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Saldaris J, Weisenberg J, Pestana-Knight E, Marsh ED, Suter B, Rajaraman R, Heidary G, Olson HE, Devinsky O, Price D, Jacoby P, Leonard H, Benke TA, Demarest S, Downs J. Content Validation of Clinician-Reported Items for a Severity Measure for CDKL5 Deficiency Disorder. J Child Neurol 2021;36(11):998-1006.Abstract
CDKL5 deficiency disorder (CDD) results in early-onset seizures and severe developmental impairments. A CDD clinical severity assessment (CCSA) was previously developed with clinician and parent-report items to capture information on a range of domains. Consistent with US Food and Drug Administration (FDA) guidelines, content validation is the first step in evaluating the psychometric properties of an outcome measure. The aim of this study was to validate the content of the clinician-reported items in the CCSA (CCSA-Clinician). Eight neurologists leading the USA CDD Center of Excellence clinics were interviewed using the "think aloud" technique to critique 26 clinician-reported items. Common themes were aggregated, and a literature search of related assessments informed item modifications. The clinicians then participated in 2 consensus meetings to review themes and finalize the items. A consensus was achieved for the content of the CCSA-Clinician. Eight of the original items were omitted, 11 items were added, and the remaining 18 items were revised. The final 29 items were classified into 2 domains: functioning and neurologic impairments. This study enabled refinement of the CCSA-Clinician and provided evidence for its content validity. This preliminary validation is essential before field testing and further validation, in order to advance the instrument toward clinical trial readiness.
Zhang M, Chen T, Zhong Y. Demographic and prognostic factors of optic nerve astrocytoma: a retrospective study of surveillance, epidemiology, and end results (SEER). BMC Cancer 2021;21(1):976.Abstract
BACKGROUND: Optic nerve astrocytomas (ONAs) are neurological neoplasms in the central nervous system (CNS), and they have the highest incidence rate among all the tumor types in the visual pathway. In this study, we conducted a Surveillance, Epidemiology, and End Results (SEER) -based research to explore the demographic, survival, and prognostic factors of patients diagnosed with ONAs. METHODS: Utilizing the SEER database, we retrospectively evaluated data of patients diagnosed with ONAs of all ages from 1984 to 2016. We used the Student's t distribution to test variables of patients and various characteristics, and Kaplan-Meier curve to illustrate overall survival (OS) with 95.0% confidence intervals (CIs). We also performed univariate and multivariate analyses to evaluate various variables' validity on overall survival. RESULTS: A total of 1004 cases were analyzed, and revealed that age (P<0.001, hazard ratio (HR) = 8.830, 95% CI: 4.088-19.073), tumor grade (P<0.001, HR = 1.927, 95% CI: 1.516-2.450), diagnostic confirmation (P<0.001, HR = 2.444, 95% CI: 1.632-3.660), and histology type (P = 0.046, HR = 1.563, 95% CI: 1.008-2.424) of the tumor were associated with decreased survival. CONCLUSIONS: From this large, comparative study of ONAs, we found that younger age may be considered as a protective indicator, while high-grade astrocytic tumors have a worse prognosis. We also found that diagnostic confirmation and tumor grade were independent prognostic factors in this patient population.
