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Roh M, Tesfaye H, Kim SC, Zabotka LE, Patorno E. Cardiovascular and Mortality Risk with Intravitreal Vascular Endothelial Growth Factor Inhibitors in Patients with Diabetic Retinopathy. Ophthalmol Retina 2022;6(12):1145-1153.Abstract
OBJECTIVE: To investigate the cardiovascular (CV) safety associated with intravitreal anti-VEGF injections (IAVIs) in patients with diabetic retinopathy (DR). DESIGN: Population-based cohort study using Medicare and 2 commercial insurance claims databases in the United States from January 2009 to December 2017. SUBJECTS: Patients with DR aged ≥ 18 years in whom treatment with either IVAIs or laser procedure or intravitreal steroid injections was initiated. METHODS: We estimated the propensity score (PS) using multivariable logistic regression models, including 85 baseline covariates and PS-matched patients in a 1:1 ratio. We estimated the pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analyses based on prior history of CV events were also conducted. MAIN OUTCOME MEASURES: A composite CV outcome of myocardial infarction (MI) or stroke, its individual components, and all-cause mortality in 180 and 365 days after treatment initiation. RESULTS: We identified 61 508 PS-matched patients in a 1:1 ratio in whom either IVAIs or laser or steroid treatment was initiated. Compared with laser or steroid treatment, IAVIs were not associated with an increased risk of the composite CV outcome (HR, 0.95; 95% CI, 0.83-1.09), MI (HR, 0.93; 95% CI, 0.76-1.13), or stroke (HR, 0.98; 95% CI, 0.80-1.19) or the risk of all-cause mortality (HR, 1.25; 95% CI, 0.97-1.62) at 180 days of follow-up. At 365 days, the risk of the composite CV outcome, stroke, and MI remained similar between the 2 groups, although the risk of all-cause mortality was increased with IAVIs (HR, 1.35; 95% CI, 1.14-1.60). The subgroup analysis showed that the risk of all-cause mortality was increased in patients with a prior history of CV events. CONCLUSIONS: Among > 60 000 patients with DR, those who received IAVIs had a risk of CV events similar to those who received laser or steroid treatment. However, the risk of all-cause mortality was higher in patients who received IAVIs for DR.
Saini C, Davies EC, Chodosh J, Shen LQ. Glaucoma in Patients With Endothelial Keratoplasty. Cornea 2022;41(12):1584-1599.Abstract
Endothelial keratoplasty (EK), including Descemet stripping endothelial keratoplasty and Descemet membrane endothelial keratoplasty, is now the most performed corneal transplant procedure in the United States. Intraocular pressure (IOP) elevation and glaucoma are common complications and can cause irreversible vision loss and corneal graft failure. This review will cover the incidence, risk factors, and management of glaucoma and IOP elevation after EK. Higher preoperative IOP, preoperative glaucoma, and certain indications for EK, such as bullous keratopathy, are associated with increased risk of glaucoma and glaucoma progression in patients undergoing EK. In addition, we summarize the studies assessing graft outcomes in EK patients with glaucoma or glaucoma surgery. Finally, we provide future directions to improve clinical care in EK patients with glaucoma.
Belanger NL, Kim SJ, Bispo PJM. Molecular characterization of fungal Endophthalmitis and keratitis caused by yeasts. Med Mycol 2022;Abstract
Candida species are the most common causes of sight-threatening fungal ocular infections in temperate regions of the world. Despite their relevance, little is known about the emergence of novel species and the molecular epidemiology of these infections. Here we molecularly characterized 38 yeast isolates collected from patients diagnosed with endophthalmitis or keratitis at Massachusetts Eye and Ear from 2014-2021. Sequencing of the ITS1-5.8S-/ITS2 regions demonstrated that this population of yeasts was dominated by Candida spp. (37 out of 38; 97%), with 58% of the cases caused by C. albicans (n = 22), and the remaining by emerging non-albicans species, predominantly by C. parapsilosis (n = 8) and C. dubliniensis (n = 6). One isolate each was identified as C. tropicalis and Clavispora lusitaniae. Interestingly, all C. dubliniensis were isolated from endophthalmitis and most C. parapsilosis from keratitis. MLST analysis of C. albicans showed a prevalence of CC-1 isolates that has DST69 as the putative founder, with 64% of them belonging to this clonal complex. Isolates grouped within this cluster were more predominant in endophthalmitis (10 out of 14; 71%). One C. albicans CC-1 isolate was multi-azole resistant. In conclusion, we observed that nearly half of the ocular infections caused by yeasts are associated with C. albicans, with evidence for the emergence of non-albicans species that are differentially enriched in distinct ocular niches. Candida albicans isolates clustered within the predominant CC-1 group were particularly more common in endophthalmitis, demonstrating a potential pattern of ocular disease enrichment within this clade.
