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2020

Global Retinoblastoma Study Group, Fabian ID, Abdallah E, Abdullahi S, Abdulqader R, Adamou Boubacar S, Ademola-Popoola D, Adio A, Afshar A, Aggarwal P, Aghaji A, Ahmad A, Akib M, Al Harby L, Al Ani M, Alakbarova A, Portabella SA, Al-Badri S, Alcasabas AP, Al-Dahmash S, Alejos A, Alemany-Rubio E, Alfa Bio A, Alfonso Carreras Y, Al-Haddad C, Al-Hussaini H, Ali A, Alia D, Al-Jadiry M, Al-Jumaly U, Alkatan H, All-Eriksson C, Al-Mafrachi A, Almeida A, Alsawidi K, Al-Shaheen A, Al-Shammary E, Amiruddin P, Antonino R, Astbury N, Atalay H, Atchaneeyasakul LO, Atsiaya R, Attaseth T, Aung T, Ayala S, Baizakova B, Balaguer J, Balayeva R, Balwierz W, Barranco H, Bascaran C, Beck Popovic M, Benavides R, Benmiloud S, Bennani Guebessi N, Berete R, Berry J, Bhaduri A, Bhat S, Biddulph S, Biewald E, Bobrova N, Boehme M, Boldt, Bonanomi MT, Bornfeld N, Bouda G, Bouguila H, Boumedane A, Brennan R, Brichard B, Buaboonnam J, Calderón-Sotelo P, Calle Jara D, Camuglia J, Cano M, Capra M, Cassoux N, Castela G, Castillo L, Català-Mora J, Chantada G, Chaudhry S, Chaugule S, Chauhan A, Chawla B, Chernodrinska V, Chiwanga F, Chuluunbat T, Cieslik K, Cockcroft R, Comsa C, Correa Z, Correa Llano M, Corson T, Cowan-Lyn K, Csóka M, Cui X, Da Gama I, Dangboon W, Das A, Das S, Davanzo J, Davidson A, De Potter P, Delgado K, Demirci H, Desjardins L, Diaz Coronado R, Dimaras H, Dodgshun A, Donaldson C, Donato Macedo C, Dragomir M, Du Y, Du Bruyn M, Edison K, Eka Sutyawan W, El Kettani A, Elbahi A, Elder J, Elgalaly D, Elhaddad A, Elhassan MA, Elzembely M, Essuman V, Evina TG, Fadoo Z, Fandiño A, Faranoush M, Fasina O, Fernández D, Fernández-Teijeiro A, Foster A, Frenkel S, Fu L, Fuentes-Alabi S, Gallie B, Gandiwa M, Garcia J, García Aldana D, Gassant P, Geel J, Ghassemi F, Girón A, Gizachew Z, Goenz M, Gold A, Goldberg-Lavid M, Gole G, Gomel N, Gonzalez E, Gonzalez Perez G, González-Rodríguez L, Garcia Pacheco H, Graells J, Green L, Gregersen P, Grigorovski N, Guedenon K, Gunasekera S, Gündüz A, Gupta H, Gupta S, Hadjistilianou T, Hamel P, Hamid S, Hamzah N, Hansen E, Harbour W, Hartnett E, Hasanreisoglu M, Hassan S, Hassan S, Hederova S, Hernandez J, Hernandez LMC, Hessissen L, Hordofa D, Huang L, Hubbard, Hummlen M, Husakova K, Hussein Al-Janabi A, Ida R, Ilic V, Jairaj V, Jeeva I, Jenkinson H, Ji X, Jo DH, Johnson K, Johnson W, Jones M, Kabesha TA, Kabore R, Kaliki S, Kalinaki A, Kantar M, Kao LY, Kardava T, Kebudi R, Kepak T, Keren-Froim N, Khan Z, Khaqan H, Khauv P, Kheir W, Khetan V, Khodabande A, Khotenashvili Z, Kim J, Kim JH, Kiratli H, Kivelä T, Klett A, Komba Palet JEK, Krivaitiene D, Kruger M, Kulvichit K, Kuntorini M, Kyara A, Lachmann E, Lam C, Lam G, Larson S, Latinovic S, Laurenti K, Le BH, Lecuona K, Leverant A, Li C, Limbu B, Long QB, López J, Lukamba R, Lumbroso L, Luna-Fineman S, Lutfi D, Lysytsia L, Magrath G, Mahajan A, Majeed