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Nilsson AK, Andersson MX, Sjöbom U, Hellgren G, Lundgren P, Pivodic A, Smith LEH, Hellström A. Sphingolipidomics of serum in extremely preterm infants: Association between low sphingosine-1-phosphate levels and severe retinopathy of prematurity. Biochim Biophys Acta Mol Cell Biol Lipids 2021;1866(7):158939.Abstract
BACKGROUND: Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP) that can cause impaired vision or blindness. Changes in blood lipids have been associated with ROP. This study aimed to monitor longitudinal changes in the serum sphingolipidome of extremely preterm infants and investigate the relationship to development of severe ROP. METHODS: This is a prospective study that included 47 infants born <28 gestational weeks. Serum samples were collected from cord blood and at postnatal days 1, 7, 14, and 28, and at postmenstrual weeks (PMW) 32, 36, and 40. Serum sphingolipids and phosphatidylcholines were extracted and analyzed by LC-MS/MS. Associations between sphingolipid species and ROP were assessed using mixed models for repeated measures. RESULTS: The serum concentration of all investigated lipid classes, including ceramide, mono- di- and trihexosylceramide, sphingomyelin, and phosphatidylcholine displayed distinct temporal patterns between birth and PMW40. There were also substantial changes in the lipid species composition within each class. Among the analyzed sphingolipid species, sphingosine-1-phosphate showed the strongest association with severe ROP, and this association was independent of gestational age at birth and weight standard deviation score change. CONCLUSIONS: The serum phospho- and sphingolipidome undergoes significant remodeling during the first weeks of the preterm infant's life. Low postnatal levels of the signaling lipid sphingosine-1-phosphate are associated with the development of severe ROP.
Yang S-A, Mitchell W, Hall N, Elze T, Lorch AC, Miller JW, Zebardast N, Zebardast N. Trends and Usage Patterns of Minimally Invasive Glaucoma Surgery in the United States: IRIS® Registry Analysis 2013-2018. Ophthalmol Glaucoma 2021;4(6):558-568.Abstract
PURPOSE: Understanding trends and patterns in the use of minimally invasive glaucoma surgery (MIGS) and patient profiles undergoing each procedure is important given their relative expense and unknown long-term safety and effectiveness. DESIGN: Retrospective analysis. PARTICIPANTS: Minimally invasive glaucoma surgeries and standard glaucoma surgeries recorded in the American Academy of Ophthalmology Intelligent Research in Sight (IRIS®) Registry. METHODS: We used the data from IRIS Registry between 2013 and 2018 (inclusive) to measure the annual number of MIGS and standard surgical techniques (trabeculectomy or glaucoma drainage device [GDD] placement) performed in the United States, stratified by demographic characteristics. Secondary analyses of concurrent surgeries and of subsequent surgeries for MIGS and standard surgical technique also were conducted. MAIN OUTCOME MEASURES: Trends and sociodemographic characteristics of MIGS use in the United States. RESULTS: Two hundred three thousand three hundred thirty-two eyes and 232 537 unique procedures had associated, documented International Statistical Classification of Diseases and Related Health Problems (ICD), Ninth or Tenth Revision, codes for glaucoma and were included in final analyses. Among eyes with documented glaucoma diagnoses, a substantial increase in annual MIGS procedures occurred over the study period (from 7586 in 2013 to 39 677) and a smaller decrease in standard glaucoma procedures (from 16 215 to 13 701). The proportion of iStent procedures almost tripled during the study period (from 14% to 40%), and by 2017 accounted for almost half (43.7%) of all glaucoma surgeries in the United States. Twenty-one thousand twenty-five of all eyes (10.3%) underwent multiple procedures: 7638 (36.3%) on the same day and 13 387 (63.7%) on subsequent days. Endocyclophotocoagulation and iStent placement were the most common concurrent procedures (55.4% of all concurrent procedures). Trabeculectomy and GDD placement were most commonly followed by another standard glaucoma surgery, but when followed by sequential MIGS, endocyclophotocoagulation and goniotomy were the most common procedures performed (33.0% and 21.9%, respectively). CONCLUSIONS: A significant increase in MIGS use occurred over the recent 6-year period, despite limited evidence of their long-term safety or effectiveness, highlighting the need for trials comparing safety and outcomes of novel MIGS versus traditional surgical treatments for glaucoma.