Nakamichi K, Akileswaran L, Meirick T, Lee MD, Chodosh J, Rajaiya J, Stroman D, Wolf-Yadlin A, Jackson Q, Holtz BW, Lee AY, Lee CS, Van Gelder RN, Van Gelder RN. Machine Learning Prediction of Adenovirus D8 Conjunctivitis Complications from Viral Whole-Genome Sequence. Ophthalmol Sci 2022;2(4):100166.Abstract
OBJECTIVE: To obtain complete DNA sequences of adenoviral (AdV) D8 genome from patients with conjunctivitis and determine the relation of sequence variation to clinical outcomes. DESIGN: This study is a post hoc analysis of banked conjunctival swab samples from the BAYnovation Study, a previously conducted, randomized controlled clinical trial for AdV conjunctivitis. PARTICIPANTS: Ninety-six patients with AdV D8-positive conjunctivitis who received placebo treatment in the BAYnovation Study were included in the study. METHODS: DNA from conjunctival swabs was purified and subjected to whole-genome viral DNA sequencing. Adenovirus D8 variants were identified and correlated with clinical outcomes, including 2 machine learning methods. MAIN OUTCOME MEASURES: Viral DNA sequence and development of subepithelial infiltrates (SEIs) were the main outcome measures. RESULTS: From initial sequencing of 80 AdV D8-positive samples, full adenoviral genome reconstructions were obtained for 71. A total of 630 single-nucleotide variants were identified, including 156 missense mutations. Sequence clustering revealed 3 previously unappreciated viral clades within the AdV D8 type. The likelihood of SEI development differed significantly between clades, ranging from 83% for Clade 1 to 46% for Clade 3. Genome-wide analysis of viral single-nucleotide polymorphisms failed to identify single-gene determinants of outcome. Two machine learning models were independently trained to predict clinical outcome using polymorphic sequences. Both machine learning models correctly predicted development of SEI outcomes in a newly sequenced validation set of 16 cases (P = 1.5 × 10-5). Prediction was dependent on ensemble groups of polymorphisms across multiple genes. CONCLUSIONS: Adenovirus D8 has ≥ 3 prevalent molecular substrains, which differ in propensity to result in SEIs. Development of SEIs can be accurately predicted from knowledge of full viral sequence. These results suggest that development of SEIs in AdV D8 conjunctivitis is largely attributable to pathologic viral sequence variants within the D8 type and establishes machine learning paradigms as a powerful technique for understanding viral pathogenicity.
Guo X, Collins ME, Block SS, Repka MX, Friedman DS. Reply. Ophthalmology 2022;129(12):e157-e158.
Raevis JJ, Lemire CA, Ramsey DJ, Riccobono J, Gonzalez E. Deformation of Aflibercept and Ranibizumab Syringes Causes Variation in Intravitreal Injection Volume and Risks Retinal Tear Formation. Ophthalmol Sci 2022;2(4):100202.Abstract
PURPOSE: The intravitreal injection volume is known to vary with plunger alignment and the speed of injection. We investigated the role that syringe stopper deformation plays in allowing excess volumes to be injected into the eye and the potential for the vitreous humor to become incarcerated when excess force is released within the eye. DESIGN: Experimental study. METHODS: Aflibercept prefilled syringes (PFSs), ranibizumab PFSs, and 1-ml tuberculin (TB) syringes were subjected to increasing injection force to assess the extent to which each design allowed for excess volumes to be expelled after the stopper reached the bottom of the syringe barrel (i.e., after the 50-μl dose was expelled). MAIN OUTCOME MEASURES: Additional volume expelled with stopper deformation. RESULTS: Syringe stoppers are capable of deformation into the dead space when additional force is applied. This allows for progressively greater medication doses to be administered. At an additional force of 3.92 N after the syringe stopper came in contact with the bottom of the syringe barrel, the aflibercept PFSs, ranibizumab PFSs, and 1-ml TB syringes dispensed an additional 17.2%, 11.4%, and 0.8% higher volume than the intended volume of 50 μl, respectively. Upon release of this force, a proportional volume was observed to be drawn back into the needle. CONCLUSIONS: The intravitreal injection volume varies with the force applied to fully depressed syringes because of syringe stopper deformation. We advise that performing forceful intravitreal injections be avoided to prevent excessive dosing of medication. We also caution that pressure applied to the plunger during intravitreal injections not be released while the needle is in the vitreous cavity to guard against vitreous incarceration, which could lead to retinal tear formation or detachment.
