In Situ LSPR Sensing of Secreted Insulin in Organ-on-Chip

Organ-on-a-chip (OOC) devices offer new approaches for metabolic disease modeling and drug discovery by providing biologically relevant models of tissues and organs in vitro with a high degree of control over experimental variables for high-content screening applications. Yet, to fully exploit the potential of these platforms, there is a need to interface them with integrated non-labeled sensing modules, capable of monitoring, in situ, their biochemical response to external stimuli, such as stress or drugs. In order to meet this need, we aim here to develop an integrated technology based on coupling a localized surface plasmon resonance (LSPR) sensing module to an OOC device to monitor the insulin in situ secretion in pancreatic islets, a key physiological event that is usually perturbed in metabolic diseases such as type 2 diabetes (T2D). As a proof of concept, we developed a biomimetic islet-on-a-chip (IOC) device composed of mouse pancreatic islets hosted in a cellulose-based scaffold as a novel approach. The IOC was interfaced with a state-of-the-art on-chip LSPR sensing platform to monitor the in situ insulin secretion. The developed platform offers a powerful tool to enable the in situ response study of microtissues to external stimuli for applications such as a drug-screening platform for human models, bypassing animal testing

The European Solar Telescope

Full list of authors: Noda, C. Quintero; Schlichenmaier, R.; Bellot Rubio, L. R.; Lofdahl, M. G.; Khomenko, E.; Leenaarts, J.; Kuckein, C.; Gonzalez Manrique, S. J.; Gunar, S.; Nelson, C. J.; Rodriguez, J. de la Cruz; Tziotziou, K.; Tsiropoula, G.; Aulanier, G.; Aboudarham, J.; Allegri, D.; Alsina Ballester, E.; Amans, J. P.; Asensio Ramos, A.; Bailen, F. J.; Balaguer, M.; Baldini, V; Balthasar, H.; Barata, T.; Barczynski, K.; Barreto Cabrera, M.; Baur, A.; Bechet, C.; Beck, C.; Belio-Asin, M.; Bello-Gonzalez, N.; Belluzzi, L.; Bentley, R. D.; Berdyugina, S., V; Berghmans, D.; Berlicki, A.; Berrilli, F.; Berkefeld, T.; Bettonvil, F.; Bianda, M.; Bienes Perez, J.; Bonaque-Gonzalez, S.; Brajsa, R.; Bommier, V; Bourdin, P-A; BurgosMartin, J.; Calchetti, D.; Calcines, A.; Calvo Tovar, J.; Campbell, R. J.; Carballo-Martin, Y.; Carbone, V; Carlin, E. S.; Carlsson, M.; Castro Lopez, J.; Cavaller, L.; Cavallini, F.; Cauzzi, G.; Cecconi, M.; Chulani, H. M.; Cirami, R.; Consolini, G.; Coretti, I; Cosentino, R.; Cozar-Castellano, J.; Dalmasse, K.; Danilovic, S.; Ovelar, M. De Juan; Del Moro, D.; del Pino Aleman, T.; del Toro Iniesta, J. C.; Denker, C.; Dhara, S. K.; Di Marcantonio, P.; Baso, C. J. Diaz; Diercke, A.; Dineva, E.; Diaz-Garcia, J. J.; Doerr, H-P; Doyle, G.; Erdelyi, R.; Ermolli, I; Escobar Rodriguez, A.; Esteban Pozuelo, S.; Faurobert, M.; Felipe, T.; Feller, A.; Feijoo Amoedo, N.; Femenia Castella, B.; Fernandes, J.; Ferro Rodriguez, I; Figueroa, I; Fletcher, L.; Franco Ordovas, A.; Gafeira, R.; Gardenghi, R.; Gelly, B.; Giorgi, F.; Gisler, D.; Giovannelli, L.; Gonzalez, F.; Gonzalez, J. B.; Gonzalez-Cava, J. M.; Gonzalez Garcia, M.; Gomory, P.; Gracia, F.; Grauf, B.; Greco, V; Grivel, C.; Guerreiro, N.; Guglielmino, S. L.; Hammerschlag, R.; Hanslmeier, A.; Hansteen, V; Heinzel, P.; Hernandez-Delgado, A.; Hernandez Suarez, E.; Hidalgo, S. L.; Hill, F.; Hizberger, J.; Hofmeister, S.; Jagers, A.; Janett, G.; Jarolim, R.; Jess, D.; Jimenez Mejias, D.; Jolissaint, L.; Kamlah, R.; Kapitan, J.; Kasparova, J.; Keller, C. U.; Kentischer, T.; Kiselman, D.; Kleint, L.; Klvana, M.; Kontogiannis, I; Krishnappa, N.; Labrosse, N.; Lagg, A.; Degl'Innocenti, E. Landi; Langlois, M.; Lafon, M.; Laforgue, D.; Le Men, C.; Lepori, B.; Lepreti, F.; Lindberg, B.; Lilje, P. B.; Ariste, A. Lopez; Lopez Fernandez, V. A.; Lopez Jimenez, A. C.; Lopez Lopez, R.; Sainz, R. Manso; Marassi, A.; Marco de la Rosa, J.; Marino, J.; Marrero, J.; Martin, A.; Martin Galvez, A.; Martin