Caranfa JT, Yoon MK. Septic cavernous sinus thrombosis: A review. Surv Ophthalmol 2021;66(6):1021-1030.Abstract
Septic cavernous sinus thrombosis (SCST) is a rare, yet severe, process typically arising from infections of the paranasal sinuses (predominately ethmoid and/or sphenoid sinusitis) and less commonly, otogenic, odontogenic, and pharyngeal sources. Clinical symptoms of SCST arise from obstruction of venous drainage from the orbit and compression of the cranial nerves within the cavernous sinus. In the preantibiotic era SCST was considered universally fatal (80-100%); however, with the introduction of antibiotics the overall incidence, morbidity, and mortality of SCST have greatly declined. In spite of dramatic improvements, morbidity and mortality remain high, with the majority of patients experiencing neurological sequalae, highlighting the severity of the disease and the need for prompt recognition, diagnosis, and treatment. Here we review of the literature on SCST with a focus on the current recommendations and recent evidence for diagnostic and medical management of this condition.
Lonfat N, Wang S, Lee C, Garcia M, Choi J, Park PJ, Cepko C. Cis-regulatory dissection of cone development reveals a broad role for Otx2 and Oc transcription factors. Development 2021;148(9)Abstract
The vertebrate retina is generated by retinal progenitor cells (RPCs), which produce >100 cell types. Although some RPCs produce many cell types, other RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). We used genome-wide assays of chromatin structure to compare the profiles of a restricted cone/HC RPC and those of other RPCs in chicks. These data nominated regions of regulatory activity, which were tested in tissue, leading to the identification of many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. Two transcription factors, Otx2 and Oc1, were found to bind to many of these CRMs, including those near genes important for cone development and function, and their binding sites were required for activity. We also found that Otx2 has a predicted autoregulatory CRM. These results suggest that Otx2, Oc1 and possibly other Onecut proteins have a broad role in coordinating cone development and function. The many newly discovered CRMs for cones are potentially useful reagents for gene therapy of cone diseases.
Deitch I, Ferenchak K, Miller JB. Quantitative autofluorescence: Review of Current Technical Aspects and Applications in Chorioretinal Disease. Semin Ophthalmol 2021;36(4):346-350.Abstract
Purpose: In this review we discuss the broad clinical application of qAF and provide a descriptive summary of the phenotypic findings of different chorioretinal pathologies.Background: Quantitative Fundus autofluorescence (qAF) is a novel developing technology that can aid in diagnosis and longitudinal disease monitoring by measuring and comparing autofluorescence intensities. Fundus autofluorescence (FAF) is a noninvasive imaging method that creates a density map of the fluorophores of the ocular fundus and provides both functional and topographic anatomic information about retinal cells. Fluorophores are molecules that have the ability to temporarily absorb irradiated light, and emit a small amount of light of a different wavelength. Different endogenous fluorophores can be found in the ocular fundus. Changes in accumulation of retinal fluorophores usually indicate retinal pathology and create characteristic patterns of hyper-autofluorescence and hypo-autofluorescence that help establish a diagnosis.Conclusion: qAF allows a safe non-invasive visualization of the retina, enables a standard for AF intensities comparison and aids to the understanding of the genotype-phenotype correlations.
