2020

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Glassman AR, Wells JA, Josic K, Maguire MG, Antoszyk AN, Baker C, Beaulieu WT, Elman MJ, Jampol LM, Sun JK. Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study). Ophthalmology 2020;127(9):1201-1210.Abstract
PURPOSE: Assess follow-up treatment and clinical outcomes at 5 years in eyes initially treated with anti-VEGF therapy for center-involved diabetic macular edema (CI-DME) in a 2-year randomized clinical trial. DESIGN: Multicenter cohort study. PARTICIPANTS: Participants with diabetic macular edema (DME) and visual acuity (VA) 20/32 to 20/320 enrolled in DRCR.net Protocol T with visits 5 years after randomization (3 years after Protocol T completion). METHODS: Participants were assigned randomly to aflibercept, bevacizumab, or ranibizumab with protocol-defined follow-up and re-treatment for 2 years. Thereafter, participants were managed at clinician discretion and recalled for a 5-year visit. MAIN OUTCOME MEASURES: Anti-vascular endothelial growth factor (VEGF) treatment, VA letter score, and central subfield thickness (CST). RESULTS: Sixty-eight percent (317/463) of eligible participants completed the 5-year visit. Between years 2 and 5, 68% (217/317) of study eyes received at least 1 anti-VEGF treatment (median, 4; interquartile range [IQR], 0-12). At 5 years, mean VA improved from baseline by 7.4 letters (95% confidence interval [CI], 5.9-9.0) but decreased by 4.7 letters (95% CI, 3.3-6.0) between 2 and 5 years. When baseline VA was 20/50 to 20/320, mean 5-year VA was 11.9 letters (95% CI, 9.3-14.5) better than baseline but 4.8 letters (95% CI, 2.5-7.0) worse than 2 years. When baseline VA was 20/32 to 20/40, mean 5-year VA was 3.2 letters (95% CI, 1.4-5.0) better than baseline but 4.6 letters (95% CI, 3.1-6.1) worse than 2 years. Mean CST decreased from baseline to 5 years by 154 μm (95% CI, 142-166) and was stable between 2 and 5 years (-1 μm; 95% CI, -12 to 9). CONCLUSIONS: Among the two-thirds of eligible Protocol T participants who completed a 5-year visit, mean VA improved from baseline to 5 years without protocol-defined treatment after follow-up ended at 2 years. Although mean retinal thickness was similar at 2 and 5 years, mean VA worsened during this period. Additional investigation into strategies to improve long-term outcomes in eyes with DME seems warranted to determine if VA can be better maintained with different management approaches.
Glassman AR, Beaulieu WT, Stockdale CR, Beck RW, Bressler NM, Labriola LT, Melia M, Oliver K, Sun JK. Effect of telephone calls from a centralized coordinating center on participant retention in a randomized clinical trial. Clin Trials 2020;:1740774519894229.Abstract
BACKGROUND/AIMS: In clinical trials, participant retention is critical to reduce bias and maintain statistical power for hypothesis testing. Within a multi-center clinical trial of diabetic retinopathy, we investigated whether regular phone calls to participants from the coordinating center improved long-term participant retention. METHODS: Among 305 adults in the Diabetic Retinopathy Clinical Research Retina Network Protocol S randomized trial, 152 participants were randomly assigned to receive phone calls at baseline, 6 months, and annually through 3 years (annual contact group) while 153 participants were assigned to receive a phone call at baseline only (baseline contact group). All participants could be contacted if visits were missed. The main outcomes were visit completion, excluding deaths, at 2 years (the primary outcome time point) and at 5 years (the final time point). RESULTS: At baseline, 77% (117 of 152) of participants in the annual contact group and 76% (116 of 153) in the baseline contact group were successfully contacted. Among participants in the annual contact group active at each annual visit (i.e. not dropped from the study or deceased), 85% (125 of 147), 79% (108 of 136), and 88% (110 of 125) were contacted successfully by telephone around the time of the 1-, 2-, and 3-year visits, respectively. In the annual and baseline contact groups, completion rates for the 2-year primary outcome visit were 88% (129 of 147) versus 87% (125 of 144), respectively, with a risk ratio of 1.01 (95% confidence interval: 0.93-1.10,  = .81). At 5 years, the final study visit, participant completion rates were 67% (96 of 144) versus 66% (88 of 133) with a risk ratio of 1.01 (95% confidence interval = 0.85-1.19,  = .93). At 2 years, the completion rate of participants successfully contacted at baseline was 89% (202 of 226) versus 80% (52 of 65) among those not contacted successfully (risk ratio = 1.12, 95% confidence interval = 0.98-1.27,  = .09); at 5 years, the completion percentages by baseline contact success were 69% (148 of 213) versus 56% (36 of 64; risk ratio = 1.24, 95% confidence interval = 0.98-1.56,  = .08). CONCLUSION: Regular phone calls from the coordinating center to participants during follow-up in this randomized clinical trial did not improve long-term participant retention.
