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Abstract Background Central nervous system (CNS) infection is a nearly universal feature of untreated systemic HIV infection with a clinical spectrum that ranges from chronic asymptomatic infection to severe cognitive and motor dysfunction. Analysis of cerebrospinal fluid (CSF) has played an important part in defining the character of this evolving infection and response to treatment. To further characterize CNS HIV infection and its effects, we applied advanced high-throughput proteomic methods to CSF to identify novel proteins and their changes with disease progression and treatment. Results After establishing an accurate mass and time (AMT) tag database containing 23,141 AMT tags for CSF peptides, we analyzed 91 CSF samples by LC-MS from 12 HIV-uninfected and 14 HIV-infected subjects studied in the context of initiation of antiretroviral therapy and correlated abundances of identified proteins a) within and between subjects, b) with all other proteins across the entire sample set, and c) with "external" CSF biomarkers of infection (HIV RNA), immune activation (neopterin) and neural injury (neurofilament light chain protein, NFL). We identified a mean of 2,333 +/- 328 (SD) peptides covering 307 +/-16 proteins in the 91 CSF sample set. Protein abundances differed both between and within subjects sampled at different time points and readily separated those with and without HIV infection. Proteins also showed inter-correlations across the sample set that were associated with biologically relevant dynamic processes. One-hundred and fifty proteins showed correlations with the external biomarkers. For example, using a threshold of cross correlation coefficient (Pearson's) ≤ -0.3 and ≥0.3 for potentially meaningful relationships, a total of 99 proteins correlated with CSF neopterin (43 negative and 56 positive correlations) and related principally to neuronal plasticity and survival and to innate immunity. Pathway analysis defined several networks connecting the identified proteins, including one with amyloid precursor protein as a central node. Conclusions Advanced CSF proteomic analysis enabled the identification of an array of novel protein changes across the spectrum of CNS HIV infection and disease. This initial analysis clearly demonstrated the value of contemporary state-of-the-art proteomic CSF analysis as a discovery tool in HIV infection with likely similar application to other neurological inflammatory and degenerative diseases.

Abstract Background Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) are related human tumor viruses that cause primary effusion lymphomas (PEL) and Burkitt's lymphomas (BL), respectively. Viral genes expressed in naturally-infected cancer cells contribute to disease pathogenesis; knowing which viral genes are expressed is critical in understanding how these viruses cause cancer. To evaluate the expression of viral genes, we used high-resolution separation and mass spectrometry coupled with custom tiling arrays to align the viral proteomes and transcriptomes of three PEL and two BL cell lines under latent and lytic culture conditions. Results The majority of viral genes were efficiently detected at the transcript and/or protein level on manipulating the viral life cycle. Overall the correlation of expressed viral proteins and transcripts was highly complementary in both validating and providing orthogonal data with latent/lytic viral gene expression. Our approach also identified novel viral genes in both KSHV and EBV, and extends viral genome annotation. Several previously uncharacterized genes were validated at both transcript and protein levels. Conclusions This systems biology approach coupling proteome and transcriptome measurements provides a comprehensive view of viral gene expression that could not have been attained using each methodology independently. Detection of viral proteins in combination with viral transcripts is a potentially powerful method for establishing virus-disease relationships.

