Predictive value of peripheral blood inflammatory biomarkers in immunotherapy for extensive-stage small-cell lung cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Predictive value of peripheral blood inflammatory biomarkers in immunotherapy for extensive-stage small-cell lung cancer meiyi you, Chunchu kong, MU Mei, Wenjun Pei This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7744188/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The clinical management of extensive-stage small-cell lung cancer (ES-SCLC) is challenged by the lack of reliable biomarkers to identify patients resistant to first-line immunotherapy. Peripheral blood inflammatory biomarkers are emerging as promising prognostic tools in oncology, but their predictive role in ES-SCLC remains unclear. Methods We conducted a multicenter retrospective study of patients with ES-SCLC treated between January 2020 and January 2024 in two hospitals. Baseline clinical data and peripheral blood inflammatory indices—including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), mean platelet volume (MPV), modified Glasgow Prognostic Score (mGPS), and Lung Immune Prognostic Index (LIPI)—were collected before treatment and after four cycles of immunochemotherapy. Optimal cut-off values were determined using X-tile software, and dynamic changes (Δ) were calculated. Survival analyses were performed with Kaplan–Meier and Cox proportional hazards models. Prognostic nomograms were developed and validated with calibration curves and receiver operating characteristic (ROC) analysis. Results A total of 212 patients were included, with a median follow-up of 16.2 months. The objective response rate (ORR) and disease control rate (DCR) were 46.7% and 72.2%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 8.4 and 15.3 months. High pre-treatment NLR, high pre-treatment MPV, increased ΔNLR, pre-mGPS score of 2, and elevated ΔmGPS or ΔLIPI were independent predictors of shorter PFS. For OS, high pre-treatment NLR, pre-mGPS score of 2, pre-LIPI score of 2, and increased ΔNLR, ΔmGPS, or ΔLIPI were independent risk factors. The nomograms demonstrated good predictive accuracy for both PFS and OS, with area under the curve (AUC) values ranging from 0.728 to 0.946. Conclusion Peripheral blood inflammatory biomarkers, particularly pre-NLR, ΔNLR, pre-mGPS, and ΔLIPI, are independent predictors of outcomes in ES-SCLC patients receiving first-line immunotherapy. The proposed nomograms provide effective tools for individualized risk stratification and treatment optimization. extensive-stage small-cell lung cancer immunotherapy peripheral blood inflammatory biomarkers neutrophil-to-lymphocyte ratio prognostic model Full Text Additional Declarations No competing interests reported. Supplementary Files file.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7744188","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":558510512,"identity":"e3170429-279d-4f97-a40d-bafa066d09eb","order_by":0,"name":"meiyi you","email":"","orcid":"","institution":"The First People's Hospital of Changde","correspondingAuthor":false,"prefix":"","firstName":"meiyi","middleName":"","lastName":"you","suffix":""},{"id":558510517,"identity":"ab7ff31a-e1b3-489e-a89d-d1e668717b19","order_by":1,"name":"Chunchu kong","email":"","orcid":"","institution":"Hunan Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chunchu","middleName":"","lastName":"kong","suffix":""},{"id":558510519,"identity":"e594047a-4483-4a65-bdda-7401ba1791bf","order_by":2,"name":"MU Mei","email":"","orcid":"","institution":"The First People's Hospital of Changde","correspondingAuthor":false,"prefix":"","firstName":"MU","middleName":"","lastName":"Mei","suffix":""},{"id":558510520,"identity":"ad2ede58-1346-4e33-910f-b474d1af9d62","order_by":3,"name":"Wenjun Pei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIie3RsQqCQBzH8b8I13LUehGd9ACBcBAJ4bP8D8FeodHpJh9B6iEC5wPBSXdHXZpc3NzKsSavLei++wf+P/4ANtsPRhbJecTxxAkU2owsqW5Zl8Zi6ZRoRjiT7bolhby6lW94GEToI3WlItXQ9BDyfTJLSkQ8EqFofQ8yiMRBzxEnRY2UbhWr8w0FLfNZ4q6GBAlzlNc/DMk0BpD4OwUVMSQUYpApimmUCDLfYIt3a2NnHJ/cS4qu6S8hnyUfMWr4mnfyrbDZbLa/6AXB10GeBwBGSQAAAABJRU5ErkJggg==","orcid":"","institution":"The First People's Hospital of Changde","correspondingAuthor":true,"prefix":"","firstName":"Wenjun","middleName":"","lastName":"Pei","suffix":""}],"badges":[],"createdAt":"2025-09-29 16:53:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7744188/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7744188/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98327027,"identity":"2dd25146-6938-4b7c-888b-33cf308bbee7","added_by":"auto","created_at":"2025-12-16 14:50:01","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1660260,"visible":true,"origin":"","legend":"","description":"","filename":"Figuresandtables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/24b15cd1fda6e10c5dbebdea.docx"},{"id":98327029,"identity":"9e45f19e-1106-4b83-a2da-f8b4d6999b38","added_by":"auto","created_at":"2025-12-16 14:50:01","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1699285,"visible":true,"origin":"","legend":"","description":"","filename":"Predictivevalueofperipheralbloodinflammatory.docx","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/d17a919bfe5b9bfc22922717.docx"},{"id":98438366,"identity":"f8bb275a-b9f5-47f4-80e9-edd5ad671f7a","added_by":"auto","created_at":"2025-12-17 16:59:07","extension":"json","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7384,"visible":true,"origin":"","legend":"","description":"","filename":"bd0053eb1d64429b9141355c3c558f45.json","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/abb66b6df2a5d023840a6cf0.json"},{"id":98436924,"identity":"99039d33-eb2b-4422-a683-38cfd9455e2f","added_by":"auto","created_at":"2025-12-17 16:56:28","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2584104,"visible":true,"origin":"","legend":"","description":"","filename":"83849ce7bda229d249288e7c7ff35ac1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/99625557811cef7929d68278.jpg"},{"id":98436950,"identity":"871af274-d267-4042-bf78-33538bbf52bf","added_by":"auto","created_at":"2025-12-17 16:56:30","extension":"jpg","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2555845,"visible":true,"origin":"","legend":"","description":"","filename":"8c0eff5053617c8e1963f5867231eeac.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/8bc1e43d8de4ac815107609c.jpg"},{"id":98327041,"identity":"1e30f9e1-c31d-4541-af6e-4b048c564353","added_by":"auto","created_at":"2025-12-16 14:50:01","extension":"jpg","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3128133,"visible":true,"origin":"","legend":"","description":"","filename":"c1704b2dfa2e78e96760e81b95e8f7c4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/553819f4032fa4beeced9e77.jpg"},{"id":98438140,"identity":"7771e754-439e-4d62-a3b1-c421e199f06e","added_by":"auto","created_at":"2025-12-17 16:58:42","extension":"jpg","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3181705,"visible":true,"origin":"","legend":"","description":"","filename":"fb96ed9cb9e04d796cd83fbf788f4c9d.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/24f508efbaf5dafbcf8561a1.jpg"},{"id":98438584,"identity":"64d572c5-5957-4ae9-89b4-3dc81e0acd61","added_by":"auto","created_at":"2025-12-17 16:59:33","extension":"xlsx","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":194581,"visible":true,"origin":"","legend":"","description":"","filename":"file.