, Fabian ID, Abdallah E, Abdullahi SU, Abdulqader RA, Adamou Boubacar S, Ademola-Popoola DS, Adio A, Afshar AR, Aggarwal P, Aghaji AE, Ahmad A, Akib MNR, Al Harby L, Al Ani MH, Alakbarova A, Portabella SA, Al-Badri SAF, Alcasabas APA, Al-Dahmash SA, Alejos A, Alemany-Rubio E, Alfa Bio AI, Alfonso Carreras Y, Al-Haddad C, Al-Hussaini HHY, Ali AM, Alia DB, Al-Jadiry MF, Al-Jumaly U, Alkatan HM, All-Eriksson C, Al-Mafrachi AARM, Almeida AA, Alsawidi KM, Al-Shaheen AASM, Al-Shammary EH, Amiruddin PO, Antonino R, Astbury NJ, Atalay HT, Atchaneeyasakul L-O, Atsiaya R, Attaseth T, Aung TH, Ayala S, Baizakova B, Balaguer J, Balayeva R, Balwierz W, Barranco H, Bascaran C, Beck Popovic M, Benavides R, Benmiloud S, Bennani Guebessi N, Berete RC, Berry JL, Bhaduri A, Bhat S, Biddulph SJ, Biewald EM, Bobrova N, Boehme M, Boldt HC, Bonanomi MTBC, Bornfeld N, Bouda GC, Bouguila H, Boumedane A, Brennan RC, Brichard BG, Buaboonnam J, Calderón-Sotelo P, Calle Jara DA, Camuglia JE, Cano MR, Capra M, Cassoux N, Castela G, Castillo L, Català-Mora J, Chantada GL, Chaudhry S, Chaugule SS, Chauhan A, Chawla B, Chernodrinska VS, Chiwanga FS, Chuluunbat T, Cieslik K, Cockcroft RL, Comsa C, Correa ZM, Correa Llano MG, Corson TW, Cowan-Lyn KE, Csóka M, Cui X, Da Gama IV, Dangboon W, Das A, Das S, Davanzo JM, Davidson A, De Potter P, Delgado KQ, Demirci H, Desjardins L, Diaz Coronado RY, Dimaras H, Dodgshun AJ, Donaldson C, Donato Macedo CR, Dragomir MD, Du Y, Du Bruyn M, Edison KS, Eka Sutyawan WI, El Kettani A, Elbahi AM, Elder JE, Elgalaly D, Elhaddad AM, Elhassan MAM, Elzembely MM, Essuman VA, Evina TGA, Fadoo Z, Fandiño AC, Faranoush M, Fasina O, Fernández DDPG, Fernández-Teijeiro A, Foster A, Frenkel S, Fu LD, Fuentes-Alabi SL, Gallie BL, Gandiwa M, Garcia JL, García Aldana D, Gassant PY, Geel JA, Ghassemi F, Girón AV, Gizachew Z, Goenz MA, Gold AS, Goldberg-Lavid M, Gole GA, Gomel N, Gonzalez E, Gonzalez Perez G, González-Rodríguez L, Garcia Pacheco HN, Graells J, Green L, Gregersen PA, Grigorovski NDAK, Guedenon KM, Gunasekera SD, Gündüz AK, Gupta H, Gupta S, Hadjistilianou T, Hamel P, Hamid SA, Hamzah N, Hansen ED, Harbour WJ, Hartnett EM, Hasanreisoglu M, Hassan S, Hassan S, Hederova S, Hernandez J, Hernandez LMC, Hessissen L, Hordofa DF, Huang LC, Hubbard GB, Hummlen M, Husakova K, Hussein Al-Janabi AN, Ida R, Ilic VR, Jairaj V, Jeeva I, Jenkinson H, Ji X, Jo DH, Johnson KP, Johnson WJ, Jones MM, Kabesha TAB, Kabore RL, Kaliki S, Kalinaki A, Kantar M, Kao L-Y, Kardava T, Kebudi R, Kepak T, Keren-Froim N, Khan ZJ, Khaqan HA, Khauv P, Kheir WJ, Khetan V, Khodabande A, Khotenashvili Z, Kim JW, Kim JH, Kiratli H, Kivelä TT, Klett A, Komba Palet JEK, Krivaitiene D, Kruger M, Kulvichit K, Kuntorini MW, Kyara A, Lachmann ES, Lam CPS, Lam GC, Larson SA, Latinovic S, Laurenti KD, Le BHA, Lecuona K, Leverant AA, Li C, Limbu B, Long QB, López JP, Lukamba RM, Lumbroso L, Luna-Fineman S, Lutfi D, Lysytsia L, Magrath GN, Mahajan A, Majeed AR, Maka E, Makan M, Makimbetov EK, Manda C, Martín Begue N, Mason L, Mason JO, Matende IO, Materin M, Mattosinho CCDS, Matua M, Mayet I, Mbumba FB, McKenzie JD, Medina-Sanson A, Mehrvar A, Mengesha AA, Menon V, Mercado GJVD, Mets MB, Midena E, Mishra DKC, Mndeme FG, Mohamedani AA, Mohammad MT, Moll AC, Montero MM, Morales RA, Moreira C, Mruthyunjaya P, Msina MS, Msukwa G, Mudaliar SS, Muma KI, Munier FL, Murgoi G, Murray TG, Musa KO, Mushtaq A, Mustak H, Muyen OM, Naidu G, Nair AG, Naumenko L, Ndoye Roth PA, Nency YM, Neroev V, Ngo H, Nieves RM, Nikitovic M, Nkanga ED, Nkumbe H, Nuruddin M, Nyaywa M, Obono-Obiang G, Oguego NC, Olechowski A, Oliver SCN, Osei-Bonsu P, Ossandon D, Paez-Escamilla MA, Pagarra H, Painter SL, Paintsil V, Paiva L, Pal BP, Palanivelu MS, Papyan R, Parrozzani R, Parulekar M, Pascual Morales CR, Paton KE, Pawinska-Wasikowska K, Pe'er J, Peña A, Peric S, Pham CTM, Philbert R, Plager DA, Pochop P, Polania RA, Polyakov VG, Pompe MT, Pons JJ, Prat D, Prom V, Purwanto I, Qadir AO, Qayyum S, Qian J, Rahman A, Rahman S, Rahmat J, Rajkarnikar P, Ramanjulu R, Ramasubramanian A, Ramirez-Ortiz MA, Raobela Léa, Rashid R, Reddy AM, Reich E, Renner LA, Reynders D, Ribadu D, Riheia MM, Ritter-Sovinz P, Rojanaporn D, Romero L, Roy SR, Saab RH, Saakyan S, Sabhan AH, Sagoo MS, Said AMA, Saiju R, Salas B, San Román Pacheco S, Sánchez GL, Sayalith P, Scanlan TA, Schefler AC, Schoeman J, Sedaghat A, Seregard S, Seth R, Shah AS, Shakoor SA, Sharma MK, Sherief ST, Shetye NG, Shields CL, Siddiqui SN, Sidi Cheikh S, Silva S, Singh AD, Singh N, Singh U, Singha P, Sitorus RS, Skalet AH, Soebagjo HD, Sorochynska T, Ssali G, Stacey AW, Staffieri SE, Stahl ED, Stathopoulos