Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Adipocyte and Cell Biology

Systemic adiponectin levels in colorectal cancer and adenoma: a systematic review and meta-analysis

International Journal of Obesity volume 47, pages 911–921 (2023)Cite this article

Subjects

Abstract

Background

Obesity is a well-established risk factor in the development of colorectal cancer; however, the mechanism mediating this relationship is not well understood. The adipokine, adiponectin, has an inverse relationship with obesity. Experimental studies have shown adiponectin to have dichotomous inflammatory and tumorigenic roles. Its role in the development of colorectal cancer, including the potential effect of its increase following bariatric surgery, is not yet clear. There are conflicting results from studies evaluating this relationship. This study sought to provide a systematic review and meta-analysis to examine the association between systemic adiponectin levels in patients with colorectal cancer and adenoma.

Methods

An electronic literature search was performed using PubMed, EMBASE, Web of Science as well as gray literature. Articles were screened for inclusion criteria and assessed for quality using the Newcastle–Ottawa Scale. Pooled mean differences were calculated using a random effects model. Subgroup and meta-regression analyses were performed to identify potential sources of heterogeneity.

Results

Thirty-two observational studies comparing systemic adiponectin in colorectal cancer vs healthy controls were included. Colorectal cancer cases had lower systemic adiponectin levels (overall pooled mean difference = −1.05 μg/ml [95% CI: −1.99; −0.12] p = 0.03); however, significant heterogeneity was present (I2 = 95% p < 0.01). Subgroup and meta- regression analyses results could not identify a source of the significant heterogeneity across the studies.

Conclusions

Studies suggest a trend towards lower systemic adiponectin levels in colorectal cancer patients, but the heterogeneity observed showed current evidence is not sufficient to definitively draw any conclusions. These data, however, suggest rising adiponectin is unlikely to account for the reported observation of increased CRC following bariatric surgery. Further studies with prospective age, race, and BMI-matched cohorts, and standardized adiponectin measurements may provide a better understanding of this relationship.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: PRISMA flow chart of study screening and selection of studies.
Fig. 2: Forest plot of studies (n = 32) of adiponectin in CRC vs controls.
Fig. 3: Funnel plot of studies included in meta-analysis on the difference in adiponectin in colorectal cancer or adenoma vs normal control.

Data availability

All data included and analyzed is available via contacting corresponding author.

References

  1. Hanyuda A, Lee DH, Ogino S, Wu K, Giovannucci EL. Long-term status of predicted body fat percentage, body mass index and other anthropometric factors with risk of colorectal carcinoma: Two large prospective cohort studies in the US. Int J Cancer. 2020;146:2383–93.

    Article  CAS  PubMed  Google Scholar 

  2. Bardou M, Barkun AN, Martel M. Obesity and colorectal cancer. Gut. 2013;62:933–47.

    Article  CAS  PubMed  Google Scholar 

  3. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–91.

    Article  CAS  PubMed  Google Scholar 

  4. Pu X, Chen D. Targeting adipokines in obesity-related tumors. Front Oncol. 2021;11:685923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Scheurlen KM, Chariker JH, Kanaan Z, Littlefield AB, George JB, Seraphine C, et al. The NOTCH4-GATA4-IRG1 axis as a novel target in early-onset colorectal cancer. Cytokine Growth Factor Rev. 2022;67:25–34.

    Article  CAS  PubMed  Google Scholar 

  6. van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev. 2009;18:2569–78.

    Article  PubMed  Google Scholar 

  7. Chakraborty D, Jin W, Wang J. The bifurcated role of adiponectin in colorectal cancer. Life Sci. 2021;278:119524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wei T, Ye P, Peng X, Wu LL, Yu GY. Circulating adiponectin levels in various malignancies: an updated meta-analysis of 107 studies. Oncotarget. 2016;7:48671–91.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Luo Y, Liu M. Adiponectin: a versatile player of innate immunity. J Mol Cell Biol. 2016;8:120–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Olecki EJ, Perez Hoguin RA, King S, Razavi N, Scow JS. High-grade dysplasia in inflammatory bowel disease: indication for colectomy. Dis Colon Rectum. 2023;66:262–8.

    Article  PubMed  Google Scholar 

  11. Olén O, Erichsen R, Sachs MC, Pedersen L, Halfvarson J, Askling J, et al. Colorectal cancer in ulcerative colitis: a Scandinavian population-based cohort study. Lancet. 2020;395:123–31.

    Article  PubMed  Google Scholar 

  12. Yoon YS, Kwon AR, Lee YK, Oh SW. Circulating adipokines and risk of obesity related cancers: a systematic review and meta-analysis. Obes Res Clin Pract. 2019;13:329–39.

    Article  PubMed  Google Scholar 

  13. Ogunwobi OO, Beales IL. Adiponectin stimulates proliferation and cytokine secretion in colonic epithelial cells. Regul Pept. 2006;134:105–13.