Putra I, Shen X, Anwar KN, Rabiee B, Samaeekia R, Almazyad E, Giri P, Jabbehdari S, Hayat MR, Elhusseiny AM, Ghassemi M, Mahmud N, Edward DP, Joslin CE, Rosenblatt MI, Dana R, Eslani M, Hematti P, Djalilian AR. Preclinical Evaluation of the Safety and Efficacy of Cryopreserved Bone Marrow Mesenchymal Stromal Cells for Corneal Repair. Transl Vis Sci Technol 2021;10(10):3.Abstract
Purpose: Mesenchymal stromal cells (MSCs) have been shown to enhance tissue repair as a cell-based therapy. In preparation for a phase I clinical study, we evaluated the safety, dosing, and efficacy of bone marrow-derived MSCs after subconjunctival injection in preclinical animal models of mice, rats, and rabbits. Methods: Human bone marrow-derived MSCs were expanded to passage 4 and cryopreserved. Viability of MSCs after thawing and injection through small-gauge needles was evaluated by vital dye staining. The in vivo safety of human and rabbit MSCs was studied by subconjunctivally injecting MSCs in rabbits with follow-up to 90 days. The potency of MSCs on accelerating wound healing was evaluated in vitro using a scratch assay and in vivo using 2-mm corneal epithelial debridement wounds in mice. Human MSCs were tracked after subconjunctival injection in rat and rabbit eyes. Results: The viability of MSCs after thawing and immediate injection through 27- and 30-gauge needles was 93.1% ± 2.1% and 94.9% ± 1.3%, respectively. Rabbit eyes demonstrated mild self-limiting conjunctival inflammation at the site of injection with human but not rabbit MSCs. In scratch assay, the mean wound healing area was 93.5% ± 12.1% in epithelial cells co-cultured with MSCs compared with 40.8% ± 23.1% in controls. At 24 hours after wounding, all MSC-injected murine eyes had 100% corneal wound closure compared with 79.9% ± 5.5% in controls. Human MSCs were detectable in the subconjunctival area and peripheral cornea at 14 days after injection. Conclusions: Subconjunctival administration of MSCs is safe and effective in promoting corneal epithelial wound healing in animal models. Translational Relevance: These results provide preclinical data to support a phase I clinical study.
Halawa OA, Friedman DS, Roldan AM, Zebardast N. Changing trends in ocular trauma during the COVID-19 pandemic in the USA. Br J Ophthalmol 2021;Abstract
BACKGROUND/AIMS: The COVID-19 pandemic has been associated with a decline in emergency department (ED) presentations for trauma. The purpose of this study is to compare the estimated number and characteristics of eye injuries in 2020, the year of the COVID-19 pandemic, to those in 2011-2019. METHODS: A stratified probability sample of US ED-treated eye injuries was used to calculate the estimated annual number and incidence of these injuries in 2020, the year of the pandemic, and 2011-2019 (prepandemic years). Two-sample t-tests and Pearson χ2 were used to assess differences in demographics and injury characteristics. For multiple comparisons, Bonferroni correction was applied. RESULTS: The estimated number of ED-treated eye injuries per year was 152 957 (95% CI 132 637 to 176 153) in 2020 and 194 142 (95% CI 191 566 to 196 401) in 2011-2019. The annual incidence of ED-treated eye injuries was lower in 2020, at 46 per 100 000 population than in 2011-2019, at 62 per 100 000 per year (p<0.001). In 2020 vs 2011-2019, there was a higher incidence of ruptured globes (0.5 per 100 000 vs 0.3 per 100 000 per year, p<0.001), hyphemas (0.6 per 100 000 vs 0.4 per 100 000 per year, p<0.001), lacerations (1.0 per 100 000 in 2020 vs 0.8 per 100 000 per year, p<0.001) and orbital fractures (0.3 per 100 000 vs 0.03). CONCLUSION: The estimated incidence of eye injuries presenting to the ED was significantly lower in 2020 than in 2011-2019, but there was a higher estimated incidence of severe eye injuries. Changes in living and work environments due to the COVID-19 pandemic were likely associated with the differences in ocular trauma presentations observed in this study.
