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van Velthoven AJH, Utheim TP, Notara M, Bremond-Gignac D, Figueiredo FC, Skottman H, Aberdam D, Daniels JT, Ferrari G, Grupcheva C, Koppen C, Parekh M, Ritter T, Romano V, Ferrari S, Cursiefen C, Lagali N, LaPointe VLS, Dickman MM. Future directions in managing aniridia-associated keratopathy. Surv Ophthalmol 2023;68(5):940-956.Abstract
Congenital aniridia is a panocular disorder that is typically characterized by iris hypoplasia and aniridia-associated keratopathy (AAK). AAK results in the progressive loss of corneal transparency and thereby loss of vision. Currently, there is no approved therapy to delay or prevent its progression, and clinical management is challenging because of phenotypic variability and high risk of complications after interventions; however, new insights into the molecular pathogenesis of AAK may help improve its management. Here, we review the current understanding about the pathogenesis and management of AAK. We highlight the biological mechanisms involved in AAK development with the aim to develop future treatment options, including surgical, pharmacological, cell therapies, and gene therapies.
Zeleznik OA, Kang JH, Lasky-Su J, Eliassen HA, Frueh L, Clish CB, Rosner BA, Elze T, Hysi P, Khawaja A, Wiggs JL, Pasquale LR, and Consortium UKBEV. Plasma metabolite profile for primary open-angle glaucoma in three US cohorts and the UK Biobank. Nat Commun 2023;14(1):2860.Abstract
Glaucoma is a progressive optic neuropathy and a leading cause of irreversible blindness worldwide. Primary open-angle glaucoma is the most common form, and yet the etiology of this multifactorial disease is poorly understood. We aimed to identify plasma metabolites associated with the risk of developing POAG in a case-control study (599 cases and 599 matched controls) nested within the Nurses' Health Studies, and Health Professionals' Follow-Up Study. Plasma metabolites were measured with LC-MS/MS at the Broad Institute (Cambridge, MA, USA); 369 metabolites from 18 metabolite classes passed quality control analyses. For comparison, in a cross-sectional study in the UK Biobank, 168 metabolites were measured in plasma samples from 2,238 prevalent glaucoma cases and 44,723 controls using NMR spectroscopy (Nightingale, Finland; version 2020). Here we show higher levels of diglycerides and triglycerides are adversely associated with glaucoma in all four cohorts, suggesting that they play an important role in glaucoma pathogenesis.
Androudi S, Kaufman AR, Kouvalakis A, Mitsios A, Sapounas S, Al-Khatib D, Schibler M, Pineda R, Baglivo E. Non-Healing Corneal Ulcer and Uveitis Following Monkeypox Disease: Diagnostic and Therapeutic Challenges. Ocul Immunol Inflamm 2023;:1-6.Abstract
PURPOSE: The ocular manifestations of Monkeypox virus (Mpox) infection remain incompletely characterized. Our goal is to present a case series of non-healing corneal ulcers with associated uveitis caused by Mpox infection as well as management recommendations for Mpox-related ophthalmic disease (MPXROD). METHODS: Retrospective case series. RESULTS: Two male patients with recent hospitalization for systemic Mpox infection presented with non-healing corneal ulcer associated with anterior uveitis and severe IOP elevation. Despite initiation of conservative medical treatment including corticosteroid treatment for uveitis, in both cases, there was clinical progression with enlarging cornea lesions. Both cases received oral tecovirimat with complete healing of the corneal lesion. CONCLUSIONS: Corneal ulcer and anterior uveitis are rare complications of Mpox infection. Although Mpox disease is generally anticipated to be self-limited, tecovirimat may be an effective intervention in poorly healing Mpox keratitis. Corticosteroids should be used with caution in Mpox uveitis, as they might lead to worsening infection.
Blanco T, Musayeva A, Singh RB, Nakagawa H, Lee S, Alemi H, Gonzalez-Nolasco B, Ortiz G, Wang S, Kahale F, Dohlman TH, Chen Y, Dana R. The impact of donor diabetes on corneal transplant immunity. Am J Transplant 2023;23(9):1345-1358.Abstract
Corneal transplantation is the most common form of solid tissue grafting, with an approximately 80% to 90% success rate. However, success rates may decline when donor tissues are derived from patients with a history of diabetes mellitus (DM). To evaluate the underlying immunopathologic processes that cause graft rejection, we used streptozotocin-induced type 1 DM (DM1) and transgenic Lepob/ob type 2 DM (DM2) diabetic murine models as donors and nondiabetic BALB/c as recipients. DM resulted in an increased frequency of corneal antigen-presenting cells (APCs) with an acquired immunostimulatory phenotype. Following transplantation, recipients that received either type of diabetic graft showed increased APC migration and T helper type 1 alloreactive cells, impaired functional regulatory T cells, and graft survival. Insulin treatment in streptozotocin-induced diabetic mice led to an increased tolerogenic profile of graft APC, lower T helper type 1 sensitization, and a higher frequency of functional regulatory T cells with high suppressive capacity, reflected in increased graft survival. We conclude that both DM1 and DM2 in donors can impact corneal APC functional phenotype, rendering the tissue more immunogenic and thereby increasing the risk of graft failure.