Mazumder AG, Julé AM, Cullen PF, Sun D. Astrocyte heterogeneity within white matter tracts and a unique subpopulation of optic nerve head astrocytes. iScience 2022;25(12):105568.Abstract
Much of what we know about astrocyte form and function is derived from the study of gray matter protoplasmic astrocytes, whereas white matter fibrous astrocytes remain relatively unexplored. Here, we used the ribotag approach to isolate ribosome-associated mRNA and investigated the transcriptome of uninjured fibrous astrocytes from three regions: unmyelinated optic nerve head, myelinated optic nerve proper, and corpus callosum. Astrocytes from each region were transcriptionally distinct and we identified region-specific astrocyte genes and pathways. Energy metabolism, particularly oxidative phosphorylation and mitochondrial protein translation emerged as key differentiators of astrocyte populations. Optic nerve astrocytes expressed higher levels of neuroinflammatory pathways than corpus callosum astrocytes and we further identified CARTPT as a new marker of optic nerve head astrocytes. These previously uncharacterized transcriptional profiles of white matter astrocyte types reveal their functional diversity and a greater heterogeneity than previously appreciated.
Feldt J, Garriz A, Rodriguez Benavente MC, Woodward AM, Zoukhri D, Argüeso P. The Matricellular Protein SPARC Decreases in the Lacrimal Gland At Adulthood and During Inflammation. Invest Ophthalmol Vis Sci 2022;63(13):8.Abstract
PURPOSE: Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein abundantly expressed in basement membranes and capsules surrounding a variety of organs and tissues. It mediates extracellular matrix organization and has been implicated in cell contraction. Here, we evaluated the expression of SPARC in the murine lacrimal gland at adulthood and during inflammation. METHODS: Lacrimal glands of young mice (4-6 weeks old) and adult mice (32-40 weeks old) were used for extraction of DNA, RNA, and protein. The presence of SPARC was assessed by quantitative PCR, ELISA, and immunofluorescence microscopy. 5-Methylcytosine and DNA methylation were evaluated using ELISA and bisulfite genomic sequencing, respectively. The effects of cytokines and inflammation in Sparc expression were evaluated in vitro and in the non-obese diabetic (NOD) mouse model of Sjögren's syndrome. RESULTS: The mRNA and protein levels of SPARC were downregulated in lacrimal glands of mature adult mice presenting age-related histological alterations such as increased deposition of lipofuscin and lipids. Epigenetic analyses indicated that glands in adult mice contain higher levels of global DNA methylation and show increased hypermethylation of specific CpG sites within the Sparc gene promoter. Analysis of smooth muscle actin (SMA)-green fluorescent protein (GFP) transgenic mice revealed that SPARC localizes primarily to myoepithelial cells within the gland. Treatment of myoepithelial cells with IL-1β or TNF-α and the development of inflammation in the NOD mice led to decreased transcription of Sparc. CONCLUSIONS: SPARC is a novel matricellular glycoprotein expressed by myoepithelial cells in the lacrimal gland. Loss of SPARC during adulthood and chronic inflammation might have detrimental consequences on myoepithelial cell contraction and the secretion of tear fluid.
