{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T16:19:06Z","timestamp":1776701946947,"version":"3.51.2"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Nephrol"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tacrolimus is a cornerstone of lifelong immunosuppressive therapy to prevent acute rejection post-kidney transplantation. Tacrolimus intra-patient variability (IPV) is characterized by several pharmacokinetic metrics, including the standard deviation (SD) of tacrolimus troughs, coefficient of variation (CV%), dose-normalized concentration (DNC), and time in therapeutic range (TTR). This study aimed to investigate the influence of TTR, alongside other IPV metrics, on the incidence of acute rejection in the first year after kidney transplantation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single-center retrospective study evaluated the relationship between IPV measures including coefficient of variation (CV%), standard deviation (SD), dose-normalized concentration (DNC), time in therapeutic range (TTR), and acute rejection during the first post-transplant year in 100 pediatric kidney recipients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Patients were stratified by TTR into two subgroups: TTR\u2009&lt;\u200978% (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200980) and TTR\u2009\u2265\u200978% (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200920). The mean CV% of tacrolimus concentration was 37.1\u2009\u00b1\u200916.6%, with significantly higher variability observed in those with rejection (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.031). Longitudinal analysis showed that differences in trough levels between TTR groups became evident after 3\u00a0months (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Multivariable modeling demonstrated that rejection risk was independently associated with higher age (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.002) and post-transplant period beyond 3\u00a0months (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.004), rather than TTR itself.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In pediatric kidney transplant patients, the rejection risk was significantly associated with the magnitude of CV% rather than TTR. Special attention is warranted for therapeutic drug monitoring, especially beyond 3\u00a0months post-transplant, due to the increased risk of rejection compared to earlier stages post-transplantation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                    <jats:p>A higher resolution version of the Graphical abstract is available as Supplementary information<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00467-025-07028-1","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T12:03:12Z","timestamp":1766404992000},"page":"1477-1488","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Influence of intrapatient variability in tacrolimus trough levels on acute rejection in pediatric kidney transplant recipients"],"prefix":"10.1007","volume":"41","author":[{"given":"Fatina I.","family":"Fadel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel H.","family":"Makar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esraa Ehab","family":"Abbas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmoud Ibrahim","family":"Mostafa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed Ahmed","family":"Mobarez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shorouk A.","family":"Othman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"7028_CR1","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1159\/000514550","volume":"52","author":"JS Thurlow","year":"2021","unstructured":"Thurlow JS, Joshi M, Yan G, Norris KC, Agodoa LY, Yuan CM, Nee R (2021) Global epidemiology of end-stage kidney disease and disparities in kidney replacement therapy. Am J Nephrol 52:98\u2013107","journal-title":"Am J Nephrol"},{"key":"7028_CR2","doi-asserted-by":"publisher","first-page":"2824","DOI":"10.1111\/ajt.16463","volume":"21","author":"ED Poggio","year":"2021","unstructured":"Poggio ED, Augustine JJ, Arrigain S, Brennan DC, Schold JD (2021) Long-term kidney transplant graft survival making progress when most needed. Am J Transplant 21:2824\u20132832","journal-title":"Am J Transplant"},{"key":"7028_CR3","first-page":"905","volume-title":"Pediatric Kidney Disease","author":"B T\u00f6nshoff","year":"2008","unstructured":"T\u00f6nshoff B, Melk A (2008) Immunosuppression in pediatric kidney transplantation. In: Geary D, Schaefer F (eds) Pediatric Kidney Disease. Mosby, Maryland Heights, MO, pp 905\u2013929"},{"key":"7028_CR4","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/ajt.15672","volume":"20","author":"A Hart","year":"2020","unstructured":"Hart A, Smith JM, Skeans MA, Gustafson SK, Wilk AR, Castro S, Israni A (2020) OPTN\/SRTR 2018 annual data report: kidney. Am J Transplant 20:20\u2013130","journal-title":"Am J Transplant"},{"key":"7028_CR5","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.anclin.2017.04.001","volume":"35","author":"CD