Halawa O, Mitchell W, Zebardast N. Fall-related eye injury among older adults in the United States. Am J Ophthalmol 2021;Abstract
PURPOSE: To identify common causes of emergency department-treated eye injury among older adults in the United States (US), and to characterize of fall-related ocular trauma in this population. DESIGN: Retrospective cohort study METHODS: Data from the National Electronic Injury Surveillance System, a nationally representative database of US emergency department-treated injuries, was used to assemble a cohort of adults 65 years and older with eye injuries between January 1, 2000 and December 31, 2019. Demographic information, diagnosis, disposition, injury location and consumer product associated with injury were collected. Narrative descriptions of all injuries were reviewed to identify eye injuries secondary to falls. RESULTS: 4,953 eye injuries among older adults were reported from 2000 to 2019, a stratified probability sample representing approximately 238,162 injuries, with an average annual frequency of 12,000 injuries. Falls accounted for 11.5% of these injuries. Fall-related eye injuries commonly presented from home (66.5%) and were more likely to occur in the winter than eye injuries from other causes (28.1% vs. 18.4%, p<0.01). Risk factors for fall-related eye injury included older age (Odds ratio [OR] 1.11, 95% confidence intervals [CI] 1.10-1.13 per year), female sex (OR 2.3, 95% CI 1.6-3.1 vs. male), Black race (OR 2.4, 95% CI 1.3-4.5 vs. White) and presentation from a nursing home (OR 12.7, 95% CI 4.9-32.8 vs. other locations). Older adults with fall-related injury were more likely to be hospitalized (OR 22.8, 95% CI 15.3-33.9) and to suffer from a ruptured globe (OR 14.1, 95% CI 6.5-30.6) than those with fall-unrelated injury. CONCLUSIONS: Falls are an important mechanism of ocular trauma in older adults and are associated with worse outcomes compared to eye injuries from other causes.
Soh Z, Yu M, Betzler BK, Majithia S, Thakur S, Tham YC, Wong TY, Aung T, Friedman DS, Cheng C-Y. The Global Extent of Undetected Glaucoma in Adults: A Systematic Review and Meta-analysis. Ophthalmology 2021;128(10):1393-1404.Abstract
TOPIC: Glaucoma is the leading cause of irreversible blindness, despite having good prognosis with early treatment. We evaluated the global extent of undetected glaucoma and the factors associated with it in this systematic review and meta-analysis. CLINICAL RELEVANCE: Undetected glaucoma increases the risk of vision impairment, which leads to detrimental effects on the quality-of-life and socioeconomic well-being of those affected. Detailed information on the extent and factors associated with undetected glaucoma aid in the development of public health interventions. METHODS: We conducted a systematic review and meta-analysis of population-based studies published between January 1, 1990, and June 1, 2020. Article search was conducted in online databases (PubMED, Web-of-Science), grey literatures (OpenGrey), and nongovernment organization reports. Our outcome measure was the proportion of glaucoma cases that were undetected previously. Manifest glaucoma included any form of glaucoma reported in the original studies and may include primary open-angle glaucoma (POAG), primary angle-closure-glaucoma, secondary glaucoma, or a combination thereof. Undetected glaucoma was defined as glaucoma cases that were undetected prior to diagnosis in the respective study. Random-effect meta-analysis was used to estimate the pooled proportion of undetected glaucoma. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Meta-analysis of Observational Studies in Epidemiology guidelines in our study. RESULTS: We identified 61 articles from 55 population-based studies (n = 189 359 participants; n = 6949 manifest glaucoma). Globally, more than half of all glaucoma cases were undetected previously on average in each geographical region. Africa (odds ratio [OR], 12.70; 95% confidence interval [CI], 4.91-32.86) and Asia (OR, 3.41; 95% CI, 1.63-7.16) showed higher odds of undetected glaucoma as compared with Europe. Countries with low Human Development Index (HDI; <0.55) showed a higher proportion of undetected manifest glaucoma as compared with countries of medium to very high HDI (≥0.55; all P < 0.001). In 2020, 43.78 million POAG cases were projected to be undetected, of which 76.7% were in Africa and Asia. DISCUSSION: Undetected glaucoma is highly prevalent across diverse communities worldwide and more common in Africa and Asia. Strategies to improve detection are needed to prevent excess visual disability and blindness resulting from glaucoma.