C, Stirn Kranjc B, Stones DK, Strahlendorf C, Suarez MEC, Sultana S, Sun X, Sundy M, Superstein R, Supriyadi E, Surukrattanaskul S, Suzuki S, Svojgr K, Sylla F, Tamamyan G, Tan D, Tandili A, Tarrillo Leiva FF, Tashvighi M, Tateshi B, Tehuteru ES, Teixeira LF, Teh KH, Theophile T, Toledano H, Trang DL, Traoré F, Trichaiyaporn S, Tuncer S, Tyau-Tyau H, Umar AB, Unal E, Uner OE, Urbak SF, Ushakova TL, Usmanov RH, Valeina S, van Hoefen Wijsard M, Varadisai A, Vasquez L, Vaughan LO, Veleva-Krasteva NV, Verma N, Victor AA, Viksnins M, Villacís Chafla EG, Vishnevskia-Dai V, Vora T, Wachtel AE, Wackernagel W, Waddell K, Wade PD, Wali AH, Wang Y-Z, Weiss A, Wilson MW, Wime ADC, Wiwatwongwana A, Wiwatwongwana D, Wolley Dod C, Wongwai P, Xiang D, Xiao Y, Yam JC, Yang H, Yanga JM, Yaqub MA, Yarovaya VA, Yarovoy AA, Ye H, Yousef YA, Yuliawati P, Zapata López AM, Zein E, Zhang C, Zhang Y, Zhao J, Zheng X, Zhilyaeva K, Zia N, Ziko OAO, Zondervan M, Bowman R. Global Retinoblastoma Presentation and Analysis by National Income Level. JAMA Oncol 2020;Abstract
Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.
Golan S, Vingopoulos F, Olson LC, Patel HH, Pinchover S, Magro CM, Levine B, Lelli GJ. Lacrimal tissue resection in Fasanella Servat operation and the correlation to dry eye. Orbit 2020;39(3):171-174.Abstract
: Fasanella-Servat operation (FSO) was previously reported to be associated with post-operative dry eyes due to accessory lacrimal gland resection during the surgery.We performed a retrospective, cohort study to determine the frequency of lacrimal tissue resection during FSO and its correlation with post-operative eye dryness and keratopathy.: Review of all patients who underwent FSO at New York-Presbyterian Weill Cornell Hospital over a two-year period (2013-2015). Patients were included only if they had adequate histopathological specimens of the resected tissue obtained during surgery. Outcomes included the study of the pathological specimen for the presence of lacrimal tissue; Post-operative dry eye symptoms and pre- and post-operative corneal epitheliopathy.: 46 patients with a total of 58 eyelid resections were studied.Eight eyelids (13.7%) were found to have lacrimal tissue present in the pathology specimens.Postoperatively, nine patients reported some symptoms of dry eye and new-onset keratopathy was noted in four eyes (6.8%), only one of which had lacrimal tissue present in histopathology specimen obtained from surgery.: Previous studies found lacrimal tissue present in up to 43% of specimens resected during FSO. Our data found a lower rate of lacrimal tissue resection during FSO, and did not find an association between lacrimal tissue resection and post-operative dryness or epitheliopathy.: Our study is one of few to examine histopathological resections from the FSO.We found that lacrimal tissue is not frequently resected during FSO, and when it is resected, there is no increased incidence of post-operative dryness or keratopathy.
Gonzalez-Andrades M, Jalimarada SS, Rodriguez-Benavente M, Feeley MN, Woodward AM, AbuSamra DB, Argüeso P. Golgi α1,2-mannosidase I induces clustering and compartmentalization of CD147 during epithelial cell migration. Cell Adh Migr 2020;14(1):96-105.Abstract
CD147 is a widely expressed matrix metalloproteinase inducer involved in the regulation of cell migration. The high glycosylation and ability to undergo oligomerization have been linked to CD147 function, yet there is limited understanding on the molecular mechanisms behind these processes. The current study demonstrates that the expression of Golgi α1,2-mannosidase I is key to maintaining the cell surface organization of CD147 during cell migration. Using an in vitro model of stratified human corneal epithelial wound healing, we show that CD147 is clustered within lateral plasma membranes at the leading edge of adjacent migrating cells. This localization correlates with a surge in matrix metalloproteinase activity and an increase in the expression of α1,2-mannosidase subtype IC (MAN1C1). Global inhibition of α1,2-mannosidase I activity with deoxymannojirimycin markedly attenuates the glycosylation of CD147 and disrupts its surface distribution at the leading edge, concomitantly reducing the expression of matrix metalloproteinase-9. Likewise, treatment with deoxymannojirimycin or siRNA-mediated knockdown of MAN1C1 impairs the ability of the carbohydrate-binding protein galectin-3 to stimulate CD147 clustering in unwounded cells. We conclude that the mannose-trimming activity of α1,2-mannosidase I coordinates the clustering and compartmentalization of CD147 that follows an epithelial injury.