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/82a268e4ff095ef681fb723c.xlsx"},{"id":98438473,"identity":"d845b0bb-50d7-4be5-b175-1eef65d16702","added_by":"auto","created_at":"2025-12-17 16:59:18","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":387970,"visible":true,"origin":"","legend":"","description":"","filename":"bd0053eb1d64429b9141355c3c558f451enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/45c4ff52bbb6d6148948ed12.xml"},{"id":98436807,"identity":"c5fd5656-f9be-45a9-a1c8-c7e13b06ba94","added_by":"auto","created_at":"2025-12-17 16:56:17","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4316,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/16b5d34587e8f6c994cb8eb1.png"},{"id":98327032,"identity":"534124fd-06e6-40e6-af16-5e08601ab026","added_by":"auto","created_at":"2025-12-16 14:50:01","extension":"jpeg","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1074,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/bbb46d6855f6d9a3aebfefcd.jpeg"},{"id":98436100,"identity":"854343e1-5a16-4edd-b5e7-1f75cebf6508","added_by":"auto","created_at":"2025-12-17 16:54:56","extension":"wmf","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":472,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage11.wmf","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/28439ba7c2efee47122b422f.wmf"},{"id":98438562,"identity":"e9a4f184-1946-455b-be5f-b47964a96ace","added_by":"auto","created_at":"2025-12-17 16:59:33","extension":"jpeg","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":150982,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage12.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/54bb61065c8ac602b7732c6f.jpeg"},{"id":98327035,"identity":"82c7192f-2336-4496-808b-359382bb91c0","added_by":"auto","created_at":"2025-12-16 14:50:01","extension":"jpeg","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":195219,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage13.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/d780e305d68ca722685d63bc.jpeg"},{"id":98436978,"identity":"40102040-b3d9-4a39-9d56-08ba2a333d00","added_by":"auto","created_at":"2025-12-17 16:56:33","extension":"jpeg","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":157205,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage14.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/bdf2023cd63742d5cf242d63.jpeg"},{"id":98437021,"identity":"31f5bbc5-69f0-4d48-9def-90568fc544d6","added_by":"auto","created_at":"2025-12-17 16:56:48","extension":"jpeg","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":156276,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage15.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/baeb57d70eb66032dbad0315.jpeg"},{"id":98327045,"identity":"3d34d20e-ba9e-42c8-8f2b-5110a953ce76","added_by":"auto","created_at":"2025-12-16 14:50:01","extension":"jpeg","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":163604,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage16.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/3f1a11506ed6b04d7820d8df.jpeg"},{"id":98436137,"identity":"33cb4463-b092-4f70-90dd-04d8aa6f3ed9","added_by":"auto","created_at":"2025-12-17 16:54:58","extension":"jpeg","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":172065,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage17.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/1c51df9cbe830fc15a02c405.jpeg"},{"id":98327044,"identity":"b6e10083-4803-4528-ad1c-3c75f33a92e6","added_by":"auto","created_at":"2025-12-16 14:50:01","extension":"jpeg","order_by":20,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":61974,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage18.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/5db97e0a4df9c75e2600d7a6.jpeg"},{"id":98438249,"identity":"926e9d0e-43f7-4907-9c14-ac29064dbc80","added_by":"auto","created_at":"2025-12-17 16:58:51","extension":"wmf","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":472,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage11.wmf","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/edf92a12dacd6385e47a7c96.wmf"},{"id":98623174,"identity":"60e2ee77-926c-4b9a-abde-995599eba45e","added_by":"auto","created_at":"2025-12-19 17:05:01","extension":"png","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4316,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/e3f919c0c82a51e114b035e7.png"},{"id":98437447,"identity":"e2edcf45-0771-4b7a-a797-5f2a6239b65e","added_by":"auto","created_at":"2025-12-17 16:57:21","extension":"jpeg","order_by":23,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":180213,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage20.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/0b17654dc86034e897fa4487.jpeg"},{"id":98327057,"identity":"83b5f29a-6ac6-4d4f-b7b0-b93ae4f02183","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"jpeg","order_by":24,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":196573,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage21.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/987a1103f9ff685dcb1541b0.jpeg"},{"id":98436965,"identity":"abbd68f7-0cea-4841-b5dc-786b5e3de622","added_by":"auto","created_at":"2025-12-17 16:56:31","extension":"jpeg","order_by":25,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":169146,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage22.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/2f95af0289221674f8283c86.jpeg"},{"id":98327052,"identity":"1ff72266-b8e5-4044-b712-8cd88b38ea18","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"jpeg","order_by":26,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":159372,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage23.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/775f57462a94a05c96a3b871.jpeg"},{"id":98327058,"identity":"ed581358-a08a-4e3c-87d8-2e13ece157ba","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"jpeg","order_by":27,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":165604,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage24.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/85f246282264c169a26dde07.jpeg"},{"id":98436159,"identity":"1f05f160-0b44-4ccf-b7b8-40ddf0773679","added_by":"auto","created_at":"2025-12-17 16:55:00","extension":"jpeg","order_by":28,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":171219,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage25.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/4c38d293e99e9cdc239d641e.jpeg"},{"id":98436952,"identity":"39e791a2-ef84-4242-a380-2ddba5dc8379","added_by":"auto","created_at":"2025-12-17 16:56:30","extension":"jpeg","order_by":29,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":84872,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage26.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/deb15a9ad71c585b6e6583ec.jpeg"},{"id":98327071,"identity":"3689db7b-afeb-4056-b58e-85f8d2ac397b","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"png","order_by":30,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":60615,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage27.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/41d3ea9f16d2e83c88f42f00.png"},{"id":98327091,"identity":"d4e65505-15c9-471e-8e0f-2d74ea60166c","added_by":"auto","created_at":"2025-12-16 14:50:03","extension":"jpeg","order_by":31,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":209171,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage28.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/0f869e459977c99327531b3f.jpeg"},{"id":98327059,"identity":"9dc69efb-1664-4439-80b9-74a764913b3e","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"png","order_by":32,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":50640,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage29.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/03528cccc6ba12c4cdd85e22.png"},{"id":98437301,"identity":"a4200ca8-b2c6-4dca-adec-5b55f0aeaeb3","added_by":"auto","created_at":"2025-12-17 16:57:11","extension":"png","order_by":33,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5801,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/97430ae9eb770b29647fbcd2.png"},{"id":98327054,"identity":"d61444ed-b537-403a-8029-021c3a660b65","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"jpeg","order_by":34,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":200496,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage30.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/fe8847468129d698fd76c4f7.jpeg"},{"id":98438278,"identity":"ccbc81ce-b7e3-4fdc-9cc7-8032c76e4159","added_by":"auto","created_at":"2025-12-17 16:58:54","extension":"png","order_by":35,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":58015,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage31.