Hernando, Y.; Masciadri, E.; MartinezGonzalez, M.; Matta-Gomez, A.; Mato, A.; Mathioudakis, M.; Matthews, S.; Mein, P.; Merlos Garcia, F.; Moity, J.; Montilla, I; Molinaro, M.; Molodij, G.; Montoya, L. M.; Munari, M.; Murabito, M.; Nunez Cagigal, M.; Oliviero, M.; Orozco Suarez, D.; Ortiz, A.; Padilla-Hernandez, C.; Paez Mana, E.; Paletou, F.; Pancorbo, J.; Pastor Canedo, A.; Yabar, A. Pastor; Peat, A. W.; Pedichini, F.; Peixinho, N.; Penate, J.; Perez de Taoro, A.; Peter, H.; Petrovay, K.; Piazzesi, R.; Pietropaolo, E.; Pleier, O.; Poedts, S.; Potzi, W.; Podladchikova, T.; Prieto, G.; Quintero Nehrkorn, J.; Ramelli, R.; Ramos Sapena, Y.; Rasilla, J. L.; Reardon, K.; Rebolo, R.; Regalado Olivares, S.; Reyes Garcia-Talavera, M.; Riethmuller, T. L.; Rimmele, T.; Rodriguez Delgado, H.; Rodriguez Gonzalez, N.; Rodriguez-Losada, J. A.; Rodriguez Ramos, L. F.; Romano, P.; Roth, M.; vander Voort, L. Rouppe; Rudawy, P.; Ruiz de Galarreta, C.; Rybak, J.; Salvade, A.; Sanchez-Capuchino, J.; Sanchez Rodriguez, M. L.; Sangiorgi, M.; Sayede, F.; Scharmer, G.; Scheiffelen, T.; Schmidt, W.; Schmieder, B.; Scire, C.; Scuderi, S.; Siegel, B.; Sigwarth, M.; Simoes, P. J. A.; Snik, F.; Sliepen, G.; Sobotka, M.; Socas-Navarro, H.; Sola La Serna, P.; Solanki, S. K.; Soler Trujillo, M.; Soltau, D.; Sordini, A.; Sosa Mendez, A.; Stangalini, M.; Steiner, O.; Stenflo, J. O.; Stepan, J.; Strassmeier, K. G.; Sudar, D.; Suematsu, Y.; Sutterlin, P.; Tallon, M.; Temmer, M.; Tenegi, F.; Tritschler, A.; Trujillo Bueno, J.; Turchi, A.; Utz, D.; van Harten, G.; VanNoort, M.; van Werkhoven, T.; Vansintjan, R.; Vaz Cedillo, J. J.; Vega Reyes, N.; Verma, M.; Veronig, A. M.; Viavattene, G.; Vitas, N.; Vogler, A.; von der Luhe, O.; Volkmer, R.; Waldmann, T. A.; Walton, D.; Wisniewska, A.; Zeman, J.; Zeuner, F.; Zhang, L. Q.; Zuccarello, F.; Collados, M.--This is an Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The European Solar Telescope (EST) is a project aimed at studying the magnetic connectivity of the solar atmosphere, from the deep photosphere to the upper chromosphere. Its design combines the knowledge and expertise gathered by the European solar physics community during the construction and operation of state-of-the-art solar telescopes operating in visible and near-infrared wavelengths: the Swedish 1m Solar Telescope, the German Vacuum Tower Telescope and GREGOR, the French Télescope Héliographique pour l’Étude du Magnétisme et des Instabilités Solaires, and the Dutch Open Telescope. With its 4.2 m primary mirror and an open configuration, EST will become the most powerful European ground-based facility to study the Sun in the coming decades in the visible and near-infrared bands. EST uses the most innovative technological advances: the first adaptive secondary mirror ever used in a solar telescope, a complex multi-conjugate adaptive optics with deformable mirrors that form part of the optical design in a natural way, a polarimetrically compensated telescope design that eliminates the complex temporal variation and wavelength dependence of the telescope Mueller matrix, and an instrument suite containing several (etalon-based) tunable imaging spectropolarimeters and several integral field unit spectropolarimeters. This publication summarises some fundamental science questions that can be addressed with the telescope, together with a complete description of its major subsystems. © C. Q. Noda et al. 2022.C.Q.N. was supported by the EST Project Office, funded by the Canary Islands Government (file SD 17/01) under a direct grant awarded to the IAC on ground of public interest. This project has received funding from the European Union’s Horizon 2020 Research and Innovation programme under Grant Agreements No 739500 (PRE-EST) and 653982 (GREST). This project was supported by the European Commission’s FP7 Capacities Programme under Grant Agreements No 212482 (EST Design Study) and No. 312495 (SOLARNET). It was also supported by the European Union’s Horizon 2020 Research and Innovation programme under