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For: Jost G, Lenhard DC, Sieber MA, Lohrke J, Frenzel T, Pietsch H. Signal Increase on Unenhanced T1-Weighted Images in the Rat Brain After Repeated, Extended Doses of Gadolinium-Based Contrast Agents: Comparison of Linear and Macrocyclic Agents. Invest Radiol 2016;51:83-9. [PMID: 26606548 DOI: 10.1097/RLI.0000000000000242] [Cited by in Crossref: 117] [Cited by in F6Publishing: 47] [Article Influence: 19.5] [Reference Citation Analysis]
Number Citing Articles
1 Smith TE, Steven A, Bagert BA. Gadolinium Deposition in Neurology Clinical Practice. Ochsner J 2019;19:17-25. [PMID: 30983897 DOI: 10.31486/toj.18.0111] [Cited by in Crossref: 8] [Cited by in F6Publishing: 4] [Article Influence: 2.7] [Reference Citation Analysis]
2 Endrikat J, Anzalone N. Gadobutrol in India-A Comprehensive Review of Safety and Efficacy. Magn Reson Insights 2017;10:1178623X17730048. [PMID: 28932122 DOI: 10.1177/1178623X17730048] [Cited by in Crossref: 1] [Cited by in F6Publishing: 1] [Article Influence: 0.2] [Reference Citation Analysis]
3 Unruh C, Van Bavel N, Anikovskiy M, Prenner EJ. Benefits and Detriments of Gadolinium from Medical Advances to Health and Ecological Risks. Molecules 2020;25:E5762. [PMID: 33297578 DOI: 10.3390/molecules25235762] [Cited by in Crossref: 2] [Cited by in F6Publishing: 1] [Article Influence: 1.0] [Reference Citation Analysis]
4 Hoggard N, Roditi GH. T1 hyperintensity on brain imaging subsequent to gadolinium-based contrast agent administration: what do we know about intracranial gadolinium deposition? Br J Radiol 2017;90:20160590. [PMID: 27653560 DOI: 10.1259/bjr.20160590] [Cited by in Crossref: 9] [Cited by in F6Publishing: 8] [Article Influence: 1.5] [Reference Citation Analysis]
5 Kasper E, Schemuth HP, Horry S, Kinner S. Changes in signal intensity in the dentate nucleus at unenhanced T1-weighted magnetic resonance imaging depending on class of previously used gadolinium-based contrast agent. Pediatr Radiol 2018;48:686-93. [PMID: 29417165 DOI: 10.1007/s00247-018-4080-5] [Cited by in Crossref: 15] [Cited by in F6Publishing: 13] [Article Influence: 3.8] [Reference Citation Analysis]
6 Minaeva O, Hua N, Franz ES, Lupoli N, Mian AZ, Farris CW, Hildebrandt AM, Kiernan PT, Evers LE, Griffin AD, Liu X, Chancellor SE, Babcock KJ, Moncaster JA, Jara H, Alvarez VE, Huber BR, Guermazi A, Latour LL, McKee AC, Soto JA, Anderson SW, Goldstein LE. Nonhomogeneous Gadolinium Retention in the Cerebral Cortex after Intravenous Administration of Gadolinium-based Contrast Agent in Rats and Humans. Radiology 2020;294:377-85. [PMID: 31769744 DOI: 10.1148/radiol.2019190461] [Cited by in Crossref: 10] [Cited by in F6Publishing: 8] [Article Influence: 3.3] [Reference Citation Analysis]
7 Mithal LB, Patel PS, Mithal D, Palac HL, Rozenfeld MN. Use of gadolinium-based magnetic resonance imaging contrast agents and awareness of brain gadolinium deposition among pediatric providers in North America. Pediatr Radiol 2017;47:657-64. [PMID: 28283727 DOI: 10.1007/s00247-017-3810-4] [Cited by in Crossref: 25] [Cited by in F6Publishing: 24] [Article Influence: 5.0] [Reference Citation Analysis]
8 van der Molen AJ. Gadolinium Deposition in the Brain and Body. Journal of the Belgian Society of Radiology 2019;103:71. [DOI: 10.5334/jbsr.1945] [Cited by in Crossref: 3] [Cited by in F6Publishing: 1] [Article Influence: 1.0] [Reference Citation Analysis]