AR, Maka E, Makan M, Makimbetov E, Manda C, Martín Begue N, Mason L, Mason J, Matende I, Materin M, Mattosinho C, Matua M, Mayet I, Mbumba F, McKenzie J, Medina-Sanson A, Mehrvar A, Mengesha A, Menon V, Mercado GJ, Mets M, Midena E, Mishra D, Mndeme F, Mohamedani A, Mohammad M, Moll A, Montero M, Morales R, Moreira C, Mruthyunjaya P, Msina M, Msukwa G, Mudaliar S, Muma K, Munier F, Murgoi G, Murray T, Musa K, Mushtaq A, Mustak H, Muyen O, Naidu G, Nair AG, Naumenko L, Ndoye Roth PA, Nency Y, Neroev V, Ngo H, Nieves R, Nikitovic M, Nkanga E, Nkumbe H, Nuruddin M, Nyaywa M, Obono-Obiang G, Oguego N, Olechowski A, Oliver S, Osei-Bonsu P, Ossandon D, Paez-Escamilla M, Pagarra H, Painter S, Paintsil V, Paiva L, Pal B, Palanivelu MS, Papyan R, Parrozzani R, Parulekar M, Pascual Morales C, Paton K, Pawinska-Wasikowska K, Pe’er J, Peña A, Peric S, Pham C, Philbert R, Plager D, Pochop P, Polania R, Polyakov V, Pompe M, Pons J, Prat D, Prom V, Purwanto I, Qadir A, Qayyum S, Qian J, Rahman A, Rahman S, Rahmat J, Rajkarnikar P, Ramanjulu R, Ramasubramanian A, Ramirez-Ortiz M, Raobela, Rashid R, Reddy A, Reich E, Renner L, Reynders D, Ribadu D, Riheia M, Ritter-Sovinz P, Rojanaporn D, Romero L, Roy S, Saab R, Saakyan S, Sabhan A, Sagoo M, Said A, Saiju R, Salas B, San Román Pacheco S, Sánchez G, Sayalith P, Scanlan T, Schefler A, Schoeman J, Sedaghat A, Seregard S, Seth R, Shah A, Shakoor S, Sharma M, Sherief S, Shetye N, Shields C, Siddiqui SN, Sidi Cheikh S, Silva S, Singh A, Singh N, Singh U, Singha P, Sitorus R, Skalet A, Soebagjo H, Sorochynska T, Ssali G, Stacey A, Staffieri S, Stahl E, Stathopoulos C, Stirn Kranjc B, Stones D, Strahlendorf C, Suarez MEC, Sultana S, Sun X, Sundy M, Superstein R, Supriyadi E, Surukrattanaskul S, Suzuki S, Svojgr K, Sylla F, Tamamyan G, Tan D, Tandili A, Tarrillo Leiva F, Tashvighi M, Tateshi B, Tehuteru E, Teixeira L, Teh KH, Theophile T, Toledano H, Trang D, Traoré F, Trichaiyaporn S, Tuncer S, Tyau-Tyau H, Umar A, Unal E, Uner O, Urbak S, Ushakova T, Usmanov R, Valeina S, Hoefen Wijsard M, Varadisai A, Vasquez L, Vaughan L, Veleva-Krasteva N, Verma N, Victor A, Viksnins M, Villacís Chafla E, Vishnevskia-Dai V, Vora T, Wachtel A, Wackernagel W, Waddell K, Wade P, Wali A, Wang YZ, Weiss A, Wilson M, Wime A, Wiwatwongwana A, Wiwatwongwana D, Wolley Dod C, Wongwai P, Xiang D, Xiao Y, Yam J, Yang H, Yanga J, Yaqub M, Yarovaya V, Yarovoy A, Ye H, Yousef Y, Yuliawati P, Zapata López A, Zein E, Zhang C, Zhang Y, Zhao J, Zheng X, Zhilyaeva K, Zia N, Ziko O, Zondervan M, Bowman R. Global Retinoblastoma Presentation and Analysis by National Income Level. JAMA Oncol. 2020;
Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.
Akbari A, Jabbari N, Sharifi R, Ahmadi M, Vahhabi A, Seyedzadeh SJ, Nawaz M, Szafert S, Mahmoodi M, Jabbari E, Asghari R, Rezaie J. Free and hydrogel encapsulated exosome-based therapies in regenerative medicine. Life Sci. 2020;249:117447.
