DEGs was performed to analyze over-represented biological processes in the RPE/choroid of GF-HFD mice relative to GF-ND mice. GO analysis revealed the upregulation of processes related to angiogenesis, immune response, and the inflammatory response. Additionally, molecular functions that were altered involved extracellular matrix (ECM) binding, ECM structural constituents, and heparin binding. This study demonstrates novel data showing that HFDs can alter RPE/choroid tissue transcription in the absence of the gut microbiome.

Exudative Retinal Detachment Following Chimeric Antigen Receptor T-Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia.

Chimeric antigen receptor (CAR) T-cell therapy has become a novel approach in the treatment of many hematologic malignancies. However, ocular adverse effects have not been well described. This report presents a case of a pediatric patient with relapsed B-cell acute lymphoblastic leukemia with ocular involvement treated with CAR T-cell therapy who developed an exudative retinal detachment likely secondary to an inflammatory response to CAR T-cell therapy. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:113-115.].

Metformin and retinal diseases in preclinical and clinical studies: Insights and review of literature.

Metformin is one of the most prescribed drugs in the world giving potential health benefits beyond that of type 2 diabetes (T2DM). Emerging evidence suggests that it may have protective effects for retinal/posterior segment diseases including diabetic retinopathy (DR), age-related macular degeneration (AMD), inherited retinal degeneration such as retinitis pigmentosa (RP), primary open angle glaucoma (POAG), retinal vein occlusion (RVO), and uveitis. Metformin exerts potent anti-inflammatory, antiangiogenic, and antioxidative effects on the retina in response to pathologic stressors. In this review, we highlight the broad mechanism of action of metformin through key preclinical studies on animal models and cell lines used to simulate human retinal disease. We then explore the sparse but promising retrospective clinical data on metformin's potential protective role in DR, AMD, POAG, and uveitis. Prospective clinical data is needed to clarify metformin's role in management of posterior segment disorders. However, given metformin's proven broad biochemical effects, favorable safety profile, relatively low cost, and promising data to date, it may represent a new therapeutic preventive and strategy for retinal diseases.

Gonioscopy-assisted transluminal trabeculotomy in neovascular glaucoma: Salvaging the conventional outflow pathway.

Purpose: To report a case of acute neovascular glaucoma with partial synechial angle closure secondary to central retinal vein occlusion that underwent gonioscopy-assisted transluminal trabeculotomy as well as near-monthly anti-vascular endothelial growth factor (VEGF) injections and panretinal photocoagulation (PRP) treatments. Observations: Nine months after GATT, the patient had achieved intraocular pressure control on no medications. However, she was lost to follow up for 4 months and received no anti-VEGF or PRP during that time; she re-presented with acute NVG and complete synechial closure, and ultimately underwent aqueous shunt implantation. Conclusions and Importance: To our knowledge, this is the first reported attempt of an ab interno angle surgery to successfully restore aqueous outflow through the conventional outflow pathway in an eye with acute NVG and partial synechial angle closure. We posit that this can be an effective approach to achieve IOP control in NVG with at least partially open angles, as long as sufficient anti-neovascular treatments are administered until the underlying neovascular drive achieves quiescence.

Automated Detection of Vascular Leakage in Fluorescein Angiography - A Proof of Concept.

Purpose: The purpose of this paper was to develop a deep learning algorithm to detect retinal vascular leakage (leakage) in fluorescein angiography (FA) of patients with uveitis and use the trained algorithm to determine clinically notable leakage changes. Methods: An algorithm was trained and tested to detect leakage on a set of 200 FA images (61 patients) and evaluated on a separate 50-image test set (21 patients). The ground truth was leakage segmentation by two clinicians. The Dice Similarity Coefficient (DSC) was used to measure concordance. Results: During training, the algorithm achieved a best average DSC of 0.572 (95% confidence interval [CI] = 0.548-0.596). The trained algorithm achieved a DSC of 0.563 (95% CI = 0.543-0.582) when tested on an additional set of 50 images. The trained algorithm was then used to detect leakage on pairs of FA images from longitudinal patient visits. Longitudinal leakage follow-up showed a >2.21% change in the visible retina area covered by leakage (as detected by the algorithm) had a sensitivity and specificity of 90% (area under the curve [AUC] = 0.95) of detecting a clinically notable change compared to the gold standard, an expert clinician's assessment. Conclusions: This deep learning algorithm showed modest concordance in identifying vascular leakage compared to ground truth but was able to aid in identifying vascular FA leakage changes over time. Translational Relevance: This is a proof-of-concept study that vascular leakage can be detected in a more standardized way and that tools can be developed to help clinicians more objectively compare vascular leakage between FAs.

Secondary Spontaneous Pneumothorax in a COVID-19 Recovered Patient.