Greiner JV, Glonek T, Korb DR, Lindsay ME, Oliver PJ, Olson MCD. Corneal Cryopreservation Using Glycerylphosphorylcholine-Enriched Medium. Cornea 2020;39(3):370-375.Abstract
PURPOSE: To determine the effects of prolonged cryopreservation at subzero-degree temperatures on corneal transparency and histology after treatment with preservation medium containing the phosphodiester glycerylphosphorylcholine (GPC). METHODS: Rabbit corneas (n = 30) were immersed for 3 hours in K-Sol preservation medium containing 30 mM GPC. Three groups with 6 corneas each were refrigerated at -8°C for 2 weeks and liquid nitrogen temperature for 2 and 6 weeks, respectively. Two groups with 6 corneas each immersed in K-Sol preservation medium only were refrigerated at -8°C for 2 weeks and liquid nitrogen temperature for 6 weeks, respectively. Postthawing corneal transparency was measured on a grading scale after which corneas were prepared for and analyzed by light and transmission electron microscopy. RESULTS: All 3 groups of corneas preserved with GPC maintained a greater degree of corneal transparency compared with corneas preserved without GPC. The number of corneas retaining epithelial and endothelial layers increased in all groups where corneas were preserved in medium containing GPC, in contrast to corneas preserved in medium without GPC. Cytoplasmic vacuolization or nuclear damage was greater in corneas preserved without GPC. Similar findings were found in corneas stored at -8°C and liquid nitrogen temperatures. CONCLUSIONS: This study demonstrates a cryoprotective effect of corneas preserved in K-Sol containing the phosphodiester GPC at subzero-degree temperatures. In corneas immersed in preservation medium containing GPC, a higher degree of transparency is maintained and a lesser degree of histopathologic changes is observed with storage at both -8°C and in liquid nitrogen.
Greiner JV, Glonek T. Hydrotropic function of ATP in the crystalline lens. Exp Eye Res 2020;190:107862.Abstract
The hypothesis proposed herein is presented to explain the unexpectedly high concentration of ATP and provide evidence to support its hydrotropic function in the crystalline lens determined using P NMR. The lens, historically considered to be a metabolically quiescent organ, has the requisite machinery to synthesize ATP, such that the homeostatic level is maintained at about 3 mM. This relatively high concentration of ATP has been found to be consistent among multiple mammalian species including humans. This millimolar quantity is many times greater than the micromolar amounts required for the other known functions of ATP. The recent postulation that ATP at millimolar concentrations functions as a hydrotrope in various cell/tissue homogenates preventing protein aggregation coupled with observations presented herein, provide support for extending the hypothesis that ATP functions as a hydrotrope not only in homogenates but in an intact functioning organ, the crystalline lens. Concentrations of ATP of this magnitude are hypothesized to be required to maintain protein solubility and effectively prevent protein aggregation. This concept is important considering protein aggregation is the etiology for age-related cataractogenesis. ATP is a common ubiquitous intracellular molecule possessing the requisite hydrotropic properties for maintaining intracellular proteins in a fluid, non-aggregated state. It is proposed that the amphiphilic ATP molecule shields the hydrophobic regions on intralenticular fiber cell protein molecules and provides a hydrophilic interfacial surface comprised of the ATP negatively charged triphosphate side chain. Evidence is presented that this side chain is exposed to and has been reported to organize intracellular interstitial water to form an interfacial rheologically dynamic water layer. Such organization of water is substantiated with the effect of deuterium oxide (heavy water) on ATP line widths of the side chain phosphates measured ex vivo by P NMR. A novel model is presented to propose how this water layer separates adjacent lens fiber cell proteins, keeping them from aggregating. This hypothesis proposes that ATP can prevent protein aggregation in normal intact lenses, and with declining concentrations can be related to the disease process in age-related cataractogenesis, an affliction that affects every older human being.