Grant Agreement No. 824135 (SOLARNET). This work has been partially funded by the Spanish Ministry of Science and Innovation through project RTI2018-096886-B-C51, including a percentage from FEDER funds, and through the Centro de Excelencia Severo Ochoa grant SEV-2017-0709 awarded to the Instituto de Astrofísica de Andalucía in the period 2018-2022. The EST preparatory phase was supported by a grant for research infrastructures of national importance from the Swedish Research Council (registration number 2017-00625). J.J. was supported by the Ministry of Education, Youth and Sports of the Czech Republic through the EST-CZ project (LM2018095). C.K. acknowledges funding received from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 895955. Queen’s University Belfast acknowledges support from the Science and Technology Facilities Council (STFC) under grant No. ST/V003739/1. This work was supported by Fundação para a Ciência e a Tecnologia (FCT) through the research grants [UID/FIS/04434/2019], UIDB/04434/2020, UIDP/04434/2020, UIDB/00611/2020 and UIDP/00611/2020. This work was partly funded by a grant of the Austrian Science Fund (FWF): P 32958-N. J.C.R., C.J.D.B. and A.P.Y. gratefully acknowledge financial support from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (SUNMAG, grant agreement 759548). J.A. was supported by Centre National d’Etudes Spatiales (CNES). G.A., M.C., L.F., V.H., A.O. and L.R.V.V acknowledge support by the Research Council of Norway through its Centres of Excellence scheme, project number 262622. L.B., M.B., R.R. acknowledge State Secretariat for Education, Research, and Innovation (SERI), Canton Ticino and Swiss National Science Foundation (grants 200020_184952, 200021_175997, CRSII5_180238) for the financial support. R. Brajša and D. Sudar acknowledge the support by the Croatian Science Foundation under project 7549 ‘Millimeter and submillimeter observations of the solar chromosphere with ALMA’. The NSO is operated by the Association of Universities for Research in Astronomy, Inc., under cooperative agreement with the National Science Foundation. The work of A.B. was partially supported by the programme ‘Excellence Initiative – Research University’ for years 2020–2026 for University of Wrocław, project no. BPIDUB.4610.15.2021.KP.B. E.S.C. acknowledges financial support from the Spanish Ministry of Science and Innovation (MICINN) through the Spanish State Research Agency, under Severo Ochoa Centres of Excellence Programme 2020-2023 (CEX2019-000920-S). L.F. and N.L. would like to acknowledge support from UK Research and Innovation Science and Technology Facilities Council grants ST/L006200/1 and ST/T000422/1. J.F. acknowledges visiting facilities at Rosseland Centre for Solar Physics (University of Oslo), in 2019. P. Gömöry, A.K. and J.R. were supported by the Science Grant Agency project VEGA 2/0048/20. I. Kontogiannis is supported by KO 6283/2-1 of the Deutsche Forschungsgemeinschaft (DFG). C.J.N. is thankful to the Science and Technology Facilities Council (STFC), for support received through grant ST/T00021X/1, and ESA, for support as an ESA Research Fellow. K.P. was supported by the Hungarian National Research, Development and Innovation Fund (grants no. NKFI K-128384 and TKP2021-NKTA-64). P.J.A. Simões acknowledges support from CNPq (contract 307612/2019-8). J.T.B. acknowledges the funding received from the European Research Council (ERC) under de European Union’s Horizon 2020 research and innovation programme (ERC Advanced Grant Agreement No. 742265). M.V. is supported by VE 1112/1-1 of the Deutsche Forschungsgemeinschaft (DFG). L.Q.Z. acknowledges that this work was supported by the National Natural Science Foundation of China (Grant No. 11727805, No. 1210030348). F.Z. acknowledges that this work was supported by the Italian MIUR-PRIN grant 2017APKP7T and by the Università degli Studi di Catania (Piano per la Ricerca Università di Catania 2020-2022, Linea di intervento 2).Peer reviewe