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/c65d9e9a88fea43e57e5615b.png"},{"id":98436788,"identity":"01299739-14ae-475f-b940-9f3441a20181","added_by":"auto","created_at":"2025-12-17 16:56:15","extension":"jpeg","order_by":36,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":204219,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage32.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/0a75429260a58fc3457347b2.jpeg"},{"id":98327050,"identity":"66b6d629-bca5-4548-8de3-b50f727738cd","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"png","order_by":37,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":51008,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage33.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/9b82ee112633a41e5c6b6bea.png"},{"id":98436610,"identity":"2fb44a54-0282-4ee8-b794-6d08c1d2b069","added_by":"auto","created_at":"2025-12-17 16:55:59","extension":"jpeg","order_by":38,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":197453,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage34.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/4813ea26e05f9da979c044e2.jpeg"},{"id":98327066,"identity":"f9ecf9eb-c61b-419b-b57b-5813977afc0a","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"png","order_by":39,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4316,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/077c696ec59b66ec13fc94c9.png"},{"id":98327047,"identity":"888365a6-b2f3-4d00-af9f-acafd5200717","added_by":"auto","created_at":"2025-12-16 14:50:01","extension":"png","order_by":40,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4316,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/8655310ba9ca801e96bdaad5.png"},{"id":98327049,"identity":"5db9badf-a823-4b20-9437-1c6bd4c2654d","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"png","order_by":41,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5801,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/95b881cbe8681ab7332193e1.png"},{"id":98437561,"identity":"2d4af718-e016-47de-8944-017435697ebe","added_by":"auto","created_at":"2025-12-17 16:57:28","extension":"png","order_by":42,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4166,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage38.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/636ab7d504e51e52e1c73535.png"},{"id":98327072,"identity":"3bbf22d6-30e4-478d-8ff6-929a6bb6158a","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"png","order_by":43,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5873,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage39.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/0c0008aec19084bf34bd184a.png"},{"id":98438218,"identity":"c8811bdb-e15e-4ca4-baf1-a227b60f394c","added_by":"auto","created_at":"2025-12-17 16:58:49","extension":"png","order_by":44,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4166,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage38.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/b89db3e33813845ffd0f498f.png"},{"id":98327061,"identity":"67a4a475-e15c-470e-ac2a-65a3fffcd42d","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"png","order_by":45,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4383,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage40.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/afc55acd83e6522b7e47e5a3.png"},{"id":98327075,"identity":"b858ce1e-5a17-4d4b-83a5-c488bdffe34d","added_by":"auto","created_at":"2025-12-16 14:50:03","extension":"png","order_by":46,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5740,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage41.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/880b20d699038527916fe1a0.png"},{"id":98438277,"identity":"9649b577-617b-4225-868f-0890f41675bc","added_by":"auto","created_at":"2025-12-17 16:58:54","extension":"jpeg","order_by":47,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":272125,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage42.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/472657a1eed7b9173d72a42d.jpeg"},{"id":98327080,"identity":"da249f7f-57af-4833-92cb-f92feaf411a0","added_by":"auto","created_at":"2025-12-16 14:50:03","extension":"wmf","order_by":48,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":472,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage11.wmf","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/9cfd3f95a8672a3c35f5971c.wmf"},{"id":98438563,"identity":"219a546b-c649-4ba4-a560-a34d10c9c356","added_by":"auto","created_at":"2025-12-17 16:59:33","extension":"jpeg","order_by":49,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":150982,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage12.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/2b9515d243564bdf5c5d7e41.jpeg"},{"id":98327087,"identity":"619b7e93-144e-4434-a4b2-18f164c71a8e","added_by":"auto","created_at":"2025-12-16 14:50:03","extension":"jpeg","order_by":50,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":195219,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage13.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/c569f6c0a1d42aec48c73ec6.jpeg"},{"id":98327105,"identity":"cc15cd87-ab9d-4072-9d97-a27ff31e3dbc","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"jpeg","order_by":51,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":157205,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage14.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/da6b27f61003480413f6e2fc.jpeg"},{"id":98437023,"identity":"d9427e97-85ed-440c-b4ed-0b50e16ef6bc","added_by":"auto","created_at":"2025-12-17 16:56:48","extension":"jpeg","order_by":52,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":156276,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage15.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/6997c1d311ff6c9906ec88e3.jpeg"},{"id":98438019,"identity":"86e43a8f-35ff-4a7f-97a4-d9605292b2e3","added_by":"auto","created_at":"2025-12-17 16:58:27","extension":"jpeg","order_by":53,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":163604,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage16.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/255b6d033026be3667ee78fb.jpeg"},{"id":98438281,"identity":"f7080325-f669-466d-9047-38f58a9ba24a","added_by":"auto","created_at":"2025-12-17 16:58:56","extension":"jpeg","order_by":54,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":172065,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage17.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/7d35cd79fd3c0a252b899e30.jpeg"},{"id":98438261,"identity":"01a063e7-eaa0-4649-b6d6-436bb0be3e46","added_by":"auto","created_at":"2025-12-17 16:58:53","extension":"png","order_by":55,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5873,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage39.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/0db4ed1a6c8eb057a20cd8c2.png"},{"id":98327077,"identity":"fd64fd7c-84a7-4f49-834a-2b1ad0fd0cc4","added_by":"auto","created_at":"2025-12-16 14:50:03","extension":"jpeg","order_by":56,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":61974,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage18.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/11c5001e07d207ff82e58ace.jpeg"},{"id":98327081,"identity":"db2b8dc5-a7c4-4ffe-b09f-1d9b713fb99c","added_by":"auto","created_at":"2025-12-16 14:50:03","extension":"wmf","order_by":57,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":472,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage11.wmf","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/ab2ee22a4f3b9d1bf4629728.wmf"},{"id":98436395,"identity":"e0d55ce7-bf65-4a81-bd8b-3c6b4ef46248","added_by":"auto","created_at":"2025-12-17 16:55:37","extension":"jpeg","order_by":58,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":180213,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage20.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/eaa29bb4136096b628e2cb94.jpeg"},{"id":98437179,"identity":"0424dbd3-90ca-4148-8cf9-ca1299ef50a2","added_by":"auto","created_at":"2025-12-17 16:57:05","extension":"jpeg","order_by":59,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":196573,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage21.