The Oral-Systemic Link: A Review about the strong Correlation between Diabetes mellitus, Periodontitis and COVID-19 Outcome

Main Article Content

Andreas Pfützner Marie Schaedlich Peter Möller Shipra Gupta Tommi Pätilä Ismo T. Räisänen Timo A. Sorsa


The SARS-CoV-2 virus leads to symptoms ranging from mild flu symptoms to severe COVID-19 pneumonia requiring mechanical ventilation and even death. According to epidemiological observations, diabetes mellitus is a major risk factor for severe outcome, next to older age, s, hypertension, and other serious chronic illnesses. Recent studies have determined that the oral cavity mucosa is the main entry portal for the SARS-CoV-2 virus into the body. The viruses accumulate in the mouth at locations where the main viral receptor is highly expressed. The oral pathway of the virus into the body and the contributing factors are described in this review. The immune system of people with diabetes is generally impaired. Diabetes induces chronic systemic inflammation, which regularly manifests as periodontitis in the oral cavity. Furthermore, frequent hyperglycemia leads to additional weakening of the mucosal immune barrier. These findings provide plausible explanations for the more frequent severe courses of respiratory viral infections in diabetes patients. An oral examination helps to identify patients at elevated  risk. Activated matrix metalloproteinase-8 (aMMP-8) is an established biomarker for measuring the degree of oral inflammation and is an indicator of the destruction of collagen and bone structures in the mouth. aMMP-8 point-of-care tests are readily available. We propose that the current recommendations for the prevention of SARS-CoV-2-associated severe COVID-19 disease should be extended to consider the aspects of measuring and sanitizing oral health, as well as to include preventive regular daily disinfection of the mouth and the pharynx.

Article Details

How to Cite
PFÜTZNER, Andreas et al. The Oral-Systemic Link: A Review about the strong Correlation between Diabetes mellitus, Periodontitis and COVID-19 Outcome. Medical Research Archives, [S.l.], v. 11, n. 1, jan. 2023. ISSN 2375-1924. Available at: <>. Date accessed: 20 may 2024. doi:
Research Articles


1. Lovic D, Piperidou A, Zografou I, Grassos H, Pittaras A, Manolis A. The Growing Epidemic of Diabetes Mellitus. Curr Vasc Pharmacol. 2020;18(2):104-109. doi: 10.2174/1570161117666190405165911. PMID: 30961501.
2. Bommer C, Heesemann E, Sagalova V, Manne-Goehler J, Atun R, Bärnighausen T, Vollmer S. The global economic burden of diabetes in adults aged 20-79 years: a cost-of-illness study. Lancet Diabetes Endocrinol. 2017 Jun;5(6):423-430. doi: 10.1016/S2213-8587(17)30097-9. Epub 2017 Apr 26. PMID: 28456416.
3. Kumar A, Arora A, Sharma P, Anikhindi SA, Bansal N, Singla V, Khare S, Srivastava A. Is diabetes mellitus associated with mortality and severity of COVID-19? A meta-analysis. Diabetes Metab Syndr. 2020 Jul-Aug;14(4):535-545. doi: 10.1016/j.dsx.2020.04.044. Epub 2020 May 6. PMID: 32408118; PMCID: PMC7200339
4. Miller LE, Bhattacharyya R, Miller AL. Diabetes mellitus increases the risk of hospital mortality in patients with Covid-19: Systematic review with meta-analysis. Medicine (Baltimore). 2020 Oct 2;99(40):e22439. doi: 10.1097/MD.0000000000022439. PMID: 33019426; PMCID: PMC7535849.
5. Pfützner A, Lazzara M, Jantz J. Why Do People With Diabetes Have a High Risk for Severe COVID-19 Disease?-A Dental Hypothesis and Possible Prevention Strategy. J Diabetes Sci Technol. 2020 Jul;14(4):769-771. doi: 10.1177/1932296820930287. Epub 2020 Jun 7. PMID: 32506937; PMCID: PMC7673189.
6. Li S, Wang J, Zhang B, Li X, Liu Y. Diabetes Mellitus and Cause-Specific Mortality: A Population-Based Study. Diabetes Metab J. 2019 Jun;43(3):319-341. doi: 10.4093/dmj.2018.0060. PMID: 31210036; PMCID: PMC6581547.