9 Rasschaert M, Emerit A, Fretellier N, Factor C, Robert P, Idée JM, Corot C. Gadolinium Retention, Brain T1 Hyperintensity, and Endogenous Metals: A Comparative Study of Macrocyclic Versus Linear Gadolinium Chelates in Renally Sensitized Rats. Invest Radiol 2018;53:328-37. [PMID: 29329151 DOI: 10.1097/RLI.0000000000000447] [Cited by in Crossref: 30] [Cited by in F6Publishing: 15] [Article Influence: 10.0] [Reference Citation Analysis]
10 Garcia J, Liu SZ, Louie AY. Biological effects of MRI contrast agents: gadolinium retention, potential mechanisms and a role for phosphorus. Philos Trans A Math Phys Eng Sci 2017;375:20170180. [PMID: 29038383 DOI: 10.1098/rsta.2017.0180] [Cited by in Crossref: 17] [Cited by in F6Publishing: 17] [Article Influence: 5.7] [Reference Citation Analysis]
11 Fallenberg EM, Schmitzberger FF, Amer H, Ingold-Heppner B, Balleyguier C, Diekmann F, Engelken F, Mann RM, Renz DM, Bick U, Hamm B, Dromain C. Contrast-enhanced spectral mammography vs. mammography and MRI - clinical performance in a multi-reader evaluation. Eur Radiol 2017;27:2752-64. [PMID: 27896471 DOI: 10.1007/s00330-016-4650-6] [Cited by in Crossref: 87] [Cited by in F6Publishing: 72] [Article Influence: 14.5] [Reference Citation Analysis]
12 Pullicino R, Radon M, Biswas S, Bhojak M, Das K. A Review of the Current Evidence on Gadolinium Deposition in the Brain. Clin Neuroradiol 2018;28:159-69. [PMID: 29523896 DOI: 10.1007/s00062-018-0678-0] [Cited by in Crossref: 30] [Cited by in F6Publishing: 23] [Article Influence: 7.5] [Reference Citation Analysis]
13 Frenzel T, Apte C, Jost G, Schöckel L, Lohrke J, Pietsch H. Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents: Comparative Study in Rats. Invest Radiol 2017;52:396-404. [PMID: 28125438 DOI: 10.1097/RLI.0000000000000352] [Cited by in Crossref: 141] [Cited by in F6Publishing: 48] [Article Influence: 35.3] [Reference Citation Analysis]
14 Lee JY, Park JE, Kim HS, Kim SO, Oh JY, Shim WH, Jung SC, Choi CG, Kim SJ. Up to 52 administrations of macrocyclic ionic MR contrast agent are not associated with intracranial gadolinium deposition: Multifactorial analysis in 385 patients. PLoS One 2017;12:e0183916. [PMID: 28859167 DOI: 10.1371/journal.pone.0183916] [Cited by in Crossref: 22] [Cited by in F6Publishing: 18] [Article Influence: 4.4] [Reference Citation Analysis]
15 Kartamihardja AAP, Hanaoka H, Andriana P, Kameo S, Takahashi A, Koyama H, Tsushima Y. Quantitative analysis of Gd in the protein content of the brain following single injection of gadolinium-based contrast agents (GBCAs) by size exclusion chromatography. Br J Radiol 2019;92:20190062. [PMID: 31045442 DOI: 10.1259/bjr.20190062] [Cited by in Crossref: 5] [Cited by in F6Publishing: 3] [Article Influence: 1.7] [Reference Citation Analysis]
16 Splendiani A, Corridore A, Torlone S, Martino M, Barile A, Di Cesare E, Masciocchi C. Visible T1-hyperintensity of the dentate nucleus after multiple administrations of macrocyclic gadolinium-based contrast agents: yes or no? Insights Imaging 2019;10:82. [PMID: 31482392 DOI: 10.1186/s13244-019-0767-x] [Cited by in Crossref: 3] [Cited by in F6Publishing: 3] [Article Influence: 1.0] [Reference Citation Analysis]