TGFBR1 Intralocus Epistatic Interaction as a Risk Factor for Colorectal Cancer

In colorectal cancer (CRC), an inherited susceptibility risk affects about 35% of patients, whereas high-penetrance germline mutations account for <6% of cases. A considerable proportion of sporadic tumors could be explained by the coinheritance of multiple low-penetrance variants, some of which are common. We assessed the susceptibility to CRC conferred by genetic variants at the TGFBR1 locus. We analyzed 14 polymorphisms and the allele-specific expression (ASE) of TGFBR1 in 1025 individuals from the Spanish population. A case-control study was undertaken with 504 controls and 521 patients with sporadic CRC. Fourteen polymorphisms located at the TGFBR1 locus were genotyped with the iPLEX Gold (MassARRAY-Sequenom) technology. Descriptive analyses of the polymorphisms and haplotypes and association studies were performed with the SNPator workpackage. No relevant associations were detected between individual polymorphisms or haplotypes and the risk of CRC. The TGFBR1*9A/6A polymorphism was used for the ASE analysis. Heterozygous individuals were analyzed for ASE by fragment analysis using cDNA from normal tissue. The relative level of allelic expression was extrapolated from a standard curve. The cutoff value was calculated with Youden's index. ASE was found in 25.4% of patients and 16.4% of controls. Considering both bimodal and continuous types of distribution, no significant differences between the ASE values of patients and controls were identified. Interestingly, a combined analysis of the polymorphisms and ASE for the association with CRC occurrence revealed that ASE-positive individuals carrying one of the most common haplotypes (H2: 20.7%) showed remarkable susceptibility to CRC (RR: 5.25; 95% CI: 2.547–5.250; p<0.001) with a synergy factor of 3.7. In our study, 54.1% of sporadic CRC cases were attributable to the coinheritance of the H2 haplotype and TGFBR1 ASE. These results support the hypothesis that the allelic architecture of cancer genes, rather than individual polymorphisms, more accurately defines the CRC risk

Predictive models for mutations in mismatch repair genes: implication for genetic counseling in developing countries

<p>Abstract</p> <p>Background</p> <p>Lynch syndrome (LS) is the most common form of inherited predisposition to colorectal cancer (CRC), accounting for 2-5% of all CRC. LS is an autosomal dominant disease characterized by mutations in the mismatch repair genes mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), postmeiotic segregation increased 1 (PMS1), post-meiotic segregation increased 2 (PMS2) and mutS homolog 6 (MSH6). Mutation risk prediction models can be incorporated into clinical practice, facilitating the decision-making process and identifying individuals for molecular investigation. This is extremely important in countries with limited economic resources. This study aims to evaluate sensitivity and specificity of five predictive models for germline mutations in repair genes in a sample of individuals with suspected Lynch syndrome.</p> <p>Methods</p> <p>Blood samples from 88 patients were analyzed through sequencing MLH1, MSH2 and MSH6 genes. The probability of detecting a mutation was calculated using the PREMM, Barnetson, MMRpro, Wijnen and Myriad models. To evaluate the sensitivity and specificity of the models, receiver operating characteristic curves were constructed.</p> <p>Results</p> <p>Of the 88 patients included in this analysis, 31 mutations were identified: 16 were found in the MSH2 gene, 15 in the MLH1 gene and no pathogenic mutations were identified in the MSH6 gene. It was observed that the AUC for the PREMM (0.846), Barnetson (0.850), MMRpro (0.821) and Wijnen (0.807) models did not present significant statistical difference. The Myriad model presented lower AUC (0.704) than the four other models evaluated. Considering thresholds of ≥ 5%, the models sensitivity varied between 1 (Myriad) and 0.87 (Wijnen) and specificity ranged from 0 (Myriad) to 0.38 (Barnetson).</p> <p>Conclusions</p> <p>The Barnetson, PREMM, MMRpro and Wijnen models present similar AUC. The AUC of the Myriad model is statistically inferior to the four other models.</p

