The susceptibility of COVID-19 to a worse prognosis in the presence of metabolic syndrome

Authors

DOI:

https://doi.org/10.33448/rsd-v11i14.36329

Keywords:

Pandemic; Coronavirus; Hypertension; Blood glucose; Triglycerides; Obesity.

Abstract

COVID-19 has variable clinical manifestations, ranging from an asymptomatic carrier, mild respiratory disease, pneumonia, acute respiratory distress syndrome (ARDS), multiple organ failure, and even death. Some important examples of comorbidities that can worsen the development of the disease are the components of the metabolic syndrome (MS), such as hypertension, type 2 diabetes mellitus (DM2), and obesity. The present study aimed to evaluate the susceptibility of COVID-19 cases in patients with or without criteria characterizing MS. This is an analytical cross-sectional study with a quantitative approach based on data from a sample of individuals seen at the Military Policeman's Hospital (MPH). The results were: 43% of patients with MS were infected by SARS-CoV-2 (p < 0,05); Of all infected, 50,56% were classified by BMI with obesity, 40.90% with fasting glucose > 99 mg/dL, 43,50% with HDL-c below normal value, 39,91% with triglycerides above normal value, 41,94% in use of antihypertensives, 40,74% in use of hypoglycemic agents and 32,89% in use of hypolipemic agents. The acquired and analyzed data concluded that patients with MS have a higher risk of contracting COVID-19.

References

Alamdari, N. M., Rahimi, F. S., Afaghi, S., Zarghi, A., Qaderi, S., Tarki, F. E., Ghafouri, S. R., & Besharat, S. (2020). The impact of metabolic syndrome on morbidity and mortality among intensive care unit admitted COVID-19 patients. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 14(6), 1979–1986. https://doi.org/10.1016/j.dsx.2020.10.012

Atlas, D. (2014). Voltage-gated calcium channels function as Ca2+-activated signaling receptors. Trends in Biochemical Sciences, 39(2), 45–52. https://doi.org/10.1016/j.tibs.2013.12.005

Bansal, R., Gubbi, S., & Muniyappa, R. (2020). Metabolic Syndrome and COVID 19: Endocrine-Immune-Vascular Interactions Shapes Clinical Course. Endocrinology, 161(10). https://doi.org/10.1210/endocr/bqaa112

Bernstein, K. E., Khan, Z., Giani, J. F., Cao, D.-Y., Bernstein, E. A., & Shen, X. Z. (2018). Angiotensin-converting enzyme in innate and adaptive immunity. Nature Reviews Nephrology, 14(5), 325–336. https://doi.org/10.1038/nrneph.2018.15

Cantuti-Castelvetri, L., Ojha, R., Pedro, L. D., Djannatian, M., Franz, J., Kuivanen, S., van der Meer, F., Kallio, K., Kaya, T., Anastasina, M., Smura, T., Levanov, L., Szirovicza, L., Tobi, A., Kallio-Kokko, H., Österlund, P., Joensuu, M., Meunier, F. A., Butcher, S. J., … Simons, M. (2020). Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science, 370(6518), 856–860. https://doi.org/10.1126/science.abd2985

Catapano, A. L., Pirillo, A., Bonacina, F., & Norata, G. D. (2014). HDL in innate and adaptive immunity. Cardiovascular Research, 103(3), 372–383. https://doi.org/10.1093/cvr/cvu150

Chang, D., Xu, H., Rebaza, A., Sharma, L., & Dela Cruz, C. S. (2020). Protecting health-care workers from subclinical coronavirus infection. The Lancet Respiratory Medicine, 8(3), e13. https://doi.org/10.1016/S2213-2600(20)30066-7

Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., Qiu, Y., Wang, J., Liu, Y., Wei, Y., Xia, J., Yu, T., Zhang, X., & Zhang, L. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet, 395(10223), 507–513. https://doi.org/10.1016/S0140-6736(20)30211-7

Cho, D.-H., Choi, J., & Gwon, J. G. (2021). Metabolic syndrome and the risk of COVID-19 infection: A nationwide population-based case-control study. Nutrition, Metabolism and Cardiovascular Diseases, 31(9), 2596–2604. https://doi.org/10.1016/j.numecd.2021.05.016

Cho, K.-H., Kim, J.-R., Lee, I.-C., & Kwon, H.-J. (2021). Native High-Density Lipoproteins (HDL) with Higher Paraoxonase Exerts a Potent Antiviral Effect against SARS-CoV-2 (COVID-19), While Glycated HDL Lost the Antiviral Activity. Antioxidants, 10(2), 209. https://doi.org/10.3390/antiox10020209

