All

Xiong J, Yu C, Su T, Ge Q-M, Shi W-Q, Tang L-Y, Shu H-Y, Pan Y-C, Liang R-B, Li Q-Y, Shao Y. Altered brain network centrality in patients with mild cognitive impairment: an fMRI study using a voxel-wise degree centrality approach. Aging (Albany NY) 2021;13(11):15491-15500.Abstract
PURPOSE: Previous studies in patients with Alzheimer's disease have shown amyloid beta accumulation in the brain and abnormal brain activity, with mild cognitive impairment (MCI) in early stages of the disease. The aim of the current study was to investigate functional connectivity in patients with MCI. METHODS: We recruited 24 subjects in total, including 12 patients with MCI (6 men and 6 women) and 12 healthy controls (HCs) (6 men and 6 women), matched for age, gender, and lifestyle factors. All subjects underwent resting-state functional magnetic resonance imaging scans and voxel-wise degree centrality (DC) was used to evaluate alterations in the strength of brain network connectivity. RESULTS: The DC value of the left inferior temporal gyrus was lower in MCI but significantly higher in the right fusiform gyrus and the left supplementary motor area, compared with HCs. The DC value in left inferior temporal gyrus correlated positively with disease duration and negatively with Mini-Mental State Examination. ROC curve analysis of brain regions showed acceptable specificity and accuracy of DC values between MCIs and HCs in the area under the curve (right fusiform gyrus, 0.955; left supplementary motor area, 0.992; left inferior temporal gyrus, 1.000). CONCLUSIONS: Abnormal functional connectivity in brain regions of patients with MCI may reflect the pathological process of Alzheimer's disease development and could prove useful in clinical diagnosis and treatment.
Oswald J, Kegeles E, Minelli T, Volchkov P, Baranov P. Transplantation of miPSC/mESC-derived retinal ganglion cells into healthy and glaucomatous retinas. Mol Ther Methods Clin Dev 2021;21:180-198.Abstract
Optic neuropathies, including glaucoma, are a group of neurodegenerative diseases, characterized by the progressive loss of retinal ganglion cells (RGCs), leading to irreversible vision loss. While previous studies demonstrated the potential to replace RGCs with primary neurons from developing mouse retinas, their use is limited clinically. We demonstrate successful transplantation of mouse induced pluripotent stem cell (miPSC)/mouse embryonic stem cell (mESC)-derived RGCs into healthy and glaucomatous mouse retinas, at a success rate exceeding 65% and a donor cell survival window of up to 12 months. Transplanted Thy1-GFP+ RGCs were able to polarize within the host retina and formed axonal processes that followed host axons along the retinal surface and entered the optic nerve head. RNA sequencing of donor RGCs re-isolated from host retinas at 24 h and 1 week post-transplantation showed upregulation of cellular pathways mediating axonal outgrowth, extension, and guidance. Additionally, we provide evidence of subtype-specific diversity within miPSC-derived RGCs prior to transplantation.
Ozawa H, Usui Y, Takano Y, Horiuchi N, Kuribayashi T, Kurihara T, Smith LEH, Tsubota K, Tomita Y. Iris metastasis as the initial presentation of metastatic esophageal cancer diagnosed by fine needle aspiration biopsy: A case report. Medicine (Baltimore) 2021;100(22):e26232.Abstract
RATIONALE: Metastasis of neoplasms to the eye is quite uncommon. In this case report, we describe a patient where primary esophageal cancer was diagnosed by fine needle aspiration biopsy (FNAB) of an iris tumor. PATIENT CONCERNS: A 70-year-old male complained of redness and discomfort in the right eye. DIAGNOSIS AND INTERVENTIONS: The patient's right eye was diagnosed as idiopathic uveitis, and a topical steroid was administered. As vitreous opacities were observed even after topical therapy, oral prednisolone was administered. On slit-lamp examination of the right eye, an iris mass with neovascularization was seen in the anterior chamber. A metastatic tumor was suspected, and FNAB was performed. Histology revealed squamous cell carcinoma. Systemic workup revealed esophageal cancer with several metastases. Best-corrected visual acuity decreased to 20/400, and intraocular pressure was 40 mmHg in the right eye. Two iris tumors with neovascularization were present extending into the anterior chamber with posterior iris synechiae and 360 degree peripheral anterior synechiae. Intraocular pressure in the right eye was medically managed with hypotensive eye drops and oral acetazolamide. Iris metastases were treated with 40 Gray of radiation therapy and concurrent chemotherapy. OUTCOMES: The tumor regressed, but intraocular pressure was refractory to treatment because of 360 degree goniosynechial closure. The right eye lost light perception six months after treatment commenced, and the patient died 9 months after the onset of therapy due to multiple systemic metastases. LESSONS: This is a rare case of masquerade syndrome without systemic symptoms in which FNAB of an iris tumor led to a diagnosis of metastatic esophageal squamous cell carcinoma. Although the patient lost his sight due to uncontrollable ocular hypertension, systemic chemotherapy, and radiation therapy were initially effective in the treatment of the metastatic iris tumor. As the prognosis of patients with metastatic iris tumors is poor, it is important for ophthalmologists to consider such diagnoses and conduct systemic investigations when necessary.