Greiner JV, Glonek T, Korb DR, Lindsay ME, Oliver PJ. Corneal absorption of glycerylphosphorylcholine. Exp Eye Res 2020;192:107932.Abstract
This study documents the absorption of glycerylphosphorylcholine (GPC) into corneas ex vivo. Corneas in quadruplicate were incubated in preservation medium containing 30 mM GPC, which is used as a reference marker. The GPC reference marker is used to calibrate P nuclear magnetic resonance (NMR) spectral chemical-shift positions for identification of phosphatic metabolites and to calculate intracorneal pH in intact tissues ex vivo. Following baseline NMR ex vivo analysis, corneas were stored in eye bank chambers in preservation medium containing 30 mM GPC at 4 °C overnight for 8 h. After returning to room temperature, NMR analysis was repeated on the same corneas in fresh GPC-free preservation medium. NMR analysis also was performed on the 30 mM GPC preservation medium alone from the eye bank chambers for detection of the GPC signal. The elevated GPC signal unexpectedly persisted in corneas incubated at 4 °C overnight even though GPC was not present in the fresh GPC-free preservation medium. In fact, the concentration of GPC in the intact cornea was many times higher than that found in the cornea endogenously. The levels of phosphatic metabolites and the energy modulus, after subtracting the spectral contribution of the 30 mM exogenous GPC, as well as the intracorneal pH remained unchanged from pre-refrigeration analyses. Corneas also retained transparency through the time-course of this study irrespective of temperature or change in temperature. The GPC signal in the NMR analysis of the preservation medium from the eye bank chambers was nearly undetectable. GPC was unexpectedly absorbed into the corneal tissue without detectable metabolic or physical toxicity. The intracorneal uptake of GPC at reduced temperatures parallels the increase in GPC that occurs naturally in muscle tissue in animals during wintering periods and the very high concentration of GPC in sperm, a cryogenically compatible cell, suggestive of a potential role for GPC in cryopreservation.
for the Group WCPEDI, Pineles SL, Repka MX, Liu GT, Waldman AT, Borchert MS, Khanna S, Heidary G, Graves JS, Shah VS, Kupersmith MJ, Kraker RT, Wallace DK, Cotter SA, Holmes JM. Assessment of Pediatric Optic Neuritis Visual Acuity Outcomes at 6 Months. JAMA Ophthalmol 2020;Abstract
Importance: Optic neuritis (ON) in children is uncommon. There are limited prospective data for visual acuity (VA) outcomes, associated diseases, and neuroimaging findings. Prospective data from a large sample would be useful for counseling families on treatment decisions and prognosis. Objective: To prospectively study children with a first episode of ON, describe VA after 6 months, and ascertain the network's (Pediatric Eye Disease Investigator Group and Neuro-Ophthalmology Research Disease Investigator Consortium) ability to enroll pediatric patients with ON prospectively. Design, Setting, and Participants: This nonrandomized cohort study was conducted from September 20, 2016, to July 20, 2018, at 23 sites in the United States and Canada in pediatric ophthalmology or neuro-ophthalmology clinics. A total of 44 children (aged 3-15 years) presented with a first episode of ON (visual loss, pain on eye movements, or both) within 2 weeks of symptom onset and at least 1 of the following in the affected eye: a distance high-contrast VA (HCVA) deficit of at least 0.2 logMAR below age-based norms, diminished color vision, abnormal visual field, or optic disc swelling. Exclusion criteria included preexisting ocular abnormalities or a previous episode of ON. Main Outcomes and Measures: Primary outcomes were monocular HCVA and low-contrast VA at 6 months. Secondary outcomes were neuroimaging, associated diagnoses, and antibodies for neuromyelitis optica and myelin oligodendrocyte glycoprotein. Results: A total of 44 children (mean age [SD], 10.2 [3.5] years; 26 boys [59%]; 23 White individuals [52%]; 54 eyes) were enrolled in the study. Sixteen patients (36%) had bilateral ON. Magnetic resonance imaging revealed white matter lesions in 23 children (52%). Of these children, 8 had myelin oligodendrocyte glycoprotein-associated demyelination (18%), 7 had acute disseminated encephalomyelitis (16%), 5 had multiple sclerosis (11%), and 3 had neuromyelitis optica (7%). The baseline mean HCVA was 0.95 logMAR (20/200), which improved by a mean 0.76 logMAR (95% CI, 0.54-0.99; range, -0.70 to 1.80) to 0.12 logMAR (20/25) at 6 months. The baseline mean distance low-contrast VA was 1.49 logMAR (20/640) and improved by a mean 0.72 logMAR (95% CI, 0.54-0.89; range, -0.20 to 1.50) to 0.73 logMAR (20/100) at 6 months. Baseline HCVA was worse in younger participants (aged <10 years) with associated neurologic autoimmune diagnoses, white matter lesions, and in those of non-White race and non-Hispanic ethnicity. The data did not suggest a statistically significant association between baseline factors and improvement in HCVA. Conclusions and Relevance: The study network did not reach its targeted enrollment of 100 pediatric patients with ON over 2 years. This indicates that future treatment trials may need to use different inclusion criteria or plan a longer enrollment period to account for the rarity of the disease. Despite poor VA at presentation, most children had marked improvement by 6 months. Associated neurologic autoimmune diagnoses were common. These findings can be used to counsel families about the disease.
Guan J-T, Li X-X, Peng D-W, Zhang W-M, Qu J, Lu F, D'Amato RJ, Chi Z-L. MicroRNA-18a-5p Administration Suppresses Retinal Neovascularization by Targeting FGF1 and HIF1A. Front Pharmacol 2020;11:276.Abstract
Pathologic ocular neovascularization commonly results in visual impairment or even blindness in numerous fundus diseases, including proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and age-related macular degeneration (AMD). MicroRNAs regulate angiogenesis through modulating target genes and disease progression, making them a new class of targets for drug discovery. In this study, we investigated the potential role of miR-18a-5p in retinal neovascularization using a mouse model of oxygen-induced proliferative retinopathy (OIR). We found that miR-18a-5p was highly expressed in the retina of pups as well as retinal endothelial cells, and was consistently down-regulated during retinal development. On the other hand, miR-18a-5p was increased significantly during pathologic neovascularization in the retinas of OIR mice. Moreover, intravitreal administration of miRNA mimic, agomiR-18a-5p, significantly suppressed retinal neovascularization in OIR models. Accordingly, agomir-18a-5p markedly suppressed human retinal microvascular endothelial cell (HRMEC) function including proliferation, migration, and tube formation ability. Additionally, we demonstrated that miR-18a-5p directly down-regulated known vascular growth factors, fibroblast growth factor 1 (FGF1) and hypoxia-inducible factor 1-alpha (HIF1A), as the target genes. In conclusion, miR-18a-5p may be a useful drug target for pathologic ocular neovascularization.