Ludwig CA, Vail D, Rajeshuni NA, Al-Moujahed A, Rosenblatt T, Callaway NF, Pasricha MV, Ji MH, Moshfeghi DM. Statins and the progression of age-related macular degeneration in the United States. PLoS One 2021;16(8):e0252878.Abstract
PURPOSE: To study the effect of statin exposure on the progression from non-exudative to exudative age-related macular degeneration (AMD). METHODS: Retrospective cohort study of commercially insured patients diagnosed with non-exudative AMD (n = 231,888) from 2007 to 2015. Time-to-event analysis of the association between exposure to lipid-lowering medications and time from non-exudative AMD to exudative AMD diagnosis was conducted. Outcome measures included progression to exudative AMD, indicated by diagnosis codes for exudative AMD or procedural codes for intravitreal injections. RESULTS: In the year before and after first AMD diagnosis, 11,330 patients were continuously prescribed lipid-lowering medications and 31,627 patients did not take any lipid-lowering medication. Of those taking statins, 21 (1.6%) patients were on very-high-dose lipophilic statins, 644 (47.6%) on high-dose lipophilic statins, and 689 (50.9%) on low-dose lipophilic statins. We found no statistically significant relationship between exposure to low (HR 0.89, 95% CI 0.83 to 1.38) or high-dose lipophilic statins (HR 1.12, 95% CI 0.86 to 1.45) and progression to exudative AMD. No patients taking very-high-dose lipophilic statins converted from non-exudative to exudative AMD, though this difference was not statistically significant due to the subgroup size (p = .23, log-rank test). CONCLUSIONS: No statistically significant relationship was found between statin exposure and risk of AMD progression. Interestingly, no patients taking very-high-dose lipophilic statins progressed to exudative AMD, a finding that warrants further exploration.
Coyle S, Khan MN, Chemaly M, Callaghan B, Doyle C, Willoughby CE, Atkinson SD, Gregory-Ksander M, McGilligan V. Targeting the NLRP3 Inflammasome in Glaucoma. Biomolecules 2021;11(8)Abstract
Glaucoma is a group of optic neuropathies characterised by the degeneration of retinal ganglion cells, resulting in damage to the optic nerve head (ONH) and loss of vision in one or both eyes. Increased intraocular pressure (IOP) is one of the major aetiological risk factors in glaucoma, and is currently the only modifiable risk factor. However, 30-40% of glaucoma patients do not present with elevated IOP and still proceed to lose vision. The pathophysiology of glaucoma is therefore not completely understood, and there is a need for the development of IOP-independent neuroprotective therapies to preserve vision. Neuroinflammation has been shown to play a key role in glaucoma and, specifically, the NLRP3 inflammasome, a key driver of inflammation, has recently been implicated. The NLRP3 inflammasome is expressed in the eye and its activation is reported in pre-clinical studies of glaucoma. Activation of the NLRP3 inflammasome results in IL-1β processing. This pro inflammatory cytokine is elevated in the blood of glaucoma patients and is believed to drive neurotoxic inflammation, resulting in axon degeneration and the death of retinal ganglion cells (RGCs). This review discusses glaucoma as an inflammatory disease and evaluates targeting the NLRP3 inflammasome as a therapeutic strategy. A hypothetical mechanism for the action of the NLRP3 inflammasome in glaucoma is presented.
Cox SM, Kheirkhah A, Aggarwal S, Abedi F, Cavalcanti BM, Cruzat A, Hamrah P. Alterations in corneal nerves in different subtypes of dry eye disease: An in vivo confocal microscopy study. Ocul Surf 2021;22:135-142.Abstract
PURPOSE: To evaluate corneal subbasal nerve alterations in evaporative and aqueous-deficient dry eye disease (DED) as compared to controls. METHODS: In this retrospective, cross-sectional, controlled study, eyes with a tear break-up time of less than 10 s were classified as DED. Those with an anesthetized Schirmer's strip of less than 5 mm were classified as aqueous-deficient DED. Three representative in vivo confocal microscopy images were graded for each subject for total, main, and branch nerve density and numbers. RESULTS: Compared to 42 healthy subjects (42 eyes), the 70 patients with DED (139 eyes) showed lower total (18,579.0 ± 687.7 μm/mm2 vs. 21,014.7 ± 706.5, p = 0.026) and main (7,718.9 ± 273.9 vs. 9,561.4 ± 369.8, p < 0.001) nerve density, as well as lower total (15.5 ± 0.7/frame vs. 20.5 ± 1.3, p = 0.001), main (3.0 ± 0.1 vs. 3.8 ± 0.2, p = 0.001) and branch (12.5 ± 0.7 vs. 16.5 ± 1.2, p = 0.004) nerve numbers. Compared to the evaporative DED group, the aqueous-deficient DED group showed reduced total nerve density (19,969.9 ± 830.7 vs. 15,942.2 ± 1,135.7, p = 0.006), branch nerve density (11,964.9 ± 749.8 vs. 8,765.9 ± 798.5, p = 0.006), total nerves number (16.9 ± 0.8/frame vs. 13.0 ± 1.2, p = 0.002), and branch nerve number (13.8 ± 0.8 vs. 10.2 ± 1.1, p = 0.002). CONCLUSIONS: Patients with DED demonstrate compromised corneal subbasal nerves, which is more pronounced in aqueous-deficient DED. This suggests a role for neurosensory abnormalities in the pathophysiology of DED.