7. Mealey BL, Ocampo GL. Diabetes mellitus and periodontal disease. Periodontol 2000. 2007;44:127–153. doi: 10.1111/j.1600-0757.2006.00193.x.
8. Preshaw PM, Alba AL, Herrera D, Jepsen S, Konstantinidis A, Makrilakis K, Taylor R. Periodontitis and diabetes: a two-way relationship. Diabetologia. 2012 Jan;55(1):21-31. doi: 10.1007/s00125-011-2342-y. Epub 2011 Nov 6. PMID: 22057194; PMCID: PMC3228943.
9. Tsai C, Hayes C, Taylor GW. Glycemic control of type 2 diabetes and severe periodontal disease in the US adult population. Community Dent Oral Epidemiol. 2002;30:182–192. doi: 10.1034/j.1600-0528.2002.300304.x.
10. Teeuw WJ, Gerdes VEA, Loos BG. Effect of periodontal treatment on glycemic control of diabetic patients: a systematic review and meta-analysis. Diabetes Care. 2010;33:421–427. doi: 10.2337/dc09-1378
11. Skamagas M, Breen TL, LeRoith D. Update on diabetes mellitus: Prevention, treatment, and association with oral diseases. Oral Dis 2008; 14:105–14.
12. Janket SJ, Jones JA, Meurman JH, Baird AE, Van Dyke TE. Oral infection, hyperglycemia, and endothelial dysfunction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008; 105:173–9.
13. Levison ME. Pneumonia, including necrotizing pulmonary infections (lung abscess). In Harrison's Principles of Internal Medicine, 13th edn, ed. KJ Isselbacher, E Braunwald, JD Wilson et al., pp. 1197– 1206. McGraw Hill, New York, 1994
14. Sinclair DG, Evans TW. Nosocomial pneumonia in the intensive care unit. Br J Hosp Med 1994; 51:177– 180.
15. Toews GB. Nosocomial pneumonia. Am J Med Sci 1986; 291:355– 367.
16. Terpenning M, Bretz W, Lopatin D, Langmore S, Dominguez B, Loesche W. Bacterial colonization of saliva and plaque in the elderly. Clin Infect Dis 1993; 16(Suppl 4):S314– S316.
17. Scannapieco FA, Stewart EM, Mylotte JM. Colonization of dental plaque by respiratory pathogens in medical intensive care patients. Crit Care Med 1992; 20:740– 745.
18. Scannapieco FA. Pneumonia in nonambulatory patients. The role of oral bacteria and oral hygiene. J Am Dent Assoc 2006; 137(Suppl):21S–25S.
19. Russell SL, Boylan RJ, Kaslick RS, Scannapieco FA, Katz RV. Respiratory pathogen colonization of the dental plaque of institutionalized elders. Spec Care Dentist 1999; 19:128–134.
20. Lorenz KA, Weiss PJ. Capnocytophagal pneumonia in a healthy man. West J Med 1994; 160:79– 80.
21. Zijlstra EE, Swart GR, Godfroy FJ, Degener JE. Pericarditis, pneumonia and brain abscess due to a combined Actinomyces–Actinobacillus actinomycetemcomitans infection. J Infect 1992; 25:83–87.
22. Yuan A, Yang PC, Lee LN, Chang DB, Kuo SH, Luh KT. Actinobacillus actinomycetemcomitans pneumonia with chest wall involvement and rib destruction. Chest 1992; 101:1450– 1452.
23. Shinzato T, Saito A. The Streptococcus milleri group as a cause of pulmonary infections. Clin Infect Dis 1995; 21(Suppl 3):S238– S243.