Deng, G., Yin, M., Chen, X., & Zeng, F. (2020). Clinical determinants for fatality of 44,672 patients with COVID-19. Critical Care, 24(1), 179. https://doi.org/10.1186/s13054-020-02902-w

Denson, J. L., Gillet, A. S., Zu, Y., Brown, M., Pham, T., Yoshida, Y., Mauvais-Jarvis, F., Douglas, I. S., Moore, M., Tea, K., Wetherbie, A., Stevens, R., Lefante, J., Shaffer, J. G., Armaignac, D. L., Belden, K. A., Kaufman, M., Heavner, S. F., Danesh, V. C., … Gautam, S. (2021). Metabolic Syndrome and Acute Respiratory Distress Syndrome in Hospitalized Patients With COVID-19. JAMA Network Open, 4(12), e2140568. https://doi.org/10.1001/jamanetworkopen.2021.40568

Engin, A. B., Engin, E. D., & Engin, A. (2020). Two important controversial risk factors in SARS-CoV-2 infection: Obesity and smoking. Environmental Toxicology and Pharmacology, 78, 103411. https://doi.org/10.1016/j.etap.2020.103411

Ghosh, A., Anjana, R. M., Shanthi Rani, C. S., Jeba Rani, S., Gupta, R., Jha, A., Gupta, V., Kuchay, M. S., Luthra, A., Durrani, S., Dutta, K., Tyagi, K., Unnikrishnan, R., Srivastava, B. K., Ramu, M., Sastry, N. G., Gupta, P. K., Umasankari, G., Jayashri, R., … Misra, A. (2021). Glycemic parameters in patients with new-onset diabetes during COVID-19 pandemic are more severe than in patients with new-onset diabetes before the pandemic: NOD COVID India Study. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 15(1), 215–220. https://doi.org/10.1016/j.dsx.2020.12.033

Gordon, S. M., Hofmann, S., Askew, D. S., & Davidson, W. S. (2011). High density lipoprotein: it’s not just about lipid transport anymore. Trends in Endocrinology & Metabolism, 22(1), 9–15. https://doi.org/10.1016/j.tem.2010.10.001

Guan, W., Ni, Z., Hu, Y., Liang, W., Ou, C., He, J., Liu, L., Shan, H., Lei, C., Hui, D. S. C., Du, B., Li, L., Zeng, G., Yuen, K.-Y., Chen, R., Tang, C., Wang, T., Chen, P., Xiang, J., … Zhong, N. (2020). Clinical Characteristics of Coronavirus Disease 2019 in China. New England Journal of Medicine, 382(18), 1708–1720. https://doi.org/10.1056/NEJMoa2002032

Hariyanto, T. I., & Kurniawan, A. (2020). Dyslipidemia is associated with severe coronavirus disease 2019 (COVID-19) infection. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 14(5), 1463–1465. https://doi.org/10.1016/j.dsx.2020.07.054

Higham, A., & Singh, D. (2020). Increased ACE2 Expression in Bronchial Epithelium of COPD Patients who are Overweight. Obesity, 28(9), 1586–1589. https://doi.org/10.1002/oby.22907

Hodgson, K., Morris, J., Bridson, T., Govan, B., Rush, C., & Ketheesan, N. (2015). Immunological mechanisms contributing to the double burden of diabetes and intracellular bacterial infections. Immunology, 144(2), 171–185. https://doi.org/10.1111/imm.12394

Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., … Cao, B. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet, 395(10223), 497–506. https://doi.org/10.1016/S0140-6736(20)30183-5

I Diretriz Brasileira de Diagnóstico e Tratamento da Síndrome Metabólica. (2005). Arquivos Brasileiros de Cardiologia, 84, 3–28. https://doi.org/10.1590/S0066-782X2005000700001

Kane, J. P., Hardman, D. A., Dimpfl, J. C., & Levy, J. A. (1979). Apolipoprotein is responsible for neutralization of xenotropic type C virus by mouse serum. Proceedings of the National Academy of Sciences, 76(11), 5957–5961. https://doi.org/10.1073/pnas.76.11.5957

Karathanasis, S. K., Freeman, L. A., Gordon, S. M., & Remaley, A. T. (2017). The Changing Face of HDL and the Best Way to Measure It. Clinical Chemistry, 63(1), 196–210. https://doi.org/10.1373/clinchem.2016.257725

