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1. Retinoblastoma with and without Extraocular Tumor Extension

Author: Swathi Kaliki, MD, Vijitha S. Vempuluru, MD, Ido Didi Fabian, MD, Elhassan Abdallah, MD, Shehu U. Abdullahi, MD, Rula A. Abdulqader, MD, Aminatu A. Abdulrahaman, MD, Sherif Abouelnaga, MD, Dupe S. Ademola-Popoola, FMCOph, FWACS, Adedayo Adio, FWACS, Mahmoud A. Afifi, MD, Armin R. Afshar, MD, Priyanka Aggarwal, MD, Ada E. Aghaji, FMCOph MSc, Alia Ahmad, MRCPCH UK, Marliyanti N.R. Akib, MD, Adeseye M. Akinsete, MBBS, Lamis Al Harby, MD, Saleh A. Al Mesfer, MD, Mouroge H. Al Ani, MD, Silvia Alarcón Portabella, MD, Safaa A.F. Al-Badri, MD, Ana Patricia A. Alcasabas, MD, Saad A. Al-Dahmash, MD, Amanda Alejos, MD, Ernesto Alemany-Rubio, MD, Amadou I. Alfa Bio, MD, Yvania Alfonso Carreras, MD, Christiane E. Al-Haddad, MD, Hamoud H.Y. Al-Hussaini, MD, MSc, Amany M. Ali, MD, Donjeta B. Alia, MD, Mazin F. Al-Jadiry, MD, Usama Al-Jumaly, MD, Hind M. Alkatan, MD, Charlotta All-Eriksson, MD, PhD, Ali A.R.M. Al-Mafrachi, FIBMS, Argentino A. Almeida, MD, Khalifa M. Alsawidi, MD, Athar A.S.M. Al-Shaheen, MD, Entissar H. Al-Shammary, MD, Doreen Amankwaa-Frempong, MBChB, Primawita O. Amiruddin, MD, Inggar Armytasari, MD, Nicholas J. Astbury, FRCS, FRCOphth, Hatice T. Atalay, MD, Eda Ataseven, MD, La-ongsri Atchaneeyasakul, MD, Rose Atsiaya, OCO, Rudolf Autrata, MD, PhD, Julia Balaguer, MD, PhD, Ruhengiz Balayeva, PhD, Honorio Barranco, MD, PhD, Paulina Bartoszek, MD, Katarina Bartuma, MD, PhD, Covadonga Bascaran, MD, MSc, Nikolaos E. Bechrakis, MD, Maja Beck Popovic, MD, Ainura S. Begimkulova, MD, Sarra Benmiloud, MD, Rokia C. Berete, MD, PhD, Jesse L. Berry, MD, Anirban Bhaduri, MD, Sunil Bhat, MBBS, MD, Arpita Bhattacharyya, MD, Eva M. Biewald, MD, Elaine Binkley, MD, Sharon Blum, MD, Nadia Bobrova, MD, H. Culver Boldt, MD, Maria Teresa B.C. Bonanomi, MD, PhD, Gabrielle C. Bouda, MD, Hédi Bouguila, MD, PhD, Rachel C. Brennan, MD, Bénédicte G. Brichard, MD, PhD, Jassada Buaboonnam, MD, Aléine Budiongo, MD, Matthew Burton, FRCOphth, Patricia Calderón-Sotelo, MD, Doris A. Calle Jara, MD, Jayne E. Camuglia, FRANZCO, Miriam R. Cano, MD, MSc, Michael Capra, FRCPI, Shani Caspi, MD, Nathalie Cassoux, MD, PhD, Guilherme Castela, MD, Luis Castillo, MD, Jaume Català-Mora, MD, PhD, Isabel Caviedes, MD, Arthika Chandramohan, MD, Guillermo L. Chantada, MD, PhD, Shabana Chaudhry, MD, Bhavna Chawla, MD, Wensi Chen, MD, Faraja S. Chiwanga, MSc, Tsengelmaa Chuluunbat, MD, PhD, Krzysztof Cieslik, MD, Antony Clark, FRANZCO, Ruellyn L. Cockcroft, MB ChB , M Med Paed, Codruta Comsa, MD, Maria G. Correa Llano, MD, Timothy W. Corson, PhD, Line Couitchere, MD, Kristin E. Cowan-Lyn, MD, MBBS, Monika Csóka, MD, PhD, Wantanee Dangboon, MD, Anirban Das, MD, Pranab Das, MD, Sima Das, MS, Jacquelyn M. Davanzo, BSN, BSPH, Alan Davidson, MBChB, MPhil, Sonia De Francesco, MD, Patrick De Potter, MD, PhD, Karina Q. Delgado, MD, PhD, Hakan Demirci, MD, Laurence Desjardins, MD, Rosdali Y. Diaz Coronado, MD, Helen Dimaras, PhD, Andrew J. Dodgshun, M Phil, Carla R. Donato Macedo, MD, Monica D. Dragomir, MD, PhD, Yi Du, MD, Magritha Du Bruyn, MD, Johannes P. Du Plessis, MMed (Paed), Gagan Dudeja, MBBS, MS, Katrin Eerme, MD, I Wayan Eka Sutyawan, MD, Asmaa El Kettani, MD, Amal M. Elbahi, MD, James E. Elder, MBBS, Alaa M. Elhaddad, MD, PhD, Moawia M.A. Elhassan, MD, Mahmoud M. Elzembely, MD, Connor Ericksen, MD, Vera A. Essuman, FWACS, Ted Grimbert A. Evina, MD, Ifeoma R. Ezegwui, FMCOph, FWACS, FAEH, Zehra Fadoo, MBBS, Adriana C. Fandiño, MD, Mohammad Faranoush, MD, Oluyemi Fasina, FWACS, Delia D.P.G. Fernández, MSc, Ana Fernández-Teijeiro, MD, PhD, Allen Foster, FRCOphth, Shahar Frenkel, MD, PhD, Ligia D. Fu, MD, Soad L. Fuentes-Alabi, MD, MPH, Juan L. Garcia, MSc, David García Aldana, MD, Henry N. Garcia Pacheco, MD, Jennifer A. Geel, MBChB, MMed, Fariba Ghassemi, MD, Ana V. Girón, MD, Marco A. Goenz, MD, Aaron S. Gold, OD, Hila Golberg, MD, Glen A. Gole, MD, FRANZCO, Nir Gomel, MD, Efren Gonzalez, MD, Graciela Gonzalez Perez, MD, Liudmira González-Rodríguez, MD, Malka Gorfine, PhD, Jaime Graells, MD, Pernille A. Gregersen, MD, Nathalia D.A.K. Grigorovski, MD, Koffi M. Guedenon, MD, D Sanjeeva Gunasekera, MD, Ahmet K. Gündüz, MD, Himika Gupta, MD, Sanjiv Gupta, MS, Vineeta Gupta, MD, Theodora Hadjistilianou, MD, Patrick Hamel, MD, Syed A. Hamid, FCPS, Norhafizah Hamzah, MSc, Eric D. Hansen, MD, J William Harbour, MD, M. Elizabeth Hartnett, MD, Murat Hasanreisoglu, MD, Sadiq Hassan, MD, FWACS, Shadab Hassan, FRCS, FCPS, Wojciech Hautz, MD, Huda A. Haydar, CHD, Stanislava Hederova, MD, Laila Hessissen, MD, Hoby Lalaina, MD, Suradej Hongeng, MD, Diriba F. Hordofa, MD, G. Baker Hubbard, MD, Marlies Hummlen, MD, Kristina Husakova, MD, Allawi N. Hussein Al-Janabi, MD, Affiong A. Ibanga, MB.BCh, FMCOph, Russo Ida, MD, Vesna R. Ilic, MD, Ziyavuddin Islamov, MD, Vivekaraj Jairaj, DNB, Teyyeb A. Janjua, MD, FCPS, FRCSEd, Irfan Jeeva, FRCOphth, Xunda Ji, MD, Dong Hyun Jo, MD, PhD, Michael M. Jones, MD, PhD, FRANZCO, Theophile B. Amani Kabesha, MD, PhD, Rolande L. Kabore, MD, Abubakar Kalinaki, MD, Pius Kamsang, MD, Mehmet Kantar, MD, Noa Kapelushnik, MD, Tamar Kardava, PhD, Rejin Kebudi, MD, Jonny Keomisy, MD, Tomas Kepak, MD, Petra Ketteler, MD, Zohora J. Khan, MD, Hussain A. Khaqan, MD, Vikas Khetan, FRCS, FACS, Alireza Khodabande, MD, Zaza Khotenashvili, MD, Jonathan W. Kim, MD, Jeong Hun Kim, MD, PhD, Hayyam Kiratli, MD, Tero T. Kivelä, MD, Artur Klett, MD, PhD, Irem Koç, MD, Jess Elio Kosh Komba Palet, MD, Dalia Krivaitiene, MD, PhD, Mariana Kruger, Mmed Paed, PhD, Kittisak Kulvichit, MD, Mayasari W. Kuntorini, MD, Alice Kyara, BA, Geoffrey C. Lam, FRANZCO, Scott A. Larson, MD, Slobodanka Latinović, MD, PhD, Kelly D. Laurenti, MD, Yotam Lavi, MD, PhD, Alenka Lavric Groznik, MD, Amy A. Leverant, MD, Cairui Li, MD, Kaijun Li, MD, Ben Limbu, MD, Chun-Hsiu Liu, MD, Quah Boon Long, FRCS (Ed), MMed ( Ophth), FAMS, Juan P. López, MD, Robert M. Lukamba, MD, Sandra Luna-Fineman, MD, Delfitri Lutfi, MD, Lesia Lysytsia, MD, Shiran Madgar, MD, George N. Magrath, MD, Amita Mahajan, MD, Puja Maitra, MD, Erika Maka, MD, Emil K. Makimbetov, MD, Azza M.Y. Maktabi, MD, Carlos Maldonado, MD, Ashwin Mallipatna, MD, Rebecca Manudhane, MD, Lyazat Manzhuova, MD, Nieves Martín Begue, MD, PhD, Sidra Masud, MBBS, Ibrahim O. Matende, MD, M. Med (Oph), Clarissa C.D.S. Mattosinho, MD, Marchelo Matua, BAPH, Ismail Mayet, MD, Freddy B. Mbumba, MD, MMed Paed, John D. McKenzie, MD, Azim Mehrvar, MD, Aemero A. Mengesha, MD, Vikas Menon, MD, Gary John V.D.D. Mercado, MD, Marilyn B. Mets, MD, Edoardo Midena, MD, PhD, Audra Miller, MD, Divyansh K.C. Mishra, DNB, Furahini G. Mndeme, MD, Ahmed A. Mohamedani, FRCPath, Mona T. Mohammad, MD, FRCS, Annette C. Moll, MD, PhD, Margarita M. Montero, MD, Claude Moreira, MD, PhD, Prithvi Mruthyunjaya, MD, MHS, Mchikirwa S. Msina, MMed Ophth, Gerald Msukwa, MMed Ophth, Sangeeta S. Mudaliar, DNB Pediatric, Hassan Muhammad, MD, Kangwa I. Muma, MMed Ophth, FCOphth, Francis L. Munier, MD, Timothy G. Murray, MD, MBA, Kareem O. Musa, FWACS, FMCOphth, FICO, Asma Mushtaq, MD, Anne A. Musika, MD, Hamzah Mustak, MD, Tajudeen Mustapha, MBBS, FWACS, Okwen M. Muyen, MD, Khumo H. Myezo, Msc, Gita Naidu, MMed Paed, PhD, Natasha Naidu, MBCHB, FCS Ophthalmol, Akshay Gopinathan Nair, MD, Sundaram Natarajan, FRCS, Larisa Naumenko, MD, PhD, Paule Aïda Ndoye Roth, MD PhD, Yetty M. Nency, MD, Vladimir Neroev, MD, PhD, Yvonne Ng, MBChB ( Auckland) , FRANZCO, Marina Nikitovic, MD, PhD, Elizabeth D. Nkanga, FMCOph, Henry E. Nkumbe, MD, Marcel N. Numbi, MD, Kalle Nummi, MD, Murtuza Nuruddin, FRCS, Mutale Nyaywa, MD, MMed Ophth, FCOphth, Chinsisi Nyirenda, MD, Ghislaine Obono-Obiang, MD, Scott C.N. Oliver, MD, Joaquin Ooporto, MD, Miriam Ortega-Hernández, MD, Alexander Oscar, MD, Diego Ossandon, MD, Halimah Pagarra, MD, PhD, Vivian Paintsil, FWACP, Luisa Paiva, MD, Mahesh Shanmugam Palanivelu, FRCSED, Ruzanna Papyan, MD, Raffaele Parrozzani, MD, PhD, Claudia R. Pascual Morales, MD, Katherine E. Paton, MD, FRCSC, Jacob Pe'er, MD, Jesús Peralta Calvo, MD, Sanja Perić, MD, PhD, Chau T.M. Pham, MD, Remezo Philbert, MD, David A. Plager, MD, Pavel Pochop, MD, PhD, Rodrigo A. Polania, MD, Vladimir Polyakov, MD, Jimena Ponce, MD, Ali O. Qadir, MD, Seema Qayyum, FCPS, Jiang Qian, MD, Ardizal Rahman, MD, Purnima Rajkarnikar, MD, Rajesh Ramanjulu, MD, Aparna Ramasubramanian, MD, Marco A. Ramirez-Ortiz, MD, MPH, Jasmeen K. Randhawa, BA, Léa Raobela, MD, Riffat Rashid, MS, M. Ashwin Reddy, FRCOphth, Lorna A. Renner, FRCPCH (UK), David Reynders, MD, Dahiru Ribadu, FMCOph, Petra Ritter-Sovinz, MD, Anna Rogowska, MD, Duangnate Rojanaporn, MD, Livia Romero, MD, Soma R. Roy, DCO, Raya H. Saab, MD, Svetlana Saakyan, MD, PhD, Ahmed H. Sabhan, MD, Mandeep S. Sagoo, FRCS (Ed), Azza M.A. Said, MD, Rohit Saiju, MD, Beatriz Salas, MD, Sonsoles San Román Pacheco, MD, Gissela L. Sánchez, MD, Alma Janeth Sanchez Orozco, MD, Phayvanh Sayalith, MD, Trish A. Scanlan, MRCPI, MSc, Christoph Schwab, MD, Ahad Sedaghat, MD, Rachna Seth, DNB MNAMS, Mariana Sgroi, MD, Ankoor S. Shah, MD, PhD, Shawkat A. Shakoor, MS, Manoj K. Sharma, MD, Sadik T. Sherief, MD, Carol L. Shields, MD, David Sia, MB ChB, FRANZCO, Sorath Noorani Siddiqui, MD, Sidi Sidi cheikh, MD, PhD, Sónia Silva, MD, Arun D. Singh, MD, Usha Singh, MS, Penny Singha, MD, Rita S. Sitorus, MD, PhD, Alison H. Skalet, MD, PhD, Hendrian D. Soebagjo, MD, PhD, Tetyana Sorochynska, MD, PhD, Grace Ssali, MD, Andrew W. Stacey, MD, Sandra E. Staffieri, PhD, Erin D. Stahl, MD, David M. Steinberg, PhD, David K. Stones, MBChB, FCPaed, Caron Strahlendorf, MD, Maria Estela Coleoni Suarez, MD, Sadia Sultana, FCPS, Xiantao Sun, MD, Rosanne Superstein, MD, Eddy Supriyadi, MD, PhD, Supawan Surukrattanaskul, MD, Shigenobu Suzuki, MD, PhD, Karel Svojgr, MD, PhD, Fatoumata Sylla, MD, Gevorg Tamamyan, MD, PhD, Deborah Tan, MBBS, Alketa Tandili, MD, PhD, Jing Tang, MD, Fanny F. Tarrillo Leiva, MD, Maryam Tashvighi, MD, Bekim Tateshi, MD, PhD, Kok Hoi Teh, MD, Edi S. Tehuteru, MD, Luiz F. Teixeira, MD, Manca Tekavcic Pompe, MD, PhD, Abdullah Dahan M. Thawaba, MD, Tuyisabe Theophile, MSc, Helen Toledano, MBChB, Doan L. Trang, MD, Fousseyni Traoré, MD, Devjyoti Tripathy, MD, Samuray Tuncer, MD, Harba Tyau-Tyau, MD, Ali B. Umar, MD, FMCPath, Emel Unal, MD, Ogul E. Uner, BA, Steen F. Urbak, MD, PhD, Tatiana L. Ushakova, MD, Rustam H. Usmanov, MD, Sandra Valeina, MD, Paola Valente, MD, Milo van Hoefen Wijsard, MD, Jacqueline Karina Vasquez Anchaya, MD, Leon O. Vaughan, FRCS (Ed), Nevyana V. Veleva-Krasteva, MD, PhD, Nishant Verma, MD, Andi A. Victor, MD, PhD, Maris Viksnins, MD, Edwin G. Villacís Chafla, MD, Victor M. Villegas, MD, Victoria Vishnevskia-Dai, MD, Keith Waddell, DM, FRCP, FRCS, FRCOphth, Amina H. Wali, MD, FMCOph Nigeria, Yi-Zhuo Wang, MD, Nutsuchar Wangtiraumnuay, MD, FICO, Julie A. Wetter, MMed Rad Onc, FCRad Onc, Widiarti P. Riono, MD, Matthew W. Wilson, MD, Amelia D.C. Wime, MD, Atchareeya Wiwatwongwana, MD, Damrong Wiwatwongwana, MD, Charlotte Wolley Dod, MD, Emily S. Wong, FCOphth HK, FHKAM, Phanthipha Wongwai, MD, PhD, Si-qi Wu, MSc, Daoman Xiang, MD, PhD, Yishuang Xiao, MSc, Bing Xu, MD, Kang Xue, MD, Antonio Yaghy, MD, Jason C. Yam, FRCSEd, Huasheng Yang, MD, Jenny M. Yanga, MD, Muhammad A. Yaqub, MD, FCPS, FRCSEd, Vera A. Yarovaya, MD, Andrey A. Yarovoy, MD, PhD, Huijing Ye, MD, Roberto I. Yee, MD, Yacoub A. Yousef, MD, Putu Yuliawati, MD, Arturo M. López, MD, Ekhtelbenina Zein, MD, Yi Zhang, MD, PhD, Katsiaryna Zhilyaeva, MD, Nida Zia, MBBS, MCPS, Othman A.O. Ziko, MD, PhD, Marcia Zondervan, MBA, Sabrina Schlüter, MD, and Richard Bowman, FRCOphth
Subjects: External beam radiotherapy, Extraocular extension, Multimodal treatment, Retinoblastoma, Tumor, Ophthalmology, RE1-994
Abstract: Purpose: To study the treatment and outcomes of children with retinoblastoma (RB) with extraocular tumor extension (RB-EOE) and compare them with RB without extraocular tumor extension (RB-w/o-EOE). Design: Multicenter intercontinental collaborative prospective study from 2017 to 2020. RB-EOE cases included those with overt orbital tumor extension in treatment-naive patients. Cases with microscopic orbital extension detected postenucleation were excluded from the study. Participants: A total of 319 children with RB-EOE and 3116 children with RB-w/o-EOE. Intervention: Chemotherapy, enucleation, exenteration, radiotherapy. Main Outcome Measures: Systemic metastasis and death. Results: Of the 3435 RB patients included in this study, 309 (9%) were from low-income countries (LIC), 1448 (42%) from lower-middle income, 1012 (29%) from upper-middle income, and 666 (19%) patients from high-income countries. There was an inverse relationship between the percentage of RB-EOE and national income level, with 96 (31%) patients from LIC, 197 (6%) lower-middle income, 20 (2%) upper-middle income, and 6 (1%) patients from high-income countries (P = 0.0001). The outcomes were statistically significant for RB-EOE compared with RB-w/o-EOE: systemic metastasis (32% vs. 4% respectively; P = 0.0001) and metastasis-related death (63% vs. 6% respectively; P = 0.0001). Multimodal treatment was the most common form of treatment (n = 177; 54%) for RB-EOE, with most cases undergoing a combination of intravenous chemotherapy and enucleation (n = 97; 30%). Adjuvant external beam radiotherapy (EBRT) after surgery (enucleation/orbital exenteration) was given in only 68 (21%) cases. Kaplan–Meier analysis for systemic metastasis and metastasis-related death in RB-EOE was 28% and 57% at 1 year, 29% and 60% at 2 years, and 29% and 61% at 3 years, respectively. Cox regression analysis revealed that the risk of death from RB-EOE was greater in patients aged >4 years than
Published: 2025
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2. Rationale of Basic and Cellular Mechanisms Considered in Updating the Staging System for Diabetic Retinal Disease