24. Wood LF, Chahroudi A, Chen HL, Jaspan HB, Sodora DL. The oral mucosa immune environment and oral transmission of HIV/SIV. Immunol. Rev. 254:10.1111/imr.12078, 2013
25. Embree JE, Njenga S, Datta P, Nagelkerke NJ, Ndinya-Achola JO, Mohammed Z, Ramdahin S, Bwayo JJ, Plummer FA. Risk factors for postnatal mother-child tranmission of HIV-1, AIDS 10:2535-2541, 2000
26. Yang LC, Suen YJ, Wang YH, Lin TC, Yu HC, Chang YC. The Association of Periodontal Treatment and Decreased Pneumonia: A Nationwide Population-Based Cohort Study. Int. J.. Environ. Res. Public Health. 17:3356, 2020
27. Almirall J, Serra-Prat M, Bolibar I, Balasso V. Risk factors for community-accquired pneumonia in adults: a systematic review of observational studies. Respiration 94:299-311, 2017
28. Sands KM, Wilson MJ, Lewis MAO, Wise MP, Palmer N, Hayes AJ, Barnes RA, Williams DW, Respiratory pathogen colonization of dental plaque, the lower airways, and endotracheal tube biofilms during mechanical ventilation. J. Critical Care, 37:45-49, 2017
29. El-Sohl AA, Pietrantoni C, Bhat A, Okada M, Zambon J, Aquilina A, Berbary E. Colonization of dental plaques. Chest 126:1575-1582, 2004
30. Sjörgren P, Nilsson E, Forsell M, Johansson O, Hoogstraate J. A Systematic Review of the Preventive Effect of Oral Hygiene on Pneumonia and Respiratory Tract Infection in Elderly People in Hospitals and Nursing Homes: Effect Estimates and Methodological Quality of Randomized Controlled Trials. J. Am. Geriatric Soc. 56:2124-2130, 2008
31. Hua F, Xie H, Worthington HV, Furness S, Zhang Q, Li C. Oral hygiene care for critically ill patients to prevent ventilator‐associated pneumonia. Cochrane Database of Sytem. Rev. 10:CD008367, 2016
32. Scannapieco FA, Binkley CJ. Modest reduction in risk for ventilator‐associated pneumonia in critically ill patients receiving mechanical ventilation following topical oral chlorhexidine. J Evid Based Dent Pract 2012; 12:15– 17.
33. Yoneyama T, Hashimoto K, Fukuda H, Ishida M, Arai H, Sekizawa K, Yamaya M, Sasaki H. Oral hygiene reduces respiratory infections in elderly bed‐bound nursing home patients. Arch Gerontol Geriatr 1996; 22:11– 19.
34. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579:270-273.
35. Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 2020; 12:8.
36. Wu C, Zheng M. Single-cell RNA expression profiling shows that ACE2, the putative receptor of COVID-2019, has significant expression in nasal and mouth tissue, and is co-expressed with TMPRSS2 and not co-expressed with SLC6A19 in the tissues. BMC Infectious Diseses (under review),
37. To KKW, Tsang OTY, Leung WS, Tam AR, Wu TC, Lung DC, Yip CCY, Cai JP, Chan JMC, Chik TSH, Lau DPL, Choi CYC, Chen LL, Chan WM, Chan KH, Ip JD, Ng ACK, Poon RWS, Luo CT, Cheng VCC, Chan JFW, Hung IFN, Chen Z, Chen H, Yuen KY. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis (published online).
38. Chen L, Zhao J, Peng J, Li X, Deng X, Geng Z, Shen Z, Guo F, Zhang Q, Jin Y, Wang L, Wang S. 1/ 24Detection of 2019-nCoV in Saliva and Characterization of Oral Symptoms in COVID-19 Patients. SSRN (published online)
39. To KKW, Tsang OTY, Yip CCY, Chan KH, Wu TC, Chan JMC, Leung WS, Chik TSH, Choi CYC, Kandamby DH, Lung DC, Tam AR, Poon RWS, Fung AYF, Hung IFN, Cheng VCC, Chan JFW, Yuen KY. Consistent Detection of 2019 Novel Coronavirus in Saliva. Clin Infect Dis. (epub ahead of print, 2020)
40. Santosh ABR, Muddana K. Viral infections of oral cavity. J. Family Med Prim Care 9:36-42, 2020
41. Ortiz AP, Gonzalez D, Vivaldi-Olivier J, Castaneda M, Rivera V, Diaz E, Centeno H, Munoz C, Palefsky J, Joshipura K, Perez CM. Periodontitis and oral human papillomavirus infection among Hispanic adults. Papillomavirus Res. 5:128-133, 2018
42. Giacomelli A, Pezzati L, Conti F, Bernacchia D, Siano M, Oreni L, Rusconi S, Gervasoni C, Ridolfo AL, Rizzardini G, Antinori A, Galli M. Self-reported Olfactory and Taste Disorders in Patients With Severe Acute Respiratory Coronavirus 2 Infection: A Cross-sectional Study Cin. Infect. Dis. 2020.