Over the last few decades, mesenchymal stem cells-derived exosomes (MSCs-Ex) have attracted a lot of attention as a therapeutic tool in regenerative medicine. Exosomes are extracellular vehicles (EVs) that play important roles in cell-cell communication through various processes such as stress response, senescence, angiogenesis, and cell differentiation. Success in the field of regenerative medicine sparked exploration of the potential use of exosomes as key therapeutic effectors of MSCs to promote tissue regeneration. Various approaches including direct injection, intravenous injection, intraperitoneal injection, oral administration, and hydrogel-based encapsulation have been exploited to deliver exosomes to target tissues in different disease models. Despite significant advances in exosome therapy, it is unclear which approach is more effective for administering exosomes. Herein, we critically review the emerging progress in the applications of exosomes in the form of free or association with hydrogels as therapeutic agents for applications in regenerative medicine.
Feldstein I, Dyszak G. Road crossing decisions in real and virtual environments: A comparative study on simulator validity. Accid Anal Prev. 2020;137:105356.
Virtual reality (VR) is a valuable tool for the assessment of human perception and behavior in a risk-free environment. Investigators should, however, ensure that the used virtual environment is validated in accordance with the experiment's intended research question since behavior in virtual environments has been shown to differ to behavior in real environments. This article presents the street crossing decisions of 30 participants who were facing an approaching vehicle and had to decide at what moment it was no longer safe to cross, applying the step-back method. The participants executed the task in a real environment and also within a highly immersive VR setup involving a head-mounted display (HMD). The results indicate significant differences between the two settings regarding the participants' behaviors. The time-to-contact of approaching vehicles was significantly lower for crossing decisions in the virtual environment than for crossing decisions in the real one. Additionally, it was demonstrated that participants based their crossing decisions in the real environment on the temporal distance of the approaching vehicle (i.e., time-to-contact), whereas the crossing decisions in the virtual environment seemed to depend on the vehicle's spatial distance, neglecting the vehicle's velocity. Furthermore, a deeper analysis suggests that crossing decisions were not affected by factors such as the participant's gender or the order in which they faced the real and the virtual environment.
Razeghinejad R, Lin M, Lee D, Katz J, Myers J. Pathophysiology and management of glaucoma and ocular hypertension related to trauma. Surv Ophthalmol. 2020;65(5):530–547.
Ocular trauma is a significant cause of blindness worldwide, particularly if associated with glaucoma. Direct damage from blunt or penetrating trauma, bleeding, inflammation, lens-related problems, orbital and brain vascular pathologies related to trauma, and chemical injuries may increase intraocular pressure and lead to traumatic glaucoma. Treatment may be as simple as eliminating the underlying cause in some conditions or management can be challenging, depending on the mechanism of damage. If proper management is not undertaken, visual outcomes can be poor. We discuss a broad spectrum of trauma-related mechanisms of intraocular pressure elevation, as well as their management.
Pamir Z, Canoluk U, Jung JH, Peli E. Poor resolution at the back of the tongue is the bottleneck for spatial pattern recognition. Sci Rep. 2020;10(1):2435.
Spatial patterns presented on the tongue using electro-tactile sensory substitution devices (SSDs) have been suggested to be recognized better by tracing the pattern with the tip of the tongue. We examined if the functional benefit of tracing is overcoming the poor sensitivity or low spatial resolution at the back of the tongue or alternatively compensating for limited information processing capacity by fixating on a segment of the spatial pattern at a time. Using a commercially available SSD, the BrainPort, we compared letter recognition performance in three presentation modes; tracing, static, and drawing. Stimulation intensity was either constant or increased from the tip to the back of the tongue to partially compensate for the decreasing sensitivity. Recognition was significantly better for tracing, compared to static and drawing conditions. Confusion analyses showed that letters were confused based on their characteristics presented near the tip in static and drawing conditions. The results suggest that recognition performance is limited by the poor spatial resolution at the back of the tongue, and tracing seems to be an effective strategy to overcome this. Compensating for limited information processing capacity or poor sensitivity by drawing or increasing intensity at the back, respectively, does not improve the performance.
Liu Y, Baniasadi N, Ratanawongphaibul K, Chen T. Effect of partial posterior vitreous detachment on spectral-domain optical coherence tomography retinal nerve fibre layer thickness measurements. Br J Ophthalmol. 2020;104(11):1524–1527.