Author: M. Elizabeth Hartnett, MD, Ward Fickweiler, MD, PhD, Anthony P. Adamis, MD, Michael Brownlee, MD, Arup Das, MD, PhD, Elia J. Duh, MD, Edward P. Feener, PhD, George King, MD, Renu Kowluru, PhD, Ulrich F.O. Luhmann, PhD, Federica Storti, PhD, Charles C. Wykoff, MD, PhD, and Lloyd Paul Aiello, MD, PhD
Subjects: Basic mechanisms, Cellular mechanisms, Diabetic retinal disease, Diabetic retinopathy, Staging, Ophthalmology, RE1-994
Abstract: Purpose: Hyperglycemia is a major risk factor for early lesions of diabetic retinal disease (DRD). Updating the DRD staging system to incorporate relevant basic and cellular mechanisms pertinent to DRD is necessary to better address early disease, disease progression, the use of therapeutic interventions, and treatment effectiveness. Design: We sought to review preclinical and clinical evidence on basic and cellular mechanisms potentially pertinent to DRD that might eventually be relevant to update the DRD staging system. Participants: Not applicable. Methods: The Basic and Cellular Mechanisms Working Group (BCM-WG) of the Mary Tyler Moore Vision Initiative carefully and extensively reviewed available preclinical and clinical evidence through multiple iterations and classified these. Main Outcome Measures: Classification was made into evidence grids, level of supporting evidence, and anticipated future relevance to DRD. Results: A total of 40 identified targets based on pathophysiology and other parameters for DRD were grouped into concepts or evaluated as specific candidates. VEGFA, peroxisome proliferator-activated receptor-alpha related pathways, plasma kallikrein, and angiopoietin 2 had strong agreement as promising for use as biomarkers in diagnostic, monitoring, predictive, prognostic, and pharmacodynamic responses as well as for susceptibility/risk biomarkers that could underlie new assessments and eventually be considered within an updated DRD staging system or treatment, based on the evidence and need for research that would fit within a 2-year timeline. The BCM-WG found there was strong reason also to pursue the following important concepts regarding scientific research of DRD acknowledging their regulation by hyperglycemia: inflammatory/cytokines, oxidative signaling, vasoprotection, neuroprotection, mitophagy, and nutrients/microbiome. Conclusion: Promising targets that might eventually be considered within an updated DRD staging system or treatment were identified. Although the BCM-WG recognizes that at this stage little can be incorporated into a new DRD staging system, numerous potential targets and important concepts deserve continued support and research, as they may eventually serve as biomarkers and/or therapeutic targets with measurable benefits to patients with diabetes. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Published: 2024
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3. Genome-wide association identifies novel ROP risk loci in a multiethnic cohort

Author: Xiaohui Li, Leah A. Owen, Kent D. Taylor, Susan Ostmo, Yii-Der Ida Chen, Aaron S. Coyner, Kemal Sonmez, M. Elizabeth Hartnett, Xiuqing Guo, Eli Ipp, Kathryn Roll, Pauline Genter, R. V. Paul Chan, Margaret M. DeAngelis, Michael F. Chiang, J. Peter Campbell, Jerome I. Rotter, and on behalf of the i-ROP Consortium
Subjects: Biology (General), QH301-705.5
Abstract: Abstract We conducted a genome-wide association study (GWAS) in a multiethnic cohort of 920 at-risk infants for retinopathy of prematurity (ROP), a major cause of childhood blindness, identifying 1 locus at genome-wide significance level (p
Published: 2024
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4. Editorial: Identification of novel biomarkers for retinopathy of prematurity in preterm infants by use of innovative technologies and artificial intelligence

Author: Carina Slidsborg, Alistair Fielder, and M. Elizabeth Hartnett
Subjects: prematurity, retinopathy of prematurity (ROP), biomarker discovery, innovative technologies, artificial intelligence, risk stratification, predictive factors, Pediatrics, RJ1-570
Published: 2024
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5. The value of pre-symptomatic genetic risk assessment for age-related macular degeneration: the Moran AMD Genetic Testing Assessment (MAGENTA) study—a study protocol for a randomized controlled trial

