{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:28:14Z","timestamp":1785414494355,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T00:00:00Z","timestamp":1780704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014538","name":"Indonesian Endowment Fund for Education","doi-asserted-by":"publisher","award":["4298\/B3\/DT.03.08\/2025"],"award-info":[{"award-number":["4298\/B3\/DT.03.08\/2025"]}],"id":[{"id":"10.13039\/501100014538","id-type":"DOI","asserted-by":"publisher"}]},{"award":["4298\/B3\/DT.03.08\/2025"],"award-info":[{"award-number":["4298\/B3\/DT.03.08\/2025"]}],"id":[{"id":"https:\/\/ror.org\/05p2xef58","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Doxorubicin and trastuzumab are effective breast cancer therapies but carry cardiotoxicity risk, indicated by decreased left ventricular ejection fraction (LVEF). This study aimed to analyze LVEF decline trends, cardiotoxicity incidence, and associated risk factors in breast cancer patients receiving doxorubicin with or without trastuzumab at Dharmais National Cancer Center Hospital, Jakarta. Methods: A retrospective cohort study was conducted using medical records of female patients aged \u226518 years with serial echocardiography (baseline and \u22651 follow-up) and \u22653 years of follow-up. Cardiotoxicity was defined as an absolute LVEF decline of \u226510% from baseline to &lt;53%. We used the Mann\u2013Whitney U test for LVEF trends, the Chi-square or Fisher\u2019s exact for risk factor associations, and Firth\u2019s Cox proportional hazards model for relative risk estimation. Results: Among the 301 patients, LVEF declined significantly at the fourth and sixth chemotherapy cycles and remained reduced during follow-up beyond 3 years. Cardiotoxicity occurred in 20 patients (6.65%), while 72 patients (23.92%) had borderline low LVEF. Significant risk factors for cardiotoxicity were continued trastuzumab-based chemotherapy (adjHR 3.79; 95% CI 1.39\u20139.23) and a history of hypertension (adjHR 0.2; 95% CI 0.02\u20130.81). This apparent protective effect of hypertension is likely due to the concurrent use of cardioprotective anti-hypertensive medications in this subgroup. Conclusions: Intensive cardiac monitoring is essential for breast cancer patients receiving sequential trastuzumab therapy, especially those with cardiovascular risk factors. Additional study with extended monitoring, more sensitive cardiac parameters, and detailed evaluation of concurrent cardioprotective therapies are warranted.<\/jats:p>","DOI":"10.3390\/ph19060901","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T07:43:02Z","timestamp":1780904582000},"page":"901","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Trajectory and Determinants of Left Ventricular Dysfunction Following Anthracycline-Based Therapy Among Breast Cancer Patients: A Three-Year Cohort Analysis in Indonesia"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6848-6396","authenticated-orcid":false,"given":"Nadea Olyvia","family":"Wardani","sequence":"first","affiliation":[{"name":"Doctoral Program in Pharmacy, School of Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Risani Andalasia","family":"Putri","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Dharmais National Cancer Center Hospital, Jakarta 11420, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia","family":"Amalia","sequence":"additional","affiliation":[{"name":"Department of Pharmacology\u2013Clinical Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Hanum","sequence":"additional","affiliation":[{"name":"Department of Pharmacology\u2013Clinical Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin Martinez","family":"Faller","sequence":"additional","affiliation":[{"name":"College of Allied Health Sciences, Holy Child Central Colleges Inc., Surallah 9512, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernieda","family":"Hatah","sequence":"additional","affiliation":[{"name":"Center for Quality Management of Medicines, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1264-9558","authenticated-orcid":false,"given":"Zulfan","family":"Zazuli","sequence":"additional","affiliation":[{"name":"Department of Pharmacology\u2013Clinical Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia"},{"name":"Center of Excellence for Innovative Cosmeceuticals and Natural Medicines for Degenerative Disease, Center for Pharma Valorisation, School of Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,6]]},"reference":[{"key":"ref_1","unstructured":"Ferlay, J., Ervik, M., Lam, F., Laversanne, M., Colombet, M., Mery, L., Pi\u00f1eros, M., Znaor, A., Soerjomataram, I., and Bray, F. (2024). Global Cancer Observatory: Cancer Today, International Agency for Research on Cancer. Available online: https:\/\/gco.iarc.who.int\/media\/globocan\/factsheets\/cancers\/20-breast-fact-sheet.pdf."},{"key":"ref_2","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","unstructured":"The International Agency for Research on Cancer (IARC) (2025). Breast Cancer Cases and Deaths Are Projected to Rise Globally, The International Agency for Research on Cancer (IARC). Available online: https:\/\/www.iarc.who.int\/wp-content\/uploads\/2025\/02\/pr361_E.pdf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1038\/s41591-025-03502-3","article-title":"Global patterns and trends in breast cancer incidence and mortality across 185 countries","volume":"31","author":"Kim","year":"2025","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1093\/cvr\/cvp289","article-title":"Native and reconstituted HDL protect cardiomyocytes from doxorubicin-induced apoptosis","volume":"85","author":"Frias","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1126\/science.3798106","article-title":"Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the HER-2\/neu