Oremosu J, Ung L, Chodosh J, Cañete-Gibas C, Wiederhold NP, Davies EC, Bispo PJM. Fungal keratitis caused by Coniochaeta mutabilis-A case report. J Mycol Med 2023;33(2):101384.Abstract
We present a rare case of recalcitrant fungal keratitis caused by Coniochaeta mutabilis, successfully managed with a course of oral, topical, intrastromal, and intracameral antifungals. A 57-year-old male on their fourth week of treatment for presumed left herpes simplex keratitis presented to clinic with severe left-sided foreign body sensation after gardening in his yard. On examination, a white corneal plaque was observed at 8 o'clock, shown to be a dense collection of fungal hyphae on confocal microscopy. Corneal cultures revealed yeast-like cells, initially identified as Kabatiella zeae by matching 100% identity with K. zeae strains CBS 767.71 and CBS 265.32 in BLASTn search using the internal transcribed spacer (ITS) sequence. Treated for over four months with topical amphotericin B and oral voriconazole without improvement, recourse to intrastromal and intracameral amphotericin B injections, coupled with the application of cyanoacrylate glue to the lesion and a bandage contact lens, led to eventual resolution. The patient subsequently underwent cataract surgery, achieving a BCVA of 20/20 in the eye. Surprisingly, upon further sequence analyses of combined ITS and large subunit ribosomal ribonucleic acid (LSU) and investigation of the K. zeae German strain CBS 767.71, the organism was revealed to be Coniochaeta mutabilis (formerly Lecythospora mutabilis). This means that the correct name for CBS 767.71 and CBS 265.32 is C. mutabilis and should be corrected in the GenBank record to avoid misleading identification in the future. This case also underscores the urgent unmet need for improved molecular diagnostic modalities in the care of corneal infections.
Gold NB, Adelson SM, Shah N, Williams S, Bick SL, Zoltick ES, Gold JI, Strong A, Ganetzky R, Roberts AE, Walker M, Holtz AM, Sankaran VG, Delmonte O, Tan W, Holm IA, Thiagarajah JR, Kamihara J, Comander J, Place E, Wiggs J, Green RC. Perspectives of Rare Disease Experts on Newborn Genome Sequencing. JAMA Netw Open 2023;6(5):e2312231.Abstract
IMPORTANCE: Newborn genome sequencing (NBSeq) can detect infants at risk for treatable disorders currently undetected by conventional newborn screening. Despite broad stakeholder support for NBSeq, the perspectives of rare disease experts regarding which diseases should be screened have not been ascertained. OBJECTIVE: To query rare disease experts about their perspectives on NBSeq and which gene-disease pairs they consider appropriate to evaluate in apparently healthy newborns. DESIGN, SETTING, AND PARTICIPANTS: This survey study, designed between November 2, 2021, and February 11, 2022, assessed experts' perspectives on 6 statements related to NBSeq. Experts were also asked to indicate whether they would recommend including each of 649 gene-disease pairs associated with potentially treatable conditions in NBSeq. The survey was administered between February 11 and September 23, 2022, to 386 experts, including all 144 directors of accredited medical and laboratory genetics training programs in the US. EXPOSURES: Expert perspectives on newborn screening using genome sequencing. MAIN OUTCOMES AND MEASURES: The proportion of experts indicating agreement or disagreement with each survey statement and those who selected inclusion of each gene-disease pair were tabulated. Exploratory analyses of responses by gender and age were conducted using t and χ2 tests. RESULTS: Of 386 experts invited, 238 (61.7%) responded (mean [SD] age, 52.6 [12.8] years [range 27-93 years]; 126 [52.9%] women and 112 [47.1%] men). Among the experts who responded, 161 (87.9%) agreed that NBSeq for monogenic treatable disorders should be made available to all newborns; 107 (58.5%) agreed that NBSeq should include genes associated with treatable disorders, even if those conditions were low penetrance; 68 (37.2%) agreed that actionable adult-onset conditions should be sequenced in newborns to facilitate cascade testing in parents, and 51 (27.9%) agreed that NBSeq should include screening for conditions with no established therapies or management guidelines. The following 25 genes were recommended by 85% or more of the experts: OTC, G6PC, SLC37A4, CYP11B1, ARSB, F8, F9, SLC2A1, CYP17A1, RB1, IDS, GUSB, DMD, GLUD1, CYP11A1, GALNS, CPS1, PLPBP, ALDH7A1, SLC26A3, SLC25A15, SMPD1, GATM, SLC7A7, and NAGS. Including these, 42 gene-disease pairs were endorsed by at least 80% of experts, and 432 genes were endorsed by at least 50% of experts. CONCLUSIONS AND RELEVANCE: In this survey study, rare disease experts broadly supported NBSeq for treatable conditions and demonstrated substantial concordance regarding the inclusion of a specific subset of genes in NBSeq.