Ung L, Chodosh J. Urgent unmet needs in the care of bacterial keratitis: An evidence-based synthesis. Ocul Surf 2021;Abstract
Bacterial corneal infections, or bacterial keratitis (BK), are ophthalmic emergencies that frequently lead to irreversible visual impairment. Though increasingly recognized as a major cause of global blindness, modern paradigms of evidence-based care in BK have remained at a diagnostic and therapeutic impasse for over half a century. Current standards of management - based on the collection of corneal cultures and the application of broad-spectrum topical antibiotics - are beset by important yet widely underrecognized limitations, including approximately 30% of all patients who will develop moderate to severe vision loss in the affected eye. Though recent advances have involved a more clearly defined role for adjunctive topical corticosteroids, and novel therapies such as corneal crosslinking, overall progress to improve patient and population-based outcomes remains incommensurate to the chronic morbidity caused by this disease. Recognizing that the care of BK is guided by the clinical axiom, "time equals vision", this chapter offers an evidence-based synthesis for the clinical management of these infections, underscoring critical unmet needs in disease prevention, diagnosis, and treatment.
Ebrahimiadib N, Fadakar K, Riazi-Esfahani H, Zarei M, Maleki A, Bojabadi L, Ahmadi A, Look-Why S, Foster CS. COVID-19 and Immunosuppressive Therapy in Ocular Inflammatory Disease, a Telemedicine Survey. Ocul Immunol Inflamm 2021;:1-7.Abstract
Purpose: Determine the risk of immunomodulatory therapy (IMT) for COVID-19 infection morbidity.Method: A telemedicine survey on patients of a referral uveitis clinic was performed. Signs of infection, habits, and hospitalizations during the 7 months of the COVID-19 pandemic prior to the study date were recorded. Suggestive findings in chest CT scan and/or positive RT-PCR were considered as confirmed COVID-19 infection while those with only suggestive symptoms were considered as suspected cases. Risk factors including sanitary measures and IMT were compared between patients with confirmed cases and patients without infection.Result: 694 patients were included. Eight patients were identified as confirmed cases and 22 patients as suspected cases of COVID-19 infection. Close contact with infected persons was the only significant risk factor for contracting COVID-19.Conclusion: Using IMT did not affect hospitalization and/or ICU admission and can thus be continued during the pandemic, provided that instructions for preventive measures are followed.
Guo X, Nguyen AM, Vongsachang H, Kretz AM, Mukherjee RM, Neitzel AJ, Shakarchi AF, Friedman DS, Repka MX, Collins ME. Refractive Error Findings in Students Who Failed School-based Vision Screening. Ophthalmic Epidemiol 2021;:1-9.Abstract
PURPOSE: To report refractive error findings in Baltimore City schoolchildren who failed school-based vision screenings. METHODS: In this cross-sectional analysis, students pre-kindergarten through 8th grade who failed screenings during school years 2016-2019 received an eye examination, including non-cycloplegic autorefraction and visual acuity (VA) measurements. Refractive error was identified when there was at least: -0.50 diopter (D) spherical equivalent (SE) myopia, +0.50D SE hyperopia, 1.00D astigmatism, or 1.00D anisometropia in either eye. Generalized estimating equation models were used to identify factors associated with clinically significant refractive error, defined as decreased VA and more severe refractive error. RESULTS: Of 7520 students who failed screening, 6627 (88%) were analyzed. Clinically significant refractive error and any refractive error were found in 2352 (35.5%) and 5952 (89.8%) students, respectively. Mild myopia (45%, -0.50 D to <-3.00 D SE) and low astigmatism (47%, 1.00 D to <3.00 D cylinder) were the most prevalent types of refractive error. Proportions of students with myopia increased with higher grade levels (Ptrend<0.001). Myopia and astigmatism were more common in black and Latinx. Risk factors for clinically significant refractive error included higher grades (odds ratios [OR] ranged from 1.30 to 2.19 compared with 1st grade, P < .05) and Latinx ethnicity (OR = 1.31, 95%CI: 1.08-1.59). CONCLUSION: A Baltimore school-based vision program identified a substantial number of students with refractive error in a high-poverty urban community. Over 1/3 students who failed vision screening had clinically significant refractive error, with black and Latinx students at higher risk of having myopia and astigmatism.
