Longitudinal Metabolic Trajectories in Diabetes Prevention Program Participants Reveal Subgroups With Varying Micro- and Macrovascular Complication Risks.

Objective: Type 2 diabetes (T2D) and its associated complications develop heterogeneously over decades, but few studies span the progression from prediabetes to clinical events. We investigated whether long-term metabolic trajectories beginning in prediabetes delineate subgroups with differential complication risk.

Research Design And Methods: Clinical data from 1,732 Diabetes Prevention Program/Outcomes Study participants (follow-up 19 years) were analyzed across 12 phenotypes.

The Sialome of the Retina, Alteration in Age-Related Macular Degeneration Pathology, and Potential Impacts on Complement Factor H.

Purpose: Little is known about sialic acids of the human retina, despite their integral role in self /non-self-discrimination by complement factor H (FH), the alternative complement pathway inhibitor.

Methods: A custom sialoglycan microarray was used to characterize the sialic acid-binding specificity of native FH or recombinant molecules where IgG Fc was fused to FH domains 16 to 20 (which contains a sialic acid-binding site), domains 6 and 7 (which contains a glycosaminoglycan-binding site), or the FH-related proteins (FHRs) 1 and 3. We analyzed macular and peripheral retinal tissue from postmortem ocular globes for the amount, type, and presentation (glycosidic linkage type) of sialic acid in individuals with age-related macular degeneration (AMD) and age-matched controls using fluorescent lectins and antibodies to detect sialic acid and endogenous FH.

Bruch's membrane heparan sulfate retains lipoproteins in the early stages of age-related macular degeneration.

Lipoprotein retention in Bruch's membrane is a key event in the pathobiology of early and intermediate age-related macular degeneration (AMD). However, the mechanism of lipoprotein retention in BrM is unknown. Given the established role of glycosaminoglycans (GAG) in binding lipoproteins, our laboratory sought to determine the role of GAGs in AMD BrM.

The sialome of the retina, alteration in age-related macular degeneration (AMD) pathology and potential impacts on Complement Factor H.

Purpose: Little is known about sialic acids of the human retina, despite their integral role in self/non-self-discrimination by complement factor H (CFH), the alternative complement pathway inhibitor.

Methods: A custom sialoglycan microarray was used to characterize the sialic acid-binding specificity of native CFH or recombinant molecules where IgG Fc was fused to CFH domains 16-20 (contains a sialic acid-binding site), domains 6-7 (contains a glycosaminoglycan-binding site) or the CFH-related proteins (CFHRs) 1 and 3. We analyzed macular and peripheral retinal tissue from post-mortem ocular globes for amount, type, and presentation (glycosidic linkage type) of sialic acid in individuals with age-related macular degeneration (AMD) and age-matched controls using fluorescent lectins and antibodies to detect sialic acid and endogenous CFH.

Development of an image-guided non-vitrectomy subretinal access approach for trans-scleral cell and gene therapy delivery.

Purpose: Regenerative therapies for retinal diseases include cell and gene therapy modalities that are targeted to the subretinal space. Several recent clinical trials have shown that the morbidity of surgical access is the major limitation of safe subretinal space delivery. We aimed to develop an image-guided procedure for minimally invasive subretinal access (MISA) as a platform to deliver therapeutic agents for the treatment of degenerative retinal diseases.

High-Density Lipoproteins Associated with Age-Related Macular Degeneration in the All of Us Research Program.

Purpose: Extracellular lipoprotein aggregation is a critical event in age-related macular degeneration (AMD) pathogenesis. In this study, we sought to analyze associations between clinical and genetic-based factors related to lipoprotein metabolism and risk for AMD in the All of Us research program.

Design: Cross-sectional retrospective data analysis.

OCT Changes Observed during the Progression of Early Age-Related Macular Degeneration.

Purpose: Automated retinal cell layer segmentation empowers OCT as a precise tool for characterizing morphologic features of retinal health throughout age-related macular degeneration (AMD) progression, particularly in advance of more visible biomarkers such as drusen and macular pigmentary changes. Few studies have examined OCT changes in eyes progressing from early to intermediate disease, or combined examinations of cell layer thickness, reflectivity, and heterogeneity. Therefore, this study analyzed OCTs from eyes progressing from early to intermediate AMD to identify changes in retinal morphology and reflectivity that may serve as biomarkers of early progression.