Shuldiner SR, Boland MV, Ramulu PY, De Moraes GC, Elze T, Myers J, Pasquale L, Wellik S, Yohannan J. Predicting eyes at risk for rapid glaucoma progression based on an initial visual field test using machine learning. PLoS One 2021;16(4):e0249856.Abstract
OBJECTIVE: To assess whether machine learning algorithms (MLA) can predict eyes that will undergo rapid glaucoma progression based on an initial visual field (VF) test. DESIGN: Retrospective analysis of longitudinal data. SUBJECTS: 175,786 VFs (22,925 initial VFs) from 14,217 patients who completed ≥5 reliable VFs at academic glaucoma centers were included. METHODS: Summary measures and reliability metrics from the initial VF and age were used to train MLA designed to predict the likelihood of rapid progression. Additionally, the neural network model was trained with point-wise threshold data in addition to summary measures, reliability metrics and age. 80% of eyes were used for a training set and 20% were used as a test set. MLA test set performance was assessed using the area under the receiver operating curve (AUC). Performance of models trained on initial VF data alone was compared to performance of models trained on data from the first two VFs. MAIN OUTCOME MEASURES: Accuracy in predicting future rapid progression defined as MD worsening more than 1 dB/year. RESULTS: 1,968 eyes (8.6%) underwent rapid progression. The support vector machine model (AUC 0.72 [95% CI 0.70-0.75]) most accurately predicted rapid progression when trained on initial VF data. Artificial neural network, random forest, logistic regression and naïve Bayes classifiers produced AUC of 0.72, 0.70, 0.69, 0.68 respectively. Models trained on data from the first two VFs performed no better than top models trained on the initial VF alone. Based on the odds ratio (OR) from logistic regression and variable importance plots from the random forest model, older age (OR: 1.41 per 10 year increment [95% CI: 1.34 to 1.08]) and higher pattern standard deviation (OR: 1.31 per 5-dB increment [95% CI: 1.18 to 1.46]) were the variables in the initial VF most strongly associated with rapid progression. CONCLUSIONS: MLA can be used to predict eyes at risk for rapid progression with modest accuracy based on an initial VF test. Incorporating additional clinical data to the current model may offer opportunities to predict patients most likely to rapidly progress with even greater accuracy.
Fu Z, Smith LEH. Cellular senescence in pathologic retinal angiogenesis. Trends Endocrinol Metab 2021;32(7):415-416.Abstract
Pathologic angiogenesis causes blindness in many eye diseases. Crespo-Garcia, Tsuruda, and Dejda et al. employed bioinformatics to characterize cell senescence as a primary factor in the common pathogenesis of retinopathies. They validated their findings using human and mouse retina with proliferative retinopathy. Clearance of senescent cells suppressed neovessel growth.
Seto B, Singh MK, Lemire CA, Arroyo JG. Anterior versus posterior endoscopic cyclophotocoagulation: comparison of indications, populations, and outcomes. Int Ophthalmol 2021;41(9):3021-3028.Abstract
PURPOSE: To examine how indications, patient characteristics, and outcomes differ between anterior and posterior approaches of endoscopic cyclophotocoagulation (ECP) in the treatment of glaucoma. METHODS: This is a retrospective chart review of 9 anterior and 20 posterior ECP cases (n = 29). RESULTS: Posterior ECP cases were typically associated with a dramatic increase in intraocular pressure (IOP), whereas the anterior ECP was associated with chronically elevated pressures. The initial IOPs in mm Hg of posterior ECP cases (26.8 non-NVG; 35.2 NVG) were much greater than anterior ECP cases (17.8), and a greater overall reduction in IOP was observed in the posterior versus anterior ECP cases (10.3 posterior non-NVG; 21.3 posterior NVG; 3.6 anterior, P < .001). With procedural success defined as 6-month post-operative IOP falling within normal ranges and a decrease in either IOP or number of prescribed glaucoma medications, the success rate of ECP was 92% for posterior NVG, 89% for anterior and 75% for posterior non-NVG cases (P = .34), similar to the previous literature. Of the four unsuccessful cases, two resulted in a normal IOP but lacked a drop in pressure or reduction in medication burden, one resulted in a 6-point drop in IOP but remained at 23 mm Hg, and one resulted in phthisis bulbi (3%) from an initial pressure above 40 mm Hg. CONCLUSION: Endoscopic cyclophotocoagulation is an effective and safe procedure for severe glaucoma cases from both an anterior and posterior approach. Ophthalmologists should consider this procedure as part of their glaucoma treatment arsenal.