Khovidhunkit, W., Kim, M.-S., Memon, R. A., Shigenaga, J. K., Moser, A. H., Feingold, K. R., & Grunfeld, C. (2004a). Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host. Journal of Lipid Research, 45(7), 1169–1196. https://doi.org/10.1194/jlr.R300019-JLR200

Khovidhunkit, W., Kim, M.-S., Memon, R. A., Shigenaga, J. K., Moser, A. H., Feingold, K. R., & Grunfeld, C. (2004b). Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host. Journal of Lipid Research, 45(7), 1169–1196. https://doi.org/10.1194/jlr.R300019-JLR200

Lauer, S. A., Grantz, K. H., Bi, Q., Jones, F. K., Zheng, Q., Meredith, H. R., Azman, A. S., Reich, N. G., & Lessler, J. (2020). The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Annals of Internal Medicine, 172(9), 577–582. https://doi.org/10.7326/M20-0504

Li, B., Yang, J., Zhao, F., Zhi, L., Wang, X., Liu, L., Bi, Z., & Zhao, Y. (2020). Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clinical Research in Cardiology, 109(5), 531–538. https://doi.org/10.1007/s00392-020-01626-9

Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., Ren, R., Leung, K. S. M., Lau, E. H. Y., Wong, J. Y., Xing, X., Xiang, N., Wu, Y., Li, C., Chen, Q., Li, D., Liu, T., Zhao, J., Liu, M., … Feng, Z. (2020). Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia. New England Journal of Medicine, 382(13), 1199–1207. https://doi.org/10.1056/NEJMoa2001316

Lohia, P., Kapur, S., Benjaram, S., Pandey, A., Mir, T., & Seyoum, B. (2021). Metabolic syndrome and clinical outcomes in patients infected with COVID‐19: Does age, sex, and race of the patient with metabolic syndrome matter? Journal of Diabetes, 13(5), 420–429. https://doi.org/10.1111/1753-0407.13157

Longmore, D. K., Miller, J. E., Bekkering, S., Saner, C., Mifsud, E., Zhu, Y., Saffery, R., Nichol, A., Colditz, G., Short, K. R., Burgner, D. P., Anfasa, F., Benfield, T. L., Blaauw, M. J. T., Boonman-de Winter, L. J. M., Brucato, A. L., Buanes, E. A., Burhan, E., Calabro, E., … Young, B. E. (2021). Diabetes and Overweight/Obesity Are Independent, Nonadditive Risk Factors for In-Hospital Severity of COVID-19: An International, Multicenter Retrospective Meta-analysis. Diabetes Care, 44(6), 1281–1290. https://doi.org/10.2337/dc20-2676

Madsen, C. M., Varbo, A., Tybjærg-Hansen, A., Frikke-Schmidt, R., & Nordestgaard, B. G. (2018). U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies. European Heart Journal, 39(14), 1181–1190. https://doi.org/10.1093/eurheartj/ehx665

Masana, L., Correig, E., Ibarretxe, D., Anoro, E., Arroyo, J. A., Jericó, C., Guerrero, C., Miret, M., Näf, S., Pardo, A., Perea, V., Pérez-Bernalte, R., Plana, N., Ramírez-Montesinos, R., Royuela, M., Soler, C., Urquizu-Padilla, M., Zamora, A., & Pedro-Botet, J. (2021). Low HDL and high triglycerides predict COVID-19 severity. Scientific Reports, 11(1), 7217. https://doi.org/10.1038/s41598-021-86747-5

Misra, A., Ghosh, A., & Gupta, R. (2021). Heterogeneity in presentation of hyperglycaemia during COVID-19 pandemic: A proposed classification. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 15(1), 403–406. https://doi.org/10.1016/j.dsx.2021.01.018

Mizumoto, K., Kagaya, K., Zarebski, A., & Chowell, G. (2020). Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Eurosurveillance, 25(10). https://doi.org/10.2807/1560-7917.ES.2020.25.10.2000180

Muniyappa, R., & Gubbi, S. (2020). COVID-19 pandemic, coronaviruses, and diabetes mellitus. American Journal of Physiology-Endocrinology and Metabolism, 318(5), E736–E741. https://doi.org/10.1152/ajpendo.00124.2020

Noveanu, M., Breidthardt, T., Reichlin, T., Gayat, E., Potocki, M., Pargger, H., Heise, A., Meissner, J., Twerenbold, R., Muravitskaya, N., Mebazaa, A., & Mueller, C. (2010). Effect of oral beta-blocker on short and long-term mortality in patients with acute respiratory failure: results from the BASEL-II-ICU study. Critical Care, 14(6), R198. https://doi.org/10.1186/cc9317

Onder, G., Rezza, G., & Brusaferro, S. (2020). Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA. https://doi.org/10.1001/jama.2020.4683

Pereira, A. S., Shitsuka, D. M., Parreira, F. J., & Shitsuka, R. (2018). Metodologia da pesquisa científica (1a). UFMS.