Evaluation of Retinal Arterial Occlusion and its Visual and Systemic Prognosis after Hyperbaric Oxygen Therapy.

Purpose: To evaluate the systemic and ocular outcomes of patients with branch retinal artery occlusion (BRAO) and central retinal artery occlusion (CRAO) after hyperbaric oxygen therapy (HBOT).

Methods: This is a single-institution study of 75 subjects diagnosed with BRAO (28, 37.3%) and CRAO (47, 62.

The Sensitivity of Ultra-Widefield Fundus Photography Versus Scleral Depressed Examination for Detection of Retinal Horseshoe Tears.

Purpose: Ultra-widefield (UWF) imaging is commonly used in ophthalmology in tandem with scleral depressed examinations (SDE) to evaluate peripheral retinal disease. Because of the increased reliance on this technology in tele-ophthalmology, it is critical to evaluate its efficacy for detecting the peripheral retina when performed in isolation. Therefore, we sought to evaluate UWF imaging sensitivity in detecting retinal horseshoe tears (HSTs).

Greater Outflow Facility Increase After Targeted Trabecular Bypass in Angiographically Determined Low-low Regions.

Purpose: To investigate the impact of trabecular bypass surgery targeted to angiographically determined high- vs. low-aqueous humor outflow areas on outflow facility (C) and intraocular pressure (IOP).

Design: Ex vivo comparative study.

Prevalence of subclinical retinal ischemia in patients with cardiovascular disease - a hypothesis driven study.

Background: Cardiovascular disease is the leading cause of mortality and disability worldwide. A noninvasive test that can detect underlying cardiovascular disease has the potential to identify patients at risk prior to the occurrence of adverse cardiovascular events. We sought to determine whether an easily observed imaging finding indicative of retinal ischemia, which we term ' (RIPLs), could serve as a biomarker for cardiovascular disease.

Mechanisms of Environment-Induced Autoimmunity.

Although numerous environmental exposures have been suggested as triggers for preclinical autoimmunity, only a few have been confidently linked to autoimmune diseases. For disease-associated exposures, the lung is a common site where chronic exposure results in cellular toxicity, tissue damage, inflammation, and fibrosis. These features are exacerbated by exposures to particulate material, which hampers clearance and degradation, thus facilitating persistent inflammation.

Rifabutin-Cobicistat Drug Interaction Resulting in Severe Bilateral Panuveitis.

We report a novel case of severe bilateral panuveitis with hypopyon secondary to rifabutin and cobicistat drug interaction in the setting of human immunodeficiency virus (HIV) infection and latent tuberculosis (TB). A 63-year-old woman presented with bilateral conjunctival injection and decreasing vision of 5 days' duration. She had a history of well-controlled HIV infection, latent TB, and non-alcoholic steatohepatitis for which she was inadvertently being treated, due to a pharmacy error, concurrently with the anti-TB medicine rifabutin and the highly active antiretroviral therapy combination Genvoya® (elvitegravir 150 mg - cobicistat 150 mg - emtricitabine 200 mg - tenofovir alafenamide 10 mg).

PREVALENCE OF MISMATCH REPAIR GENE MUTATIONS IN UVEAL MELANOMA.

Purpose: Uveal melanomas are associated with characteristic genetic changes. Germline mutations in mismatch repair (MMR) genes and microsatellite instability have been implicated in the development of numerous malignant neoplasms such as colon and ovarian cancers. The frequency of MMR defects in uveal melanomas has yet to be determined.

A Case of Unilateral Coccidioidal Chorioretinitis in a Patient with HIV-Associated Meningoencephalitis.

Intraocular coccidioidomycosis is a rare condition, with the most commonly reported presentation being an idiopathic iritis in patients who live in or have traveled thorough endemic areas. A paucity of reports exists describing the chorioretinal manifestations of coccidioidomycosis. Here we report a case of unilateral coccidioidal chorioretinitis and meningoencephalitis in an AIDS patient that led to near complete unilateral loss of vision.