McKay MK, Apostolopoulos N, Dahrouj M, Nguyen HV, Reddy A, Blazes M, Lacy M, Pepple KL, Lee AY, Lee CS. Assessing the Uniformity of Uveitis Clinical Concepts and Associated ICD-10 Codes Across Health Care Systems Sharing the Same Electronic Health Records System. JAMA Ophthalmol 2021;Abstract
Importance: Big data studies may allow for the aggregation of patients with rare diseases such as uveitis to answer important clinical questions. Standardization of uveitis-related variables will be necessary, including the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes used to identify patients of interest. There are currently limited data on the uniformity of diagnosis mapping to ICD-10 codes for uveitis diagnoses among different health systems. Objective: To assess the degree of uniformity in mapping of uveitis clinical concepts to ICD-10 codes across health care systems using the same electronic health record (EHR) system. Design, Setting, and Participants: This multicenter survey study was conducted between September 14 and October 9, 2020, at 5 academic health care systems that use the Epic EHR. Researchers from the University of Washington, Harvard University, Stanford University, Yale University, and the University of California, San Francisco queried 54 uveitis-related diagnostic terms and recorded the associated ICD-10 codes. Main Outcomes and Measures: The degree of uniformity for uveitis clinical concepts and associated ICD-10 codes. Results: Fifty-four uveitis-related diagnostic terms were queried within the Epic EHR at 5 different health care systems. There was perfect agreement among all 5 centers for 52 of the 54 diagnostic terms. Two diagnostic terms had differences in ICD-10 coding: juvenile idiopathic arthritis associated chronic uveitis and intermediate uveitis. Intermediate uveitis was associated with codes H20.1x (ICD-10 description: chronic iridocyclitis) or H20.9 (ICD-10 description: unspecified iridocyclitis) in 3 centers while being associated with code H30.2x (ICD-10 description: posterior cyclitis) at the 2 remaining centers. The discrepancies appear to be related to a recent update in diagnostic mapping in the Epic EHR. Conclusions and Relevance: This study suggests that ICD-10 code mapping to uveitis diagnostic terminology appears to be highly uniform at different centers with the Epic EHR. However, temporal changes in diagnosis mapping to ICD-10 codes and a lack of 1-to-1 mapping of diagnosis to ICD-10 code add additional sources of complexity to the interpretation of big data studies in uveitis.