43. Paju S, Scannapieco FA. Oral biofilms, periodontitis, and pulmonary infections. Oral Dis 2007; 13:508– 512.
44. Li X, Kolltveit KM, Tronstad L, Olsen I. Systemic diseases caused by oral infection. Clin Microbiol Rev 2007; 13:547– 558.
45. Heo SM, Choi KS, Kazim LA, Reddy MS, Haase EM, Scannapieco FA, Ruhl S. Host defense proteins derived from human saliva bind to staphylococcus aureus. Infection and Immunity, 81:1364-1373, 2020.
46. Biesbrock AR, Reddy MS, Levine MJ. Interaction of a Salivary mucin-secretory immunoglobulin A complex with mucosal pathogens. Infection and Immunity 59:3492-3497, 1991
47. Sanchez GA, Miozza V, Delgado A, Busch L. Determination of salivary levels of mucin and amylase in chronic periodontitis patients. J. Periodontal Res. 46:221-227
48. Gomez-Filho IS, Passos JS, Seixas da Cruz S. Respiratory disease and the role of bacteria. J. Oral Microbiol 2:10.3402/jom.v2i0.5811. doi: 10.3402/jom.v2i0.5811
49. Chan HH, Rahim ZHA, Jessie K, Hashim OH, Taiyeb-Ali TB. Salivary Proteins Associated with Periodontitis in Patients with Type 2 Diabetes Mellitus. Int. J. Mol. Sci. 13:4642-4654
50. Gaeckle NT, Pragman AA, Pendleton KM, Baldomaro AK, Criner GA. The Oral-Lung Axis: The Impact of Oral Health on Lung Health. Respiratory Care (paper in print, epub ahead of print) 2020, doi: 10.4187/respcare.07332
51. Sun K, Chen J, Viboud C. Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study Lancet Digital Health 2020; 2:e201-208
52. Thornton-Evans G, Eke P, Wie L, Palmer A, Moeti R, Hutchins S, Borrell LN. Periodontitis Among Adults Aged ≥30 Years — United States, 2009–2010, Morbidity and Mortality Weekly Report (MMWR) 2013, 62:129-135
53. Groeger S, Meyle J. Oral Mucosal Epithelial Cells. Front Immunol 2019;10:208. doi: 10.3389/fimmu.2019.00208
54. Chi AC, Neville BW, Krayer JW, Gonsalves WC. Oral manifestations of systemic disease. Am Fam Physician. 2010; 82:1381–8.
55. Kiran M, Arpak N, Unsal E, Erdoǧan MF. The effect of improved periodontal health on metabolic control in type 2 diabetes mellitus. J Clin Periodontol. 2005; 32:266–72.
56. Kinane DF, Stathopoulou PG, Papapanou PN. (2017). Periodontal diseases. Nature Reviews. Diseases Primers, 22(3), 17038.
57. Tonetti MS, Greenwell H, Kornman KS. (2018). Staging and grading of periodontitis: Framework and proposal of a new classification and case definition. Journal of Clinical Periodontology, 45(Suppl. 20), 149–161.
58. Leite FRM, Nascimento GG, Scheutz F, López R. Effect of Smoking on Periodontitis: A Systematic Review and Meta-regression. Am. J. Prev. Med. 2018;54:831–841. doi: 10.1016/j.amepre.2018.02.014.
59. Cervino G, Terranova A, Briguglio F, De Stefano R, Famà F, D’Amico C, Amoroso G, Marino S, Gorassini F, Mastroieni R, et al. Diabetes: Oral Health Related Quality of Life and Oral Alterations. Biomed. Res. Int. 2019;2019:5907195. doi: 10.1155/2019/5907195.
60. Nascimento GG, Leite FRM, Vestergaard P, Scheutz F, López R. Does diabetes increase the risk of periodontitis? A systematic review and meta-regression analysis of longitudinal prospective studies. Acta Diabetol. 2018;55:653–667. doi: 10.1007/s00592-018-1120-4.