17 Grahl S, Bussas M, Pongratz V, Kirschke JS, Zimmer C, Berthele A, Hemmer B, Mühlau M. T1-Weighted Intensity Increase After a Single Administration of a Linear Gadolinium-Based Contrast Agent in Multiple Sclerosis. Clin Neuroradiol 2021;31:235-43. [PMID: 32055874 DOI: 10.1007/s00062-020-00882-6] [Reference Citation Analysis]
18 Kanal E, Patton TJ, Krefting I, Wang C. Nephrogenic Systemic Fibrosis Risk Assessment and Skin Biopsy Quantification in Patients with Renal Disease following Gadobenate Contrast Administration. AJNR Am J Neuroradiol 2020;41:393-9. [PMID: 32115422 DOI: 10.3174/ajnr.A6448] [Cited by in Crossref: 4] [Cited by in F6Publishing: 1] [Article Influence: 2.0] [Reference Citation Analysis]
19 Guo BJ, Yang ZL, Zhang LJ. Gadolinium Deposition in Brain: Current Scientific Evidence and Future Perspectives. Front Mol Neurosci 2018;11:335. [PMID: 30294259 DOI: 10.3389/fnmol.2018.00335] [Cited by in Crossref: 65] [Cited by in F6Publishing: 61] [Article Influence: 16.3] [Reference Citation Analysis]
20 Kanda T, Nakai Y, Hagiwara A, Oba H, Toyoda K, Furui S. Distribution and chemical forms of gadolinium in the brain: a review. Br J Radiol 2017;90:20170115. [PMID: 28749164 DOI: 10.1259/bjr.20170115] [Cited by in Crossref: 33] [Cited by in F6Publishing: 31] [Article Influence: 6.6] [Reference Citation Analysis]
21 Rasschaert M, Idée JM, Robert P, Fretellier N, Vives V, Violas X, Ballet S, Corot C. Moderate Renal Failure Accentuates T1 Signal Enhancement in the Deep Cerebellar Nuclei of Gadodiamide-Treated Rats. Invest Radiol 2017;52:255-64. [PMID: 28067754 DOI: 10.1097/RLI.0000000000000339] [Cited by in Crossref: 35] [Cited by in F6Publishing: 16] [Article Influence: 7.0] [Reference Citation Analysis]
22 Lohrke J, Frisk AL, Frenzel T, Schöckel L, Rosenbruch M, Jost G, Lenhard DC, Sieber MA, Nischwitz V, Küppers A, Pietsch H. Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents. Invest Radiol 2017;52:324-33. [PMID: 28323657 DOI: 10.1097/RLI.0000000000000344] [Cited by in Crossref: 105] [Cited by in F6Publishing: 44] [Article Influence: 26.3] [Reference Citation Analysis]
23 Stojanov D, Aracki-Trenkic A, Benedeto-Stojanov D. Gadolinium deposition within the dentate nucleus and globus pallidus after repeated administrations of gadolinium-based contrast agents-current status. Neuroradiology. 2016;58:433-441. [PMID: 26873830 DOI: 10.1007/s00234-016-1658-1] [Cited by in Crossref: 88] [Cited by in F6Publishing: 71] [Article Influence: 14.7] [Reference Citation Analysis]
24 Schneider GK, Stroeder J, Roditi G, Colosimo C, Armstrong P, Martucci M, Buecker A, Raczeck P. T1 Signal Measurements in Pediatric Brain: Findings after Multiple Exposures to Gadobenate Dimeglumine for Imaging of Nonneurologic Disease. AJNR Am J Neuroradiol 2017;38:1799-806. [PMID: 28642266 DOI: 10.3174/ajnr.A5270] [Cited by in Crossref: 24] [Cited by in F6Publishing: 9] [Article Influence: 4.8] [Reference Citation Analysis]
25 Tedeschi E, Cocozza S, Borrelli P, Ugga L, Morra VB, Palma G. Longitudinal Assessment of Dentate Nuclei Relaxometry during Massive Gadobutrol Exposure. Magn Reson Med Sci 2018;17:100-4. [PMID: 28367903 DOI: 10.2463/mrms.cr.2016-0137] [Cited by in Crossref: 6] [Cited by in F6Publishing: 7] [Article Influence: 1.2] [Reference Citation Analysis]