Author: Emmanuel K. Addo, M. Elizabeth Hartnett, and Paul S. Bernstein
Subjects: Carotenoids, Age-related macular degeneration, Genetic testing, Immediate and deferred disclosure, Lutein and zeaxanthin, Lifestyle modification, Medicine (General), R5-920
Abstract: Abstract Background Age-related macular degeneration (AMD) is an irreversible blinding eye condition with complex genetic and environmental etiologies. Genetic testing for AMD for previously identified multiple-risk single nucleotide polymorphisms can help determine an individual’s future susceptibility. However, such testing has been discouraged until evidence shows that providing such information to symptomatic or pre-symptomatic individuals will alter their disease course. Therefore, we designed this study to investigate whether knowledge of AMD risk could stimulate the adoption of a healthier lifestyle that could lower the incidence of AMD later in life. We hypothesize that pre-symptomatic individuals informed of a high genetic risk of AMD are more likely to make quantifiable, positive lifestyle changes relative to participants informed of lower genetic risk or randomized to deferred disclosure of genetic testing results. Methods The Moran AMD Genetic Testing Assessment (MAGENTA) study is a phase 2, single-center, prospective, double-masked, randomized controlled trial conducted at the John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. Participants are randomized by a 3:1 allocation ratio to immediate and deferred disclosure groups and followed for 12 months. Skin, ocular, and serum carotenoid status, as well as nutritional and social surveys, are assessed at study visits. Skin carotenoid assessment is by resonance Raman spectroscopy and reflectance spectroscopy, ocular carotenoids are measured with Heidelberg Spectralis autofluorescence imaging and fluorescence lifetime imaging ophthalmoscopy (FLIO), and serum carotenoids are quantified using high-performance liquid chromatography. The primary outcome evaluates changes in skin carotenoid status in response to genetic risk disclosure. The secondary outcomes examine changes in ocular and serum carotenoid status in response to genetic risk disclosure. Also, we will correlate AMD genetic risk with baseline ocular and systemic carotenoid status and FLIO. Discussion MAGENTA will provide much-needed evidence on whether pre-symptomatic testing for AMD risk can lead to quantifiable long-term changes in behavior and lifestyle associated with a lower incidence of AMD later in life. Findings from the MAGENTA trial will facilitate the design of a future larger, longer-term, multicenter phase 3 trial that could feature subgroup analysis, expanded measures of lifestyle modification, and potential active nutritional interventions. Trial registration ClinicalTrials.gov NCT05265624 . Registered on March 3, 2022.
Published: 2023
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6. Laser versus Anti-VEGF: A Paradigm Shift for Treatment-Warranted Retinopathy of Prematurity

Author: M. Elizabeth Hartnett and Andreas Stahl
Subjects: Vitreoretinal surgery, Laser, Anti-VEGF, Retinopathy of prematurity, ROP, Ophthalmology, RE1-994
Abstract: Abstract Retinopathy of prematurity (ROP), a leading cause of childhood blindness, has historically been associated with blindness from overgrowth of blood vessels from the retina into the vitreous that lead to complex retinal detachments. Our understanding of ROP has evolved with the survival of extremely low-birthweight infants and includes not only overgrowth of blood vessels, but also insufficient developmental retinal vascular growth in early phases of the disease. Our current treatments of ROP have focused on methods to improve perinatal and prenatal care, reduce premature birth, and prevent early phases of ROP. Nonetheless, addressing vasoproliferation in treatment-warranted eyes remains the mainstay of management. Two main treatment strategies co-exist today: laser treatment, which has been the standard of care since the 1990s, and anti-VEGF injections, which have been used since early reports in 2007 (Travassos et al. in Ophthalmic Surg Lasers Imaging, 38:233–237, https://doi.org/10.3928/15428877-20070501-09 , 2007, Shah et al. in Indian J Ophthalmol 55:75–76, https://doi.org/10.4103/0301-4738.29505 , 2007, Quiroz-Mercado et al. in Semin Ophthalmol 22:109–125, https://doi.org/10.1080/08820530701420082 , 2007).
Published: 2023
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7. The roles of sex and gender in women’s eye health disparities in the United States

Author: Irene O. Aninye, Kathleen Digre, M. Elizabeth Hartnett, Kira Baldonado, Erin M. Shriver, Laura M. Periman, Julie Grutzmacher, Janine A. Clayton, and Society for Women’s Health Research Women’s Eye Health Working Group
Subjects: Dry eye, Retinopathy, Gender inequity, Health disparities, Macular degeneration, Telehealth, Medicine, Physiology, QP1-981
Abstract: Abstract Background In the United States, women are at a higher risk of developing vision impairment or a serious eye disease (such as age-related macular degeneration, thyroid eye disease, or chronic dry eye disease) than men. Disparities in eye diseases due to biology widen even further when considering factors such as social determinants of health; gaps in research data, literature, and policy; insufficient provider and patient education; and limitations in screening and treatment options. Sex and gender disparities in eye health are clinically under-addressed and burdensome on both patient quality of life and the health care and economic systems, resulting in a pressing population health issue that negatively impacts women. Design The Society for Women’s Health Research convened a working group of expert clinicians, researchers, and patient advocates to review the current state of science regarding sex and gender disparities in women’s eye health, identify knowledge gaps and unmet needs, and explore better means to advance research, improve patient care, and raise awareness of key issues. Discussion The SWHR Women’s Eye Health Working Group identified priority areas in research, clinical care, and education to reduce disparities and improve patient care in women’s eye health. The working group recommends using a systems approach that incorporates a comprehensive research framework with a sex and gender lens to guide future work and that increases health care provider and public education, as well as engagement by expanding partnerships among ophthalmologic providers, researchers, and non-vision stakeholders.
Published: 2021
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8. The long-term effects of anti-vascular endothelial growth factor therapy on the optical coherence tomography angiographic appearance of neovascularization in age-related macular degeneration

Author: Emily S. Levine, Eugenia Custo Greig, Luísa S. M. Mendonça, Shilpa Gulati, Ivana N. Despotovic, A. Yasin Alibhai, Eric Moult, Nora Muakkassa, Maddalena Quaranta-El Maftouhi, Adil El Maftouhi, Usha Chakravarthy, James G. Fujimoto, Caroline R. Baumal, Andre J. Witkin, Jay S. Duker, M. Elizabeth Hartnett, and Nadia K. Waheed
Subjects: Macular neovascularization, Optical coherence tomography angiography, Anti-VEGF, Ophthalmology, RE1-994
Abstract: Abstract Background The short-term effects of anti-vascular endothelial growth factor (anti-VEGF) treatment on macular neovascularization (MNV) morphology is well described, but long-term studies on morphologic changes and correlation of such changes to the type of MNV have not been conducted. This study aims to determine if different types of MNVs in neovascular AMD (nAMD) behave differently with anti-VEGF treatment as visualized on optical coherence tomography angiography (OCTA). Methods Treatment-naïve nAMD patients were retrospectively screened for baseline and follow-up OCTA imaging 10 or more months after initial treatment. Images were graded for MNV type, area, activity, mature versus immature vessels, vessel density, presence of atrophy, atrophy location and area. Growth rate was calculated as the percent change in lesion area from baseline over the years of follow-up. In addition, the occurrence of complete regression and the percent of lesions that grew, remained stable, and shrunk per type was also evaluated. Results Forty-three eyes from 43 patients with a mean follow-up of 2 years were evaluated. On structural OCT, 26 lesions were classified as pure type 1 MNVs, 12 MNVs had a type 2 component, and 5 MNVs had a type 3 component. Of these cases, 2 mixed-type MNVs were considered to have completely regressed. There was no significant differences in MNV area and growth rate between type 1 and type 2 lesions, but all cases of type 3 lesions shrunk in the follow-up period. There was no correlation between the number of injections per year and growth rate, endpoint MNV area or endpoint activity status for any MNV type. There was no significant association between the development of atrophy and the number of injections, baseline MNV area, baseline vessel density, or lesion growth rate. Conclusions In nAMD, complete regression of an MNV network exposed to anti-VEGF is rare. This work emphasizes the role of anti-VEGF as anti-leakage rather than vascular regression agents in nAMD.
Published: 2020
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9. Vitreous hemorrhage in X-linked retinoschisis

Author: M. Margarita Parra and M. Elizabeth Hartnett
Subjects: X-linked retinoschisis, Ischemia, Neovascularization, Vitreous hemorrhage, Optical coherence tomography, Ophthalmology, RE1-994
Abstract: Purpose: To report a case of preretinal hemorrhage from extraretinal neovascularization related to capillary non-perfused retina within a large schisis in a pediatric patient with X-linked retinoschisis (XLRS). Observations: A 4-year old male with an RS1 mutation and XLRS presented with preretinal and vitreous hemorrhage in the right eye. Retinal imaging, including wide angle fluorescein angiography (FA) and optical coherence tomography (OCT), showed vitreoretinal traction on extraretinal neovascularization and capillary non-perfused retina in the schisis cavity. Laser treatment to the non-perfused retina within the schisis was successful in reducing extraretinal neovascularization. Conclusions: Vitreous hemorrhage is a well-known occurrence in XLRS. Imaging using wide angle FA and OCT were helpful to determine the causes of hemorrhage in order to develop a management plan.
Published: 2022
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10. Vascular Endothelial Growth Factor Signaling in Models of Oxygen-Induced Retinopathy: Insights Into Mechanisms of Pathology in Retinopathy of Prematurity

Author: Aniket Ramshekar and M. Elizabeth Hartnett
Subjects: ROP, OIR, VEGF, VEGFRs, VEGF receptors, neuropilins, Pediatrics, RJ1-570
Abstract: Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide. Blindness can occur from retinal detachment caused by pathologic retinal angiogenesis into the vitreous, termed intravitreal neovascularization (IVNV). Although agents that interfere with the bioactivity of vascular endothelial growth factor (VEGF) are now used to treat IVNV, concerns exist regarding the identification of optimal doses of anti-VEGF for individual infants and the effect of broad VEGF inhibition on physiologic angiogenesis in external organs or in the retina of a preterm infant. Therefore, it is important to understand VEGF signaling in both physiologic and pathologic angiogenesis in the retina. In this manuscript, we review the role of receptors that interact with VEGF in oxygen-induced retinopathy (OIR) models that represent features of ROP pathology. Specifically, we discuss our work regarding the regulation of VEGFR2 signaling in retinal endothelial cells to not only reduce severe ROP but also facilitate physiologic retinal vascular and neuronal development.
Published: 2021
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11. Deepfakes in Ophthalmology

Author: Jimmy S. Chen, MD, Aaron S. Coyner, PhD, R.V. Paul Chan, MD, M. Elizabeth Hartnett, MD, Darius M. Moshfeghi, MD, Leah A. Owen, MD, PhD, Jayashree Kalpathy-Cramer, PhD, Michael F. Chiang, MD, MA, and J. Peter Campbell, MD, MPH
Subjects: Deep learning, Generative adversarial networks, Ophthalmology, Synthetic images, RE1-994
Abstract: Purpose: Generative adversarial networks (GANs) are deep learning (DL) models that can create and modify realistic-appearing synthetic images, or deepfakes, from real images. The purpose of our study was to evaluate the ability of experts to discern synthesized retinal fundus images from real fundus images and to review the current uses and limitations of GANs in ophthalmology. Design: Development and expert evaluation of a GAN and an informal review of the literature. Participants: A total of 4282 image pairs of fundus images and retinal vessel maps acquired from a multicenter ROP screening program. Methods: Pix2Pix HD, a high-resolution GAN, was first trained and validated on fundus and vessel map image pairs and subsequently used to generate 880 images from a held-out test set. Fifty synthetic images from this test set and 50 different real images were presented to 4 expert ROP ophthalmologists using a custom online system for evaluation of whether the images were real or synthetic. Literature was reviewed on PubMed and Google Scholars using combinations of the terms ophthalmology, GANs, generative adversarial networks, ophthalmology, images, deepfakes, and synthetic. Ancestor search was performed to broaden results. Main Outcome Measures: Expert ability to discern real versus synthetic images was evaluated using percent accuracy. Statistical significance was evaluated using a Fisher exact test, with P values ≤ 0.05 thresholded for significance. Results: The expert majority correctly identified 59% of images as being real or synthetic (P = 0.1). Experts 1 to 4 correctly identified 54%, 58%, 49%, and 61% of images (P = 0.505, 0.158, 1.000, and 0.043, respectively). These results suggest that the majority of experts could not discern between real and synthetic images. Additionally, we identified 20 implementations of GANs in the ophthalmology literature, with applications in a variety of imaging modalities and ophthalmic diseases. Conclusions: Generative adversarial networks can create synthetic fundus images that are indiscernible from real fundus images by expert ROP ophthalmologists. Synthetic images may improve dataset augmentation for DL, may be used in trainee education, and may have implications for patient privacy.
Published: 2021
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12. Role of Erythropoietin Receptor Signaling in Macrophages or Choroidal Endothelial Cells in Choroidal Neovascularization