Lin JB, Murakami Y, Miller JW, Vavvas DG. Neuroprotection for Age-Related Macular Degeneration. Ophthalmol Sci 2022;2(4):100192.Abstract
Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. Early to intermediate AMD is characterized by the accumulation of lipid- and protein-rich drusen. Late stages of the disease are characterized by the development of choroidal neovascularization, termed "exudative" or "neovascular AMD," or retinal pigment epithelium (RPE) cell and photoreceptor death, termed "geographic atrophy" (GA) in advanced nonexudative AMD. Although we have effective treatments for exudative AMD in the form of anti-VEGF agents, they have no role for patients with GA. Neuroprotection strategies have emerged as a possible way to slow photoreceptor degeneration and vision loss in patients with GA. These approaches include reduction of oxidative stress, modulation of the visual cycle, reduction of toxic molecules, inhibition of pathologic protein activity, prevention of cellular apoptosis or programmed necrosis (necroptosis), inhibition of inflammation, direct activation of neurotrophic factors, delivery of umbilical tissue-derived cells, and RPE replacement. Despite active investigation in this area and significant promise based on preclinical studies, many clinical studies have not yielded successful results. We discuss selected past and current neuroprotection trials for AMD, highlight the lessons learned from these past studies, and discuss our perspective regarding remaining questions that must be answered before neuroprotection can be successfully applied in the field of AMD research.
Shareef O, Kwan JT, Lau S, Tahboub MA, Saeed HN. An alternative model for assessing mortality risk in Stevens Johnson syndrome/toxic epidermal necrolysis using a random forests classifier: A pilot study. Front Med (Lausanne) 2022;9:935408.Abstract
INTRODUCTION: Mortality risk prediction is an important part of the clinical assessment in the Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) patient. The SCORTEN and ABCD-10 scoring systems have been used as predictive clinical tools for assessing this risk. However, some of the metrics required in calculating these scores, such as the total body surface area (TBSA) involvement, are difficult to calculate. In addition, TBSA involvement is calculated in a variety of ways and is observer dependent and subjective. The goal of this study was to develop an alternative method to predict mortality in patients with SJS/TEN. METHODS: Data was split into training and test datasets and preprocessed. Models were trained using five-fold cross validation. Out of several possible candidates, a random forests model was evaluated as being the most robust in predictive power for this dataset. Upon feature selection, a final random forests model was developed which was used for comparison against SCORTEN. RESULTS: The differences in both accuracy (p = 0.324) and area under the receiver operating characteristic curve (AUROC) (p = 0.318) between the final random forests model and the SCORTEN and ABCD-10 models were not statistically significant. As such, this alternative method performs similarly to SCORTEN while only requiring simple laboratory tests from the day of admission. DISCUSSION: This new alternative can make the mortality prediction process more efficient, along with providing a seamless implementation of the patient laboratory tests directly into the model from existing electronic health record (EHR) systems. Once the model was developed, a web application was built to deploy the model which integrates with the Epic EHR system on the Fast Healthcare Interoperability Resources (FHIR) Application Programming Interface (API); this only requires the patient medical record number and a date of the lab tests as parameters. This model ultimately allows clinicians to calculate patient mortality risk with only a few clicks. Further studies are needed for validation of this tool.
Wang Z, Yemanyi F, Blomfield AK, Bora K, Huang S, Liu C-H, Britton WR, Cho SS, Tomita Y, Fu Z, Ma J-X, Li W-H, Chen J. Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis. Elife 2022;11Abstract
Amino acid (AA) metabolism in vascular endothelium is important for sprouting angiogenesis. SLC38A5 (solute carrier family 38 member 5), an AA transporter, shuttles neutral AAs across cell membrane, including glutamine, which may serve as metabolic fuel for proliferating endothelial cells (ECs) to promote angiogenesis. Here, we found that Slc38a5 is highly enriched in normal retinal vascular endothelium, and more specifically, in pathological sprouting neovessels. Slc38a5 is suppressed in retinal blood vessels from Lrp5-/- and Ndpy/- mice, both genetic models of defective retinal vascular development with Wnt signaling mutations. Additionally, Slc38a5 transcription is regulated by Wnt/β-catenin signaling. Genetic deficiency of Slc38a5 in mice substantially delays retinal vascular development and suppresses pathological neovascularization in oxygen-induced retinopathy modeling ischemic proliferative retinopathies. Inhibition of SLC38A5 in human retinal vascular ECs impairs EC proliferation and angiogenic function, suppresses glutamine uptake, and dampens vascular endothelial growth factor receptor 2. Together these findings suggest that SLC38A5 is a new metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in ECs.