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/e71e4525001b99596f2d5317.jpeg"},{"id":98436614,"identity":"3c0e0e3b-3c9a-4da7-bf23-52438bdf4a7a","added_by":"auto","created_at":"2025-12-17 16:55:59","extension":"jpeg","order_by":60,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":169146,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage22.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/0826415787106af2c04505b2.jpeg"},{"id":98437183,"identity":"23a11d8a-cca6-4fdc-8753-1eadf08a8f92","added_by":"auto","created_at":"2025-12-17 16:57:06","extension":"jpeg","order_by":61,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":159372,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage23.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/67992ccba42c2dcf940e0a5c.jpeg"},{"id":98327063,"identity":"f06caf79-4b10-436d-a763-f3e6e7a22da7","added_by":"auto","created_at":"2025-12-16 14:50:02","extension":"jpeg","order_by":62,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":165604,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage24.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/1d76ab7ba77a99d4015b8387.jpeg"},{"id":98327084,"identity":"5f5d5336-a134-48f2-b4a5-42e3fd36fc10","added_by":"auto","created_at":"2025-12-16 14:50:03","extension":"jpeg","order_by":63,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":171219,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage25.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/68165c35c47eb0b935d9835d.jpeg"},{"id":98436926,"identity":"4495b0ac-ff21-4753-974f-ea68f864c6f7","added_by":"auto","created_at":"2025-12-17 16:56:28","extension":"jpeg","order_by":64,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":84872,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage26.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/a3ab1968e2a39f83002e7171.jpeg"},{"id":98436692,"identity":"020a5408-1d5e-4195-8b2f-ac352a6b3834","added_by":"auto","created_at":"2025-12-17 16:56:04","extension":"png","order_by":65,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":60615,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage27.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/4385b95bd54e834f6f2fb687.png"},{"id":98437338,"identity":"6cc553a8-3cdd-4f66-9556-ba0c557b9815","added_by":"auto","created_at":"2025-12-17 16:57:13","extension":"png","order_by":66,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4383,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage40.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/c138c45b4a6e2e345412602e.png"},{"id":98437465,"identity":"b6fb6bca-1475-43c1-bf8d-6ba9a2ad3ddf","added_by":"auto","created_at":"2025-12-17 16:57:22","extension":"jpeg","order_by":67,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":209171,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage28.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/0a6c62d5f465427232b00f63.jpeg"},{"id":98327099,"identity":"3183f019-2118-4feb-b49f-061ebe728262","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"png","order_by":68,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":50640,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage29.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/60dee648b4aee09ec67404b8.png"},{"id":98327108,"identity":"34e0fd62-3dc6-4023-b84f-ed39bc41f3d8","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"jpeg","order_by":69,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":200496,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage30.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/94aa04b64825b69022ed2720.jpeg"},{"id":98436890,"identity":"5317cb55-269f-4135-be52-4f0ee720781c","added_by":"auto","created_at":"2025-12-17 16:56:24","extension":"png","order_by":70,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":58015,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage31.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/43b37f6d9bb4d72e875049a3.png"},{"id":98438129,"identity":"d21a082d-67b4-4f72-9d2d-4c14b2329899","added_by":"auto","created_at":"2025-12-17 16:58:41","extension":"jpeg","order_by":71,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":204219,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage32.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/461a2d8e53a1350d1061ca37.jpeg"},{"id":98437731,"identity":"5a4d64eb-b740-409b-940f-0c4e28e45298","added_by":"auto","created_at":"2025-12-17 16:57:37","extension":"png","order_by":72,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":51008,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage33.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/871dd7ea6d43ceb463f6881d.png"},{"id":98327137,"identity":"ce97f03e-470a-45f4-b039-57bc7856b91d","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"jpeg","order_by":73,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":197453,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage34.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/60e82355ce84fc57385bf114.jpeg"},{"id":98438753,"identity":"a2f3d3f3-e13b-4c41-8483-ff1a1153733a","added_by":"auto","created_at":"2025-12-17 16:59:59","extension":"png","order_by":74,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5740,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage41.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/9c05bf721edd6b60f6e6cc0c.png"},{"id":98327106,"identity":"baca1058-d4f5-40cc-9af8-a6ea99d5943a","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"png","order_by":75,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4592,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/2f3047e27de5ba2a3df4eeff.png"},{"id":98327093,"identity":"2896bd25-2046-4bd6-9cad-577fcf58ca49","added_by":"auto","created_at":"2025-12-16 14:50:03","extension":"png","order_by":76,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5823,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/6b96b83ba6dfbc413a3b4c1f.png"},{"id":98327102,"identity":"43706ce6-1a8e-4d8c-a79c-07fc845efbe2","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"jpeg","order_by":77,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":69085,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/4f96728a24d44efd7652dba2.jpeg"},{"id":98436371,"identity":"12dc8717-104e-4950-8621-5acbd85f2051","added_by":"auto","created_at":"2025-12-17 16:55:31","extension":"jpeg","order_by":78,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":885,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/57a1f1d1a31a0e6f7477e6ce.jpeg"},{"id":98327111,"identity":"b24ff2c3-a3f7-40f3-984d-4d63a211b830","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"jpeg","order_by":79,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":886,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage11.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/a547bbec523d8c655c20e762.jpeg"},{"id":98327153,"identity":"331fb521-6365-4260-8ccb-95a84ef77126","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"jpeg","order_by":80,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":67390,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/592a4b9ebbb948392df4fc13.jpeg"},{"id":98438392,"identity":"0d4b0487-f8e1-4b09-8e97-2dd4106b808a","added_by":"auto","created_at":"2025-12-17 16:59:10","extension":"jpeg","order_by":81,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":974,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/6e8e2f49c8a5399fef209fcc.jpeg"},{"id":98327139,"identity":"94bf79ba-4d92-422e-adc6-665ea404a032","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"jpeg","order_by":82,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":885,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage10.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/c7dd708d348bdd2591c125f1.jpeg"},{"id":98437660,"identity":"e0c114b0-8be8-4317-a032-4ce954479388","added_by":"auto","created_at":"2025-12-17 16:57:32","extension":"jpeg","order_by":83,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":886,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage11.