Author: Aniket Ramshekar, Colin A. Bretz, Eric Kunz, Thaonhi Cung, Burt T. Richards, Gregory J. Stoddard, Gregory S. Hageman, Brahim Chaqour, and M. Elizabeth Hartnett
Subjects: EPOR, EPO, CNV, AMD, CECs, macrophages, Biology (General), QH301-705.5
Abstract: Erythropoietin (EPO) has been proposed to reduce the progression of atrophic age-related macular degeneration (AMD) due to its potential role in neuroprotection. However, overactive EPO receptor (EPOR) signaling increased laser-induced choroidal neovascularization (CNV) and choroidal macrophage number in non-lasered mice, which raised the question of whether EPOR signaling increased CNV through the recruitment of macrophages to the choroid that released pro-angiogenic factors or through direct angiogenic effects on endothelial cells. In this study, we addressed the hypothesis that EPOR signaling increased CNV by direct effects on macrophages or endothelial cells. We used tamoxifen-inducible macrophage-specific or endothelial cell-specific EPOR knockout mice in the laser-induced CNV model, and cultured choroidal endothelial cells isolated from adult human donors. We found that macrophage-specific knockout of EPOR influenced laser-induced CNV in females only, whereas endothelial-specific knockout of EPOR reduced laser-induced CNV in male mice only. In cultured human choroidal endothelial cells, knockdown of EPOR reduced EPO-induced signal transducer and activator of transcription 3 (STAT3) activation. Taken together, our findings suggest that EPOR signaling in macrophages or choroidal endothelial cells regulates the development of CNV in a sex-dependent manner. Further studies regarding the role of EPO-induced signaling are required to assess EPO safety and to select or develop appropriate therapeutic approaches.
Published: 2022
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13. The Effects of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Erythropoietin, and Their Interactions in Angiogenesis: Implications in Retinopathy of Prematurity

Author: Thaonhi Cung, Haibo Wang, and M. Elizabeth Hartnett
Subjects: ROP, angiogenesis, ROS, oxidative stress, NADPH oxidase, NOX, Cytology, QH573-671
Abstract: Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in premature infants. Oxidative stress is implicated in its pathophysiology. NADPH oxidase (NOX), a major enzyme responsible for reactive oxygen species (ROS) generation in endothelial cells, has been studied for its involvement in physiologic and pathologic angiogenesis. Erythropoietin (EPO) has gained interest recently due to its tissue protective and angiogenic effects, and it has been shown to act as an antioxidant. In this review, we summarize studies performed over the last five years regarding the role of various NOXs in physiologic and pathologic angiogenesis. We also discuss the effect of EPO in tissue and vasoprotection, and the intersection of EPO and NOX-mediated oxidative stress in angiogenesis and the pathophysiology of ROP.
Published: 2022
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14. Regulation of Rac1 Activation in Choroidal Endothelial Cells: Insights into Mechanisms in Age-Related Macular Degeneration

Author: Aniket Ramshekar, Haibo Wang, and M. Elizabeth Hartnett
Subjects: age-related macular degeneration, macular neovascularization, choroidal endothelial cells, rho gtpases, Cytology, QH573-671
Abstract: Age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide. Vision loss from the neovascular form is associated with the invasion of choroidal endothelial cells into the neural retina to form vision-threatening macular neovascularization (MNV). Anti-angiogenic agents are the current standard of care but are effective in only ~50% of AMD cases. The molecular mechanisms involved in invasive MNV point to the importance of regulating signaling pathways that lead to pathologic biologic outcomes. In studies testing the effects of AMD-related stresses, activation of the Rho GTPase, Rac1, was found to be important for the choroidal endothelial cell invasion into the neural retina. However, current approaches to prevent Rac1 activation are inefficient and less effective. We summarize active Rac1-mediated mechanisms that regulate choroidal endothelial cell migration. Specifically, we discuss our work regarding the role of a multidomain protein, IQ motif containing GTPase activating protein 1 (IQGAP1), in sustaining pathologic Rac1 activation and a mechanism by which active Rap1, a Ras-like GTPase, may prevent active Rac1-mediated choroidal endothelial cell migration.
Published: 2021
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15. Familial exudative vitreoretinopathy presentation as persistent fetal vasculature

Author: Jeffrey Z. Kartchner and M. Elizabeth Hartnett
Subjects: Familial exudative vitreoretinopathy, Exudative retinal detachment, Persistent fetal vasculature, Retinopathy, Leukocoria, Ophthalmology, RE1-994
Abstract: Purpose: To illustrate a presentation of familial exudative vitreoretinopathy (FEVR) that can be mistaken for persistent fetal vasculature (PFV) and the importance of wide angle fluorescein angiography in making this distinction. A patient was referred with a unilateral retrolental membrane and retinal detachment from PFV but was found to have FEVR. Observations: A 4 month-old full-term infant was referred with the diagnosis of PFV based on findings of a dense retrolental membrane and microphthalmia in the left eye. The patient had a near-complete retinal detachment with some exudation. Wide-field fluorescein angiography of the right eye revealed avascular retina and leakage at the vascular/avascular junction. Genetic testing confirmed a mutation in FZD4, supporting the clinical diagnosis of FEVR. Prompt laser therapy to the avascular area in the right eye was performed and lensectomy/vitrectomy with membrane dissection was performed in the left eye. Conclusions and importance: FEVR can present with great variability between eyes. In patients presenting with findings suggestive of PFV, careful bilateral examination with wide-field fluorescein angiography is helpful. Early diagnosis and treatment are important to preserve visual acuity, especially in the less affected eye.
Published: 2017
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16. A case of coats disease and concurrent anisometropic amblyopia

Author: Nathan G. Lambert, Robert O. Hoffman, and M. Elizabeth Hartnett
Subjects: Coats disease, Amblyopia, Anisometropia, Retina, Pediatrics, Ophthalmology, RE1-994
Abstract: Purpose: The aim of this report was to demonstrate a case of Coats disease in a patient with concurrent anisometropic amblyopia. Observations: A 10-year-old boy was diagnosed with Coats disease during routine ophthalmic examination. Visual acuity was 20/20 OD and 20/50 OS with cycloplegic refraction of +1.25 (OD) and +3.25 (OS). Examination under anesthesia showed macular exudates in the left eye that encroached near the fovea superotemporally. Despite the poor visual acuity and macular exudates, the foveal architecture of both eyes appeared normal on spectral domain optical coherence tomography. Because of the differing refractive error between the two eyes in the presence of foveal-sparing exudates, anisometropic amblyopia was suspected. After initial laser therapy, the patient was started on a daily patching regimen of the right eye. The patient's vision steadily improved to 20/25 OS with a final cycloplegic refraction of +1.00 (OD), +3.00 (OS) at 2 years. This report demonstrates the importance of assessing for other common and treatable causes of vision loss in the setting of Coats disease. Conclusions and importance: This case demonstrates the importance of detecting and correcting for concurrent amblyopia in pediatric retina conditions that may, on fundus examination alone, appear to have a retinal cause for reduced visual acuity.
Published: 2016
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17. Roles of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase in Angiogenesis: Isoform-Specific Effects

Author: Haibo Wang and M. Elizabeth Hartnett
Subjects: nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), NOX2, NOX4, NOX1, NOX5, vascular endothelial cell, angiogenesis, neovascularization, vascular inflammation, oxygen-induced retinopathy, eye, retina, Therapeutics. Pharmacology, RM1-950
Abstract: Angiogenesis is the formation of new blood vessels from preexisting ones and is implicated in physiologic vascular development, pathologic blood vessel growth, and vascular restoration. This is in contrast to vasculogenesis, which is de novo growth of vessels from vascular precursors, or from vascular repair that occurs when circulating endothelial progenitor cells home into an area and develop into blood vessels. The objective of this review is to discuss the isoform-specific role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in physiologic and pathologic angiogenesis and vascular repair, but will not specifically address vasculogenesis. As the major source of reactive oxygen species (ROS) in vascular endothelial cells (ECs), NOX has gained increasing attention in angiogenesis. Activation of NOX leads to events necessary for physiologic and pathologic angiogenesis, including EC migration, proliferation and tube formation. However, activation of different NOX isoforms has different effects in angiogenesis. Activation of NOX2 promotes pathologic angiogenesis and vascular inflammation, but may be beneficial in revascularization in the hindlimb ischemic model. In contrast, activation of NOX4 appears to promote physiologic angiogenesis mainly by protecting the vasculature during ischemia, hypoxia and inflammation and by restoring vascularization, except in models of oxygen-induced retinopathy and diabetes where NOX4 activation leads to pathologic angiogenesis.
Published: 2017
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18. The Incidence of Central Serous Chorioretinopathy after Photorefractive Keratectomy and Laser In Situ Keratomileusis

Author: Majid Moshirfar, Maylon Hsu, Julia Schulman, Joseph Armenia, Shameema Sikder, and M. Elizabeth Hartnett
Subjects: Ophthalmology, RE1-994
Abstract: Purpose. To assess the incidence of central serous chorioretinopathy (CSCR) following laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK). Methods. A chart review was performed to identify all patients with CSCR and a previous history of LASIK or PRK. Results. Over the 6-year study period, 1 of 4,876 eyes which had LASIK or PRK at the Moran Eye Center was diagnosed with CSCR. One other patient was referred from an outside center, developed CSCR symptoms one month after PRK. Both patients were managed conservatively with a final visual acuity of 20/20 or better. All other patients presented 4 or more years after refractive surgery. Conclusions. We report the first 2 CSCR cases developing within one month after PRK. The low incidence argues against a causal association. Topical corticosteroids or anxiety may elevate cortisol levels presenting therapeutic challenges for the management of CSCR after PRK or LASIK.
Published: 2012
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19. Comparison in Retreatments between Bevacizumab and Ranibizumab Intravitreal Injections for Retinopathy of Prematurity

Author: Nimesh A. Patel, Luis A. Acaba-Berrocal, Sandra Hoyek, Kenneth C. Fan, Maria Ana Martinez-Castellanos, Caroline R. Baumal, C. Armitage Harper, Audina M. Berrocal, Wu Wei-Chi, Rand Spencer, Shunji Kusaka, Polly Quiram, Jose Asilis, Michael P. Blair, Swati Agarwal, Anna Ells, Cagri G. Besirli, Irena Tsui, Thomas C. Lee, Aaron Nagiel, Andres Kychenthal, Jessica Kovarik, Anton Orlin, Janet Alexander, Vaidehi S. Dedania, Sengul Ozdek, Michel J. Shami, Cornelius Regan, Shilpa Desai, Moran Roni Levin, Deborah Y. Chong, Mrinali Gupta, Adam Pflugrath, Ashkan Abbey, Christopher G. Fuller, Lori E. Coors, Nicolas Yannuzzi, Catherine Negron, Hasenin Al-khersan, Paul Runge, Huseyin Baran Ozdemir, Tugce Kucukbalci, Chiharu Iwahashi, Mark Solinski, David Sutter, Jonathan Sears, Christine Sonnie, David Portney, Jake Duker, Tamara Lenis, Andreas Di-Luciano, Pablo Chamartin, Nikisha Kothari, Grecia Yael Ortiz-Ramirez, Gabriela Patricia Amadeo Oreggioni, Ameay V. Naravane, Peter J. Belin, Nahomy Ledesma Vicioso, Demetrios Vavvas, M. Elizabeth Hartnett, Robinson V.P. Chan, Eric Nudleman, Darius M. Moshfeghi, Atchara Amphornphruet, Michael Chiang, Michael J. Shapiro, J. Peter Campbell, Lejla Vajzovic, Mario Capecchi, G. Baker Hubbard, Jason Horowtiz, Rabia Karani, Rosina Negrin Martin, and Emmanuel Chang
Subjects: Ophthalmology
Published: 2023
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20. How can the safety of antibody therapy for retinopathy of prematurity be improved?