Parmar UPS, Ichhpujani P, Chahal R, Singh RB. Reliability of Ahmed glaucoma valve surgical videos for educational purposes. Int Ophthalmol 2023;43(9):3425-3432.Abstract
PURPOSE: The use of video-based social media platforms is increasing among trainee residents, fellows, and practicing ophthalmologists. In this study, we objectively evaluate the quality of Ahmed glaucoma valve (AGV) implantation videos on open access, video-based internet platforms. DESIGN: Internet-based cross-sectional study. PARTICIPANTS: Not applicable. METHODS: In this cross-sectional study, 23 websites publishing medical surgery training video content were queried using the keyword "Ahmed glaucoma valve implantation". MAIN OUTCOME MEASURES: The descriptive statistics of video parameters were noted, and the videos were assessed using established scoring systems-Sandvik, Health on the Net Foundation Code of Conduct (HON code), mDISCERN, and Global Quality Score (GQS) scores. Video Quality Score (VQS) was determined based on the 14 steps per the AGV implantation rubric. RESULTS: One hundred and nineteen videos were evaluated, and 35 were excluded. The total quality of all 84 videos according to their Sandvik, HON Code, GQS, DISCERN, and VQS scores was 11.79 ± 1.70 (excellent quality), 6.86 ± 0.75 (excellent quality), 3.97 ± 0.93 (good quality), 3.26 ± 0.66 (fair quality) and 11.45 ± 2.67 (good quality), respectively. No significant correlation was found between the descriptive parameters and video quality score. However, no significant correlation was found between the descriptive parameters and video quality score. CONCLUSIONS: The objective analysis showed that the video quality ranged from good to excellent. AGV implantation videos were sparse on exclusive ophthalmology surgical video portals. Therefore, more peer-reviewed videos following standardized rubric are needed on open-access surgical video platforms.
Diaz-Torres S, He W, Thorp J, Seddighi S, Mullany S, Mullany S, Hammond CJ, Hysi PG, Pasquale LR, Khawaja AP, Hewitt AW, Craig JE, Mackey DA, Wiggs JL, van Duijn C, Lupton MK, Ong J-S, Macgregor S, Gharahkhani P. Disentangling the genetic overlap and causal relationships between primary open-angle glaucoma, brain morphology and four major neurodegenerative disorders. EBioMedicine 2023;92:104615.Abstract
BACKGROUND: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by progressive degeneration of the optic nerve that leads to irreversible visual impairment. Multiple epidemiological studies suggest an association between POAG and major neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease). However, the nature of the overlap between neurodegenerative disorders, brain morphology and glaucoma remains inconclusive. METHOD: In this study, we performed a comprehensive assessment of the genetic and causal relationship between POAG and neurodegenerative disorders, leveraging genome-wide association data from studies of magnetic resonance imaging of the brain, POAG, and four major neurodegenerative disorders. FINDINGS: This study found a genetic overlap and causal relationship between POAG and its related phenotypes (i.e., intraocular pressure and optic nerve morphology traits) and brain morphology in 19 regions. We also identified 11 loci with a significant local genetic correlation and a high probability of sharing the same causal variant between neurodegenerative disorders and POAG or its related phenotypes. Of interest, a region on chromosome 17 corresponding to MAPT, a well-known risk locus for Alzheimer's and Parkinson's disease, was shared between POAG, optic nerve degeneration traits, and Alzheimer's and Parkinson's diseases. Despite these local genetic overlaps, we did not identify strong evidence of a causal association between these neurodegenerative disorders and glaucoma. INTERPRETATION: Our findings indicate a distinctive and likely independent neurodegenerative process for POAG involving several brain regions although several POAG or optic nerve degeneration risk loci are shared with neurodegenerative disorders, consistent with a pleiotropic effect rather than a causal relationship between these traits. FUNDING: PG was supported by an NHMRC Investigator Grant (#1173390), SM by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144), DM by an NHMRC Fellowship, LP is funded by the NEIEY015473 and EY032559 grants, SS is supported by an NIH-Oxford Cambridge Fellowship and NIH T32 grant (GM136577), APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award.