E J-Y, Mihailovic A, Garzon C, Schrack JA, Li T, West SK, Gitlin LN, Friedman DS, Ramulu PY. Association Between Visual Field Damage and Gait Dysfunction in Patients With Glaucoma. JAMA Ophthalmol 2021;139(10):1053-1060.Abstract
Importance: Gait dysfunction is common in older people with visual impairment and is a major cause of falls. Objective: To compare 3-year longitudinal changes in gait measures across the spectrum of baseline visual field (VF) damage in glaucoma. Design, Setting, and Participants: A post hoc analysis was designed on September 1, 2018, following a prospective cohort study, which enrolled older adults with glaucoma or suspected glaucoma from September 2013 to March 2015 and followed up for up to 3 years. Baseline VF damage was defined by integrated VF (IVF) sensitivity and categorized as normal/mild (IVF >28 dB), moderate (IVF, 23-28 dB), and severe (IVF, <23 dB). Each participant walked on an electronic walkway back and forth twice at normal pace each study year. Linear mixed-effects models evaluated longitudinal change in gait outcomes (1) stratified within each VF severity category and (2) across the range of IVF sensitivity. Analysis took place from October 2019 to October 2020. Main Outcomes and Measures: Three-year changes in 7 gait assessments under usual-pace walking, including base support and its coefficient of variation, stride length and its coefficient of variation, stride velocity and its coefficient of variation, and cadence. Results: Of 241 participants, the mean (SD) age was 70.8 (7.7) years, 116 (48.2%) were women, and 70 (29.0%) were African American. When comparing longitudinal gait changes over 3 years across the spectrum of IVF sensitivity, each 5-unit (dB) decrement was associated with more rapid declines in stride velocity (-0.05 z score unit/y; 95% CI, -0.09 to -0.01; P = .01) and cadence (-0.07 z score unit/y; 95% CI, -0.10 to -0.03; P < .001). When evaluating gait changes within each glaucoma severity group, shorter stride length was associated with persons with normal/mild (-0.06 z score unit/y; 95% CI, -0.10 to -0.03; P = .001), moderate (-0.08 z score unit/y; 95% CI, -0.12 to -0.04; P < .001), and severe VF damage (-0.16 z score unit/y; 95% CI, -0.24 to -0.07; P < .001), while stride velocity (-0.18 z score unit; 95% CI, -0.28 to -0.07; P = .002) and slower cadence (-0.15 z score unit; 95% CI, -0.25 to -0.04; P = .006) were associated with those with severe VF damage. Conclusions and Relevance: At worse levels of baseline VF damage, patients with glaucoma in this study demonstrated an exacerbated decline in walking speeds (ie, stride velocity and cadence), indicating that mobility speeds decrease faster over time in older adults with glaucoma.
Papageorgiou GI, Symeonidis DG, Tsakatikas SA, Liatsos AD, Douglas KA, Douglas VP, Moschos MM, Kosmas C. Central neurotoxicity induced by trastuzumab emtansine (T-DM1): a case report. Anticancer Drugs 2021;32(10):1146-1149.Abstract
Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (Her2) - targeted antibody-drug conjugate that is approved for patients previously treated with trastuzumab and a taxane for Her2-positive advanced breast cancer and those who have progressed within 6 months of completion of adjuvant chemotherapy, as well as for patients with residual invasive Her2-positive disease after the completion of adjuvant chemotherapy. Peripheral neuropathy is a common adverse event; however, ocular events have also been described. With the current report we present the case of a 67-year old woman who developed transient grade 2-3 blurred vision after the first T-DM1 infusion, which was complicated with grade 2 diplopia causing vertigo after the second infusion. After extended investigation, this symptomatology was attributed to central neurotoxicity, and gradually resolved after T-DM1 discontinuation.
Kaiser T, Allen HM, Kwon O, Barak B, Wang J, He Z, Jiang M, Feng G. MyelTracer: A Semi-Automated Software for Myelin -Ratio Quantification. eNeuro 2021;8(4)Abstract
In the central and peripheral nervous systems, the myelin sheath promotes neuronal signal transduction. The thickness of the myelin sheath changes during development and in disease conditions like multiple sclerosis. Such changes are routinely detected using electron microscopy through g-ratio quantification. While g-ratio is one of the most critical measurements in myelin studies, a major drawback is that g-ratio quantification is extremely laborious and time-consuming. Here, we report the development and validation of MyelTracer, an installable, stand-alone software for semi-automated g-ratio quantification based on the Open Computer Vision Library (OpenCV). Compared with manual g-ratio quantification, using MyelTracer produces consistent results across multiple tissues and animal ages, as well as in remyelination after optic nerve crush, and reduces total quantification time by 40-60%. With g-ratio measurements via MyelTracer, a known hypomyelination phenotype can be detected in a Williams syndrome mouse model. MyelTracer is easy to use and freely available for Windows and Mac OS X (https://github.com/HarrisonAllen/MyelTracer).

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