Author: M. Elizabeth Hartnett
Subjects: Ophthalmology, Biomedical Engineering, Optometry
Published: 2023
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21. The Prevalence of Retinal Disease and Associated CNS Disease in Young Patients with Incontinentia Pigmenti

Author: Ian D. Danford, Brittni A. Scruggs, Antonio Capone, Michael T. Trese, Kim A. Drenser, Aristomenis Thanos, Eric Nudleman, Atchara Amphornphruet, Boontip Tipsuriyaporn, G. Baker Hubbard, Anna Ells, C. Armitage Harper, Jessica Goldstein, Charles Calvo, Chris Wallace-Carrete, Duncan Berry, Emmanuel Chang, Lisa Leishman, Michael Shapiro, Michael Blair, Mikel Mikhail, Carol L. Shields, Rachel Schwendeman, Yoshihiro Yonekawa, Mrinali P. Gupta, Anton Orlin, Supalert Prakhunhungsit, Shizuo Mukai, Audina Berrocal, M. Elizabeth Hartnett, and J. Peter Campbell
Subjects: Ophthalmology, Retinal Diseases, Central Nervous System Diseases, Prevalence, Humans, Infant, Vascular Diseases, Incontinentia Pigmenti, Child, Article, Retina, Retrospective Studies
Abstract: PURPOSE: To evaluate the prevalence of retinal disease on fluorescein angiography (FA) in patients with incontinentia pigmenti (IP) and to compare the severity of retinal disease in those with and without known central nervous system (CNS) disease. DESIGN: Multi-institutional consecutive retrospective case series. SUBJECTS: New patients with a diagnosis of IP were seen at the Casey Eye Institute at the Oregon Health and Science University (OHSU), Moran Eye Center, University of Utah, or Bascom Palmer Eye Institute, University of Miami from December 2011 to September 2018. METHODS: Detailed ophthalmoscopic examination and FA were recommended for all new patients and performed on every patient who had parental consent. Ophthalmoscopic findings and FA images were graded for severity by 2 masked graders on a 3-point scale: 0 = no disease, 1 = vascular abnormalities without leakage, 2 = leakage or neovascularization, and 3 = retinal detachment. The presence of known CNS disease was documented. Additional cases were obtained from a pediatric retina listserv for examples of phenotypic variation. MAIN OUTCOME MEASURES: The proportion of eyes noted to have disease on ophthalmoscopy compared with FA and the severity of retinal disease in those with and without known CNS disease. RESULTS: Retinal pathology was detected in 18 of 35 patients (51%) by indirect ophthalmoscopy and 26 of 35 patients (74%) by FA (P = 0.048) in a predominantly pediatric population (median age, 9 months). Ten patients (29%) had known CNS disease at the time of the eye examination. A Wilcoxon rank-sum test indicated that the retinal severity scores for patients with CNS disease (median, 2) were significantly higher than the retinal severity scores for patients without CNS disease (median, 1), z = −2.12, P = 0.034. CONCLUSIONS: Retinal disease is present in the majority of patients with IP, and ophthalmoscopic examination is less sensitive than FA for detection of disease. There may be a correlation between the severity of retinal and CNS disease.
Published: 2022
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22. Practice Patterns and Outcomes of Intravitreal Anti-VEGF Injection for Retinopathy of Prematurity

Author: Nimesh A. Patel, Luis A. Acaba-Berrocal, Sandra Hoyek, Kenneth C. Fan, Maria Ana Martinez-Castellanos, Caroline R. Baumal, C. Armitage Harper, Audina M. Berrocal, Wu Wei-Chi, Rand Spencer, Shunji Kusaka, Polly Quiram, Jose Asilis, Michael P. Blair, Swati Agarwal, Anna Ells, Cagri G. Besirli, Irena Tsui, Thomas C. Lee, Aaron Nagiel, Andrés Kychenthal, Jessica Kovarik, Anton Orlin, Janet Alexander, Vaidehi S. Dedania, Sengul Ozdek, Michel J. Shami, Cornelius Regan, Shilpa Desai, Moran Roni Levin, Deborah Y. Chong, Mrinali Gupta, Adam Pflugrath, Ashkan Abbey, Christopher G. Fuller, Lori E. Coors, Nicolas Yannuzzi, Catherine Negron, Hasenin Al-khersan, Paul Runge, Huseyin Baran Ozdemir, Tugce Kucukbalci, Chiharu Iwahashi, Mark Solinski, David Sutter, Jonathan Sears, Christine Sonnie, David Portney, Jake Duker, Tamara Lenis, Andreas Di-Luciano, Pablo Chamartin, Nikisha Kothari, Grecia Yael Ortiz-Ramirez, Gabriela Patricia Amadeo Oreggioni, Ameay V. Naravane, Peter J. Belin, Nahomy Ledesma Vicioso, Demetrios Vavvas, M. Elizabeth Hartnett, Robinson V.P. Chan, Eric Nudleman, Darius M. Moshfeghi, Atchara Amphornphruet, Michael Chiang, and Michael J. Shapiro
Subjects: Ophthalmology
Published: 2022
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23. The Frequency of Visual Field Testing in a US Nationwide Cohort of Individuals with Open-Angle Glaucoma

Author: Brian C. Stagg, Joshua D. Stein, Felipe A. Medeiros, Joshua Horns, M. Elizabeth Hartnett, Kensaku Kawamoto, and Rachel Hess
Subjects: Cohort Studies, Humans, Visual Field Tests, General Medicine, Visual Fields, United States, Glaucoma, Open-Angle, Retrospective Studies
Abstract: Visual field testing that is not frequent enough results in delayed identification of open-angle glaucoma (OAG) progression. Guidelines recommend at least annual testing. It is not known how frequently patients with OAG across the United States receive visual field testing and how patient characteristics and circumstances influence this frequency. If US patients with OAG do not receive visual field tests frequently enough, interventions to increase this frequency or to develop other forms of testing visual function may reduce unidentified OAG vision loss.Retrospective cohort study.The TruvenHealth MarketScan Commercial Claims Database (IBM) contains demographic and claims data for160 million individuals across the United States from 2008 to 2017. We identified enrollees in the database with a recorded diagnosis of OAG (International Classification of Diseases, Ninth Revision, Clinical Modification and International Classification of Diseases, Tenth Revision, Clinical Modification codes 356.1x and H40.1x, respectively). We excluded those aged40 years at the time of their first OAG diagnosis, those without at least 1 confirmatory OAG diagnosis at a subsequent visit, and those with4 years of follow-up data after OAG diagnosis.We calculated the number of visual field tests that each enrollee with OAG underwent per year and categorized the enrollees based on that number (0,0 to0.9, ≥ 0.9 to ≤ 1.1,1.1 to ≤ 2.1, and2.1). We used negative binomial regression to investigate the demographic or health variables that were associated with the frequency of visual field tests that enrollees with OAG received.Frequency of visual field testing among enrollees with OAG.Of the 380 029 enrollees included in the study, 33 267 (8.8%) did not receive a visual field test during the study period, 259 349 (68.2%) underwent0 to0.9 visual field tests per year, 42 129 (11.1%) underwent ≥ 0.9 to ≤ 1.1 visual field tests per year, 42 301 (11.1%) underwent1.1 to ≤ 2.1 visual field tests per year, and 2983 (0.8%) underwent ≥ 2.1 visual field tests per year. The median number of visual field tests per year was 0.63 (interquartile range, 0.33-0.88; mean, 0.65).More than 75% of enrollees with OAG received1 visual field test per year and, thus, did not receive guideline-adherent glaucoma monitoring.
Published: 2022
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24. Vitrectomy-Assisted Excision in the Treatment of Juxtapapillary Retinal Capillary Hemangioma

Author: M Margarita, Parra, Juan D, Arias, Eduardo J, Viteri, Isabel, Bolivar, Laura Y, Vega, and M Elizabeth, Hartnett
Subjects: von Hippel-Lindau Disease, Adolescent, Retinal Neoplasms, Vitrectomy, Humans, Epiretinal Membrane, Female, Hemangioma, Capillary, Retinal Perforations, Hemangioblastoma
Abstract: Juxtapapillary retinal capillary hemangiomas are sight-threatening hamartomas located on or adjacent to the optic nerve. Nonsurgical approaches including laser photocoagulation and cryotherapy have been shown to be effective to reduce exudation in peripheral hemangiomas. However, in juxtapapillary hemangiomas, the functional outcomes are limited due to associated potential damage of the retinal nerve fiber layer. We present an 18-year-old female patient with von Hippel–Lindau (VHL) disease who presented with a juxtapapillary retinal capillary hemangioma associated with a tractional epiretinal membrane (ERM) and secondary macular hole. After vitrectomy-assisted excision of the lesion and inner limiting membrane (ILM) peeling around the macular hole, visual acuity and macular anatomy were recovered at 10 months of follow-up. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:570–573.]
Published: 2022
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25. Pathophysiology of Retinopathy of Prematurity

Author: M. Elizabeth Hartnett
Subjects: Ophthalmology, Neurology (clinical)
Abstract: Retinopathy of prematurity (ROP) is a complex disease involving development of the neural retina, ocular circulations, and other organ systems of the premature infant. The external stresses of the ex utero environment also influence the pathophysiology of ROP through interactions among retinal neural, vascular, and glial cells. There is variability among individual infants and presentations of the disease throughout the world, making ROP challenging to study. The methods used include representative animal models, cell culture, and clinical studies. This article describes the impact of maternal–fetal interactions; stresses that the preterm infant experiences; and biologic pathways of interest, including growth factor effects and cell–cell interactions, on the complex pathophysiology of ROP phenotypes in developed and emerging countries. Expected final online publication date for the Annual Review of Vision Science, Volume 9 is September 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Published: 2023
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26. Retinopathy of prematurity protection conferred by uteroplacental insufficiency through erythropoietin signaling in an experimental Murine Model

Author: Camille Fung, Thaonhi Cung, Caroline Nelson, Haibo Wang, Colin Bretz, Aniket Ramshekar, Ashley Brown, Gregory J. Stoddard, and M. Elizabeth Hartnett
Subjects: Pediatrics, Perinatology and Child Health
Abstract: Background Recent clinical studies suggest that preeclampsia, characterized by uteroplacental insufficiency (UPI) and infant intrauterine growth restriction (IUGR), may be protective against retinopathy of prematurity (ROP) in preterm infants. Experimental models of UPI/IUGR have found an association of erythropoietin (EPO) with less severe oxygen-induced retinopathy (OIR); however, it is unclear if EPO/EPO receptor (EPOR) signaling was involved. We hypothesized that maternal UPI and resultant infant IUGR would protect against features of ROP through EPO/EPOR signaling. Methods We compared transgenic mice with hypoactive EPOR signaling (hWtEPOR) to littermate wild-type mice (mWtEpoR) in a novel combined model of IUGR and ROP. Thromboxane A2 (TXA2) was infused into pregnant C57Bl/6J dams to produce UPI/IUGR; postnatal pups and their foster dams were subjected to a murine OIR model. Results Following hyperoxia, hematocrits were similar between littermate wild-type (mWtEpoR) TXA2/OIR and vehicle/OIR pups. mWtEpoR TXA2/OIR had increased serum EPO, retinal EPO and VEGF, and decreased avascular retinal area (AVA) compared to vehicle/OIR pups. In comparison to the mWtEpoR TXA2/OIR pups, AVA was not reduced in hWtEPOR TXA2/OIR pups. Conclusion Our findings provide biologic evidence that UPI/OIR-induced endogenous EPOR signaling confers protection against hyperoxia-induced vascular damage that may be related to pathophysiology in ROP. Impact Maternal preeclampsia and infant growth restriction confer retinovascular protection against high oxygen-induced damage through endogenous erythropoietin signaling.
Published: 2023
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27. Optical coherence tomography as retinal imaging biomarker of neuroinflammation/neurodegeneration in systemic disorders in adults and children