Ramesh S, Zhang QE, Sharpe J, Penne R, Haller J, Lum F, Lee AY, Lee CS, Pershing S, Miller JW, Lorch A, Hyman L, Hyman L. Thyroid Eye Disease and its Vision-Threatening Manifestations in the Academy IRIS Registry: 2014-2018. Am J Ophthalmol 2023;253:74-85.Abstract
PURPOSE: To evaluate prevalence of thyroid eye disease (TED) and associated factors in the American Academy of Ophthalmology IRISⓇ Registry (Intelligent Research in Sight). DESIGN: Cross-sectional analysis of the IRIS Registry. METHODS: IRIS Registry patients (18-90 years old) were classified as TED (ICD-9: 242.00, ICD-10: E05.00 on ≥2 visits) or non-TED cases, and prevalence was estimated. Odds ratios (OR) and 95% Confidence Intervals (CIs) were estimated using logistic regression. RESULTS: 41,211 TED patients were identified. TED prevalence was 0.09%, showed a unimodal age distribution (highest prevalence in ages 50-59 years (y) (0.12%)), higher rates in females than males (0.12% vs. 0.04%) and in non-Hispanics than Hispanics (0.10% vs. 0.05%). Prevalence differed by race (from 0.08% in Asians to 0.12% in Black/African-Americans), with varying peak ages of prevalence. Factors associated with TED in multivariate analysis included age: ((18-<30y (reference), 30-39y: OR (95%CI) 2.2 (2.0, 2.4), 40-49y: 2.9 (2.7,3.1), 50-59y: 3.3 (3.1, 3. 5), 60-69y: 2.7 (2.54, 2.85), 70+: 1.5 (1.46, 1.64)); female sex vs male (reference), 3.5 (3.4,3.6), race: White (reference), Blacks: 1.1 (1.1,1.2), Asian: 0.9 (0.8,0.9), Hispanic ethnicity vs not Hispanic (reference), 0.68 (0.6,0.7), smoking status: (never (ref), former: 1.64 (1.6,1.7), current 2.16: (2.1,2.2)) and Type 1 diabetes (yes vs no (reference): 1.87 (1.8, 1.9). CONCLUSIONS: This epidemiologic profile of TED includes new observations such as a unimodal age distribution and racial variation in prevalence. Associations with female sex, smoking, and Type 1 diabetes are consistent with prior reports. These findings raise novel questions about TED in different populations.
Elhusseiny AM, Hassan AK, Azhari JO, Elkheniny FD, Chauhan MZ, Chang TC, VanderVeen DK, Oke I, Mansour M, Pakravan M, Shaarawy T, Sallam AB. Ahmed and Baerveldt Glaucoma Drainage Devices in Childhood Glaucoma: A Meta-Analysis. J Glaucoma 2023;32(8):686-694.Abstract
PRCIS: The effectiveness of Ahmed glaucoma valve (AGV) and Baerveldt glaucoma implant (BGI) was comparable in the management of childhood glaucoma over the long term despite initial better success rate with BGI. There were higher tube block and retraction rates in the BGI group and higher tube exposure rates in the AGV group. PURPOSE: To evaluate the outcomes and safety of AGV and BGI in childhood glaucoma. MATERIALS AND METHODS: We performed a systematic literature review of publications from 1990 to 2022 in PubMed, EMBASE, ClinicalTrials.gov, Ovid MEDLINE, Cochrane CENTRAL, and google scholar for studies evaluating AGV and BGI in childhood glaucoma. Primary outcome measures were intraocular pressure (IOP) reduction and glaucoma medication reduction. The secondary outcome measures were the success rates and incidence of postoperative complications. We conducted a meta-analysis using a random effects model. RESULTS: Thirty-two studies met the inclusion criteria. A total of 1480 eyes were included. The mean IOP reduction was 15.08 mm Hg ( P < 0.00001) for AGV and 14.62 ( P < 0.00001) for the BGI group. The mean difference between pre and postoperative glaucoma medications was 1 ( P < 0.00001) fewer medications in the AGV group and 0.95 ( P < 0.0001) fewer medications in the BGI group. There was a lower success rate in the AGV versus BGI groups at 2 years [63% vs 83%, respectively ( P < 0.0001) and 3 years (43% vs 79%, respectively ( P < 0.0001)]; however, the success was higher for AGV at 5 years (63% vs 56% in the BGI group, P < 0.001). The incidence of postoperative complications was comparable in the AGV and BGI groups, with rates of 28% and 27%, respectively. CONCLUSIONS: The IOP and glaucoma medication reduction, success rates, and incidence of postoperative complications were comparable in Ahmed and Baerveldt groups. Most literature comes from retrospective low-quality studies on refractory childhood glaucoma. Further larger cohort studies are needed.