H
Habib LA, Wolkow N, Cohen L, Ma L, Yoon MK, Lee NG. Pyoderma gangrenosum of the eyelid associated with inflammatory bowel disease. Am J Ophthalmol Case Rep 2020;18:100623.Abstract
Purpose: Pyoderma gangrenosum (PG) of the eyelid can be difficult to diagnosis and may mimic other, more common pathologies, thereby delaying proper treatment and management. PG may be associated with systemic disorders that have significant comorbidities. Observations: The authors present two cases of pyoderma gangrenosum of the eyelid associated with inflammatory bowel disease. Conclusions and importance: This case series highlights the importance of early recognition of eyelid pyoderma gangrenosum to avoid local and systemic comorbidities with timely and appropriate management.
Hall LN, Shanbhag SS, Rashad R, Chodosh J, Saeed HN. The effects of systemic cyclosporine in acute Stevens-Johnson syndrome/toxic epidermal necrolysis on ocular disease. Ocul Surf 2020;Abstract
PURPOSE: To evaluate the effect of systemic cyclosporine (CsA) on ocular disease in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) patients. METHODS: In this retrospective, comparative cohort study at a single center, patients with a diagnosis of SJS/TEN and with at least 3 months of follow up were divided into two groups: those who received systemic CsA and those who did not receive systemic CsA. Best-corrected visual acuity (BCVA) and chronic ocular surface complications score (COCS) at final follow-up were compared between the two groups. RESULTS: The median age and follow-up period of patients was 29 years (range, 1.5-71 years) and 16.8 months (range, 3.67-91.58 months), respectively. BCVA, COCS, meibomian gland dysfunction, limbal stem cell deficiency, and the need for mucous membrane grafting and scleral lenses were not significantly different between patients who received systemic CsA as compared to patients who did not receive systemic CsA. CONCLUSIONS: In this small cohort of patients with SJS/TEN, we could identify no association between the use of systemic CsA as a component of their initial therapy and chronic ocular complications.
Hamad AE, Moinuddin O, Blair MP, Schechet SA, Shapiro MJ, Quiram PA, Mammo DA, Berrocal AM, Prakhunhungsit S, Cernichiaro-Espinosa LA, Mukai S, Yonekawa Y, Ung C, Holz ER, Harper AC, Young RC, Besirli CG, Nagiel A, Lee TC, Gupta MP, Walsh MK, Khawly JA, Campbell PJ, Kychenthal A, Nudleman ED, Robinson JE, Hartnett ME, Calvo CM, Chang EY. Late-Onset Retinal Findings and Complications in Untreated Retinopathy of Prematurity. Ophthalmol Retina 2020;4(6):602-612.Abstract
PURPOSE: To investigate late retinal findings and complications of eyes with a history of retinopathy of prematurity (ROP) that did not meet treatment criteria and did not receive treatment during infancy. DESIGN: Retrospective, nonconsecutive, noncomparative, multicenter case series. PARTICIPANTS: Three hundred sixty-three eyes of 186 patients. METHODS: Data were requested from multiple providers on premature patients with a history of ROP and no treatment during infancy who demonstrated late retinal findings or complications and included age, gender, gestational age and weight, zone and stage at infancy, visual acuity, current retina vascularization status, vitreous character, presence of peripheral retinal findings such as lattice retinal tears and detachments (RDs), retinoschisis, and fluorescein findings. MAIN OUTCOME MEASURES: Rate of RDs and factors conferring a higher risk of RDs. RESULTS: The average age was 34.5 years (range, 7-76 years), average gestational age was 26.6 weeks (range, 23-34 weeks), and average birth weight was 875 g (range, 425-1590 g). Findings included lattice in 196 eyes (54.0%), atrophic holes in 126 eyes (34.7%), retinal tears in 111 eyes (30.6%), RDs in 140 eyes (38.6 %), tractional retinoschisis in 44 eyes (11.9%), and visible vitreous condensation ridge-like interface in 112 eyes (30.5%). Fluorescein angiography (FA) was performed in 113 eyes, of which 59 eyes (52.2%) showed leakage and 16 eyes (14.2%) showed neovascularization. Incomplete vascularization posterior to zone 3 was common (71.6% of eyes). Retinal detachments were more likely in patients with a gestational age of 29 weeks or less (P < 0.05) and in eyes with furthest vascularization to posterior zone 2 eyes compared with zone 3 eyes (P = 0.009). CONCLUSIONS: Eyes with ROP not meeting the treatment threshold during infancy showed various late retinal findings and complications, of which RDs were the most concerning. Complications were seen in all age groups, including patients born after the Early Treatment for Retinopathy of Prematurity Study. Contributing factors to RDs included atrophic holes within peripheral avascular retina, visible vitreous condensation ridge-like interface with residual traction, and premature vitreous syneresis. We recommend regular examinations and consideration of ultra-widefield FA examinations. Prospective studies are needed to explore the frequency of complications and benefit of prophylactic treatment and if eyes treated with anti-vascular endothelial growth factor therapy are at risk of similar findings and complications.