61. Gul SS, Abdulkareem AA, Sha AM, Rawlinson A. (2020). Diagnostic accuracy of oral fluids biomarker profile to determine the current and future status of periodontal and peri‐implant diseases. Diagnostics (Basel), 10(10), 838.
62. Leppilahti JM, Sorsa T, Kallio MA, Tervahartiala T, Emingil G, Han B, Mäntylä P. (2015). The utility of gingival crevicular fluid matrix metalloproteinase‐8 response patterns in prediction of site‐ level clinical treatment outcome. Journal of Periodontology, 86, 777–787.
63. Pussinen PJ , Paju S , Viikari J, Salminen A, Taittonen L, Laitinen T, Burgner D, Kähönen M, Lehtimäki T, Hutri‐Kähönen N, Raitakari O, Juonala M. (2020). Childhood oral infections associate with adulthood metabolic syndrome: A longitudinal cohort study. Journal of Dental Research, 99(10), 1165–1173.
64. Kuula H, Salo T, Pirilä E, Tuomainen AM, Jauhiainen M, Uitto VJ, Tjäderhane L, Pussinen PJ, Sorsa T. (2009). Local and systemic responses in matrix metalloproteinase 8‐deficient mice during porphyromonas gingivalis‐induced periodontitis. Infection and Immunity, 77(2), 850–859.
65. Sorsa T, Gursoy UK, Nwhator S, Hernandez M, Tervahartiala T, Leppilahti J, Gursoy M, Könönen E, Emingil G, Pussinen PJ, Mäntylä, P. (2016). Analysis of matrix metalloproteinases, especially MMP‐8, in gingival creviclular fluid, mouthrinse and saliva for monitoring periodontal diseases. Periodontology 2000, 70(1), 142–163.
66. Umeizudike K, Räisänen I, Gupta S, Nwhator S, Grigoriadis A, Sakellari D, Sorsa T. Active matrix metalloproteinase-8: A potential biomarker of oral systemic link. Clin Exp Dent Res. 2022 Feb;8(1):359-365. doi: 10.1002/cre2.516. Epub 2021 Nov 19. PMID: 34800007; PMCID: PMC8874056.
67. Herr AE, Hatch AV, Throckmorton DJ, Tran HM, Brennan JS, Giannobile WV, Singh A. (2007). Microfluidic immunoassays as rapid saliva‐based clinical diagnostics. Proceedings of the National Academy of Sciences of the United States of America, 104(13), 5268–5273.
68. Nwhator SO, Ayanbadejo PO, Umeizudike KA, Opeodu OI, Agbelusi GA, Olamijulo JA, Arowojolu MO, Sorsa T, Babajide BS, Opedun, D. O. (2014). Clinical correlates of a lateral‐flow immunoassay oral risk indicator. Journal of Periodontology, 85(1), 188–194.
69. Sorsa T, Suomalainen K, Uitto, V. J. (1990). The role of gingival crevicular fluid and salivary interstitial collagenases in human periodontal diseases. Archives of Oral Biology, suppl 35, S193–S196.
70. Sorsa T, Alassiri S, Grigoriadis A, Räisänen IT, Pärnänen P, Nwhator SO, Gieselmann DR, Sakellari, D. (2020). Active MMP‐8 (aMMP‐8) as a grading and staging biomarker in the periodontitis classification. Diagnostics, 10, 61.
71. Lee W, Aitken S, Sodek J, McCulloch CA. (1995). Evidence of a direct relationship between neutrophil collagenase activity and periodontal tissue destruction in vivo: Role of active enzyme in human periodontitis. Journal of Periodontal Research, 30, 23–33.‐0765.1995.tb01249.x
72. Alassiri S, Pärnänen P, Rathnayake N, Johannsen G, Heikkinen A‐M , Lazzara R, van der Schoor P, van der Schoor JG, Tervahartiala T, Gieselmann DR, Sorsa T. (2018). The ability of quantitative, specific, and sensitive point‐of‐care/chair‐side oral fluid immunotests for aMMP‐8 to detect periodontal and peri‐implant diseases. Disease Markers, 2018, 1306396.