26 Kanda T, Nakai Y, Aoki S, Oba H, Toyoda K, Kitajima K, Furui S. Contribution of metals to brain MR signal intensity: review articles. Jpn J Radiol 2016;34:258-66. [PMID: 26932404 DOI: 10.1007/s11604-016-0532-8] [Cited by in Crossref: 17] [Cited by in F6Publishing: 15] [Article Influence: 2.8] [Reference Citation Analysis]
27 Kanda T. The New Restrictions on the Use of Linear Gadolinium-based Contrast Agents in Japan. Magn Reson Med Sci 2019;18:1-3. [PMID: 29553066 DOI: 10.2463/mrms.e.2017-0176] [Cited by in Crossref: 14] [Cited by in F6Publishing: 11] [Article Influence: 3.5] [Reference Citation Analysis]
28 Ramalho J, Semelka RC, Ramalho M, Nunes RH, AlObaidy M, Castillo M. Reply. AJNR Am J Neuroradiol 2016;37:E42. [PMID: 26915565 DOI: 10.3174/ajnr.A4744] [Cited by in Crossref: 2] [Article Influence: 0.3] [Reference Citation Analysis]
29 Robert P, Frenzel T, Factor C, Jost G, Rasschaert M, Schuetz G, Fretellier N, Boyken J, Idée JM, Pietsch H. Methodological Aspects for Preclinical Evaluation of Gadolinium Presence in Brain Tissue: Critical Appraisal and Suggestions for Harmonization-A Joint Initiative. Invest Radiol 2018;53:499-517. [PMID: 29659381 DOI: 10.1097/RLI.0000000000000467] [Cited by in Crossref: 30] [Cited by in F6Publishing: 10] [Article Influence: 10.0] [Reference Citation Analysis]
30 Eisele P, Szabo K, Ebert A, Radbruch A, Platten M, Schoenberg SO, Gass A. Diffusion-weighted imaging of the dentate nucleus after repeated application of gadolinium-based contrast agents in multiple sclerosis. Magnetic Resonance Imaging 2019;58:1-5. [DOI: 10.1016/j.mri.2019.01.007] [Cited by in Crossref: 12] [Cited by in F6Publishing: 10] [Article Influence: 4.0] [Reference Citation Analysis]
31 Choi JW, Moon WJ. Gadolinium Deposition in the Brain: Current Updates.Korean J Radiol. 2019;20:134-147. [PMID: 30627029 DOI: 10.3348/kjr.2018.0356] [Cited by in Crossref: 55] [Cited by in F6Publishing: 47] [Article Influence: 13.8] [Reference Citation Analysis]
32 Conte G, Preda L, Cocorocchio E, Raimondi S, Giannitto C, Minotti M, De Piano F, Petralia G, Ferrucci PF, Bellomi M. Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study. Eur Radiol 2017;27:4372-8. [PMID: 28357495 DOI: 10.1007/s00330-017-4810-3] [Cited by in Crossref: 22] [Cited by in F6Publishing: 20] [Article Influence: 4.4] [Reference Citation Analysis]
33 Langner S, Kromrey ML, Kuehn JP, Grothe M, Domin M. Repeated intravenous administration of gadobutrol does not lead to increased signal intensity on unenhanced T1-weighted images-a voxel-based whole brain analysis. Eur Radiol 2017;27:3687-93. [PMID: 28289935 DOI: 10.1007/s00330-017-4777-0] [Cited by in Crossref: 13] [Cited by in F6Publishing: 11] [Article Influence: 2.6] [Reference Citation Analysis]
34 Endrikat J, Vogtlaender K, Dohanish S, Balzer T, Breuer J. Safety of Gadobutrol: Results From 42 Clinical Phase II to IV Studies and Postmarketing Surveillance After 29 Million Applications. Invest Radiol 2016;51:537-43. [PMID: 26964075 DOI: 10.1097/RLI.0000000000000270] [Cited by in Crossref: 22] [Cited by in F6Publishing: 13] [Article Influence: 4.4] [Reference Citation Analysis]