Ou J, Zhou Z, Dai R, Zhang J, Zhao S, Wu X, Lan W, Ren Y, Cui L, Lan Q, Lu L, Seto D, Chodosh J, Wu J, Zhang G, Zhang Q. V367F Mutation in SARS-CoV-2 Spike RBD Emerging during the Early Transmission Phase Enhances Viral Infectivity through Increased Human ACE2 Receptor Binding Affinity. J Virol 2021;95(16):e0061721.Abstract
The current pandemic of COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring RBD mutations during the early transmission phase have altered the receptor binding affinity and infectivity, we first analyzed in silico the binding dynamics between SARS-CoV-2 RBD mutants and the human angiotensin-converting enzyme 2 (ACE2) receptor. Among 32,123 genomes of SARS-CoV-2 isolates (December 2019 through March 2020), 302 nonsynonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations (MDS). The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The MDS also indicated that it would be difficult for bat SARS-like CoV to infect humans. However, the pangolin CoV is potentially infectious to humans. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance, and pseudotyped virus assays. Phylogenetic analysis of the genomes of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F+D614G), which may derivate from recombination. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. IMPORTANCE A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and made them more infectious has been the research hot spot. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase and increasing human angiotensin-converting enzyme 2 (ACE2) receptor binding affinity and infectivity. Our study provides insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin. The continuing surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is critical to the development of new COVID-19 drugs and vaccines against these variants during the sustained COVID-19 pandemic.
Saeedi O, Boland MV, D'Acunto L, Swamy R, Hegde V, Gupta S, Venjara A, Tsai J, Myers JS, Wellik SR, DeMoraes G, Pasquale LR, Shen LQ, Li Y, Elze T. Development and Comparison of Machine Learning Algorithms to Determine Visual Field Progression. Transl Vis Sci Technol 2021;10(7):27.Abstract
Purpose: To develop and test machine learning classifiers (MLCs) for determining visual field progression. Methods: In total, 90,713 visual fields from 13,156 eyes were included. Six different progression algorithms (linear regression of mean deviation, linear regression of the visual field index, Advanced Glaucoma Intervention Study algorithm, Collaborative Initial Glaucoma Treatment Study algorithm, pointwise linear regression [PLR], and permutation of PLR) were applied to classify each eye as progressing or stable. Six MLCs were applied (logistic regression, random forest, extreme gradient boosting, support vector classifier, convolutional neural network, fully connected neural network) using a training and testing set. For MLC input, visual fields for a given eye were divided into the first and second half and each location averaged over time within each half. Each algorithm was tested for accuracy, sensitivity, positive predictive value, and class bias with a subset of visual fields labeled by a panel of three experts from 161 eyes. Results: MLCs had similar performance metrics as some of the conventional algorithms and ranged from 87% to 91% accurate with sensitivity ranging from 0.83 to 0.88 and specificity from 0.92 to 0.96. All conventional algorithms showed significant class bias, meaning each individual algorithm was more likely to grade uncertain cases as either progressing or stable (P ≤ 0.01). Conversely, all MLCs were balanced, meaning they were equally likely to grade uncertain cases as either progressing or stable (P ≥ 0.08). Conclusions: MLCs showed a moderate to high level of accuracy, sensitivity, and specificity and were more balanced than conventional algorithms. Translational Relevance: MLCs may help to determine visual field progression.