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/519f62fd8f9180225420c515.jpeg"},{"id":98436299,"identity":"cc16ac60-f8f3-4297-8885-7d8bbb51dc5b","added_by":"auto","created_at":"2025-12-17 16:55:19","extension":"jpeg","order_by":84,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":893,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage6.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/d9fecf39d2824699189e9b81.jpeg"},{"id":98436901,"identity":"f613fc18-6304-4531-b04d-2affbaf4b551","added_by":"auto","created_at":"2025-12-17 16:56:26","extension":"jpeg","order_by":85,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":69085,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/b22ac3f5eea1738ae6ae5f24.jpeg"},{"id":98327095,"identity":"c97d5a0f-e341-4ccf-9599-dedda532fa0e","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"jpeg","order_by":86,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":67390,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/b1ba2d6393fd718a62222287.jpeg"},{"id":98438161,"identity":"f61b7dc2-56ca-4c98-83ac-c44eef615f69","added_by":"auto","created_at":"2025-12-17 16:58:43","extension":"jpeg","order_by":87,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":974,"visible":true,"origin":"","legend":"","description":"","filename":"groupimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/438bcb0e9467e1ccf10f933d.jpeg"},{"id":98438769,"identity":"b4cdcbe5-78f7-44e2-96e9-369442a682f7","added_by":"auto","created_at":"2025-12-17 17:00:01","extension":"wmf","order_by":88,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":472,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage11.wmf","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/8dd4cbfffaebb8ac554ec695.wmf"},{"id":98327121,"identity":"c75ed464-6952-40c1-ae95-ad65fe1141e5","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"png","order_by":89,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2462,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/0f2f0a2cb3a4b95c372aa1d0.png"},{"id":98436625,"identity":"ba291e15-8987-4e73-aad8-6ffd3d15fe9f","added_by":"auto","created_at":"2025-12-17 16:56:00","extension":"png","order_by":90,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":935,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/e2cbd96a23d1796651958339.png"},{"id":98438219,"identity":"a35289c6-18a0-4308-98e4-a2229d7d06bf","added_by":"auto","created_at":"2025-12-17 16:58:49","extension":"png","order_by":91,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":323,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/6e216e63ac1d67ddf314ab70.png"},{"id":98436834,"identity":"a8a50ae7-b1f6-43bf-847e-d8ce7e5babdb","added_by":"auto","created_at":"2025-12-17 16:56:19","extension":"png","order_by":92,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":34643,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage12.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/a570fd16796143b10e9b9704.png"},{"id":98327147,"identity":"97d9056e-5102-4f22-85f5-50edbb222326","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"png","order_by":93,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":44877,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage13.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/88fffc28c2cb883bb8965489.png"},{"id":98327100,"identity":"06dbc7af-6e0f-4c3b-b1eb-ab4202c54780","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"png","order_by":94,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35294,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/d669121b601db91ae57c3b5f.png"},{"id":98436230,"identity":"a99f711f-1848-42e7-be70-5542c08daf92","added_by":"auto","created_at":"2025-12-17 16:55:09","extension":"png","order_by":95,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":33604,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage15.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/52d5970703fb9e61fd31a9ea.png"},{"id":98327124,"identity":"29696d88-0eff-4a58-921a-4b15a9db28ef","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"png","order_by":96,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35993,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage16.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/f7a741b671fe88c03aba0b0f.png"},{"id":98436599,"identity":"de6cbae5-ecea-4c53-b2ae-b3703ceff322","added_by":"auto","created_at":"2025-12-17 16:55:58","extension":"png","order_by":97,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37420,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage17.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/dad2fc7d6e350210aed93a0e.png"},{"id":98438725,"identity":"618bce3d-560a-4443-bba2-6d80b127340e","added_by":"auto","created_at":"2025-12-17 16:59:55","extension":"png","order_by":98,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14253,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage18.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/928bf3f8749ec44ab979eb82.png"},{"id":98438206,"identity":"52c3c91d-4429-4535-8599-cd9c8123f679","added_by":"auto","created_at":"2025-12-17 16:58:47","extension":"png","order_by":99,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":323,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/f8fa70a600a90e928b8ebe3a.png"},{"id":98438629,"identity":"4297e6f4-6314-4470-ad38-ec0d28fb73ef","added_by":"auto","created_at":"2025-12-17 16:59:40","extension":"png","order_by":100,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2462,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/4c2a9e76015981f0846539c0.png"},{"id":98327165,"identity":"77d9f87a-fc30-4489-921b-fd3bf2342d89","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":101,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38516,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage20.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/68651c51cd686518a57ffb75.png"},{"id":98327113,"identity":"687d9503-6c52-4b4a-9c38-f24d1404b908","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"png","order_by":102,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":42994,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage21.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/9a787800182674f73a522f5d.png"},{"id":98436804,"identity":"ccb79ace-021d-4773-9255-04e4ca9aa4e7","added_by":"auto","created_at":"2025-12-17 16:56:15","extension":"png","order_by":103,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35906,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage22.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/494a94feb2ab3966517bfb49.png"},{"id":98436556,"identity":"e73f6699-8804-4588-9964-6dc190a5aca6","added_by":"auto","created_at":"2025-12-17 16:55:52","extension":"png","order_by":104,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":34580,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage23.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/a954da29e40a9992f829269b.png"},{"id":98327133,"identity":"08784bf0-8575-4a3d-bac1-dcebf18807c7","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"png","order_by":105,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37360,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage24.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/4f9a90cfc9268cc6d9b0fe14.png"},{"id":98436606,"identity":"82e36c05-cd39-4368-851c-9301d7e6ba42","added_by":"auto","created_at":"2025-12-17 16:55:59","extension":"png","order_by":106,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":39340,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage25.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/a77d817b3941648c35998731.png"},{"id":98438312,"identity":"551bcb75-83a0-44ef-a2ed-aa60df1e2c13","added_by":"auto","created_at":"2025-12-17 16:58:59","extension":"png","order_by":107,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":19334,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage26.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/339717aad79cdc651450dfa2.png"},{"id":98327183,"identity":"322845e8-c127-44f2-bd48-78462f081070","added_by":"auto","created_at":"2025-12-16 14:50:07","extension":"png","order_by":108,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":22867,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage27.