Gutierrez A, Chen TC. Artificial intelligence in glaucoma: posterior segment optical coherence tomography. Curr Opin Ophthalmol 2023;34(3):245-254.Abstract
PURPOSE OF REVIEW: To summarize the recent literature on deep learning (DL) model applications in glaucoma detection and surveillance using posterior segment optical coherence tomography (OCT) imaging. RECENT FINDINGS: DL models use OCT derived parameters including retinal nerve fiber layer (RNFL) scans, macular scans, and optic nerve head (ONH) scans, as well as a combination of these parameters, to achieve high diagnostic accuracy in detecting glaucomatous optic neuropathy (GON). Although RNFL segmentation is the most widely used OCT parameter for glaucoma detection by ophthalmologists, newer DL models most commonly use a combination of parameters, which provide a more comprehensive approach. Compared to DL models for diagnosing glaucoma, DL models predicting glaucoma progression are less commonly studied but have also been developed. SUMMARY: DL models offer time-efficient, objective, and potential options in the management of glaucoma. Although artificial intelligence models have already been commercially accepted as diagnostic tools for other ophthalmic diseases, there is no commercially approved DL tool for the diagnosis of glaucoma, most likely in part due to the lack of a universal definition of glaucoma defined by OCT derived parameters alone (see Supplemental Digital Content 1 for video abstract, http://links.lww.com/COOP/A54 ).
Wang L, Liu C, Lu W, Xu L, Kuang L, Hua D. ROS-sensitive Crocin-loaded chitosan microspheres for lung targeting and attenuation of radiation-induced lung injury. Carbohydr Polym 2023;307:120628.Abstract
Radiation-induced lung injury (RILI) is one of the major complications in patients exposed to accidental radiation and radiotherapy for thoracic malignancies. However, there is no reliable radioprotector for effective clinical treatment of RILI so far. Herein, a novel Crocin-loaded chitosan microsphere is developed for lung targeting and attenuation of RILI. The chitosan microspheres are modified with 4-carboxyphenylboronic acid and loaded with the natural antioxidant Crocin-I to give the drug-loaded microspheres (~10 μm). The microspheres possess good biocompatibility in vivo and in vitro. In a mouse model, they exhibit effective passive targeting performance and a long retention time in the lung after intravenous administration. Furthermore, they improve the radioprotective effect of Crocin-I for the treatment of RILI by reducing the level of inflammatory cytokines in bronchoalveolar lavage fluid and by regulating oxidative stress in lung tissues. The targeted agents significantly improved the bioavailability and radioprotection of Crocin-I by the outstanding passive targeting effect. This work may provide a promising strategy for efficient radioprotection on RILI using passive lung targeting microspheres.
Xue Y, Sun X, Wang SK, Collin GB, Kefalov VJ, Cepko CL. Chromophore supply modulates cone function and survival in retinitis pigmentosa mouse models. Proc Natl Acad Sci U S A 2023;120(23):e2217885120.Abstract
Retinitis pigmentosa (RP) is an ocular disease characterized by the loss of night vision, followed by the loss of daylight vision. Daylight vision is initiated in the retina by cone photoreceptors, which are gradually lost in RP, often as bystanders in a disease process that initiates in their neighboring rod photoreceptors. Using physiological assays, we investigated the timing of cone electroretinogram (ERG) decline in RP mouse models. A correlation between the time of loss of the cone ERG and the loss of rods was found. To investigate a potential role of the visual chromophore supply in this loss, mouse mutants with alterations in the regeneration of the retinal chromophore, 11-cis retinal, were examined. Reducing chromophore supply via mutations in Rlbp1 or Rpe65 resulted in greater cone function and survival in a RP mouse model. Conversely, overexpression of Rpe65 and Lrat, genes that can drive the regeneration of the chromophore, led to greater cone degeneration. These data suggest that abnormally high chromophore supply to cones upon the loss of rods is toxic to cones, and that a potential therapy in at least some forms of RP is to slow the turnover and/or reduce the level of visual chromophore in the retina.

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