35 Lee B, Bae YJ, Choi BS, Choi BY, Cho SJ, Kim H, Kim JH. Radiologic Differentiation between Granulomatosis with Polyangiitis and Its Mimics Involving the Skull Base in Humans Using High-Resolution Magnetic Resonance Imaging. Diagnostics (Basel) 2021;11:2162. [PMID: 34829509 DOI: 10.3390/diagnostics11112162] [Reference Citation Analysis]
36 Jost G, Frenzel T, Lohrke J, Lenhard DC, Naganawa S, Pietsch H. Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue. Eur Radiol 2017;27:2877-85. [PMID: 27832312 DOI: 10.1007/s00330-016-4654-2] [Cited by in Crossref: 86] [Cited by in F6Publishing: 85] [Article Influence: 14.3] [Reference Citation Analysis]
37 Bussi S, Coppo A, Botteron C, Fraimbault V, Fanizzi A, De Laurentiis E, Colombo Serra S, Kirchin MA, Tedoldi F, Maisano F. Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats. J Magn Reson Imaging 2018;47:746-52. [PMID: 28730643 DOI: 10.1002/jmri.25822] [Cited by in Crossref: 68] [Cited by in F6Publishing: 60] [Article Influence: 13.6] [Reference Citation Analysis]
38 Schöckel L, Balzer T, Pietsch H. [Increased signal intensities and gadolinium levels in the brain after administration of gadolinium-based MR contrast agents : Clinical observations and results from preclinical research]. Radiologe 2019;59:359-68. [PMID: 30887087 DOI: 10.1007/s00117-019-0511-z] [Reference Citation Analysis]
39 Boyken J, Frenzel T, Lohrke J, Jost G, Pietsch H. Gadolinium Accumulation in the Deep Cerebellar Nuclei and Globus Pallidus After Exposure to Linear but Not Macrocyclic Gadolinium-Based Contrast Agents in a Retrospective Pig Study With High Similarity to Clinical Conditions. Invest Radiol 2018;53:278-85. [PMID: 29319556 DOI: 10.1097/RLI.0000000000000440] [Cited by in Crossref: 30] [Cited by in F6Publishing: 15] [Article Influence: 10.0] [Reference Citation Analysis]
40 Zhao K, Li S, Yi P, Guo Y, Yu Q, Zhu C, Feng Q, Du J, Zhang X, Feng Y. Detection of gadolinium deposition in cortical bone with ultrashort echo time T1 mapping: an ex vivo study in a rabbit model. Eur Radiol 2021;31:1569-77. [PMID: 32929642 DOI: 10.1007/s00330-020-07258-x] [Reference Citation Analysis]
41 Kanda T, Oba H, Toyoda K, Furui S. Macrocyclic Gadolinium-Based Contrast Agents Do Not Cause Hyperintensity in the Dentate Nucleus. AJNR Am J Neuroradiol 2016;37:E41. [PMID: 26915573 DOI: 10.3174/ajnr.A4710] [Cited by in Crossref: 17] [Cited by in F6Publishing: 4] [Article Influence: 2.8] [Reference Citation Analysis]
42 Bussi S, Coppo A, Celeste R, Fanizzi A, Fringuello Mingo A, Ferraris A, Botteron C, Kirchin MA, Tedoldi F, Maisano F. Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats. Insights Imaging 2020;11:11. [PMID: 32020385 DOI: 10.1186/s13244-019-0824-5] [Cited by in Crossref: 11] [Cited by in F6Publishing: 8] [Article Influence: 5.5] [Reference Citation Analysis]
43 Richter H, Bücker P, Dunker C, Karst U, Kircher PR. Gadolinium deposition in the brain of dogs after multiple intravenous administrations of linear gadolinium based contrast agents. PLoS One 2020;15:e0227649. [PMID: 32012163 DOI: 10.1371/journal.pone.0227649] [Cited by in Crossref: 5] [Cited by in F6Publishing: 4] [Article Influence: 2.5] [Reference Citation Analysis]
44 Pinter NK, Klein JP, Mechtler LL. Potential Safety Issues Related to the Use of Gadolinium-based Contrast Agents. Continuum (Minneap Minn) 2016;22:1678-84. [PMID: 27740994 DOI: 10.1212/CON.0000000000000378] [Cited by in Crossref: 3] [Article Influence: 0.5] [Reference Citation Analysis]