Oncogene","volume":"235","author":"Slamon","year":"1987","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1200\/JCO.22.00519","article-title":"Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2\u2013Positive Breast Cancer: ASCO Guideline Update","volume":"40","author":"Giordano","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1002\/ejhf.1920","article-title":"Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: A position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society","volume":"22","author":"Lyon","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1200\/JCO.2015.65.1505","article-title":"Breast Cancer Therapy\u2013Related Cardiac Dysfunction in Adult Women Treated in Routine Clinical Practice: A Population-Based Cohort Study","volume":"34","author":"Thavendiranathan","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_10","unstructured":"Klaassen, C.D. (2013). Toxic Responses of the Heart and Vascular System, McGraw-Hill Education. Available online: https:\/\/accesspharmacy.mhmedical.com\/content.aspx?bookid=958&sectionid=53483740."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e5195","DOI":"10.1097\/MD.0000000000005195","article-title":"Risk factors of trastuzumab-induced cardiotoxicity in breast cancer: A meta-analysis","volume":"95","author":"Jawa","year":"2016","journal-title":"Medicine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5532","DOI":"10.1200\/JCO.2007.14.0657","article-title":"Reversibility of Trastuzumab Cardiotoxicity: Is the Concept Alive and Well?","volume":"25","author":"Ewer","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/nm0107-14","article-title":"In reply to \u201cCardiotoxicity of the cancer therapeutic agent imatinib mesylate\u201d","volume":"13","author":"Atallah","year":"2007","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fitrianti, A.E., Wardani, N.O., Astuti, A., Anggadiredja, K., Amalia, L., Putri, R.A., and Zazuli, Z. (2025). Cardiotoxicity in Breast Cancer Therapy: Risks, Mechanisms, and Prevention Strategies. Med. Sci., 13.","DOI":"10.3390\/medsci13030130"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/nm1446","article-title":"Cardiotoxicity of the cancer therapeutic agent imatinib mesylate","volume":"12","author":"Grazette","year":"2006","journal-title":"Nat. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Qiu, Y., Jiang, P., and Huang, Y. (2023). Anthracycline-induced cardiotoxicity: Mechanisms, monitoring, and prevention. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1242596"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1200\/JCO.2002.20.5.1215","article-title":"Cardiac Dysfunction in the Trastuzumab Clinical Trials Experience","volume":"20","author":"Seidman","year":"2002","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.5603\/KP.2016.0156","article-title":"2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines","volume":"74","author":"Zamorano","year":"2016","journal-title":"Pol. Heart J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e230569","DOI":"10.1001\/jamanetworkopen.2023.0569","article-title":"Risk Prediction Models for Cardiotoxicity of Chemotherapy among Patients with Breast Cancer: A Systematic Review","volume":"6","author":"Macdonald","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"104581","DOI":"10.1016\/j.breast.2025.104581","article-title":"Evaluation of cardiotoxicity following breast cancer irradiation in an Asian cohort in real-world settings","volume":"84","author":"Yang","year":"2025","journal-title":"Breast"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"727","DOI":"10.4143\/crt.2018.262","article-title":"Early Decline in Left Ventricular Ejection Fraction Can Predict Trastuzumab-Related Cardiotoxicity in Patients with Breast Cancer: A Study Using 13 Years of Registry Data","volume":"51","author":"Kim","year":"2019","journal-title":"Cancer Res. Treat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1200\/JCO.2016.70.5400","article-title":"Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline","volume":"35","author":"Armenian","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1161\/CIRCULATIONAHA.114.013777","article-title":"Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy","volume":"131","author":"Cardinale","year":"2015","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tian, Z., Yang, Y., Yang, Y., Zhang, F., Li, P., Wang, J., Yang, J., Zhang, P., Yao, W., and Wang, X. (2020). High cumulative doxorubicin dose for advanced soft tissue sarcoma. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-07663-x"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"111708","DOI":"10.1016\/j.biopha.2021.111708","article-title":"Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management","volume":"139","author":"Rawat","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1161\/CIRCRESAHA.119.314681","article-title":"Mitochondrial Determinants of Doxorubicin-Induced Cardiomyopathy","volume":"126","author":"Wallace","year":"2020","journal-title":"Circ. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Vitale, R., Marzocco, S., and Popolo, A. (2024). Role of Oxidative Stress and Inflammation in Doxorubicin-Induced Cardiotoxicity: A Brief Account. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202405.1681.v1"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.freeradbiomed.2023.06.019","article-title":"Trastuzumab-induced cardiomyopathy via ferroptosis-mediated mitochondrial dysfunction","volume":"206","author":"Ye","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"121207","DOI":"10.1016\/j.lfs.2022.121207","article-title":"Empagliflozin attenuates trastuzumab-induced cardiotoxicity through suppression of DNA damage and ferroptosis","volume":"312","author":"Min","year":"2023","journal-title":"Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Pecoraro, M., Marzocco, S., Franceschelli, S., and Popolo, A. (2022). Trastuzumab and Doxorubicin Sequential Administration Increases Oxidative Stress and Phosphorylation of Connexin 43 on Ser368. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23126375"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1158\/1535-7163.MCT-15-0741","article-title":"Trastuzumab, but Not Pertuzumab, Dysregulates HER2 Signaling to Mediate Inhibition of Autophagy and Increase in Reactive Oxygen Species Production in Human Cardiomyocytes","volume":"15","author":"Mohan","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s00395-016-0576-z","article-title":"ErbB2 signaling at the crossing between heart failure and cancer","volume":"111","author":"Vermeulen","year":"2016","journal-title":"Basic Res. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/nm0502-459","article-title":"ErbB2 is essential in the prevention of dilated cardiomyopathy","volume":"8","author":"Crone","year":"2002","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s10549-020-05703-5","article-title":"Cumulative incidence of chemotherapy-induced cardiotoxicity during a 2-year follow-up period in breast cancer patients","volume":"182","author":"Cho","year":"2020","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1007\/s12282-024-01623-0","article-title":"Increasing survivors of anthracycline-related cardiomyopathy with breast cancer in trastuzumab era: Thirty-one-year trends in a Japanese Community","volume":"31","author":"Watanabe","year":"2024","journal-title":"Breast Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"380","DOI":"10.14740\/cr1442","article-title":"Anthracycline-Induced Cardiotoxicity in Breast Cancer Patients: A Five-Year Retrospective Study in 10 Centers","volume":"13","author":"Gerodias","year":"2022","journal-title":"Cardiol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2384","DOI":"10.1016\/j.jacc.2012.07.067","article-title":"Effect of Statin Therapy on the Risk for Incident Heart Failure in Patients with Breast Cancer Receiving Anthracycline Chemotherapy","volume":"60","author":"Seicean","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3416","DOI":"10.1200\/JCO.2009.23.6950","article-title":"Independent Adjudication of Symptomatic Heart Failure with the Use of Doxorubicin and Cyclophosphamide Followed by Trastuzumab Adjuvant Therapy: A Combined Review of Cardiac Data From the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 Clinical Trials","volume":"28","author":"Russell","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4229","DOI":"10.1093\/eurheartj\/ehac244","article-title":"2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)","volume":"43","author":"Lyon","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/S1470-2045(14)70320-1","article-title":"Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): Survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response","volume":"15","author":"Holmes","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3837","DOI":"10.1200\/JCO.2017.72.4211","article-title":"Preexisting Cardiovascular Risk and Subsequent Heart Failure Among Non-Hodgkin Lymphoma Survivors","volume":"35","author":"Salz","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1161\/CIRCULATIONAHA.116.023463","article-title":"Detailed Echocardiographic Phenotyping in Breast Cancer Patients","volume":"135","author":"Narayan","year":"2017","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1002\/cncr.10854","article-title":"Trastuzumab-associated cardiotoxicity","volume":"95","author":"Keefe","year":"2002","journal-title":"Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e000073","DOI":"10.1136\/esmoopen-2016-000073","article-title":"Twenty years of anti-HER2 therapy-associated cardiotoxicity","volume":"1","author":"Lambertini","year":"2016","journal-title":"ESMO Open"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jaccao.2024.12.007","article-title":"Risk Stratification for Trastuzumab-Induced Cardiac Dysfunction and Potential Implications for Surveillance","volume":"7","author":"Ali","year":"2025","journal-title":"JACC CardioOncology"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Qiu, S., Zhou, T., Qiu, B., Zhang, Y., Zhou, Y., Yu, H., Zhang, J., Liu, L., Yuan, L., and Yang, G. (2021). Risk Factors for Anthracycline-Induced Cardiotoxicity. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.736854"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s40959-024-00272-8","article-title":"Predictors of trastuzumab-induced cardiotoxicity among racially and ethnically diverse patients with HER2-positive breast cancer","volume":"10","author":"Vaynrub","year":"2024","journal-title":"Cardio-Oncology"},{"key":"ref_48","unstructured":"National Cancer Institute (NCI) (2025, May 18). Common Terminology Criteria for Adverse Events (CTCAE) v6.0 (MedDRA 28.0). U.S. Department of Health and Human Services, Available online: https:\/\/dctd.cancer.gov\/research\/ctep-trials\/for-sites\/adverse-events\/ctcae-v6.pdf."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.echo.2014.07.012","article-title":"Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy: A Report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging","volume":"27","author":"Plana","year":"2014","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.echo.2014.10.003","article-title":"Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging","volume":"28","author":"Lang","year":"2015","journal-title":"J. Am. Soc. Echocardiogr."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/6\/901\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T07:02:36Z","timestamp":1781161356000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/6\/901"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,6]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ph19060901"],"URL":"https:\/\/doi.org\/10.3390\/ph19060901","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,6]]}}}