GNAQ and PMS1 Mutations Associated with Uveal Melanoma, Ocular Surface Melanosis, and Nevus of Ota.

G protein mutations are common in uveal melanomas, and the vast majority target amino acid residue Q209 in either GNAQ or GNA11. The GNAQ R183Q mutation is found in a small fraction of uveal melanomas. We report a patient with an unusual presentation of uveal melanoma arising at an early age in the setting of congenital skin and ocular surface melanosis.

Beware of the sneeze.

Switch/sucrose non-fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), also known as integrase interactor 1-deficient sinonasal carcinoma, is a rare entity that was first described in 2014. Since then, there have been 39 cases published in the literature, with basaloid or plasmacytoid/rhabdoid morphology being the most common pathological subtype. We report a patient with switch/sucrose non-fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (integrase interactor 1)-deficient sinonasal carcinoma who had permanent vision loss after valsalva-induced acute hemorrhage and resultant orbital compartment syndrome.

Immediate Release of Gastrin-Releasing Peptide Mediates Delayed Radiation-Induced Pulmonary Fibrosis.

Radiation-induced pulmonary fibrosis (RTPF) is a progressive, serious condition in many subjects treated for thoracic malignancies or after accidental nuclear exposure. No biomarker exists for identifying the irradiated subjects most susceptible to pulmonary fibrosis (PF). Previously, we determined that gastrin-releasing peptide (GRP) was elevated within days after birth in newborns exposed to hyperoxia who later developed chronic lung disease.

Mercury-induced inflammation and autoimmunity.

Background: Human exposure to mercury leads to a variety of pathologies involving numerous organ systems including the immune system. A paucity of epidemiological studies and suitable diagnostic criteria, however, has hampered collection of sufficient data to support a causative role for mercury in autoimmune diseases. Nevertheless, there is evidence that mercury exposure in humans is linked to markers of inflammation and autoimmunity.

Effect of Anti-C5a Therapy in a Murine Model of Early/Intermediate Dry Age-Related Macular Degeneration.

Purpose: A large body of evidence supports a central role for complement activation in the pathobiology of age-related macular degeneration (AMD), including plasma complement component 5a (C5a). Interestingly, C5a is a chemotactic agent for monocytes, a cell type also shown to contribute to AMD. However, the role monocytes play in the pathogenesis of "dry" AMD and the pharmacologic potential of targeting C5a to regulate these cells are unclear.

Complement factor H in AMD: Bridging genetic associations and pathobiology.

Age-Related Macular Degeneration (AMD) is a complex multifactorial disease characterized in its early stages by lipoprotein accumulations in Bruch's Membrane (BrM), seen on fundoscopic exam as drusen, and in its late forms by neovascularization ("wet") or geographic atrophy of the Retinal Pigmented Epithelial (RPE) cell layer ("dry"). Genetic studies have strongly supported a relationship between the alternative complement cascade, in particular the common H402 variant in Complement Factor H (CFH) and development of AMD. However, the functional significance of the CFH Y402H polymorphism remains elusive.

From the Cover: Interplay Between IFN-γ and IL-6 Impacts the Inflammatory Response and Expression of Interferon-Regulated Genes in Environmental-Induced Autoimmunity.

IFN-γ has been found to be robustly important to disease pathogenesis in both idiopathic and induced models of murine lupus. In transgenic mice, over production of IFN-γ in the skin results in an inflammatory response and autoimmunity. This suggests that localized exposure to environmental factors that induce autoimmunity may be associated with expression of an IFN-γ-dependent inflammatory response.

Long-term survival following open versus thoracoscopic lobectomy after preoperative chemotherapy for non-small cell lung cancer.

Objectives: Video-assisted thoracoscopic (VATS) lobectomy is increasingly accepted for the management of early-stage non-small cell lung cancer (NSCLC), but its role for locally advanced cancers has not been as well characterized. We compared outcomes of patients who received induction therapy followed by lobectomy, via VATS or thoracotomy.

Methods: Perioperative complications and long-term survival of all patients with NSCLC who received induction chemotherapy (ICT) (with or without induction radiation therapy) followed by lobectomy from 1996-2012 were assessed using Kaplan-Meier and Cox proportional hazard analysis.