Author: Stela Vujosevic, M. Margarita Parra, M. Elizabeth Hartnett, Louise O’Toole, Alessia Nuzzi, Celeste Limoli, Edoardo Villani, and Paolo Nucci
Subjects: Ophthalmology, Correction
Abstract: The retina and the optic nerve are considered extensions of the central nervous system (CNS) and thus can serve as the window for evaluation of CNS disorders. Spectral domain optical coherence tomography (OCT) allows for detailed evaluation of the retina and the optic nerve. OCT can non-invasively document changes in single retina layer thickness and structure due to neuronal and retinal glial cells (RGC) modifications in systemic and local inflammatory and neurodegenerative diseases. These can include evaluation of retinal nerve fibre layer and ganglion cell complex, hyper-reflective retinal spots (HRS, sign of activated microglial cells in the retina), subfoveal neuroretinal detachment, disorganization of the inner retinal layers (DRIL), thickness and integrity of the outer retinal layers and choroidal thickness. This review paper will report the most recent data on the use of OCT as a non invasive imaging biomarker for evaluation of the most common systemic neuroinflammatory and neurodegenerative/neurocognitive disorders in the adults and in paediatric population. In the adult population the main focus will be on diabetes mellitus, multiple sclerosis, optic neuromyelitis, neuromyelitis optica spectrum disorders, longitudinal extensive transverse myelitis, Alzheimer and Parkinson diseases, Amyotrophic lateral sclerosis, Huntington's disease and schizophrenia. In the paediatric population, demyelinating diseases, lysosomal storage diseases, Nieman Pick type C disease, hypoxic ischaemic encephalopathy, human immunodeficiency virus, leukodystrophies spinocerebellar ataxia will be addressed.摘要: 视网膜和视神经是中枢神经系统 (CNS) 的延续, 因此可以作为评估CNS疾病的窗口。频域光学相干断层扫描 (SD-OCT) 可以对视网膜和视神经进行详细的评估。OCT可以无创性地记录系统性和局部炎症/神经退行性病变中, 由于神经元和视网膜胶质细胞 (RGC) 改变引起的视网膜单层厚度和结构的变化。OCT的观察的指征包括评估视网膜神经纤维层和神经节细胞复合体、视网膜高反射点 (HRS, 视网膜中小胶质细胞激活的征象) 、中心凹下神经视网膜脱离、视网膜内层结构紊乱 (DRIL) 、视网膜外层的厚度和完整性以及脉络膜厚度。本文将总结OCT作为无创成像生物标志物评估成人和儿童中最常见的系统性神经炎症和神经退行性病变/神经认知障碍的最新数据。在成人中, 我们最关注的疾病为糖尿病、多发性硬化症、视神经脊髓炎、视神经脊髓炎谱系障碍、纵向广泛横贯性脊髓炎、阿尔茨海默病和帕金森病、肌萎缩侧索硬化症、亨廷顿病和精神分裂症。在儿童中, 我们着重讨论的疾病有脱髓鞘疾病、溶酶体贮积病、尼曼-匹克病、缺氧缺血性脑病、人类免疫缺陷病毒、脑白质营养不良脊髓小脑性共济失调。.
Published: 2022
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28. Planned Preterm Delivery and Treatment of Severe Infantile FEVR With Osteoporosis-Pseudoglioma Syndrome

Author: Jared J, Ebert, Virginia M, Utz, M Elizabeth, Hartnett, Gregory, Tiao, and Robert A, Sisk
Subjects: Retinal Diseases, Pregnancy, Familial Exudative Vitreoretinopathies, Mutation, Infant, Newborn, Retinal Detachment, Humans, Premature Birth, Eye Diseases, Hereditary, Female, Osteogenesis Imperfecta
Abstract: Familial exudative vitreoretinopathy (FEVR) is a rare hereditary vitreoretinopathy resulting from mutations in the wnt signaling pathway leading to abnormalities in fetal retinal vasculogenesis, angiogenesis, and retinal vascular maintenance. Severe FEVR may result in congenital retinal detachment resembling Norrie disease. The authors report the first case of planned preterm delivery and treatment of a patient with severe FEVR from biallelic LRP5 mutations whose siblings had congenital tractional retinal detachments with light perception vision outcomes after conventional care. Early intervention allowed laser ablation of avascular retina and functional visual outcome despite a successfully repaired unilateral tractional retinal detachment. [ Ophthalmic Surg Lasers Imaging Retina . 2022;53(4):228–232.]
Published: 2022
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29. COMBINED HAMARTOMA OF THE RETINA AND RETINAL PIGMENT EPITHELIUM AT PEDIATRIC AGE: Surgical Versus Conservative Approach

Author: Sengul Ozdek, Ahmet Yucel Ucgul, M. Elizabeth Hartnett, Muberra Akdogan, Parveen Sen, Muna Bhende, Cagri Giray Besirli, Murat Karacorlu, Vaidehi Dedania, Barbara Parolini, Sangeet Mittal, Alay Banker, Ehab El Rayes, Mohamed Tawfik, Wei-Chi Wu, Yamini Attiku, Eric Hansen, David Portney, Chintan Sarvaiya, Ozlem Sahin, Huseyin Baran Ozdemir, Gokhan Gurelik, and Ozdek S., Ucgul A. Y., Hartnett M. E., Akdogan M., Sen P., Bhende M., Besirli C. G., Karacorlu M., Dedania V., Parolini B., et al.
Subjects: surgery, amblyopia treatment, pars plana vitrectomy, retina, Ophthalmology, retinal pigment epithelium, combined hamartoma of the retina and the retina pigment epithelium, General Medicine, pediatric age
Abstract: © 2023 Retina. All right reserved.Purpose:To report outcomes of pediatric patients with combined hamartoma of the retina and the retina pigment epithelium followed up conservatively or after pars plana vitrectomy.Methods:This retrospective multicenter study included 62 eyes of 59 pediatric patients with combined hamartoma of the retina and the retina pigment epithelium from 13 different international centers with an average age of 7.7 ± 4.7 (0.3-17) years at the time of the diagnosis and having undergone pars plana vitrectomy or followed conservatively. At baseline and each visit, visual acuity values, optical coherence tomography for features and central foveal thickness, and tumor location were noted. Lesions were called as Zone 1, if it involves the macular and peripapillary areas, and the others were called as Zone 2 lesions.Results:Twenty-one eyes of 20 patients in the intervention group and 41 eyes of 39 patients in the conservative group were followed for a mean of 36.2 ± 40.4 (6-182) months. Best-corrected visual acuity improved in 11 (68.8%) of 16 eyes in the intervention group and 4 (12.9%) of 31 eyes in the conservative group (P < 0.001). The mean central foveal thickness decreased from 602.0 ± 164.9 µm to 451.2 ± 184.3 µm in the intervention group, while it increased from 709.5 ± 344.2 µm to 791.0 ± 452.1 µm in Zone 1 eyes of the conservative group. Posterior location of tumor, irregular configuration of the foveal contour and ellipsoid Zone defect in optical coherence tomography, subretinal exudate and prominent vascular tortuosity were associated with poor visual acuity.Conclusion:Vitreoretinal surgery is safe and effective in improving vision and reducing retinal distortion in Zone 1 combined hamartoma of the retina and the retina pigment epithelium in children.
Published: 2023

30. Prenatal Carotenoid Supplementation with Lutein or Zeaxanthin Ameliorates Oxygen-Induced Retinopathy (OIR) inBco2-/-Macular Pigment Mice

Author: Ranganathan Arunkumar, Binxing Li, Emmanuel K. Addo, M. Elizabeth Hartnett, and Paul S. Bernstein
Abstract: PurposePremature infants at risk of retinopathy of prematurity (ROP) miss placental transfer of carotenoids, lutein (L) and zeaxanthin (Z), during the third trimester. We previously demonstrated that prenatal L and Z supplementation raises carotenoid levels in infants at birth in theLutein andZeaxanthin inPregnancy (L-ZIP) study (NCT03750968). Based on their antioxidant effects and bioavailability, we hypothesized that prenatal maternal supplementation with macular carotenoids would reduce risk of ROP. To test this hypothesis, we utilized “macular pigment mice” genetically engineered to take up L and Z into the retina in a model of oxygen-induced retinopathy (OIR).MethodsPregnantBco2-/-mice were divided into nine experimental subgroups based on the type of supplementation (L, Z, or placebo) and on maternal supplementation start date corresponding to the three trimesters of human fetal development (E0, E11, and P1). Pups and nursing mothers were exposed to 75% O2for 5 days (P7-12) and returned to room air for 5 days (P12-17). Pups were sacrificed at P12 and P17, and their retinas were analyzed for vaso-obliteration (VO) and intravitreal neovascularization (INV).ResultsPups of pregnant mice supplemented with L or Z had significant reductions in VO and INV areas compared to placebo. Prenatal carotenoid supplementation starting at E0 or E11 was significantly more protective against OIR than postnatal supplementation starting at P1.ConclusionPrenatal supplementation with L and Z was beneficial in a mouse OIR model. We recommend testing prenatal L and Z supplementation in future human clinical trials to prevent ROP.
Published: 2022
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31. Multimodal Retinal Imaging Findings in Two Cousins With VCAN-Related Vitreoretinopathy or Wagner Disease

Author: M. Margarita Parra, Emily Spoth, Cecinio C. Ronquillo, Robert Henderson, and M. Elizabeth Hartnett
Subjects: Versicans, Retinal Diseases, Retinal Degeneration, Mutation, Retinal Detachment, Humans, Retina, Pedigree
Abstract: Wagner disease is a rare, nonsyndromic vitreoretinopathy caused by autosomal dominant variants in the versican (VCAN) gene. It is associated with abnormalities of the vitreoretinal interface that can lead to peripheral traction and retinal detachments, which also occur in other vitreoretinopathies such as X-linked retinoschisis (XLRS), familial exudative vitreoretinopathy (FEVR) and Stickler syndrome. There is variability in the clinical phenotype in Wagner disease potentially due to variants in VCAN gene variants. In this article, we report a family harboring the VCAN c.9265+1G>C variant and describe the clinical and retinal findings in two members. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:639–643.]
Published: 2022

32. Retinopathy of prematurity

Author: Olaf Dammann, M. Elizabeth Hartnett, and Andreas Stahl
Subjects: Developmental Neuroscience, Pediatrics, Perinatology and Child Health, Neurology (clinical)
Abstract: Retinopathy of prematurity (ROP) is a devastating neurovascular disease of the retina in newborn infants that can lead to vision deficits or even blindness. In this concise review we discuss our current knowledge about diagnosis, etiology, pathogenesis, intervention, and outcomes of the disease. Major advancements have been made both in categorizing the disease in the new International Classification of Retinopathy of Prematurity, Third Edition classification and in treating severe ROP with anti-vascular endothelial growth factor (VEGF) agents. New development always creates new questions and opens up new areas of research. We will discuss in this review both the benefits and downsides of the new anti-VEGF treatment approaches in ROP, especially in light of our improved understanding of the underlying ROP pathophysiology. We also offer pointers to areas where more research is needed.
Published: 2022

33. RNA-Seq Provides Insights into VEGF-Induced Signaling in Human Retinal Microvascular Endothelial Cells: Implications in Retinopathy of Prematurity

Author: Aniket Ramshekar, Colin A. Bretz, and M. Elizabeth Hartnett
Subjects: Vascular Endothelial Growth Factor A, Neovascularization, Pathologic, Organic Chemistry, Infant, Newborn, Endothelial Cells, Retinal Vessels, ROP, VEGF, VEGFR2, KDR, STAT3, RNA-seq, HRMECs, General Medicine, Retinal Neovascularization, Catalysis, Computer Science Applications, Rats, Inorganic Chemistry, Rats, Sprague-Dawley, Disease Models, Animal, Animals, Humans, Retinopathy of Prematurity, RNA-Seq, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Signal Transduction
Abstract: The pathophysiology of retinopathy of prematurity (ROP) is postulated to first involve delayed intraretinal vascularization, followed by intravitreal neovascularization (IVNV). Although intravitreal agents that reduce the bioactivity of vascular endothelial growth factor (VEGF) are used to treat IVNV, concerns exist regarding their effects on intraretinal vascularization. In an experimental ROP model, VEGF receptor 2 (VEGFR2) knockdown in retinal endothelial cells reduced IVNV and promoted intraretinal vascularization, whereas knockdown of a downstream effector, signal transducer and activator of transcription 3 (STAT3) in retinal endothelial cells only reduced IVNV. In this study, we tested the hypothesis that the different pathways involved in VEGF-triggered VEGFR2 signaling and VEGF-triggered STAT3 signaling in retinal endothelial cells would allow us to delineate signaling pathways involved in IVNV from those involved in intraretinal vascularization in ROP. To address our hypothesis, we used RNA-sequencing and pathway enrichment analysis to determine changes in the transcriptome of cultured human retinal microvascular endothelial cells (HRMECs). Of the enriched pathways, inactivation of oncostatin M signaling was predicted by either KDR or STAT3 knockdown in the presence of VEGF. Activation of kinetochore metaphase signaling was predicted by KDR knockdown, whereas inactivation was predicted by STAT3 knockdown in the presence of VEGF. Inactivation of signaling by the Rho family of GTPases was predicted by KDR knockdown, but activation was predicted by STAT3 knockdown in the presence of VEGF. Taken together, our data identified unique signaling pathway differences between VEGF-triggered VEGFR2 and VEGF-triggered STAT3 in HRMECs that might have implications in ROP.
Published: 2022
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34. Genetic predictors of severe intraventricular hemorrhage in extremely low-birthweight infants