Holt","year":"2017","unstructured":"Holt CD (2017) Overview of immunosuppressive therapy in solid organ transplantation. Anesthesiol Clin 35:365\u2013380","journal-title":"Anesthesiol Clin"},{"key":"7028_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/j.trre.2024.100842","volume":"38","author":"W Xie","year":"2024","unstructured":"Xie W, Fan S, Liu R, Yan W, Su C, Zheng K, Wang Z (2024) Tacrolimus intra-patient variability measures and its associations with allograft clinical outcomes in kidney transplantation. Transplant Rev 38:100842","journal-title":"Transplant Rev"},{"key":"7028_CR7","doi-asserted-by":"publisher","first-page":"88","DOI":"10.3109\/03602532.2016.1151037","volume":"48","author":"T Vanhove","year":"2016","unstructured":"Vanhove T, Annaert P, Kuypers DR (2016) Clinical determinants of calcineurin inhibitor disposition: a mechanistic review. Drug Metab Rev 48:88\u2013112","journal-title":"Drug Metab Rev"},{"key":"7028_CR8","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.2215\/CJN.16421221","volume":"17","author":"KH Piburn","year":"2022","unstructured":"Piburn KH, Sigurjonsdottir VK, Indridason OS, Maestretti L, Patton MV, McGrath A, Palsson R, Gallo A, Chaudhuri A, Grimm PC (2022) Patterns in tacrolimus variability and association with de novo donor-specific antibody formation in pediatric kidney transplant recipients. Clin J Am Soc Nephrol 17:1194\u20131203","journal-title":"Clin J Am Soc Nephrol"},{"key":"7028_CR9","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1111\/ajt.16002","volume":"20","author":"HM Gonzales","year":"2020","unstructured":"Gonzales HM, McGillicuddy JW, Rohan V, Chandler JL, Nadig SN, Dubay DA, Taber DJ (2020) A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation. Am J Transplant 20:1969\u20131983","journal-title":"Am J Transplant"},{"key":"7028_CR10","doi-asserted-by":"publisher","DOI":"10.1111\/petr.14036","volume":"25","author":"MM Chandran","year":"2021","unstructured":"Chandran MM, Blanchette E, Goebel J, Bock M (2021) Impact of once-daily ER-tac on trough concentration variability in a stable AYA renal transplant recipient cohort. Pediatr Transplant 25:e14036","journal-title":"Pediatr Transplant"},{"key":"7028_CR11","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1007\/s00467-016-3422-5","volume":"31","author":"HP Pizzo","year":"2016","unstructured":"Pizzo HP, Ettenger RB, Gjertson DW et al (2016) Sirolimus and tacrolimus coefficient of variation is associated with rejection, donor-specific antibodies, and nonadherence. Pediatr Nephrol 31:2345\u20132352","journal-title":"Pediatr Nephrol"},{"key":"7028_CR12","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1111\/j.1399-3046.2010.01409.x","volume":"14","author":"SM Pollock-Barziv","year":"2010","unstructured":"Pollock-Barziv SM, Finkelstein Y, Manlhiot C et al (2010) Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children. Pediatr Transplant 14:968\u2013975","journal-title":"Pediatr Transplant"},{"key":"7028_CR13","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1093\/ndt\/gfw394","volume":"32","author":"B Rozen-Zvi","year":"2017","unstructured":"Rozen-Zvi B, Schneider S, Lichtenberg S et al (2017) Association of the combination of time-weighted variability of tacrolimus blood level and exposure to low drug levels with graft survival after kidney transplantation. Nephrol Dial Transplant 32:393\u2013399","journal-title":"Nephrol Dial Transplant"},{"key":"7028_CR14","doi-asserted-by":"publisher","first-page":"1037566","DOI":"10.3389\/fimmu.2022.1037566","volume":"13","author":"Y Park","year":"2022","unstructured":"Park Y, Lee H, Eum SH et al (2022) Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation. Front Immunol 13:1037566","journal-title":"Front Immunol"},{"key":"7028_CR15","doi-asserted-by":"publisher","first-page":"2954","DOI":"10.1111\/ajt.13803","volume":"16","author":"T Vanhove","year":"2016","unstructured":"Vanhove T, Vermeulen T, Annaert P et al (2016) High intrapatient variability of tacrolimus concentrations predicts accelerated progression of chronic histologic lesions in renal recipients. Am J Transplant 16:2954\u20132963","journal-title":"Am J Transplant"},{"key":"7028_CR16","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1097\/TP.0000000000002913","volume":"104","author":"S Davis","year":"2020","unstructured":"Davis S, Gralla J, Klem P, Stites E, Wiseman A, Cooper JE (2020) Tacrolimus intrapatient variability, time in therapeutic range, and risk of de novo donor\u2013specific antibodies. Transplantation 104:881\u2013887","journal-title":"Transplantation"},{"key":"7028_CR17","doi-asserted-by":"publisher","first-page":"2912","DOI":"10.3389\/fimmu.2019.02912","volume":"10","author":"T Song","year":"2019","unstructured":"Song T, Yin S, Jiang Y, Huang Z, Liu J, Wang Z et al (2019) Increasing time in therapeutic range of tacrolimus in the first year predicts better outcomes in living-donor kidney transplantation. Front Immunol 10:2912","journal-title":"Front