Liang YB, Shen R, Zhou W, Fan S, Chan PP, Tham CCY, Congdon N, Friedman DS, Wang N. Prevalence and Ocular Biometric Characteristics of Myopia in Primary Angle Closure Disease in Rural China: The Handan Eye Study. Invest Ophthalmol Vis Sci 2022;63(12):19.Abstract
PURPOSE: The purpose of this study was to determine the prevalence of myopia among patients with primary angle closure disease (PACD) in rural China and their ocular biometric characteristics. METHODS: Study subjects were recruited from the Handan Eye Study. A/B-mode scan (Cine Scan, Quantel Medical, Cedex, France) was used to measure the axial length, anterior chamber depth (ACD), and lens thickness (LT). PACD was defined as the anterior chamber angle being considered closed when 180 degrees or more of the posterior pigmented trabecular meshwork were not visible on the gonioscopy. Myopia was defined as a spherical equivalent (SE) refractive error ≤-0.5 diopter (D). Persons who did not meet PACD definition were classified as the open-angle (OA) group. RESULTS: The overall prevalence of myopia in persons with PACD was 13.7% (11.6% in primary angle closure suspect [PACS], 21.6% in primary angle closure [PAC], 62.5% in primary angle closure glaucoma [PACG]). The age-specific prevalence of myopia in PACD eyes was 41.7% at 30 to 39 years old, 12.3% at 40 to 49 years old, 8.7% at 50 to 59 years old, 10.7% at 60 to 69 years old, and 31.7% at age 70 years and over. PACD had shorter AL (22.2 ± 0.8 vs. 22.9 ± 0.9 mm, P < 0.001), shallower ACD (2.3 ± 0.3 vs. 2.8 ± 0.4 mm, P < 0.001), and greater LT (5.0 ± 0.5 vs. 4.7 ± 0.5 mm, P < 0.001). PACD had even thicker lenses and deeper ACD with age than those with OA (all P ≤ 0.025) from 30 years to 70 years of age and over. CONCLUSIONS: Myopia was common among persons with PACD who were less than 40 years of age in this rural Chinese population, and over half of those with PACG were myopic.
Keel S, Lingham G, Misra N, Block S, Bourne R, Calonge M, Cheng C-Y, Friedman DS, Furtado JM, Khanna R, Mariotti S, Mathenge W, Matoto E, Müeller A, Rabiu M, Rasengane T, Resnikoff S, Wormald R, Yasmin S, Zhao J, Evans JR, Cieza A, of Group PECID. Toward Universal Eye Health Coverage-Key Outcomes of the World Health Organization Package of Eye Care Interventions: A Systematic Review. JAMA Ophthalmol 2022;140(12):1229-1238.Abstract
IMPORTANCE: Despite persistent inequalities in access to eye care services globally, guidance on a set of recommended, evidence-based eye care interventions to support country health care planning has not been available. To overcome this barrier, the World Health Organization (WHO) Package of Eye Care Interventions (PECI) has been developed. OBJECTIVE: To describe the key outcomes of the PECI development. EVIDENCE REVIEW: A standardized stepwise approach that included the following stages: (1) selection of priority eye conditions by an expert panel after reviewing epidemiological evidence and health facility data; (2) identification of interventions and related evidence for the selected eye conditions from a systematic review of clinical practice guidelines (CPGs); stage 2 included a systematic literature search, screening of title and abstracts (excluding articles that were not relevant CPGs), full-text review to assess disclosure of conflicts of interest and affiliations, quality appraisal, and data extraction; (3) expert review of the evidence extracted in stage 2, identification of missed interventions, and agreement on the inclusion of essential interventions suitable for implementation in low- and middle-income resource settings; and (4) peer review. FINDINGS: Fifteen priority eye conditions were chosen. The literature search identified 3601 articles. Of these, 469 passed title and abstract screening, 151 passed full-text screening, 98 passed quality appraisal, and 87 were selected for data extraction. Little evidence (≤1 CPG identified) was available for pterygium, keratoconus, congenital eyelid disorders, vision rehabilitation, myopic macular degeneration, ptosis, entropion, and ectropion. In stage 3, domain-specific expert groups voted to include 135 interventions (57%) of a potential 235 interventions collated from stage 2. After synthesis across all interventions and eye conditions, 64 interventions (13 health promotion and education, 6 screening and prevention, 38 treatment, and 7 rehabilitation) were included in the PECI. CONCLUSIONS AND RELEVANCE: This systematic review of CPGs for priority eye conditions, followed by an expert consensus procedure, identified 64 essential, evidence-based, eye care interventions that are required to achieve universal eye health coverage. The review identified some important gaps, including a paucity of high-quality, English-language CPGs, for several eye diseases and a dearth of evidence-based recommendations on eye health promotion and prevention within existing CPGs.

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