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/99c7e41df7f536b4955f0d8d.png"},{"id":98437721,"identity":"cfda25b3-07d1-4720-93ad-9992bb0c4d8a","added_by":"auto","created_at":"2025-12-17 16:57:36","extension":"png","order_by":109,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38768,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage28.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/8505f24c7f5d1750a14353ee.png"},{"id":98436892,"identity":"0beed50c-5dd4-4c0d-9816-bb183c050dbe","added_by":"auto","created_at":"2025-12-17 16:56:24","extension":"png","order_by":110,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":18755,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage29.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/46dca5fcea04fad296dd8100.png"},{"id":98327117,"identity":"52268e2a-1502-410e-900a-cdc1f1a1e1eb","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"png","order_by":111,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3532,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/736db4947531cec508885b03.png"},{"id":98327177,"identity":"bb58a988-87b8-44bf-accb-c341eb14adb0","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":112,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35633,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage30.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/27a71346b461de0e1b139097.png"},{"id":98327143,"identity":"9edb8874-b874-4d0f-89a6-f18529619e38","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"png","order_by":113,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":21490,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage31.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/a31b554e212c867edf24e9b3.png"},{"id":98437335,"identity":"4d6c0e47-6ea3-46ac-9de5-d4c24b13d2eb","added_by":"auto","created_at":"2025-12-17 16:57:13","extension":"png","order_by":114,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38468,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage32.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/364a8fde8273f74a7ed46728.png"},{"id":98437236,"identity":"4c302a1f-0afb-4070-a200-7d0faab18745","added_by":"auto","created_at":"2025-12-17 16:57:09","extension":"png","order_by":115,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":18916,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage33.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/bab4feb0ff62b8cd38a27b3b.png"},{"id":98327110,"identity":"0c5ada8e-cfa2-4bdf-b2eb-1b420314314d","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"png","order_by":116,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35695,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage34.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/6e04d2c3093511cb7bbbcc42.png"},{"id":98436765,"identity":"ddfd2645-a01d-417c-94b1-3c5a4d9beb1a","added_by":"auto","created_at":"2025-12-17 16:56:13","extension":"png","order_by":117,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2462,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/30a1cbb88c83a73a4fc10f09.png"},{"id":98327180,"identity":"aa5915a3-3c21-4123-98b6-72f758e915bf","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":118,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2462,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/7bcde8699e18d5aa06a327e7.png"},{"id":98327115,"identity":"2e81a33d-6732-474c-b9d7-0d0de040d132","added_by":"auto","created_at":"2025-12-16 14:50:04","extension":"png","order_by":119,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3532,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/b3335005287cdedaad9cd3d9.png"},{"id":98327185,"identity":"4a967b8e-8b48-4d9d-b1c2-6da61753acf4","added_by":"auto","created_at":"2025-12-16 14:50:07","extension":"png","order_by":120,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2476,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage38.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/502e2f3b350f6e297af28ee7.png"},{"id":98437061,"identity":"3b415da3-10aa-455c-afc4-9a19baaaa86d","added_by":"auto","created_at":"2025-12-17 16:56:52","extension":"png","order_by":121,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3580,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage39.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/9ef8bc6c9d5d62f1e98d39e7.png"},{"id":98436858,"identity":"5fb376b2-21c2-4665-9462-4b928adf303c","added_by":"auto","created_at":"2025-12-17 16:56:21","extension":"png","order_by":122,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2476,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage38.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/137c713593b24314216aee1d.png"},{"id":98438136,"identity":"46d9969a-38a1-4181-bf47-eeae2e6b92c8","added_by":"auto","created_at":"2025-12-17 16:58:41","extension":"png","order_by":123,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2468,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage40.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/88c8544a4088944abc3d280c.png"},{"id":98327161,"identity":"27c51437-de0d-4870-b15b-a0ce818e7a55","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":124,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3509,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage41.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/0f05c29f059148bb3569c5a2.png"},{"id":98327128,"identity":"a190e026-7e91-4690-bd0f-36fe319d5d9e","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"png","order_by":125,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":42123,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage42.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/d7ae8f4759a6af6474e51529.png"},{"id":98436398,"identity":"f8178ff5-8ba9-4115-8956-61e9c857d4f1","added_by":"auto","created_at":"2025-12-17 16:55:37","extension":"png","order_by":126,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":323,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/c6e83ad9dddb6caa41eeccaa.png"},{"id":98436747,"identity":"72dafcbe-ecc9-4638-a6ed-f755b7057b18","added_by":"auto","created_at":"2025-12-17 16:56:12","extension":"png","order_by":127,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":34643,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage12.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/77b255f79c6a6b0cb32a9893.png"},{"id":98438226,"identity":"545d9a33-baf0-4003-b274-0287836f124d","added_by":"auto","created_at":"2025-12-17 16:58:50","extension":"png","order_by":128,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":44877,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage13.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/4b08f3b34e78618febc53c45.png"},{"id":98327154,"identity":"605d7958-fcf1-4ed1-bc1b-bd5246689d72","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":129,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35294,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage14.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/3f6af6733c2e45bdadb58153.png"},{"id":98327158,"identity":"c133b675-2163-457d-bf76-b24817724e84","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":130,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":33604,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage47.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/38887c503c7b4ae9f6aea72f.png"},{"id":98327187,"identity":"ece70348-c577-4c4e-ab3e-7d66a8491cae","added_by":"auto","created_at":"2025-12-16 14:50:07","extension":"png","order_by":131,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35993,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage48.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/d8ee61a155a1824910bd6227.png"},{"id":98437822,"identity":"13033c85-3bf4-476b-a90d-e9b6df598a6a","added_by":"auto","created_at":"2025-12-17 16:58:05","extension":"png","order_by":132,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37420,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage49.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/75947f3d905f299bdda90c5d.png"},{"id":98436801,"identity":"72e2de78-68e0-44c9-afda-9cc7bdd7d065","added_by":"auto","created_at":"2025-12-17 16:56:15","extension":"png","order_by":133,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3580,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage39.