Immunol"},{"key":"7028_CR18","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1097\/TP.0000000000001129","volume":"101","author":"HR Whalen","year":"2017","unstructured":"Whalen HR, Glen JA, Harkins V et al (2017) High intrapatient tacrolimus variability is associated with worse outcomes in renal transplantation using a low-dose tacrolimus immunosuppressive regime. Transplantation 101:430\u2013436","journal-title":"Transplantation"},{"key":"7028_CR19","doi-asserted-by":"publisher","first-page":"2479","DOI":"10.1097\/TP.0000000000001040","volume":"100","author":"E Rodrigo","year":"2016","unstructured":"Rodrigo E, Segundo DS, Fern\u00e1ndez-Fresnedo G et al (2016) Within-patient variability in tacrolimus blood levels predicts kidney graft loss and donor-specific antibody development. Transplantation 100:2479\u20132485","journal-title":"Transplantation"},{"key":"7028_CR20","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1055\/s-0038-1651587","volume":"69","author":"FR Rosendaal","year":"1993","unstructured":"Rosendaal FR, Cannegieter SC, van der Meer FJ, Bri\u00ebt E (1993) A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 69:236\u2013239","journal-title":"Thromb Haemost"},{"key":"7028_CR21","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1111\/ajt.12590","volume":"14","author":"M Haas","year":"2014","unstructured":"Haas M, Sis B, Racusen LC et al (2014) Banff 2013 meeting report: inclusion of c4d-negativeantibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 14:272\u2013283","journal-title":"Am J Transplant"},{"key":"7028_CR22","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1111\/ajt.14504","volume":"18","author":"S Davis","year":"2018","unstructured":"Davis S, Gralla J, Klem P, Tong S, Wedermyer G, Freed B et al (2018) Lower tacrolimus exposure and time in therapeutic range increase the risk of de novo donor-specific antibodies in the first year of kidney transplantation. Am J Transplant 18:907\u2013915","journal-title":"Am J Transplant"},{"key":"7028_CR23","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1002\/phar.2601","volume":"41","author":"AD Leino","year":"2021","unstructured":"Leino AD, Park JM, Pasternak AL (2021) Impact of CYP3A5 phenotype on tacrolimus time in therapeutic range and clinical outcomes in pediatric renal and heart transplant recipients. Pharmacotherapy 41:649\u2013657","journal-title":"Pharmacotherapy"},{"key":"7028_CR24","doi-asserted-by":"crossref","unstructured":"do Nascimento Ghizoni Pereira L, Tedesco-Silva H Jr, Koch-Nogueira PC (2021) Acute rejection in pediatric renal transplantation: retrospective study of epidemiology, risk factors, and impact on renal function. Pediatr Transplant 25:e13856","DOI":"10.1111\/petr.13856"},{"key":"7028_CR25","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1016\/j.transproceed.2019.05.007","volume":"51","author":"C Cordinh\u00e3","year":"2019","unstructured":"Cordinh\u00e3 C, Rodrigues L, Carmo C, Gomes C, Mac\u00e1rio F, Correia AJ, Figueiredo A (2019) Pediatric kidney transplantation: experience of a center over 4 decades. Transplant Proc 51:1579\u20131584","journal-title":"Transplant Proc"},{"key":"7028_CR26","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1097\/00007890-201407151-00810","volume":"98","author":"P Coates","year":"2014","unstructured":"Coates P, Dawood U, Hanf W, Bennett G, Drogemuller C, McDonald S, Grace B, Russell C, Carroll R (2014) Peri-transplant blood transfusion is associated with significant formation of HLA antibodies despite immunosuppression. Abstract# D2666. Transplantation 98:265","journal-title":"Transplantation"},{"key":"7028_CR27","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2023.38.e212","volume":"38","author":"Y Kim","year":"2023","unstructured":"Kim Y, Kim B, Kang M, Nam H, Ko DH, Park Y (2023) Associations of perioperative red blood cell transfusion with outcomes of kidney transplantation in Korea over a 16-year period. J Korean Med Sci 38:e212","journal-title":"J Korean Med Sci"},{"key":"7028_CR28","doi-asserted-by":"publisher","first-page":"3750","DOI":"10.3390\/jcm10163750","volume":"10","author":"K Lee","year":"2021","unstructured":"Lee K, Lee S, Jang EJ, Kim GH, Yoo S, Lee M, Ryu HG (2021) The association between peri-transplant RBC transfusion and graft failure after kidney transplantation: a nationwide cohort study. J Clin Med 10:3750","journal-title":"J Clin Med"},{"key":"7028_CR29","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.trim.2013.09.008","volume":"29","author":"S Fidler","year":"2013","unstructured":"Fidler S, Swaminathan R, Lim W, Ferrari P, Witt C, Christiansen FT, Irish AB (2013) Perioperative third party red blood cell transfusion in renal transplantation and the risk of antibody-mediated rejection and graft loss. Transpl Immunol 29:22\u201327","journal-title":"Transpl Immunol"},{"key":"7028_CR30","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.24969","volume":"37","author":"H Wanas","year":"2023","unstructured":"Wanas H, Kamel M, William E, Fayad T, Abdelfattah M, Elbadawy H, Mikhael