Multicentre, randomised, single-blind, parallel group trial to compare the effectiveness of a Holter for Parkinson's symptoms against other clinical monitoring methods: study protocol

Introduction In recent years, multiple studies have aimed to develop and validate portable technological devices capable of monitoring the motor complications of Parkinson's disease patients (Parkinson's Holter). The effectiveness of these monitoring devices for improving clinical control is not known. Methods and analysis This is a single-blind, cluster-randomised controlled clinical trial. Neurologists from Spanish health centres will be randomly assigned to one of three study arms (1:1:1): (a) therapeutic adjustment using information from a Parkinson?s Holter that will be worn by their patients for 7 days, (b) therapeutic adjustment using information from a diary of motor fluctuations that will be completed by their patients for 7 days and (c) therapeutic adjustment using clinical information collected during consultation. It is expected that 162 consecutive patients will be included over a period of 6 months. The primary outcome is the efficiency of the Parkinson?s Holter compared with traditional clinical practice in terms of Off time reduction with respect to the baseline (recorded through a diary of motor fluctuations, which will be completed by all patients). As secondary outcomes, changes in variables related to other motor complications (dyskinesia and freezing of gait), quality of life, autonomy in activities of daily living, adherence to the monitoring system and number of doctor?patient contacts will be analysed. The noninferiority of the Parkinson's Holter against the diary of motor fluctuations in terms of Off time reduction will be studied as the exploratory objective. Ethics and dissemination approval for this study has been obtained from the Hospital Universitari de Bellvitge Ethics Committee. The results of this study will inform the practical utility of the objective information provided by a Parkinson's Holter and, therefore, the convenience of adopting this technology in clinical practice and in future clinical trials. We expect public dissemination of the results in 2022.Funding This work is supported by AbbVie S.L.U, the Instituto de Salud Carlos III [DTS17/00195] and the European Fund for Regional Development, 'A way to make Europe'

Identification of Lynch Syndrome Among Patients With Colorectal Cancer

Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear

Risk of Cancer in Cases of Suspected Lynch Syndrome Without Germline Mutation

Background & Aims: Colorectal cancers (CRCs) with microsatellite instability (MSI) and a mismatch repair (MMR) immunohistochemical deficit without hypermethylation of the MLH1 promoter are likely to be caused by Lynch syndrome. Some patients with these cancers have not been found to have pathogenic germline mutations and are considered to have Lynch-like syndrome (LLS). The aim of this study was to determine the risk of cancer in families of patients with LLS. Methods: We studied a population-based cohort of 1705 consecutive patients, performing MSI tests and immunohistochemical analyses of MMR proteins. Patients were diagnosed with Lynch syndrome when they were found to have pathogenic germline mutations. Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylation, and no pathogenic mutation were considered to have LLS. The clinical characteristics of patients and the age- and sex-adjusted standardized incidence ratios (SIRs) of cancer in families were compared between groups. Results: The incidence of CRC was significantly lower in families of patients with LLS than in families with confirmed cases of Lynch syndrome (SIR for Lynch syndrome, 6.04; 95% confidence interval [CI], 3.58–9.54; SIR for LLS, 2.12; 95% CI, 1.16–3.56; P < .001). However, the incidence of CRC was higher in families of patients with LLS than in families with sporadic CRC (SIR for sporadic CRC, 0.48; 95% CI, 0.27–0.79; P < .001). Conclusions: The risk of cancer in families with LLS is lower that of families with Lynch syndrome but higher than that of families with sporadic CRC. These results confirm the need for special screening and surveillance strategies for these patients and their relatives.This work was supported by grants from Instituto de Salud Carlos III (PI-080726, INT-09/208, and PI11/026030), the Fondo de Investigación Sanitaria/FEDER (PS09/02368, 10/00384, 10/00918, 11/00219, and 11/00681), Fundació Olga Torres (CRP) and FP7 CHIBCHA Consortium (SCB and ACar), the Ministerio de Economía y Competitividad (SAF2010-19273), and Agència de Gestió d’Ajuts Universitaris i de Recerca (2009 SGR 849). SCB is supported by a contract from the Fondo de Investigación Sanitaria (CP03-0070). CIBERER and CIBERehd are funded by the Instituto de Salud Carlos III

Global Retinoblastoma Presentation and Analysis by National Income Level.

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

Global Retinoblastoma Presentation and Analysis by National Income Level

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- A nd 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