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/9122f5ccfff08ba3e874e117.png"},{"id":98438227,"identity":"5246e409-71f6-4b76-a51c-e215b36b12a8","added_by":"auto","created_at":"2025-12-17 16:58:50","extension":"png","order_by":134,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14253,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage18.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/7265467868c954119524d0db.png"},{"id":98622393,"identity":"11f9342d-b684-4f95-a411-f04917e7160e","added_by":"auto","created_at":"2025-12-19 16:53:55","extension":"png","order_by":135,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":323,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/e99e5df512136ce623e0a1d0.png"},{"id":98438319,"identity":"87af8665-551c-44ef-874f-a0c26b0e7084","added_by":"auto","created_at":"2025-12-17 16:58:59","extension":"png","order_by":136,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38516,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage20.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/ce4805b04d7fec6256b9a11d.png"},{"id":98327130,"identity":"28365ea7-8c45-45a1-a8ed-c347ff65fcb3","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"png","order_by":137,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":42994,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage21.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/ec5b630e23dc4a974d0d12b8.png"},{"id":98437907,"identity":"cef22039-5a2d-4299-b57a-03505d563dec","added_by":"auto","created_at":"2025-12-17 16:58:13","extension":"png","order_by":138,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35906,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage22.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/642d5a9f731b18ba5f29d63c.png"},{"id":98436845,"identity":"f9eb6594-4b44-41dd-9e91-11f8f5c8582f","added_by":"auto","created_at":"2025-12-17 16:56:19","extension":"png","order_by":139,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":34580,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage55.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/423866f7b5c19ed4880727f4.png"},{"id":98436842,"identity":"87d78c31-abfa-4da3-b7ac-19eae0befec1","added_by":"auto","created_at":"2025-12-17 16:56:19","extension":"png","order_by":140,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37360,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage56.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/2f5899f1d94b8a290912712d.png"},{"id":98438071,"identity":"c2d69550-2dc1-4314-8742-8def208622e7","added_by":"auto","created_at":"2025-12-17 16:58:37","extension":"png","order_by":141,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":39340,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage57.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/1a29b4e6c4a53ae3a59aed01.png"},{"id":98327141,"identity":"8147582d-f990-44cb-a6f8-0918155fb9a8","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"png","order_by":142,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":19334,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage58.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/ba90a2ebdc7316bca161f70f.png"},{"id":98327176,"identity":"0c73d1ab-ed74-41c9-a50b-b5b4ec97b031","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":143,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":22867,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage59.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/48a49aa5d321b12ad886c0c9.png"},{"id":98437109,"identity":"db2595dc-b5e7-41fd-b901-589fc46d582e","added_by":"auto","created_at":"2025-12-17 16:56:59","extension":"png","order_by":144,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2468,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage40.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/af7f5c5344f20c8c32bfbd65.png"},{"id":98436360,"identity":"0648250b-dd8f-47ce-a205-42d5b8508d71","added_by":"auto","created_at":"2025-12-17 16:55:30","extension":"png","order_by":145,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38768,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage60.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/e96eabcc56cf531f71a4c0af.png"},{"id":98327168,"identity":"86e4b321-534b-4eca-811d-b48a7655bca1","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":146,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":18755,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage29.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/93120308c8cd75737e6f39b3.png"},{"id":98438198,"identity":"a4c7bff6-8889-4fcb-8261-059511fc48e3","added_by":"auto","created_at":"2025-12-17 16:58:47","extension":"png","order_by":147,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35633,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage62.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/818dd84eb750c73ab36dbf4a.png"},{"id":98437024,"identity":"2ffcec2b-3207-4593-a2f2-9ce320b596b6","added_by":"auto","created_at":"2025-12-17 16:56:48","extension":"png","order_by":148,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":21490,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage63.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/1de9fe3fed7429ada7fcda07.png"},{"id":98437910,"identity":"7c7a1af8-6e9b-430c-bc73-01949d1c1d6c","added_by":"auto","created_at":"2025-12-17 16:58:13","extension":"png","order_by":149,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38468,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage64.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/dc20479ebd797f6e48f2105b.png"},{"id":98438354,"identity":"2605f4fa-eeb6-4555-a035-9d292cd0373c","added_by":"auto","created_at":"2025-12-17 16:59:04","extension":"png","order_by":150,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":18916,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage65.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/7b98265aa5ae26636853e577.png"},{"id":98327166,"identity":"12e30fcc-622f-4d19-942d-3f5b81a9988e","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":151,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35695,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage66.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/62c713cba747cfc1c923a8b3.png"},{"id":98438201,"identity":"36a97b0e-c0ae-4e38-b871-d409f51361f1","added_by":"auto","created_at":"2025-12-17 16:58:47","extension":"png","order_by":152,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3509,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage41.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/5c1ee9d65e54836a7688bdc4.png"},{"id":98438702,"identity":"7c4cd50a-3e10-4c80-8d5c-6e163284fcb0","added_by":"auto","created_at":"2025-12-17 16:59:54","extension":"png","order_by":153,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2830,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage8.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/6005b8d0d265c132ed38a8d5.png"},{"id":98327146,"identity":"0a16d7eb-bae1-4e0d-93a3-bafb59fd94be","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"png","order_by":154,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":3559,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage9.