BACKGROUND/AIMS: To assess the effect of partial posterior vitreous detachment (pPVD) on spectral-domain optical coherence tomography (OCT) peripapillary retinal nerve fibre layer thickness (RNFL) measurements. METHODS: Spectral-domain OCT RNFL thickness measurements were obtained from 684 consecutive patients who were seen in the Massachusetts Eye and Ear Glaucoma Service. Of these patients, we compared RNFL thickness measurements between 101 eyes of 101 glaucoma suspects who met inclusion criteria (55 eyes with and 46 eyes without pPVD). RESULTS: Among all 684 patients, 253 (37%) had pPVD in at least one eye. Among a subset of 101 eyes of 101 glaucoma suspects, average RNFL thickness was greater in eyes with compared to eyes without pPVD (p=0.02). Measurements were significantly greater in the inferior (p=0.004) and superior quadrants (p=0.008), but not in the nasal (p=0.10) and temporal quadrants (p=0.25). The difference in average RNFL thickness remained significant (p=0.05) even when corrected for expected age-related decline in RNFL thickness. CONCLUSION: Over a third of patients were found on peripapillary spectral-domain OCT to have a pPVD, which was associated with greater RNFL thickness measurements. Judicious clinical interpretation of this finding on spectral-domain OCT RNFL thickness scans should be factored into the assessment of glaucoma suspects.
Woodward A, Di Zazzo A, Bonini S, Argüeso P. Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface. Sci Rep. 2020;10(1):2216.
A growing body of evidence implicates endoplasmic reticulum (ER) stress in the pathogenesis of chronic inflammatory and autoimmune disorders. Here, we demonstrate that the proinflammatory cytokine TNFα stimulates matrix metalloproteinase 9 (MMP9) at the ocular surface through a c-Fos-dependent mechanism of ER stress. We found positive reactivity of the molecular chaperone BiP/GRP78 in conjunctival epithelium of patients with ocular cicatricial pemphigoid and increased levels of BiP/GRP78, sXBP1 and GRP94 in human corneal epithelial cells treated with TNFα. Pharmacological blockade of ER stress in vitro using dexamethasone or the chemical chaperones TUDCA and 4PBA attenuated MMP9 expression and secretion in the presence of TNFα. Moreover, expression analysis of genes associated with inflammation and autoimmunity identified the c-Fos proto-oncogene as a mediator of ER stress responses in epithelial cells. Substantially less TNFα-induced MMP9 expression occurred when c-Fos signaling was suppressed with a function-blocking antibody. Taken together, these results indicate that activation of ER stress contributes to promote inflammation-mediated proteolytic activity and uncovers a target for restoring tissue homeostasis in ocular autoimmune disease.
Jacobi A, Zyl T. [Recent Research Efforts to Achieve Neuroprotection, Progression and Treatment of Glaucoma]. Klin Monbl Augenheilkd. 2020;237(2):133–139.
Glaucoma is a neurodegenerative disease that leads to irreversible blindness over time. Its defining feature is the loss of retinal ganglion cells (RGCs) in the eye and their axons in the optic nerve. Increased intraocular pressure (IOP) is a major risk factor for the development of glaucoma, but is neither necessary nor sufficient for the disease and its progression; this motivates research and development of new strategies for the detection and treatment of glaucoma that focus on neuroprotection - protection of RGCs from dying. In addition, for diagnosis and treatment by reducing IOP, new approaches have been developed in recent years. This article reviews current theories of pathophysiological mechanisms underlying glaucoma and recent research - with a focus on neuroprotection and current preclinical and clinical studies to improve the diagnosis and treatment of glaucoma.
Zampaglione E, Kinde B, Place E, Navarro-Gomez D, Maher M, Jamshidi F, Nassiri S, Mazzone A, Finn C, Schlegel D, Comander J, Pierce E, Bujakowska K. Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations. Genet Med. 2020;22(6):1079–1087.
PURPOSE: Current sequencing strategies can genetically solve 55-60% of inherited retinal degeneration (IRD) cases, despite recent progress in sequencing. This can partially be attributed to elusive pathogenic variants (PVs) in known IRD genes, including copy-number variations (CNVs), which have been shown as major contributors to unsolved IRD cases. METHODS: Five hundred IRD patients were analyzed with targeted next-generation sequencing (NGS). The NGS data were used to detect CNVs with ExomeDepth and gCNV and the results were compared with CNV detection with a single-nucleotide polymorphism (SNP) array. Likely causal CNV predictions were validated by quantitative polymerase chain reaction (qPCR). RESULTS: Likely disease-causing single-nucleotide variants (SNVs) and small indels were found in 55.6% of subjects. PVs in USH2A (11.6%), RPGR (4%), and EYS (4%) were the most common. Likely causal CNVs were found in an additional 8.8% of patients. Of the three CNV detection methods, gCNV showed the highest accuracy. Approximately 30% of unsolved subjects had a single likely PV in a recessive IRD gene. CONCLUSION: CNV detection using NGS-based algorithms is a reliable method that greatly increases the genetic diagnostic rate of IRDs. Experimentally validating CNVs helps estimate the rate at which IRDs might be solved by a CNV plus a more elusive variant.