Han X, Yang S, Kam WR, Sullivan DA, Liu Y. The Carbonic Anhydrase Inhibitor Dorzolamide Stimulates the Differentiation of Human Meibomian Gland Epithelial Cells. Curr Eye Res 2020;45(12):1604-1610.Abstract
PURPOSE: Clinical studies have indicated that the long-term use of topical antiglaucoma drugs, such as carbonic anhydrase inhibitors (CAIs), may lead to meibomian gland dysfunction (MGD). We hypothesize that these adverse effects involve a direct influence on human MG epithelial cells (HMGECs). The purpose our present investigation was to test our hypothesis and determine whether exposure to dorzolamide, a CAI, impacts the proliferation, intracellular signaling and differentiation of HMGECs. MATERIALS AND METHODS: We cultured immortalized (i) HMGECs with vehicle or various concentrations of dorzolamide for 6 days. Cells were enumerated with a hemocytometer, and examined for their morphology, Akt signaling activity, accumulation of neutral lipids, phospholipids and lysosomes, and the expression of protein biomarkers for lipogenesis regulation, lysosomes and autophagosomes. RESULTS: Our results show that a high, 500 µg/ml concentration of dorzolamide causes a significant decrease in Akt signaling and the proliferation of iHMGECs. However, the high dose of dorzolamide also promotes the differentiation of iHMGECs. This response features increases in the number of lysosomes, the accumulation of phospholipids, and the expression of the light chain 3A biomarker for autophagosomes. In contrast, the therapeutic amount (50 µg/ml) of dorzolamide has no impact on the proliferative or differentiative abilities of iHMGECs. CONCLUSIONS: Our results support our hypothesis and demonstrate that the CAI dorzolamide does exert a direct influence on the proliferation and differentiation of iHMGECs. However, this effect is elicited only by a high, and not a therapeutic, amount of dorzolamide. AKT: phosphoinositide 3-kinase-protein kinase B; BPE: bovine pituitary extract; CAD: cationic amphiphilic drug; DED: dry eye disease; DMEM/F12: 1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F-12; EGF: epidermal growth factor; FBS: fetal bovine serum; iHMGECs: immortalized human meibomian gland epithelial cells; KSFM: keratinocyte serum-free medium; LAMP-1: lysosomal-associated membrane protein 1; LC3A: light chain 3A; MGD: meibomian gland dysfunction; SREBP-1: sterol regulatory element-binding protein 1.
Hanyuda A, Rosner BA, Wiggs JL, Willett WC, Tsubota K, Pasquale LR, Kang JH. Low-carbohydrate-diet scores and the risk of primary open-angle glaucoma: data from three US cohorts. Eye (Lond) 2020;34(8):1465-1475.Abstract
BACKGROUND/OBJECTIVES: To assess the long-term association between low-carbohydrate dietary patterns and incident primary open-angle glaucoma (POAG), and POAG subtypes defined by highest untreated intraocular pressure (IOP) and by pattern of visual field (VF) loss at diagnosis. SUBJECTS/METHODS: We followed 185,638 participants of three large US prospective cohorts biennially (1976-2016, 1986-2016 and 1991-2017). Deciles of three low-carbohydrate-diet scores were calculated to represent adherence to diets lower in carbohydrate and higher in protein and fat from any source, animal sources or plant sources. We confirmed POAG cases (n = 2112) by medical record review and used Cox proportional hazards models to estimate multivariable-adjusted relative risks (MVRRs) and 95% confidence intervals (CIs). RESULTS: There was no association between the three types of low-carbohydrate-diet scores and POAG: the MVRR for POAG in the highest vs. lowest deciles was 1.13 (95% CI, 0.91-1.39; P = 0.40) for the overall score; 1.10 (95% CI, 0.89-1.35; P = 0.38) for the animal score and 0.96 (95% CI, 0.79-1.18; P = 0.88) for the vegetable score. No differential associations by IOP level was found (P ≥ 0.06). However, the vegetable score showed a suggestive inverse association with early paracentral VF loss (highest vs. lowest decile MVRR = 0.78 [95% CI, 0.55-1.10]; P = 0.12) but not with peripheral VF loss only (MVRR = 1.09 [95% CI, 0.83-1.44]; P = 0.14; P = 0.03). CONCLUSIONS: Low-carbohydrate diets were not associated with risk of POAG. Our data suggested that higher consumption of fat and protein from vegetable sources substituting for carbohydrates was associated with lower risk of the POAG subtype with initial paracentral VF loss.
Haque M, Lei F, Xiong X, Ren Y, Kumar A, Das JK, Ren X, Fang D, de Figueiredo P, Yang J-M, Song J. Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HBV Replication through Production of IFN-γ and TNF-⍺. iScience 2020;23(7):101333.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 hepatitis B virus (HBV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the liver to suppress HBV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs provoke the antiviral response remain to be fully elucidated. In this study, we generated the functional HBV surface Ag-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the underlying mechanisms of the CTL-mediated antiviral replication in a murine model. We show that adoptive transfer of HBV surface Ag-specific iPSC-CTLs greatly suppressed HBV replication and prevented HBV surface Ag expression. We further demonstrate that the adoptive transfer significantly increased T cell accumulation and production of antiviral cytokines. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the liver and suppress HBV replication through producing antiviral cytokines.