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/3b478d283a104b5288c0d2ab.png"},{"id":98438386,"identity":"4a16cfcc-662f-4f68-b196-53159ad91093","added_by":"auto","created_at":"2025-12-17 16:59:10","extension":"png","order_by":155,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38509,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/b8b5dd0c74f3e9979c8b7c61.png"},{"id":98438056,"identity":"681134f9-a577-4465-b669-9a5c118b3bf6","added_by":"auto","created_at":"2025-12-17 16:58:34","extension":"png","order_by":156,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":796,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/212225fdef69419d081d74d8.png"},{"id":98327164,"identity":"9d60fd2f-a21f-4c55-ad3e-723b89217228","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":157,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":839,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/29c07a42d9cdff786f2e4ea0.png"},{"id":98438205,"identity":"94bf655d-568f-425e-b99a-9f4634a72e49","added_by":"auto","created_at":"2025-12-17 16:58:47","extension":"png","order_by":158,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38390,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/df46a6e683ca9d4c74fcb865.png"},{"id":98327194,"identity":"de50b964-ecf7-47b0-b9c1-0e0292ad20e6","added_by":"auto","created_at":"2025-12-16 14:50:07","extension":"png","order_by":159,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":894,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/ecc3b9f0b068c719010bea8c.png"},{"id":98327189,"identity":"e4b37fe5-b4a5-494d-9a5f-8a17594fd4ec","added_by":"auto","created_at":"2025-12-16 14:50:07","extension":"png","order_by":160,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":796,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/fa02ad2ea671b2a73c9d5c55.png"},{"id":98327173,"identity":"10584098-09d2-4741-af97-d014c9989898","added_by":"auto","created_at":"2025-12-16 14:50:06","extension":"png","order_by":161,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":839,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/6d8252fd2e45e74009eea904.png"},{"id":98436824,"identity":"30ab5f66-e4f5-43df-b087-c06f094141fb","added_by":"auto","created_at":"2025-12-17 16:56:18","extension":"png","order_by":162,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":852,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/bda9e5865885195758154a9c.png"},{"id":98437090,"identity":"eb3e9729-cac2-4605-b0cc-403cfc106bcc","added_by":"auto","created_at":"2025-12-17 16:56:56","extension":"png","order_by":163,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38509,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/61a02a6ba984025a8b7a9b59.png"},{"id":98438090,"identity":"1777a4a3-4433-4281-a775-3baa07de6440","added_by":"auto","created_at":"2025-12-17 16:58:37","extension":"png","order_by":164,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":38390,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/0ea223304b4e203ab0c6d895.png"},{"id":98327195,"identity":"9fea7cb5-f0a5-4490-9534-351723af5a40","added_by":"auto","created_at":"2025-12-16 14:50:07","extension":"png","order_by":165,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":894,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinegroupimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/8fa20242e19163922de2b6df.png"},{"id":98327135,"identity":"37575b69-0db5-4178-9643-ed0c1cc8f304","added_by":"auto","created_at":"2025-12-16 14:50:05","extension":"png","order_by":166,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":323,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/73e89039ab6b7ed6cb162498.png"},{"id":98437204,"identity":"e4449129-535e-4740-b341-e3a2a928280e","added_by":"auto","created_at":"2025-12-17 16:57:07","extension":"xml","order_by":167,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":383928,"visible":true,"origin":"","legend":"","description":"","filename":"bd0053eb1d64429b9141355c3c558f451structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/d67423b84e1ff238ba3c8bd4.xml"},{"id":98436930,"identity":"d4b5aed4-cd9c-4089-bfbc-13c772808f76","added_by":"auto","created_at":"2025-12-17 16:56:28","extension":"html","order_by":168,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":420383,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/d0f90180a7f183c996d256c0.html"},{"id":101202212,"identity":"752dea03-498c-46c1-8f92-d256cb29f59e","added_by":"auto","created_at":"2026-01-27 09:26:37","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1655532,"visible":true,"origin":"","legend":"","description":"","filename":"Predictivevalueofperipheralbloodinflammatory.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1_covered_b3f61c41-4790-44aa-8794-8d516da7091a.pdf"},{"id":98436537,"identity":"c56f9270-dcbc-48cd-8f8b-813bfe83dbf8","added_by":"auto","created_at":"2025-12-17 16:55:51","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":194581,"visible":true,"origin":"","legend":"","description":"","filename":"file.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7744188/v1/f5e0314e802e21947f6eb870.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Predictive value of peripheral blood inflammatory biomarkers in immunotherapy for extensive-stage small-cell lung cancer","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"
[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"extensive-stage small-cell lung cancer, immunotherapy, peripheral blood inflammatory biomarkers, neutrophil-to-lymphocyte ratio, prognostic model","lastPublishedDoi":"10.21203/rs.3.rs-7744188/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7744188/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe clinical management of extensive-stage small-cell lung cancer (ES-SCLC) is challenged by the lack of reliable biomarkers to identify patients resistant to first-line immunotherapy. Peripheral blood inflammatory biomarkers are emerging as promising prognostic tools in oncology, but their predictive role in ES-SCLC remains unclear.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a multicenter retrospective study of patients with ES-SCLC treated between January 2020 and January 2024 in two hospitals. Baseline clinical data and peripheral blood inflammatory indices\u0026mdash;including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), mean platelet volume (MPV), modified Glasgow Prognostic Score (mGPS), and Lung Immune Prognostic Index (LIPI)\u0026mdash;were collected before treatment and after four cycles of immunochemotherapy. Optimal cut-off values were determined using X-tile software, and dynamic changes (Δ) were calculated. Survival analyses were performed with Kaplan\u0026ndash;Meier and Cox proportional hazards models. Prognostic nomograms were developed and validated with calibration curves and receiver operating characteristic (ROC) analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 212 patients were included, with a median follow-up of 16.2 months. The objective response rate (ORR) and disease control rate (DCR) were 46.7% and 72.2%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 8.4 and 15.3 months. High pre-treatment NLR, high pre-treatment MPV, increased ΔNLR, pre-mGPS score of 2, and elevated ΔmGPS or ΔLIPI were independent predictors of shorter PFS. For OS, high pre-treatment NLR, pre-mGPS score of 2, pre-LIPI score of 2, and increased ΔNLR, ΔmGPS, or ΔLIPI were independent risk factors. The nomograms demonstrated good predictive accuracy for both PFS and OS, with area under the curve (AUC) values ranging from 0.728 to 0.946.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePeripheral blood inflammatory biomarkers, particularly pre-NLR, ΔNLR, pre-mGPS, and ΔLIPI, are independent predictors of outcomes in ES-SCLC patients receiving first-line immunotherapy. The proposed nomograms provide effective tools for individualized risk stratification and treatment optimization.\u003c/p\u003e","manuscriptTitle":"Predictive value of peripheral blood inflammatory biomarkers in immunotherapy for extensive-stage small-cell lung cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-16 14:49:55","doi":"10.21203/rs.3.rs-7744188/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"
[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e6fd125d-3314-4d92-9909-f5c791c655bc","owner":[],"postedDate":"December 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-27T09:26:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-16 14:49:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7744188","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7744188","identity":"rs-7744188","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}
Text is read by the "Ask this paper" AI Q&A widget below.
Extraction quality varies by source — PMC NXML preserves structure
cleanly, OA-HTML may include some navigation residue, and OA-PDF can
have broken hyphenation. The publisher copy
(via DOI)
is the canonical version.