Petrilli, C. M., Jones, S. A., Yang, J., Rajagopalan, H., O’Donnell, L., Chernyak, Y., Tobin, K. A., Cerfolio, R. J., Francois, F., & Horwitz, L. I. (2020). Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ, m1966. https://doi.org/10.1136/bmj.m1966

Rader, D. J., Alexander, E. T., Weibel, G. L., Billheimer, J., & Rothblat, G. H. (2009). The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. Journal of Lipid Research, 50, S189–S194. https://doi.org/10.1194/jlr.R800088-JLR200

Raveendran, A. V., & Misra, A. (2021). Post COVID-19 Syndrome (“Long COVID”) and Diabetes: Challenges in Diagnosis and Management. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 15(5), 102235. https://doi.org/10.1016/j.dsx.2021.102235

Richardson, S., Hirsch, J. S., Narasimhan, M., Crawford, J. M., McGinn, T., Davidson, K. W., Barnaby, D. P., Becker, L. B., Chelico, J. D., Cohen, S. L., Cookingham, J., Coppa, K., Diefenbach, M. A., Dominello, A. J., Duer-Hefele, J., Falzon, L., Gitlin, J., Hajizadeh, N., Harvin, T. G., … Zanos, T. P. (2020). Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA, 323(20), 2052. https://doi.org/10.1001/jama.2020.6775

Rudemiller, N. P., & Crowley, S. D. (2016). Interactions Between the Immune and the Renin–Angiotensin Systems in Hypertension. Hypertension, 68(2), 289–296. https://doi.org/10.1161/HYPERTENSIONAHA.116.06591

Scalsky, R. J., Desai, K., Chen, Y.-J., O’Connell, J. R., Perry, J. A., & Hong, C. C. (2020). Baseline Cardiometabolic Profiles and SARS-CoV-2 Risk in the UK Biobank. MedRxiv : The Preprint Server for Health Sciences. https://doi.org/10.1101/2020.07.25.20161091

Serné, E. H., de Jongh, R. T., Eringa, E. C., IJzerman, R. G., & Stehouwer, C. D. A. (2007). Microvascular Dysfunction. Hypertension, 50(1), 204–211. https://doi.org/10.1161/HYPERTENSIONAHA.107.089680

Simonnet, A., Chetboun, M., Poissy, J., Raverdy, V., Noulette, J., Duhamel, A., Labreuche, J., Mathieu, D., Pattou, F., Jourdain, M., Caizzo, R., Caplan, M., Cousin, N., Duburcq, T., Durand, A., el kalioubie, A., Favory, R., Garcia, B., Girardie, P., … Verkindt, H. (2020). High Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) Requiring Invasive Mechanical Ventilation. Obesity, 28(7), 1195–1199. https://doi.org/10.1002/oby.22831

Singh, I. P., Chopra, A. K., Coppenhaver, D. H., Ananatharamaiah, G. M., & Baron, S. (1999). Lipoproteins account for part of the broad non-specific antiviral activity of human serum. Antiviral Research, 42(3), 211–218. https://doi.org/10.1016/S0166-3542(99)00032-7

Srinivas, R. V., Birkedal, B., Owens, R. J., Anantharamaiah, G. M., Segrest, J. P., & Compans, R. W. (1990). Antiviral effects of apolipoprotein A-I and its synthetic amphipathic peptide analogs. Virology, 176(1), 48–57. https://doi.org/10.1016/0042-6822(90)90229-K

Straus, M. R., Tang, T., Lai, A. L., Flegel, A., Bidon, M., Freed, J. H., Daniel, S., & Whittaker, G. R. (2020). Ca2+ Ions Promote Fusion of Middle East Respiratory Syndrome Coronavirus with Host Cells and Increase Infectivity. Journal of Virology, 94(13). https://doi.org/10.1128/JVI.00426-20

Swamy, S., Koch, C. A., Hannah-Shmouni, F., Schiffrin, E. L., Klubo-Gwiezdzinska, J., & Gubbi, S. (2022). Hypertension and COVID-19: Updates from the era of vaccines and variants. Journal of Clinical & Translational Endocrinology, 27, 100285. https://doi.org/10.1016/j.jcte.2021.100285