Harris JM, Han IC, Sachdeva MM, Zhang AY, Zebardast N. Post-operative intracranial gas migration with optic nerve infiltration and atrophy following retinal detachment repair. Am J Ophthalmol Case Rep 2020;20:100920.Abstract
Purpose: To report a patient with post-operative gas migration into the optic nerve and lateral ventricles after retinal detachment repair. Observations: A 78-year-old pseudophakic man developed a temporal visual field cut in his non-operative, right eye 3 weeks after repair of a recurrent, shallow, macula-involving retinal detachment with perfluoropropane intraocular gas in the left eye. Visual acuity in the right eye measured 20/40, and static perimetry demonstrated temporal visual field loss that respected the vertical midline. Dilated fundus examination of the right eye was unrevealing for any retinal cause, raising suspicion for an intracranial etiology. An urgent CT scan of the brain demonstrated gas in all segments of the left optic nerve and lateral ventricles, consistent with intracranial gas migration along the optic nerve. Given the absence of systemic neurologic symptoms, cautious observation was advised on consultation with neuroradiology and neurosurgery, and follow-up CT scan 1 week later showed resolution of the intracranial gas. By 10-weeks post-operatively, vision returned to 20/20 in the right eye with persistent temporal field loss, and the left eye was hand motions (20/70 pre-operatively) with evidence of optic nerve atrophy and severe cupping. Conclusions: Intracranial gas migration is a rare complication of retinaldetachment repair with intraocular gas and may occur in the setting of structural defects of the optic nerve and high post-operative intraocular pressure. Clinicians should be alert to this rare but serious complication, which can cause neurologic symptoms and result in vision loss in both the operative and non-operative eyes.
Hayashi T, Yasutsugu I, Shimizu T, Kuroki T, Kobashigawa Y, Iijima Y, Yuda K. Pars plana vitrectomy combined with penetrating keratoplasty and transscleral-sutured intraocular lens implantation in complex eyes: a case series. BMC Ophthalmol 2020;20(1):369.Abstract
BACKGROUND: The aim of this study was to evaluate the clinical outcomes of pars plana vitrectomy (PPV) combined with penetrating keratoplasty (PKP) and transscleral-sutured intraocular lens (IOL) implantation (IOL-suture) in complex eyes. METHODS: In this prospective, consecutive interventional case series, patients who underwent PKP combined with PPV and IOL implantation from July 2014 to March 2018 at Yokohama Minami Kyosai Hospital were enrolled. The postoperative best corrected visual acuity (BCVA) (converted to logarithm of the minimal angle of resolution [logMAR] units), intraocular pressure (IOP, mmHg), endothelial cell density (ECD, cells/mm), graft survival, complications, astigmatism, and spherical equivalent (dioptres [D]) were evaluated. RESULTS: This study included 11 eyes of 11 patients (three females and eight males; mean age, 61.8 ± 13.9 years) with an injury (n = 6) or bullous keratopathy (n = 5). The BCVA significantly improved from 1.50 ± 0.66 logMAR preoperatively to 0.78 ± 0.59 logMAR (p < 0.001) postoperatively. The baseline ECD significantly decreased from 2396 ± 238 cells/mm preoperatively to 1132 ± 323 cells/mm (p < 0.001) postoperatively. Despite two rejection episodes, graft survival rates were 100%. The mean follow-up period was 38.0 ± 20.5 months. Two patients required combined glaucoma surgery, and three patients underwent subsequent glaucoma surgery. Postoperative astigmatism and spherical equivalent were 3.9 ± 3.2 D and 0.29 ± 2.18 D, respectively. CONCLUSION: The combination of PKP, PPV, and IOL-suture implantation could be a safe and effective approach for eyes requiring anterior segment surgery; however, these eyes are associated with a higher incidence of glaucoma surgery.
Heidary G, Hunter DG. Outcomes of strabismus surgery in genetically confirmed congenital fibrosis of the extraocular muscles. J AAPOS 2020;
Hellström A, Hellström W, Hellgren G, Smith LEH, Puttonen H, Fyhr I-M, Sävman K, Nilsson AK, Klevebro S. Docosahexaenoic Acid and Arachidonic Acid Levels Are Associated with Early Systemic Inflammation in Extremely Preterm Infants. Nutrients 2020;12(7)Abstract
Fetal and early postnatal inflammation have been associated with increased morbidity in extremely preterm infants. This study aimed to demonstrate if postpartum levels of docosahexaenoic acid (DHA) and arachidonic acid (AA) were associated with early inflammation. In a cohort of 90 extremely preterm infants, DHA and AA in cord blood, on the first postnatal day and on postnatal day 7 were examined in relation to early systemic inflammation, defined as elevated C-reactive protein (CRP) and/or interleukin-6 (IL-6) within 72 h from birth, with or without positive blood culture. Median serum level of DHA was 0.5 mol% (95% CI (confidence interval) 0.2-0.9, = 0.006) lower than the first postnatal day in infants with early systemic inflammation, compared to infants without signs of inflammation, whereas levels of AA were not statistically different between infants with and without signs of inflammation. In cord blood, lower serum levels of both DHA (correlation coefficient -0.40; = 0.010) and AA (correlation coefficient -0.54; < 0.001) correlated with higher levels of IL-6. Levels of DHA or AA did not differ between infants with and without histological signs of chorioamnionitis or fetal inflammation. In conclusion, serum levels of DHA at birth were associated with the inflammatory response during the early postnatal period in extremely preterm infants.

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