73. Keskin M, Lähteenmäki H, Rathnayake N, Räisänen IT, Tervahartiala T, Pärnänen P, Şenışık AM, Karaçetin D, Yentek Balkanay A, Heikkilä P, Hagström J, Rautava J, Haglund C, Gursoy UK, Silbereisen A, Bostanci N, Sorsa T. (2020). Active matrix metalloproteinase‐8 and interleukin‐6 detect periodontal degeneration caused by radiotherapy of head and neck cancer: a pilot study. Expert Review of Proteomics, 17, 777–784.
74. Gupta S, Sahni V, Räisänen IT, Grigoriadis A, Sakellari D, Gieselmann DR, Sorsa T. (2021). Linking oral microbial proteolysis to aMMP‐8 PoC diagnostics along with the stage and grade of periodontitis: A cross‐sectional study. Oral Diseases.
75. Mancini S, Romanelli R, Laschinger CA, Overall CM, Sodek J, McCulloch C. A. (1999). Assessment of a novel screening test for neutrophil collagenase activity in the diagnosis of periodontal diseases. Journal of Periodontology, 70, 1292–1302. https://doi. org/10.1902/jop.1999.70.11.1292
76. Räisänen IT, Lähteenmäki H, Gupta S, Grigoriadis A, Sahni V, Sorsa T. (2021). An aMMP‐8 point‐of‐care and questionnaire based real‐time diagnostic toolkit for medical practitioners. Diagnostics, 11, 711.
77. Romanelli R, Mancini S, Laschinger C, Overall CM, Sodek J, McCulloch CA. (1999). Activation of neutrophil collagenase in periodontitis. Infection and Immunity, 67, 2319–2326. https://doi. org/10.1128/IAI.67.5.2319‐2326.1999
78. Gupta S, Mohindra R, Singla M, et al. The clinical association between periodontitis and COVID-19. Clin Oral Investig 2021; 27: 1–14
79. Anand PS, Jadhav P, Kamath KP, Kumar SR, Vijayalaxmi S, Anil S. A case-control study on the association between periodontitis and coronavirus disease (COVID-19). J Periodontol 2021; published online Aug 4.
80. Gupta S, Saarikko M, Pfützner A, Raisanen IT, Sorsa T. Compromised periodontal status could increase mortality for patients with COVID-19. The Lancet (Infect. Dis.) 22:314, 2022
81. Gupta S, Mohindra R, Singla M, Khera S, Kumar A, Rathnayake N, Sorsa T, Pfützner A, Raisanen IT, Soni RK, Kanta P, Jain A, Gauba K, Goyal K, Singh MP, Ghosh A, Kajal K, Mahajan V, Suri V, Bhalla A. Validation of a noninvasive aMMP-8 point-of care diagnostic methodology in COVID-19 patients with periodontal disease. Clin. Exp. Dent. Res. 2022; 1-4; DOI: 10.1002/cre2.58935.
82. Arias-Bujanda N., Regueira-Iglesias A., Balsa-Castro C., Nibali L., Donos N., Tomás I. Accuracy of single molecular biomarkers in gingival crevicular fluid for the diagnosis of periodontitis: A systematic review and meta-analysis. J. Clin. Periodontol. 2019;46:1166–1182.
doi: 10.1111/jcpe.13188.
83. Arias-Bujanda N., Regueira-Iglesias A., Balsa-Castro C., Nibali L., Donos N., Tomás I. Accuracy of single molecular biomarkers in saliva for the diagnosis of periodontitis: A systematic review and meta-analysis. J. Clin. Periodontol. 2020;47:2–18. doi: 10.1111/jcpe.13202
84. Sukriti K.C., Wang X.Z., Gallagher J.E. Diagnostic sensitivity and specificity of host-derived salivary biomarkers in periodontal disease amongst adults: Systematic review. J. Clin. Periodontol. 2019 doi: 10.1111/jcpe.13218.
85. Zhao D, Cheng T, Koohi-Moghadam M, Wu MZ, Yu SY, Ding X, Pelekos G, You KH, Jin L. Salivary ACE2 and TMPRSS2 link to periodontal status and metabolic parameters. Clin. Transt. Disc. 2022:e37,