E (2023) The impact of CYP3A4 and CYP3A5 genetic variations on tacrolimus treatment of living-donor Egyptian kidney transplanted patients. J Clin Lab Anal 37:e24969","journal-title":"J Clin Lab Anal"},{"issue":"Supp 1","key":"7028_CR31","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfad063c_3185","volume":"38","author":"M Elsharkawy","year":"2023","unstructured":"Elsharkawy M, Ismail D, Ebid A, Lotfy N, Mahmoud M (2023) #3185 influence of combined cyp 3a4\/5 and por*28 genetic polymorphisms on tacrolimus and cyclosporine dose requirements in incident renal transplant patients. Nephrol Dial Transplant 38(Supp 1):gfad063c_3185","journal-title":"Nephrol Dial Transplant"},{"key":"7028_CR32","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1097\/TP.0b013e31822dc34f","volume":"92","author":"M Hsiau","year":"2011","unstructured":"Hsiau M, Fernandez HE, Gjertson D, Ettenger RB, Tsai EW (2011) Monitoring nonadherence and acute rejection with variation in blood immunosuppressant levels in pediatric renal transplantation. Transplantation 92:918\u2013922","journal-title":"Transplantation"},{"key":"7028_CR33","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1111\/ajt.15199","volume":"19","author":"AD Leino","year":"2019","unstructured":"Leino AD, King EC, Jiang W, Vinks AA, Klawitter J, Christians U, Woodle ES, Alloway RR, Rohan JM (2019) Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: establishing baseline values. Am J Transplant 19:1410\u20131420","journal-title":"Am J Transplant"},{"key":"7028_CR34","doi-asserted-by":"publisher","first-page":"S325","DOI":"10.1016\/j.healun.2020.01.337","volume":"39","author":"C Kao","year":"2020","unstructured":"Kao C, Segraves J, Parulekar A (2020) Tacrolimus time in therapeutic range and level variability are not associated with acute cellular rejection in lung transplant recipients. J Heart Lung Transplant 39:S325","journal-title":"J Heart Lung Transplant"},{"key":"7028_CR35","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1111\/ajt.14723","volume":"18","author":"CR Ensor","year":"2018","unstructured":"Ensor CR, Iasella CJ, Harrigan KM, Morrell MR, Moore CA, Shigemura N et al (2018) Increasing tacrolimus time-in-therapeutic range is associated with superior one-year outcomes in lung transplant recipients. Am J Transplant 18:1527\u20131533","journal-title":"Am J Transplant"},{"key":"7028_CR36","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s40780-022-00256-9","volume":"8","author":"Y Katada","year":"2022","unstructured":"Katada Y, Nakagawa S, Itohara K, Suzuki T, Kato R, Endo H, Terada T (2022) Association between time in therapeutic range of tacrolimus blood concentration and acute rejection within the first three months after lung transplantation. J Pharm Healthc Sci 8:25","journal-title":"J Pharm Healthc Sci"},{"key":"7028_CR37","doi-asserted-by":"publisher","first-page":"80","DOI":"10.5414\/CN108400","volume":"83","author":"LM Quinn","year":"2015","unstructured":"Quinn LM, Richardson R, Cameron KJ, Battistella M (2015) Evaluating time in therapeutic range for hemodialysis patients taking warfarin. Clin Nephrol 83:80\u201385","journal-title":"Clin Nephrol"},{"key":"7028_CR38","doi-asserted-by":"publisher","first-page":"178S","DOI":"10.1177\/1076029618798944","volume":"24","author":"C Ting","year":"2018","unstructured":"Ting C, Sylvester KW, Schurr JW (2018) Time in the therapeutic range for assessing anticoagulation quality in patients receiving continuous unfractionated heparin. Clin Appl Thromb Hemost 24:178S-181S","journal-title":"Clin Appl Thromb Hemost"}],"container-title":["Pediatric Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00467-025-07028-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00467-025-07028-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00467-025-07028-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T15:20:59Z","timestamp":1776698459000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00467-025-07028-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,22]]},"references-count":38,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["7028"],"URL":"https:\/\/doi.org\/10.1007\/s00467-025-07028-1","relation":{},"ISSN":["0931-041X","1432-198X"],"issn-type":[{"value":"0931-041X","type":"print"},{"value":"1432-198X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,22]]},"assertion":[{"value":"3 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 September 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 December 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved by the Research Ethical Committee, Faculty of Medicine, Cairo University (MS-402\u20132023) in view of the retrospective nature of the study, and all the procedures performed were part of the routine care. All procedures were in accordance with the Helsinki Declaration of 1964.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable (no identifying information about the data of participants is available in the article).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}