Author: Brenda B. Poindexter, Stephen W. Erickson, M Elizabeth Hartnett, Courtney D. Thornburg, Abhik Das, Erin A.S. Clark, Ricki F. Goldstein, John M. Dagle, Grier P. Page, C. Michael Cotten, Margaret M. DeAngelis, and Jeffrey C. Murray
Subjects: Pediatrics, medicine.medical_specialty, Single-nucleotide polymorphism, Infant, Premature, Diseases, Organ development, Logistic regression, Article, Child health, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, medicine, Birth Weight, Humans, 030212 general & internal medicine, Child, Genotyping, Cerebral Hemorrhage, business.industry, Infant, Newborn, Genetic variants, Infant, Obstetrics and Gynecology, medicine.disease, Neurovascular bundle, Intraventricular hemorrhage, nervous system, Infant, Extremely Low Birth Weight, Pediatrics, Perinatology and Child Health, business, Infant, Premature
Abstract: OBJECTIVE: To test associations between grades 3 or 4 (severe) intraventricular hemorrhage (IVH) and single nucleotide polymorphisms (SNPs) associated with coagulation, inflammation, angiogenesis, and organ development in an exploratory study. STUDY DESIGN: Extremely low-birthweight (ELBW) infants enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network’s (NRN) Cytokines Study were included if they had cranial ultrasound (CUS) and genotyping data available in the NRN Anonymized DNA Repository and Database. Associations between SNPs and IVH severity were tested with multivariable logistic regression analysis. RESULT: One hundred thirty-nine infants with severe IVH and 687 infants with grade 1 or 0 IVH were included. One thousand two hundred seventy-nine SNPs were genotyped. Thirteen were preliminarily associated with severe IVH including five related to central nervous system (CNS) neuronal and neurovascular development. CONCLUSION: Genetic variants for CNS neuronal and neurovascular development may be associated with severe IVH in premature infants.
Published: 2020
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35. Erythropoietin Receptor Signaling Supports Retinal Function after Vascular Injury

Author: Eric Kunz, Aniket Ramshekar, Aaron B. Simmons, Colin A. Bretz, Carson Kennedy, M. Elizabeth Hartnett, and Ivan Cardenas
Subjects: Male, 0301 basic medicine, Genetically modified mouse, medicine.medical_specialty, Mice, Transgenic, Biology, Retina, Article, Pathology and Forensic Medicine, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Retinal Diseases, Internal medicine, Electroretinography, Receptors, Erythropoietin, medicine, Animals, Outer nuclear layer, Erythropoietin, Diabetic Retinopathy, medicine.diagnostic_test, Retinal, Vascular System Injuries, medicine.disease, Erythropoietin receptor, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, chemistry, 030221 ophthalmology & optometry, Female, sense organs, Signal Transduction, medicine.drug, Retinopathy
Abstract: The investigation of erythropoietin (EPO) has expanded to include potential nonhematopoietic roles in neural and retinal diseases, including diabetic retinopathy. However, it remains unclear how EPO functions to support the neural retina. Transgenic mice with hypoactive EPO receptor (EPOR) signaling (hWtEPOR) were compared with littermate control mice (WT) to test the role of EPOR signaling under normal conditions and after vascular injury and regrowth into the retina. Although retinal function tested with OptoMotry and electroretinography was comparable to adult (8-week–old) littermate WT mice, hWtEPOR mice had thinner inner and outer plexiform layers and a greater number of amacrine cells. Injury and repair caused by the oxygen-induced retinopathy model reduced visual acuity thresholds, reduced electroretinography amplitudes, and thinned the outer plexiform and inner nuclear layers of both WT and hWtEPOR 8-week–old mice. In hWtEPOR compared with WT mice, scotopic a-wave amplitudes were reduced by injury, despite no change in outer nuclear layer thickness; and peripheral rod, but not cone number, was reduced. Scotopic b-waves were reduced in injured hWtEPOR mice compared with WT, and rod bipolar cell ectopic neurites were increased in both genotypes after injury, suggesting a potential reparative process to preserve connectivity and the b-wave. Normal EPOR signaling appeared important because ectopic neurites and b-waves were lower in the hWtEPOR than WT injured mice.
Published: 2020
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36. Retinopathy of prematurity classification updates: possible implications for treatment

Author: Alistair R. Fielder, Graham E. Quinn, R.V. Paul Chan, Gerd E. Holmström, Michael F. Chiang, Audina Berrocal, Gil Binenbaum, Michael Blair, J. Peter Campbell, Antonio Capone, Yi Chen, Shuan Dai, Anna Ells, Brian Fleck, William V. Good, M. Elizabeth Hartnett, Shunji Kusaka, Andrés Kychenthal, Domenico Lepore, Birgit Lorenz, Maria Ana Martinez-Castellanos, Susan R. Ostmo, Şengül Özdek, Dupe Ademola-Popoola, James D. Reynolds, Parag K. Shah, Michael Shapiro, Andreas Stahl, Cynthia Toth, Anand Vinekar, Linda Visser, David K. Wallace, Wei-Chi Wu, Peiquan Zhao, and Andrea Zin
Subjects: Ophthalmology, Pediatrics, Perinatology and Child Health, Infant, Newborn, Humans, Gestational Age, Retinopathy of Prematurity, Infant, Premature
Published: 2022

37. Plasma Levels of Bevacizumab and Vascular Endothelial Growth Factor After Low-Dose Bevacizumab Treatment for Retinopathy of Prematurity in Infants

Author: M Elizabeth, Hartnett, David K, Wallace, Trevano W, Dean, Zhuokai, Li, Charline S, Boente, Eniolami O, Dosunmu, Sharon F, Freedman, Richard P, Golden, Lingkun, Kong, S Grace, Prakalapakorn, Michael X, Repka, Lois E, Smith, Haibo, Wang, Raymond T, Kraker, Susan A, Cotter, and Jonathan M, Holmes
Subjects: Bevacizumab, Male, Vascular Endothelial Growth Factor A, Intravitreal Injections, Infant, Newborn, Humans, Infant, Angiogenesis Inhibitors, Female, Gestational Age, Retinopathy of Prematurity, Original Investigation
Abstract: IMPORTANCE: Intravitreal bevacizumab effectively treats severe retinopathy of prematurity (ROP), but it enters the bloodstream and may reduce serum vascular endothelial growth factor (VEGF), potentially causing detrimental effects on developing organs in the premature infant. OBJECTIVE: To evaluate the association of intravitreal bevacizumab with plasma bevacizumab and VEGF concentrations at 2 and 4 weeks after predefined, de-escalating doses of intravitreal bevacizumab were administered to infants with severe ROP. DESIGN, SETTING, AND PARTICIPANTS: This phase 1 dose de-escalation case series study was conducted at 10 US hospitals of ophthalmology institutions from May 21, 2015, to May 7, 2019. Blood samples were collected 2 and 4 weeks after intravitreal bevacizumab injection. Participants included 83 premature infants with type 1 ROP in 1 or both eyes and no previous ROP treatment. Data were analyzed from April 2017 to August 2021. INTERVENTIONS: Study eyes received a single bevacizumab injection of 0.250 mg, 0.125 mg, 0.063 mg, 0.031 mg, 0.016 mg, 0.008 mg, 0.004 mg, or 0.002 mg. When the fellow eye required treatment, one dose higher was administered. Total dose administered at baseline was defined as the sum of doses given to each eye within 3 days of initial study-eye injection. MAIN OUTCOMES AND MEASURES: Plasma bevacizumab concentration at 2 and 4 weeks after injection and the percentage change in plasma VEGF concentrations from pretreatment levels. RESULTS: A total of 83 infants (mean [SD] age, 25 [2] weeks; 48 boys [58%]) were included in this study. Higher doses of bevacizumab administered at baseline were associated with higher plasma bevacizumab concentrations at 2 weeks (ρ, 0.53; 95% CI, 0.31-0.70) and 4 weeks (ρ, 0.44; 95% CI, 0.18-0.64). Plasma VEGF concentrations decreased by 50% or more from pretreatment levels in 40 of 66 infants (61%) at 2 weeks and 31 of 61 infants (51%) at 4 weeks, but no association was observed between the total dose of bevacizumab administered at baseline and percentage change in plasma VEGF concentrations 2 weeks (ρ, −0.04; 95% CI, −0.28 to 0.20) or 4 weeks (ρ, −0.17; 95% CI, −0.41 to 0.08) after injection. CONCLUSIONS AND RELEVANCE: Results of this phase 1 dose de-escalation case series study revealed that bevacizumab doses as low as 0.002 mg were associated with reduced plasma VEGF levels for most infants at 2 and 4 weeks after intravitreal administration; however, no association was observed between total bevacizumab dose administered and reductions in plasma VEGF levels from preinjection to 2 weeks or 4 weeks. Additional studies are needed to evaluate the long-term effects of low-dose bevacizumab on neurodevelopment and retinal structure.
Published: 2022

38. Familial Exudative Vitreoretinopathy

Author: Julia Shulman, Jonathan Feistmann, and M. Elizabeth Hartnett
Published: 2022
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39. Ocular and developmental outcomes of a dosing study of bevacizumab for retinopathy of prematurity

Author: David K. Wallace, Amra Hercinovic, Sharon F. Freedman, Eric R. Crouch, Amit R. Bhatt, M. Elizabeth Hartnett, Michael B. Yang, David L. Rogers, Amy K. Hutchinson, William V. Good, Michael X. Repka, Zhuokai Li, Roy W. Beck, Raymond T. Kraker, Susan A. Cotter, and Jonathan M. Holmes
Subjects: Ophthalmology, Pediatrics, Perinatology and Child Health
Published: 2023
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40. Confocal reflectance microscopy for mapping collagen fiber organization in the vitreous gel of the eye

Author: Eileen S. Hwang, Denise J. Morgan, Jieliyue Sun, M. Elizabeth Hartnett, Kimani C. Toussaint, and Brittany Coats
Subjects: Article, Atomic and Molecular Physics, and Optics, Biotechnology
Abstract: Vitreous collagen structure plays an important role in ocular mechanics, but capturing this structure with existing vitreous imaging methods is hindered by loss of sample position and orientation, low resolution, or small field of view. The objective of this study was to evaluate confocal reflectance microscopy as a solution to these limitations. The use of intrinsic reflectance avoids staining and optical sectioning eliminates the requirement for thin sectioning, minimizing processing for optimal preservation of natural structure. We developed a sample preparation and imaging strategy usingex vivogrossly sectioned porcine eyes. Imaging revealed a network of uniform diameter crossing fibers (1.1 ± 0.3 μm for a typical image) with generally poor alignment (alignment coefficient = 0.40 ± 0.21 for a typical image). To test the utility of our approach for detecting differences in fiber spatial distribution, we imaged eyes every 1 mm along an anterior-posterior axis originating at the limbus and quantified the number of fibers in each image. Fiber density was higher anteriorly near the vitreous base, regardless of imaging plane. These data demonstrate that confocal reflectance microscopy addresses the previously unmet need for a robust, micron-scale technique to map features of collagen networksin situacross the vitreous.
Published: 2023
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41. Discovering Mechanisms in the Changing and Diverse Pathology of Retinopathy of Prematurity: The Weisenfeld Award Lecture

Author: M. Elizabeth Hartnett
Subjects: Vascular Endothelial Growth Factor A, 0303 health sciences, Retina, business.industry, Extramural, MEDLINE, Awards and Prizes, Infant, Newborn, Retinopathy of prematurity, medicine.disease, Bioinformatics, Models, Biological, 03 medical and health sciences, Vascular endothelial growth factor A, 0302 clinical medicine, medicine.anatomical_structure, 030221 ophthalmology & optometry, Medicine, Humans, Retinopathy of Prematurity, Lecture, business, Biomarkers, 030304 developmental biology
Published: 2019