Binenbaum G, Chang MY, Heidary G, Morrison DG, Trivedi RH, Galvin JA, Pineles SL. Botulinum Toxin Injection for the Treatment of Strabismus: A Report by the American Academy of Ophthalmology. Ophthalmology 2021;128(12):1766-1776.Abstract
PURPOSE: To review the available evidence comparing the effectiveness of extraocular muscle botulinum toxin type A (BTXA) injection with eye muscle surgery for restoring ocular alignment in children and adults with nonparalytic, nonrestrictive horizontal strabismus. METHODS: Literature searches in the PubMed Cochrane Library, and clinical trial databases with no date restrictions, but limited to articles published in English, were conducted last on January 10, 2021. The searches yielded 515 citations, 40 of which were reviewed in full text by the first author. Fourteen articles met the criteria for inclusion (randomized or nonrandomized comparative studies, or case series with a minimum 50 patients; evaluating extraocular muscle BTXA injection for initial or repeat treatment of horizontal, nonparalytic, nonrestrictive strabismus; with at least 6 months of follow-up) and were graded by a methodologist. RESULTS: The 14 included studies consisted of 2 randomized clinical trials, 3 nonrandomized comparative studies, and 9 case series. All 5 comparative studies were graded level II evidence, and the 9 case series were graded level III evidence. Successful motor outcomes after BTXA injection were relatively consistent across 4 of the 5 comparative studies at 60%, when adjustment was made for differential selection bias in 1 of the studies. In the 4 studies, successful motor outcomes after surgery ranged from 66% to 77% with a mean follow-up of 23 to 75 months, and the outcomes were not significantly different from those after BTXA injection. In the fifth level II study, success was significantly higher with BTXA injection than with surgery (94% vs. 72%). The level III BTXA case series demonstrated higher motor success rates of 87% to 89% when children were treated in 2 muscles at a time; rates were lower in adults treated with single-muscle BTXA injection. CONCLUSIONS: Extraocular muscle injection of BTXA achieves a high rate of successful motor alignment, comparable with that achieved after eye muscle surgery for nonparalytic, nonrestrictive horizontal strabismus. Good alignment may require multiple BTXA injections, and it is not yet clear whether sensory outcomes are equivalent for BTXA injections versus eye muscle surgery in young children.
Chen T, Jin L, Zhu W, Wang C, Zhang G, Wang X, Wang J, Yang K, Cochrane GM, Lamoureux EL, Friedman DS, Gilbert S, Lansingh VC, Resnikoff S, Zhao J, Xiao B, He M, Congdon N. Knowledge, attitudes and eye health-seeking behaviours in a population-based sample of people with diabetes in rural China. Br J Ophthalmol 2021;105(6):806-811.Abstract
AIMS: To assess knowledge of diabetes and acceptance of eye care among people with diabetes in rural China, to improve service uptake. METHODS: Population-based study of people in Guangdong, China, with glycosylated haemoglobin A1c≥6.5% and/or known history of diabetes. Between August and November 2014, participants answered a questionnaire (based on Delphi process/previous focus groups) on medical history, demographic characteristics, self-rated health and vision, knowledge about diabetes and diabetic retinopathy, quality of local healthcare, barriers to treatment, likely acceptance of eye exams and treatment, and interventions rated most likely to improve service uptake. Presenting visual acuity was assessed, fundus photography performed and images graded by trained graders. Potential predictors of accepting care were evaluated and confounders adjusted for using logistic regression. RESULTS: A total of 562 people (9.6% (256/5825), mean age 66.2±9.84 years, 207 (36.8%) men) had diabetes, 118 (22.3%) previously diagnosed. 'Very likely' or 'likely' acceptance of laser treatment (140/530=26.4%) was lower than for eye exams (317/530=59.8%, p<0.001). Predictors of accepting both exams and laser included younger age (p<.001) and prior awareness of diabetes diagnosis (p=0.004 and p=0.035, respectively). The leading barrier to receiving diabetes treatment was unawareness of diagnosis (409/454, 97.2%), while interventions rated most likely to improve acceptance of eye exams included reimbursement of travel costs (387/562, 73.0%), video or other health education (359/562, 67.7%) and phone call reminders (346/562, 65.3%). CONCLUSIONS: Improving diagnosis of diabetes, along with incentives, education and communication strategies, is most likely to enhance poor acceptance of diabetic eye care in this setting.