Coronavirus disease 2019 (COVID-19) is an infectious disease primarily affecting the lungs with a spectrum of post-viral complications. There are well-described examples of pneumonia, empyema, pneumomediastinum, and spontaneous pneumothorax cases following COVID-19 infection within the literature. However, there is insufficient evidence implicating the cause of spontaneous pneumothorax in COVID-19 recovered patients. We present a previously infected COVID-19 patient who developed a secondary spontaneous pneumothorax two weeks after recovering. A review of the literature for similar cases was limited and therefore includes a summary of recommendations. Overall, the literature establishes that pneumothorax can occur during different phases of COVID-19 in patients without a history of pulmonary disease or barotrauma and is not necessarily associated with the severity of the viral infection. As in the case of our patient, the culmination of chronic inflammatory changes and an acute exacerbation from COVID-19 further predisposed him to a secondary spontaneous pneumothorax. In summary, all cases of recovered COVID-19 patients should maintain close follow-up with their physician and seek medical attention if acute respiratory symptoms develop.

High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota.

The relationship between retinal disease, diet, and the gut microbiome has shown increasing importance over recent years. In particular, high-fat diets (HFDs) are associated with development and progression of several retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy. However, the complex, overlapping interactions between diet, gut microbiome, and retinal homeostasis are poorly understood. Using high-throughput RNA-sequencing (RNA-seq) of whole retinas, we compare the retinal transcriptome from germ-free (GF) mice on a regular diet (ND) and HFD to investigate transcriptomic changes without influence of gut microbiome. After correction of raw data, 53 differentially expressed genes (DEGs) were identified, of which 19 were upregulated and 34 were downregulated in GF-HFD mice. Key genes involved in retinal inflammation, angiogenesis, and RPE function were identified. Enrichment analysis revealed that the top 3 biological processes affected were regulation of blood vessel diameter, inflammatory response, and negative regulation of endopeptidase. Molecular functions altered include endopeptidase inhibitor activity, protease binding, and cysteine-type endopeptidase inhibitor activity. Human and mouse pathway analysis revealed that the complement and coagulation cascades are significantly affected by HFD. This study demonstrates novel data that diet can directly modulate the retinal transcriptome independently of the gut microbiome.

Intravitreal methotrexate for the treatment of proliferative vitreoretinopathy.

BACKGROUND/AIMS: Preventing and treating proliferative vitreoretinopathy (PVR) remain a serious challenge for vitreoretinal surgeons. PVR is a devastating complication of retinal detachment that results in recurrent detachment and limits visual recovery. At present, there is no effective treatment for PVR. MATERIALS AND METHODS: A retrospective review was performed on a cohort of five consecutive eyes with severe PVR and recurrent retinal detachment that were treated with relaxing retinectomy, extended perfluorocarbon liquid tamponade (4-5 weeks) and a series of intravitreal methotrexate (MTX) injections (100-200 µg/0.05 mL for 10 weeks). RESULTS: All five patients remained reattached (100%) with 11-27 months of follow-up (mean = 17.4). 4 eyes recovered ambulatory vision (>20/200) with normal intraocular pressure and non-fibrotic laser scars along with the relaxing retinectomy. The initial patient remained reattached, but only had hand motions vision. The only adverse effect noted was mild superficial punctate keratopathy in one patient. CONCLUSION: This small, retrospective study suggests that a series of MTX injections may be beneficial for treating complex retinal detachment caused by PVR. Further study is indicated.

Tubulointerstitial nephritis and uveitis (TINU) with granulomatosis: a novel report of simultaneous TINU and sarcoidosis in a pediatric patient.

We report the case of a 7-year-old girl who presented with bilateral anterior uveitis, acute interstitial nephritis, and asymptomatic pulmonary granulomas and provide novel clinical evidence of an association between tubulointerstitial nephritis and uveitis syndrome and sarcoidosis.

Anatomy of BioJS, an open source community for the life sciences.

BioJS is an open source software project that develops visualization tools for different types of biological data. Here we report on the factors that influenced the growth of the BioJS user and developer community, and outline our strategy for building on this growth. The lessons we have learned on BioJS may also be relevant to other open source software projects.

The mouse forced swim test.

The forced swim test is a rodent behavioral test used for evaluation of antidepressant drugs, antidepressant efficacy of new compounds, and experimental manipulations that are aimed at rendering or preventing depressive-like states. Mice are placed in an inescapable transparent tank that is filled with water and their escape related mobility behavior is measured. The forced swim test is straightforward to conduct reliably and it requires minimal specialized equipment. Successful implementation of the forced swim test requires adherence to certain procedural details and minimization of unwarranted stress to the mice. In the protocol description and the accompanying video, we explain how to conduct the mouse version of this test with emphasis on potential pitfalls that may be detrimental to interpretation of results and how to avoid them. Additionally, we explain how the behaviors manifested in the test are assessed.