42. A review of treatment for retinopathy of prematurity

Author: Eric D. Hansen and M. Elizabeth Hartnett
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, genetic structures, business.industry, medicine.medical_treatment, Biomedical Engineering, Childhood blindness, Retinal detachment, Retinopathy of prematurity, Vitrectomy, medicine.disease, Scleral buckle, Article, eye diseases, 03 medical and health sciences, Ophthalmology, 0302 clinical medicine, 030221 ophthalmology & optometry, medicine, sense organs, business, 030217 neurology & neurosurgery, Optometry
Abstract: INTRODUCTION: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide. AREAS COVERED: Recent methods to identify and manage treatment-warranted vascularly active ROP are recognized and being compared to standard care by laser treatment in prospective large-scale clinical studies. Pharmacologic anti-angiogenic (anti-VEGF) treatment has changed the natural history of vascularly active ROP by reducing stage 3 intravitreal neovascularization and extending physiologic retinal vascularization in many infants. Tractional retinal detachments in stage 4 ROP after treatment with anti-VEGF agents show additional fibrovascular complexity compared to eyes treated with laser only. We review current management and outcomes for vascularly active and fibrovascular retinal detachment in ROP (stages 3, 4, 5 ROP), highlighting the evidence from recent clinical studies. Included are technical details important in surgery for retinal detachment in ROP. Literature searches were employed through PubMed. EXPERT OPINION: Methods in pediatric imaging, safer pharmacologic treatments, and surgical techniques continue to advance to improve future ROP outcomes.
Published: 2019
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43. Three-dimensional pattern of extraretinal neovascular development in retinopathy of prematurity

Author: Joseph A. Izatt, Cynthia A. Toth, M. Elizabeth Hartnett, Xi Chen, Francesco LaRocca, Isaac D. Bleicher, Christian Viehland, Shwetha Mangalesh, and Sharon F. Freedman
Subjects: Vascular Endothelial Growth Factor A, medicine.medical_specialty, genetic structures, Research system, Extraretinal neovascularization, Angiogenesis Inhibitors, Gestational Age, Retinal Neovascularization, Article, Neovascularization, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Imaging, Three-Dimensional, Optical coherence tomography, Ophthalmology, medicine, Humans, Retinopathy of Prematurity, Prospective Studies, Stage (cooking), medicine.diagnostic_test, business.industry, Infant, Retinal Vessels, Retinopathy of prematurity, Retinal, medicine.disease, eye diseases, Sensory Systems, Bevacizumab, chemistry, Intravitreal Injections, sense organs, medicine.symptom, business, Infant, Premature, Tomography, Optical Coherence, After treatment
Abstract: BACKGROUND: The application of three-dimensional (3D) visualization techniques to evaluate the earliest visible onset of abnormal retinal vascular development in preterm infants with retinopathy of prematurity (ROP), using bedside non-contact optical coherence tomography (OCT) imaging to characterize morphology and sequential structural changes of abnormal extraretinal neovascularization. METHODS: Thirty-one preterm infants undergoing routine ROP screening with written informed consent for research imaging were enrolled in this prospective observational study. We imaged the macula and temporal periphery of preterm infants using a handheld OCT system (Envisu 2300 or handheld swept-source research system). The scans obtained were segmented and using enhanced ray casting were converted to 3D volumes to which color filter were applied. RESULTS: Using colorized 3D visualization, we defined extraretinal neovascular structures as buds, bridging networks and placoid lesions. We could longitudinally follow progression and regression of extraretinal neovascularization in stage 3 ROP after treatment in one infant over 12 weeks and document the appearance of early buds, and formation of florid neovascularization. From stage 2 to 3 ROP, we observed progression from sessile buds to a complex plaque that corresponded to stage 3 ROP on clinical examination. We demonstrated regression of neovascular complexes to small pre-retinal tufts after treatment with anti-VEGF. CONCLUSIONS: The extension of OCT processing to include surface flattening and colorization that further improved structural analysis rendered better understanding of extraretinal tissue. Our ability to image similar areas in the same infant over multiple visits enabled us to study the evolution of these structural components and follow pathological vascular events longitudinally in development and regression after treatment. These methods can be applied to further study which are likely contribute to our understanding of the pathophysiology of neovascularization in ROP.
Published: 2019
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44. Plasma Levels of Vascular Endothelial Growth Factor After Low-Dose Bevacizumab Treatment for Retinopathy of Prematurity Study—More Questions Than Answers?—Reply

Author: M Elizabeth, Hartnett and David K, Wallace
Subjects: Bevacizumab, Vascular Endothelial Growth Factor A, Ophthalmology, Vascular Endothelial Growth Factors, Intravitreal Injections, Infant, Newborn, Humans, Angiogenesis Inhibitors, Gestational Age, Retinopathy of Prematurity
Published: 2022
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45. Two-year ocular and developmental outcomes of a phase 1 dosing study of bevacizumab for retinopathy of prematurity

Author: David K. Wallace, Amra Hercinovic, Sharon F. Freedman, Eric R. Crouch, Amit R. Bhatt, M. Elizabeth Hartnett, Michael B. Yang, David L. Rogers, Amy K. Hutchinson, William V. Good, Michael X. Repka, Raymond T. Kraker, Susan A. Cotter, and Jonathan M. Holmes
Subjects: Ophthalmology, Pediatrics, Perinatology and Child Health
Published: 2022
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46. Active Rap1‐mediated inhibition of choroidal neovascularization requires interactions with IQGAP1 in choroidal endothelial cells

Author: M. Elizabeth Hartnett, Brahim Chaqour, Eric Kunz, Christian Matthew Pappas, David B. Sacks, Haibo Wang, Gregory S. Hageman, and Aniket Ramshekar
Subjects: Male, 0301 basic medicine, genetic structures, RAC1, Biochemistry, Article, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, IQGAP1, Cell Movement, Genetics, medicine, Animals, Protein Interaction Domains and Motifs, Molecular Biology, Tube formation, Choroid, Endothelial Cells, rap1 GTP-Binding Proteins, Transfection, Choroidal Neovascularization, eye diseases, Cell biology, Mice, Inbred C57BL, Vascular endothelial growth factor, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Choroidal neovascularization, chemistry, ras GTPase-Activating Proteins, cardiovascular system, Female, Rap1, sense organs, medicine.symptom, 030217 neurology & neurosurgery, Signal Transduction, Biotechnology, Binding domain
Abstract: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The pathophysiology involves activation of choroidal endothelial cells (CECs) to transmigrate the retinal pigment epithelial (RPE) monolayer and form choroidal neovascularization (CNV) in the neural retina. The multidomain GTPase binding protein, IQGAP1, binds active Rac1 and sustains activation of CECs, thereby enabling migration associated with vision-threatening CNV. IQGAP1 also binds the GTPase, Rap1, which when activated reduces Rac1 activation in CECs and CNV. In this study, we tested the hypothesis that active Rap1 binding to IQGAP1 is necessary and sufficient to reduce Rac1 activation in CECs, and CNV. We found that pharmacologic activation of Rap1 or adenoviral transduction of constitutively active Rap1a reduced VEGF-mediated Rac1 activation, migration, and tube formation in CECs. Following pharmacologic activation of Rap1, VEGF-mediated Rac1 activation was reduced in CECs transfected with an IQGAP1 construct that increased active Rap1-IQGAP1 binding but not in CECs transfected with an IQGAP1 construct lacking the Rap1 binding domain. Specific knockout of IQGAP1 in endothelial cells reduced laser-induced CNV and Rac1 activation in CNV lesions, but pharmacologic activation of Rap1 did not further reduce CNV compared to littermate controls. Taken together, our findings provide evidence that active Rap1 binding to the IQ domain of IQGAP1 is sufficient to interfere with active Rac1-mediated CEC activation and CNV formation.
Published: 2021
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47. Deepfakes in Ophthalmology: Applications and Realism of Synthetic Retinal Images from Generative Adversarial Networks

Author: Jimmy S, Chen, Aaron S, Coyner, R V Paul, Chan, M Elizabeth, Hartnett, Darius M, Moshfeghi, Leah A, Owen, Jayashree, Kalpathy-Cramer, Michael F, Chiang, and J Peter, Campbell
Abstract: Generative adversarial networks (GANs) are deep learning (DL) models that can create and modify realistic-appearing synthetic images, or deepfakes, from real images. The purpose of our study was to evaluate the ability of experts to discern synthesized retinal fundus images from real fundus images and to review the current uses and limitations of GANs in ophthalmology.Development and expert evaluation of a GAN and an informal review of the literature.A total of 4282 image pairs of fundus images and retinal vessel maps acquired from a multicenter ROP screening program.Pix2Pix HD, a high-resolution GAN, was first trained and validated on fundus and vessel map image pairs and subsequently used to generate 880 images from a held-out test set. Fifty synthetic images from this test set and 50 different real images were presented to 4 expert ROP ophthalmologists using a custom online system for evaluation of whether the images were real or synthetic. Literature was reviewed on PubMed and Google Scholars using combinations of the termsExpert ability to discern real versus synthetic images was evaluated using percent accuracy. Statistical significance was evaluated using a Fisher exact test, withThe expert majority correctly identified 59% of images as being real or synthetic (Generative adversarial networks can create synthetic fundus images that are indiscernible from real fundus images by expert ROP ophthalmologists. Synthetic images may improve dataset augmentation for DL, may be used in trainee education, and may have implications for patient privacy.
Published: 2021

48. The Pathophysiology of Retinopathy of Prematurity

Author: M. Elizabeth Hartnett
Subjects: Extremely premature, business.industry, Perinatal care, Retinopathy of prematurity, Prenatal care, medicine.disease, Bioinformatics, eye diseases, Pathophysiology, Vascular endothelial growth factor, chemistry.chemical_compound, Future study, chemistry, medicine, business, Retinopathy
Abstract: The pathophysiology of retinopathy of prematurity (ROP) is evolving as advances in prenatal care allow extremely premature infants to survive. In addition, throughout the world, there is variability in the presentations of ROP. In regions that lack resources to support prenatal and perinatal care, ROP develops in infants of older gestational ages and larger birth weights and has potentially different pathophysiologic factors. This chapter will review the pathophysiology of ROP and factors involved in the presentation of ROP based on what is known through clinical studies and from experimental studies using animal models of oxygen-induced retinopathy (OIR), which are critical to study molecular mechanisms and cell–cell interactions. Although the main areas involve clinical study, it is impossible to discuss pathophysiology without including evidence from the most representative animal models of oxygen-induced retinopathy (OIR) and other models adapted to study maternal–fetal interactions. Understanding the role of vascular endothelial growth factor (VEGF) in the physiology of retinal and vascular development and survival and the pathology in stage 3 and plus disease of ROP is important in discussing pathophysiology. Thoughts regarding areas of future study will be briefly described.
Published: 2021
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49. Correction: Optical coherence tomography as retinal imaging biomarker of neuroinflammation/neurodegeneration in systemic disorders in adults and children

Author: Stela Vujosevic, M. Margarita Parra, M. Elizabeth Hartnett, Louise O’Toole, Alessia Nuzzi, Celeste Limoli, Edoardo Villani, and Paolo Nucci
Subjects: Ophthalmology
Published: 2022
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50. Development and validation of a new clinical decision support tool to optimize screening for retinopathy of prematurity

Author: Ann Hellström, Staffan Nilsson, Kristina Tornqvist, Pia Lundgren, Abbas Al-Hawasi, Kerstin Albertsson-Wikland, Chatarina Löfqvist, Agneta Wallin, Bradley A. Yoder, Helena Johansson, Eva Larsson, Gerd Holmström, Marie Christine Bründer, Lotta Gränse, Carolyn Wu, Andreas Stahl, Birgitta Sunnqvist, Lois E.H. Smith, M. Elizabeth Hartnett, Aldina Pivodic, Wolf A. Lagrèze, and Anna-Lena Hård
Subjects: Peptide Nucleic Acids, Pediatrics, medicine.medical_specialty, ROP screening, Reproduktionsmedicin och gynekologi, Gestational Age, Logistic regression, Clinical decision support system, neovascularisation, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Neonatal Screening, Risk Factors, 030225 pediatrics, Obstetrics, Gynecology and Reproductive Medicine, optimized screening, medicine, retinopathy of prematurity, Humans, Birth Weight, Retinopathy of Prematurity, Retrospective Studies, business.industry, External validation, Infant, Newborn, Gestational age, Infant, Retinopathy of prematurity, medicine.disease, Decision Support Systems, Clinical, Birth characteristics, Sensory Systems, diagnostic tests/Investigation, prediction model, Ophthalmology, clinical decision support tool, Cohort, Oftalmologi, 030221 ophthalmology & optometry, National registry, preterm, business, diagnostic tests, Investigation
Abstract: Background/Aims Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights. Methods Data, including infants born at 24-30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6-14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions. Results ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6-14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%. Conclusions DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24-30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting. Funding Agencies|Swedish Medical Research CouncilSwedish Medical Research Council (SMRC)European Commission [2016-01131]; Gothenburg Medical Society and Government grants under the ALF agreement [ALFGBG-717971]; De Blindas Vanner; Knut and Alice Wallenberg Clinical Scholars; Orebro County Council Research Committee; National Eye InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [EY017017, EY030904]; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1U54HD090255]
Published: 2020

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