Abstract Background The Hedgehog (Hh) signaling pathway is important for the development of a variety of tissues in both vertebrates and invertebrates. For example, in developing nervous systems Hh signaling is required for the normal differentiation of neural progenitors into mature neurons. The molecular signaling mechanism underlying the function of Hh is not fully understood. In Drosophila, Ihog (Interference hedgehog) and Boi (Brother of Ihog) are related transmembrane proteins of the immunoglobulin superfamily (IgSF) with orthologs in vertebrates. Members of this IgSF subfamily have been shown to bind Hh and promote pathway activation but their exact role in the Hh signaling pathway has remained elusive. To better understand this role in vivo, we generated loss-of-function mutations of the ihog and boi genes, and investigated their effects in developing eye and wing imaginal discs. Results While mutation of either ihog or boi alone had no discernible effect on imaginal tissues, cells in the developing eye disc that were mutant for both ihog and boi failed to activate the Hh pathway, causing severe disruption of photoreceptor differentiation in the retina. In the anterior compartment of the developing wing disc, where different concentrations of the Hh morphogen elicit distinct cellular responses, cells mutant for both ihog and boi failed to activate responses at either high or low thresholds of Hh signaling. They also lost their affinity for neighboring cells and aberrantly sorted out from the anterior compartment of the wing disc into posterior territory. We found that ihog and boi are required for the accumulation of the essential Hh signaling mediator Smoothened (Smo) in Hh-responsive cells, providing evidence that Ihog and Boi act upstream of Smo in the Hh signaling pathway. Conclusions The consequences of boi;ihog mutations for eye development, neural differentiation and wing patterning phenocopy those of smo mutations and uncover an essential role for Ihog and Boi in the Hh signaling pathway.

Purpose: To assess whether the repeated use of intravitreal bevacizumab injections in treatment of proliferative diabetic retinopathy is associated with a long-term decline in the glomerular filtration rate (GFR)., Methods: Three hundred charts were retrospectively reviewed, of which 60 patients met the criteria for inclusion. The criteria were as follows: reception of at least one bevacizumab injection, baseline GFR before initial bevacizumab injection, and end GFR 6 to 24 months after baseline. Analysis controlled for time between baseline and end GFR measurements, blood pressure, hemoglobin A1C, race, sex, age, and use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Significance testing was performed with step-wise multiple linear regression. The significance threshold was 5%, and all tests were two-sided., Results: Patients received a range of 1 to 17 injections (average 3.6). The average baseline GFR was 76 ± 38 mL/minute, and the end GFR was 63 ± 39 mL/min. The number of injections patients received was not associated with end GFR ( P = 0.72), GFR reduction ( P = 0.88), or percent GFR reduction ( P = 0.49)., Conclusion: Increased number of intravitreal bevacizumab injections at therapeutic dosage was not associated with reduced GFR in patients with proliferative diabetic retinopathy. This study supports that intravitreal antivascular endothelial growth factor agents are renally safe.

The Ophthalmology Student Interest Group at Indiana University School of Medicine provides a free student-run eye screening clinic for an underserved community in Indianapolis. Patients with abnormal findings are referred to the ophthalmology service of the local county hospital for further evaluation. This retrospective chart review studied 180 patients referred from our free eye clinic to follow up at the ophthalmology service of a local county hospital from October 2013 to February 2020. This study investigated factors impacting follow-up of patients by analyzing demographics, medical history, insurance coverage, and final diagnoses at follow-up. Thirty-five (19.4%) of 180 patients successfully followed up at the local county hospital with an average time to follow-up of 14.4 (± 15.9) months. Mean patient age was 51 (± 13.6) with nearly equal numbers of males and females. The most common diagnoses at follow-up included refractive error (51.4%), cataract (45.7%), and glaucoma (28.6%). Patients with diabetes diagnoses or Healthy Indiana Plan insurance coverage had increased probability of follow-up. This study reveals gaps in timely follow-up to the local county hospital, demonstrating the current limitations of our free clinic in connecting patients to more definitive care and the need for an improved referral process., (© 2022. The Author(s).)