45 Kinner S, Schubert TB, Bruce RJ, Rebsamen SL, Diamond CA, Reeder SB, Rowley HA. Deep Brain Nuclei T1 Shortening after Gadobenate Dimeglumine in Children: Influence of Radiation and Chemotherapy. AJNR Am J Neuroradiol 2018;39:24-30. [PMID: 29146718 DOI: 10.3174/ajnr.A5453] [Cited by in Crossref: 11] [Cited by in F6Publishing: 7] [Article Influence: 2.2] [Reference Citation Analysis]
46 El-Khatib AH, Radbruch H, Trog S, Neumann B, Paul F, Koch A, Linscheid MW, Jakubowski N, Schellenberger E. Gadolinium in human brain sections and colocalization with other elements. Neurol Neuroimmunol Neuroinflamm 2019;6:e515. [PMID: 30568993 DOI: 10.1212/NXI.0000000000000515] [Cited by in Crossref: 13] [Cited by in F6Publishing: 8] [Article Influence: 3.3] [Reference Citation Analysis]
47 Nörenberg D, Schmidt F, Schinke K, Frenzel T, Pietsch H, Giese A, Ertl-Wagner B, Levin J. Investigation of potential adverse central nervous system effects after long term oral administration of gadolinium in mice. PLoS One 2020;15:e0231495. [PMID: 32324769 DOI: 10.1371/journal.pone.0231495] [Cited by in Crossref: 5] [Cited by in F6Publishing: 3] [Article Influence: 2.5] [Reference Citation Analysis]
48 Habermeyer J, Boyken J, Harrer J, Canneva F, Ratz V, Moceri S, Admard J, Casadei N, Jost G, Bäuerle T, Frenzel T, Schmitz C, Schütz G, Pietsch H, von Hörsten S. Comprehensive phenotyping revealed transient startle response reduction and histopathological gadolinium localization to perineuronal nets after gadodiamide administration in rats. Sci Rep 2020;10:22385. [PMID: 33372182 DOI: 10.1038/s41598-020-79374-z] [Cited by in Crossref: 1] [Cited by in F6Publishing: 1] [Article Influence: 0.5] [Reference Citation Analysis]
49 Fretellier N, Granottier A, Rasschaert M, Grindel AL, Baudimont F, Robert P, Idée JM, Corot C. Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?: A Comparative Gadoterate Versus Gadodiamide Study in Juvenile and Adult Rats. Invest Radiol 2019;54:61-71. [PMID: 30394964 DOI: 10.1097/RLI.0000000000000517] [Cited by in Crossref: 14] [Cited by in F6Publishing: 5] [Article Influence: 4.7] [Reference Citation Analysis]
50 Boyken J, Frenzel T, Lohrke J, Jost G, Schütz G, Pietsch H. Impact of Treatment With Chelating Agents Depends on the Stability of Administered GBCAs: A Comparative Study in Rats. Invest Radiol 2019;54:76-82. [PMID: 30358694 DOI: 10.1097/RLI.0000000000000522] [Cited by in Crossref: 9] [Cited by in F6Publishing: 1] [Article Influence: 3.0] [Reference Citation Analysis]
51 Jost G, Frenzel T, Boyken J, Pietsch H. Impact of brain tumors and radiotherapy on the presence of gadolinium in the brain after repeated administration of gadolinium-based contrast agents: an experimental study in rats. Neuroradiology 2019;61:1273-80. [PMID: 31297571 DOI: 10.1007/s00234-019-02256-3] [Cited by in Crossref: 2] [Cited by in F6Publishing: 2] [Article Influence: 0.7] [Reference Citation Analysis]
52 Davies J, Marino M, Smith APL, Crowder JM, Larsen M, Lowery L, Castle J, Hibberd MG, Evans PM. Repeat and single dose administration of gadodiamide to rats to investigate concentration and location of gadolinium and the cell ultrastructure. Sci Rep 2021;11:13950. [PMID: 34230532 DOI: 10.1038/s41598-021-93147-2] [Reference Citation Analysis]