Williams IM, Pineda R, Neerukonda VK, Stagner AM. Mucopolysaccharidosis Type I-Associated Corneal Disease: A Clinicopathologic Study. Am J Ophthalmol 2021;231:39-47.Abstract
PURPOSE: To report the anterior segment clinical features and histopathologic and histochemical characteristics of explanted corneas from the largest reported cohort of patients with Hurler syndrome and other variants of mucopolysaccharidosis (MPS) I undergoing corneal transplantation. DESIGN: Retrospective observational case series. METHODS: This institutional study reviewed 15 corneas from 9 patients with MPS I spectrum disease who underwent corneal transplant to treat corneal clouding between May 2011 and October 2020. We reviewed the clinical data, hematoxylin-eosin-stained sections, and histochemical stains, including those for mucopolysaccharides (Alcian blue and/or colloidal iron). The main outcome measures were pathology observed under light microscopy and postsurgical clinical outcomes. RESULTS: Nine patients underwent 15 corneal transplants for corneal clouding (14/15 procedures were deep anterior lamellar keratoplasty). All corneas had mucopolysaccharide deposition visible on hematoxylin-eosin-stained sections, which was highlighted in blue with histochemical stains. All corneas also showed alterations in Bowman's layer and the majority also showed epithelial abnormalities. CONCLUSION: MPS I shows significant corneal clouding that is successfully treated with deep anterior lamellar keratoplasty. The excised corneas show characteristic epithelial changes, disruption or breaks in Bowman's membrane, and amphophilic collections of stromal granular mucopolysaccharides which are visible on hematoxylin-eosin-stained sections and highlighted by special histochemical stains (Alcian blue and collodial iron). These changes, although subtle, should alert the pathologist to the possibility of an underlying lysosomal storage disorder.
Ma KK, Ong Tone S, Chodosh J, Saeed HN. Ochrobactrum anthropi Keratitis in a Boston Type 1 Keratoprosthesis Recipient. Cornea 2021;40(5):662-663.Abstract
PURPOSE: To report a case of Ochrobactrum anthropi keratitis in an eye with a Boston type 1 keratoprosthesis. METHODS: This is a case report and review of the literature. RESULTS: A 78-year-old man with a history of implantation of a Boston type 1 keratoprosthesis in the left eye presented for a routine follow-up with no acute complaints. In the left eye, visual acuity was 20/60 and slit-lamp examination revealed a 1.5-mm inferotemporal corneal infiltrate adjacent to the optic stem. Corneal cultures grew abundant O. anthropi. After 7 weeks of topical antimicrobial therapy and placement of a temporary tarsorrhaphy, the keratitis resolved. CONCLUSIONS: Ochrobactrum anthropi is an organism associated with indwelling medical devices and can be pathogenic in eyes with implanted keratoprostheses.
Venkateswaran N, Sripawadkul W, Karp CL. The role of imaging technologies for ocular surface tumors. Curr Opin Ophthalmol 2021;32(4):369-378.Abstract
PURPOSE OF REVIEW: This review will discuss the utility of high-resolution anterior segment optical coherence tomography (HR-OCT), in-vivo confocal microscopy (IVCM) and ultrasound biomicroscopy (UBM) in characterizing and diagnosing various ocular surface tumors, namely ocular surface squamous neoplasia (OSSN), conjunctival lymphoma and conjunctival melanoma. The strengths and limitations of each imaging modality will be discussed along with the characteristics findings of each lesion on each imaging platform. RECENT FINDINGS: HR-OCT can consistently be utilized in the clinic setting to distinguish between epithelial ocular surface tumors such as OSSN as compared with subepithelial tumors such as conjunctival lymphoma and conjunctival melanoma given their distinctive findings. IVCM can be used as an adjunct to HR-OCT to obtain cellular and surface characteristics, whereas UBM can be used to assess tumor depth and thickness for larger and highly pigmented lesions as well as to detect intraocular invasion. SUMMARY: HR-OCT, IVCM and UBM are all helpful imaging modalities to diagnose and characterize various ocular surface tumors and can serve as valuable adjuncts to monitor treatment response and assess for recurrence ocular surface tumors.