Background: The Indiana University Student Outreach Clinic (IUSOC) Eye Clinic is a monthly student-run eye clinic that provides free visual screening to the Near East Side community of Indianapolis, IN, USA. Screening includes assessments of visual acuity, intraocular pressure, peripheral visual fields, refraction, and non-mydriatic fundus photography., Methods: This is a retrospective chart review of 875 patients seen at the IUSOC Eye Clinic from October 2013 to February 2020. Data on demographics, insurance coverage, ocular history, physical examination, suspected diagnosis, referral status, and glasses provided were collected and analyzed., Results: 875 patients were seen at the IUSOC Eye Clinic from October 2013 to February 2020. 39.2% of the patients seen at the clinic reported being uninsured. 61.4% of patients were found to have visual acuity of 20/40 or worse, while 51.3% of patients were found to have a near visual acuity of 20/40 or worse. 20.3% of patients were referred to the local county hospital for further evaluation by an ophthalmologist, 14.4% of patients received free glasses prescriptions, and 27.9% of patients received free reading glasses. Common reasons for referral for further ophthalmology evaluation included glaucoma, decreased visual acuity, and diabetic retinopathy. An estimated value of services provided over the seven years of the clinic was 1271 relative value units., Conclusion: The IUSOC Eye Clinic fills an important role in advancing ocular health and preventing irreversible blindness in an underserved Indianapolis community. Additionally, the clinic demonstrates an educational model for involving medical student volunteers., (© 2021. The Author(s).)

Competing Interests: The authors declare that they have no conflicts of interest to disclose.

Purpose: Diplopia and ocular motility restriction following orbital fracture repair are common complications. The reported rates in the literature differ greatly, in part due to varying definitions of diplopia and methods of measurement. The purpose of this study is to describe a practical and efficient in-office method for examining ocular motility and diplopia in orbital trauma patients and to report the outcomes in a series of patients who underwent orbital floor fracture repair., Materials and Methods: A retrospective chart review from 2012 to 2019 was conducted in patients who underwent isolated orbital floor fracture repair within 3 weeks of trauma. All patients had examinations to assess extraocular motility and subjective diplopia using the described techniques., Results: Ninety-three patients underwent orbital floor fracture repair and had adequate follow-up. Preoperatively, 71 (76%) patients had some restriction in motility and 59 (63%) patients complained of diplopia. Postoperatively, only 1 patient (1.09%) had clinically significant diplopia. Five (5.4%) additional patients demonstrated mild restriction in supraduction upon detailed ophthalmic examination that was not discovered upon subjective history. No patients had worsening of diplopia or motility after surgery., Conclusions: Diplopia and motility restriction following orbital fracture repair can be a persistent problem for some patients. It is important to perform a careful ophthalmic examination to detect motility deficits and diplopia that can be significant to the patient. The true rate of restriction and diplopia may be higher using detailed ophthalmic diagnostic techniques compared to subjective patient history., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to evaluate retinal microvascular abnormalities following plaque radiotherapy of choroidal melanoma (CM) using wide-field swept-source optical coherence tomography angiography (OCTA)., Design: Single-centre retrospective review., Methods: Retrospective case series of 105 CM patients treated with I-125 plaque radiotherapy and imaged with wide-field (15 × 9 mm) SS-OCTA from March 2018 to August 2018 at the Ocular Oncology Service, Wills Eye Hospital (Philadelphia, PA)., Results: At mean follow-up of 49 months (range 4-297) after plaque radiotherapy, there were 52 eyes (50%) with clinically evident radiation retinopathy (CERR) and 53 eyes (50%) without CERR. Comparison (CERR vs controls) revealed foveal avascular zone enlargement (1.7 vs 0.23 mm, P = 0.03) and reduction of capillary vascular density (CVD) in the superficial and deep plexus in the total wide-field (43% vs 47%, P < 0.001, and 46% vs 48%, P = 0.001, respectively), peripapillary region (66% vs 77%, P < 0.001, and 66% vs 72%, P = 0.001, respectively), and papillomacular bundle (60% vs 68%, P < 0.001, and 61% vs 64%, P = 0.03, respectively). Comparison (no CERR vs controls) revealed nonsignificant foveal avascular zone enlargement (1.20 vs 0.23 mm, P = 0.16) and reduction of CVD in the superficial plexus (46% vs 47%, P = 0.008), and not the deep plexus (48% vs 48%, P = 0.42) of the total wide-field. Comparison of irradiated eyes (CERR vs no CERR) showed reduction of CVD in the superficial and deep plexus of the total wide-field (43% vs 46%, P < 0.006, and 46% vs 48% P < 0.02, respectively), peripapillary region (66% vs 74%, P < 0.001, and 66% vs 72% P < 0.01, respectively), and superficial plexus in the papillomacular bundle (60% vs 65%, P = 0.03)., Conclusions: Following plaque radiotherapy for choroidal melanoma, wide-field swept-source optical coherence tomography angiography demonstrates retinal microvascular abnormalities in the CVD in eyes with and without CERR. These findings are important in early detection and monitoring of radiation retinopathy.