Qiu M, Woreta FA, Boland MV. Microinvasive Glaucoma Surgery in US Ophthalmology Residency: Surgical Case Log Cross-sectional Analysis and Proposal for New Glaucoma Procedure Classification. J Glaucoma 2021;30(7):621-628.Abstract
PRECIS: A cross-sectional sample of the US ophthalmology residency graduating class of 2018 revealed that 18.4% of residents logged <5 traditional glaucoma surgeries, and 63.4% logged at least 1 microinvasive glaucoma surgery (MIGS). PURPOSE: Describe the state of MIGS in US ophthalmology residency training and propose a glaucoma procedure classification system for residents' surgical case logs. METHODS: Deidentified case logs from residents graduating in 2018 were requested from US residency program directors. RESULTS: Case logs were received for 152/488 (31%) residents from 36/115 (31%) programs. The mean number of traditional glaucoma surgeries per resident was 9.0±5.9 (range: 0 to 31). The mean number of MIGS per resident was 5.2±8.9 cases (range: 0 to 58). There were 28/152 (18.4%) residents from 16/36 (44.4%) programs who logged <5 traditional glaucoma surgeries as primary surgeon, and 3/152 (2.0%) residents from 3/36 (8.3%) programs who logged zero traditional glaucoma surgeries as primary surgeon. There were 98/152 (64.5%) residents from 32/36 (88.8%) programs who logged <5 MIGS as primary surgeon, and 48/152 (31.6%) residents from 25 of 36 (69.4%) programs who logged zero MIGS as primary surgeon. There were 104/152 (63.4%) residents from 33/36 (91.6%) programs who logged at least 1 MIGS as primary surgeon; there were 3/36 (8.3%) residency programs where no resident logged any MIGS as primary surgeon. CONCLUSIONS: US ophthalmology residents' MIGS experience varies widely. Residents can satisfy glaucoma surgery requirements with some MIGS, even in the absence of adequate traditional glaucoma surgeries. We propose a residency case log classification system that better reflects the growing role of MIGS in clinical practice and helps ophthalmic educators more accurately track procedures requiring related skills.
Webb BD, Manoli I, Engle EC, Jabs EW. A framework for the evaluation of patients with congenital facial weakness. Orphanet J Rare Dis 2021;16(1):158.Abstract
There is a broad differential for patients presenting with congenital facial weakness, and initial misdiagnosis unfortunately is common for this phenotypic presentation. Here we present a framework to guide evaluation of patients with congenital facial weakness disorders to enable accurate diagnosis. The core categories of causes of congenital facial weakness include: neurogenic, neuromuscular junction, myopathic, and other. This diagnostic algorithm is presented, and physical exam considerations, additional follow-up studies and/or consultations, and appropriate genetic testing are discussed in detail. This framework should enable clinical geneticists, neurologists, and other rare disease specialists to feel prepared when encountering this patient population and guide diagnosis, genetic counseling, and clinical care.
Haque M, Lei F, Xiong X, Ren Y, Peng H-Y, Wang L, Kumar A, Das JK, Song J. Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells. Viruses 2021;13(5)Abstract
The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.

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