Tan, K., Harazim, M., Tang, B., Mclean, A., & Nalos, M. (2019). The association between premorbid beta blocker exposure and mortality in sepsis—a systematic review. Critical Care, 23(1), 298. https://doi.org/10.1186/s13054-019-2562-y

Trinder, M., Walley, K. R., Boyd, J. H., & Brunham, L. R. (2020). Causal Inference for Genetically Determined Levels of High-Density Lipoprotein Cholesterol and Risk of Infectious Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 40(1), 267–278. https://doi.org/10.1161/ATVBAHA.119.313381

Unnikrishnan, R., & Misra, A. (2021). Diabetes and COVID19: a bidirectional relationship. Nutrition & Diabetes, 11(1), 21. https://doi.org/10.1038/s41387-021-00163-2

Vaduganathan, M., Vardeny, O., Michel, T., McMurray, J. J. V., Pfeffer, M. A., & Solomon, S. D. (2020). Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. New England Journal of Medicine, 382(17), 1653–1659. https://doi.org/10.1056/NEJMsr2005760

Vasanthakumar, N. (2020). Can beta-adrenergic blockers be used in the treatment of COVID-19? Medical Hypotheses, 142, 109809. https://doi.org/10.1016/j.mehy.2020.109809

Wargny, M., Gourdy, P., Ludwig, L., Seret-Bégué, D., Bourron, O., Darmon, P., Amadou, C., Pichelin, M., Potier, L., Thivolet, C., Gautier, J.-F., Hadjadj, S., Cariou, B., Wargny, M., Mahot, P., Cariou, B., Hadjadj, S., Pichelin, M., Fournier-Guilloux, A.-L., … Paradisi-Prieur, L. (2020). Type 1 Diabetes in People Hospitalized for COVID-19: New Insights From the CORONADO Study. Diabetes Care, 43(11), e174–e177. https://doi.org/10.2337/dc20-1217

Wilczynski, S. A., Wenceslau, C. F., McCarthy, C. G., & Webb, R. C. (2021). A Cytokine/Bradykinin Storm Comparison: What Is the Relationship Between Hypertension and COVID-19? American Journal of Hypertension, 34(4), 304–306. https://doi.org/10.1093/ajh/hpaa217

Williamson, E., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., Curtis, H. J., Mehrkar, A., Evans, D., Inglesby, P., Cockburn, J., McDonald, H. I., MacKenna, B., Tomlinson, L., Douglas, I. J., Rentsch, C. T., Mathur, R., Wong, A., Grieve, R., … Goldacre, B. (2020). penSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients. MedRxiv.

Xie, J., Zu, Y., Alkhatib, A., Pham, T. T., Gill, F., Jang, A., Radosta, S., Chaaya, G., Myers, L., Zifodya, J. S., Bojanowski, C. M., Marrouche, N. F., Mauvais-Jarvis, F., & Denson, J. L. (2021). Metabolic Syndrome and COVID-19 Mortality Among Adult Black Patients in New Orleans. Diabetes Care, 44(1), 188–193. https://doi.org/10.2337/dc20-1714

Yanai, H. (2020). Metabolic Syndrome and COVID-19. Cardiology Research, 11(6), 360–365. https://doi.org/10.14740/cr1181

Zhu, L., She, Z.-G., Cheng, X., Qin, J.-J., Zhang, X.-J., Cai, J., Lei, F., Wang, H., Xie, J., Wang, W., Li, H., Zhang, P., Song, X., Chen, X., Xiang, M., Zhang, C., Bai, L., Xiang, D., Chen, M.-M., … Li, H. (2020). Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metabolism, 31(6), 1068-1077.e3. https://doi.org/10.1016/j.cmet.2020.04.021

Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., Niu, P., Zhan, F., Ma, X., Wang, D., Xu, W., Wu, G., Gao, G. F., & Tan, W. (2020). A Novel Coronavirus from Patients with Pneumonia in China, 2019. New England Journal of Medicine, 382(8), 727–733. https://doi.org/10.1056/NEJMoa2001017

Published

02/11/2022

How to Cite

PUTON, C.; VIEIRA, R. P. .; GOMES, C. M. .; COSTA, S. H. N. . The susceptibility of COVID-19 to a worse prognosis in the presence of metabolic syndrome. Research, Society and Development, [S. l.], v. 11, n. 14, p. e472111436329, 2022. DOI: 10.33448/rsd-v11i14.36329. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/36329. Acesso em: 25 nov. 2024.

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Health Sciences