Purpose: To quantify outcomes for neonatal retinoblastoma patients treated during the pre-chemotherapy (1980-1994) and chemotherapy (1995-2018) eras., Methods: Retrospective review of retinoblastoma patients diagnosed within the first 28 days of life between 1/1/1980 and 11/30/2018. Student's t-test, Chi-square, and Fisher's exact test were performed to compare treatments and outcomes by era., Results: There were 68 patients with neonatal retinoblastoma (12% unilateral and 88% bilateral). According to era (pre-chemotherapy vs. chemotherapy), the number of treated patients was 26 (38%) vs. 42 (62%). Primary treatment was external beam radiotherapy (50% vs. 1%,P < 0.001), plaque radiotherapy (17% vs. 0%,P < 0.001), focal treatment (transpupillary thermotherapy or cryotherapy) only (21% vs. 14%,P= 0.33), intravenous chemotherapy (0% vs. 81%,P < 0.001), enucleation (10% vs. 4%,P= 0.26), or exenteration (2% vs. 0%,P= 0.37). Outcomes included tumor control (79% vs. 94%,P= 0.02), globe salvage (75% vs. 91%,P= 0.02), final gross visual acuity for salvaged eyes 20/200 or better (66% vs. 89%,P < 0.01), and death (19% vs. 0%,P < 0.01)., Conclusion: Chemotherapy advancements for neonatal retinoblastoma have improved tumor control, globe salvage, visual acuity, and patient survival., Competing Interests: None

Intravitreal chemotherapy is recognized as an effective treatment for retinoblastoma with vitreous (and occasionally subretinal) seeding refractory to intravenous or intra-arterial chemotherapy. However, this treatment carries with it the risk of toxicity to both the posterior and anterior segments of the eye, including retinal pigment epithelial mottling, ischemic/hemorrhagic retinopathy, posterior synechia, cataract, scleral necrosis, and focal iris depigmentation. We report 2 cases of iris heterochromia secondary to profound iris stromal depigmentation following intravitreal melphalan and topotecan injections., (Copyright © 2019 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Glaucoma secondary to intraocular tumors is important to consider in eyes with a known tumor and those with unilateral or refractory glaucoma. The purpose of this review is to discuss the mechanisms and management of intraocular tumors with related secondary glaucoma., Recent Findings: Several intraocular tumors can lead to glaucoma, including iris melanoma, iris metastasis, iris lymphoma, trabecular meshwork melanoma, choroidal melanoma, choroidal metastasis, retinoblastoma, and medulloepithelioma. The mechanisms for glaucoma include solid tumor invasion into the angle, tumor seeding into the angle, angle closure, and iris neovascularization. Management of the tumor can lead to resolution of glaucoma. Management of the secondary glaucoma may involve medical therapy, transscleral cyclophotocoagulation, laser trabeculoplasty, and potentially antivascular endothelial growth factor therapy. Minimally invasive glaucoma surgery (MIGS) can be considered for eyes with treated, regressed posterior segment malignancies if there is no iris or ciliary body involvement. Importantly, avoidance of MIGS, filtering, or shunting surgery in eyes with active malignancies is emphasized., Summary: Intraocular tumors can produce secondary glaucoma. Treatment of the primary tumor can sometimes resolve the glaucoma. Topical, oral, or laser therapies can be considered. Avoidance of MIGS, filtering, or shunting surgery is advised until the malignancy is completely regressed.