Geoffrion D, Robert M-C, Chodosh J, Di Polo A, Harissi-Dagher M. Perspectives for preclinical mouse models of glaucoma after Boston keratoprosthesis type 1. Exp Eye Res 2021;208:108615.Abstract
Animal models of the Boston keratoprosthesis type 1 (KPro) are needed to study glaucoma damage after KPro implantation to control for confounding comorbidities common in human KPro recipients. The purpose of this study was to determine the feasibility of establishing a reproducible mouse model of glaucoma after KPro surgery, specifically that of a miniaturized mouse model of KPro (mKPro). In the present study, a total of 20 corneas of donor C57BL/6 mice (n = 10) were implanted in one eye of each recipient BALB/C mouse (n = 20), assembled as part of the mKPro, either with or without intraoperative lensectomy. Main feasibility outcomes consisted in incidence rates of loss of tone, capsule nicking, and lens extrusion, as well as acquisition of posterior segment optical coherence tomography (OCT) images. With lensectomy (n = 10), loss of ocular tone and retinal detachment occurred in 100% of mice. Without lensectomy (n = 10), capsule nicking and opening, as well as lens extrusion, occurred in 80% of mice. Causes of these complications included the large proportion of intraocular volume occupied by the lens, the shallow anterior chamber, and thus the lack of available intraocular volume to implant the KPro if the lens remains present. Successful mouse KPro surgery may require a great deal of practice to be useful as a reproducible model. Animal KPro models ought to be pursued further by research teams in future studies.
Zhu GH, Azharuddin M, Islam R, Rahmoune H, Deb S, Kanji U, Das J, Osterrieth J, Aulakh P, Ibrahim-Hashi H, Manchanda R, Nilsson PH, Mollnes TE, Bhattacharyya M, Islam MM, Hinkula J, Slater NKH, Patra HK. Innate Immune Invisible Ultrasmall Gold Nanoparticles-Framework for Synthesis and Evaluation. ACS Appl Mater Interfaces 2021;13(20):23410-23422.Abstract
Nanomedicine is seen as a potential central player in the delivery of personalized medicine. Biocompatibility issues of nanoparticles have largely been resolved over the past decade. Despite their tremendous progress, less than 1% of applied nanosystems can hit their intended target location, such as a solid tumor, and this remains an obstacle to their full ability and potential with a high translational value. Therefore, achieving immune-tolerable, blood-compatible, and biofriendly nanoparticles remains an unmet need. The translational success of nanoformulations from bench to bedside involves a thorough assessment of their design, compatibility beyond cytotoxicity such as immune toxicity, blood compatibility, and immune-mediated destruction/rejection/clearance profile. Here, we report a one-pot process-engineered synthesis of ultrasmall gold nanoparticles (uGNPs) suitable for better body and renal clearance delivery of their payloads. We have obtained uGNP sizes of as low as 3 nm and have engineered the synthesis to allow them to be accurately sized (almost nanometer by nanometer). The synthesized uGNPs are biocompatible and can easily be functionalized to carry drugs, peptides, antibodies, and other therapeutic molecules. We have performed in vitro cell viability assays, immunotoxicity assays, inflammatory cytokine analysis, a complement activation study, and blood coagulation studies with the uGNPs to confirm their safety. These can help to set up a long-term safety-benefit framework of experimentation to reveal whether any designed nanoparticles are immune-tolerable and can be used as payload carriers for next-generation vaccines, chemotherapeutic drugs, and theranostic agents with better body clearance ability and deep tissue penetration.

Pages