    Article  CAS  PubMed  Google Scholar 

  14. Cai L, Xu S, Piao C, Qiu S, Li H, Du J. Adiponectin induces CXCL1 secretion from cancer cells and promotes tumor angiogenesis by inducing stromal fibroblast senescence. Mol Carcinog. 2016;55:1796–806.

    Article  CAS  PubMed  Google Scholar 

  15. Ferroni P, Palmirotta R, Spila A, Martini F, Raparelli V, Fossile E, et al. Prognostic significance of adiponectin levels in non-metastatic colorectal cancer. Anticancer Res. 2007;27:483–9.

    CAS  PubMed  Google Scholar 

  16. Lukanova A, Söderberg S, Kaaks R, Jellum E, Stattin P. Serum adiponectin is not associated with risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:401–2.

    Article  CAS  PubMed  Google Scholar 

  17. Zekri AR, Bakr YM, Ezzat MM, Zakaria MS, Elbaz TM. Circulating levels of adipocytokines as potential biomarkers for early detection of colorectal carcinoma in Egyptian patients. Asian Pac J Cancer Prev. 2015;16:6923–8.

    Article  PubMed  Google Scholar 

  18. Tao WJ, Artama M, von Euler-Chelpin M, Hull M, Ljung R, Lynge E, et al. Colon and rectal cancer risk after bariatric surgery in a multicountry Nordic cohort study. Int J Cancer. 2020;147:728–35.

    Article  CAS  PubMed  Google Scholar 

  19. Mackenzie H, Markar SR, Askari A, Faiz O, Hull M, Purkayastha S, et al. Obesity surgery and risk of cancer. Br J Surg. 2018;105:1650–7.

    Article  CAS  PubMed  Google Scholar 

  20. Derogar M, Hull MA, Kant P, Östlund M, Lu Y, Lagergren J. Increased risk of colorectal cancer after obesity surgery. Ann Surg. 2013;258:983–8.

    Article  PubMed  Google Scholar 

  21. Clapp B, Portela R, Sharma I, Nakanishi H, Marrero K, Schauer P, et al. Risk of non-hormonal cancer after bariatric surgery: meta-analysis of retrospective observational studies. Br J Surg. 2022;110:24–33.

    Article  PubMed  Google Scholar 

  22. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj. 2021;372:n71.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Macleod, A, Scheurlen KS, Burton J, Parks MA, Galandiuk S. A systematic review and meta-analysis of the association between plasma adiponectin levels and colorectal cancer. PROSPERO 2022 CRD42022303307. 2022. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=303307.

  24. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2021. Available from: https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

  25. McGrath S, Zhao X, Steele R, Thombs BD, Benedetti A. DEPRESsion Screening Data (DEPRESSD) Collaboration. Estimating the sample mean and standard deviation from commonly reported quantiles in meta-analysis. Stat Methods Med Res. 2020;29:2520–37. Epub 30 Jan 2020.

  26. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Taylor KS, Mahtani KR, Aronson JK. Combining and converting groups when extracting data for meta-analysis. BMJ Evid Based Med. 2021;26:85–7.

    Article  PubMed  Google Scholar 

  28. Human Development Index 2023. Updated June 2023. Available from: https://hdr.undp.org/data-center/human-development-index#/indicies/HDI.

  29. Viechtbauer W, Cheung MW. Outlier and influence diagnostics for meta-analysis. Res Synth Methods. 2010;1:112–25.

    Article  PubMed  Google Scholar 

  30. R Core Team (2022). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2022. Available from: https://www.R-project.org/.

  31. Harrer M, Cuijpers P, Furukawa TA, Ebert DD. Doing meta-analysis with R: a hands-on guide. In: Boca Raton, FL, editor. 1st ed. London: Chapman & Hall/CRC Press; 2021.

  32. Wei EK, Giovannucci E, Fuchs CS, Willett WC, Mantzoros CS. Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. J Natl Cancer Inst. 2005;97:1688–94.

    Article  CAS  PubMed  Google Scholar 

  33. Stocks T, Lukanova A, Johansson M, Rinaldi S, Palmqvist R, Hallmans G, et al. Components of the metabolic syndrome and colorectal cancer risk; a prospective study. Int J Obes (Lond). 2008;32:304–14.

    Article  CAS  PubMed  Google Scholar 

  34. Kumor A, Daniel P, Pietruczuk M, Małecka-Panas E. Serum leptin, adiponectin, and resistin concentration in colorectal adenoma and carcinoma (CC) patients. Int J Colorectal Dis. 2009;24:275–81.

    Article  PubMed  Google Scholar 

  35. Guadagni F, Roselli M, Martini F, Spila A, Riondino S, D'Alessandro R, et al. Prognostic significance of serum adipokine levels in colorectal cancer patients. Anticancer Res. 2009;29:3321–7.

    CAS  PubMed  Google Scholar 

  36. Erarslan E, Turkay C, Koktener A, Koca C, Uz B, Bavbek N. Association of visceral fat accumulation and adiponectin levels with colorectal neoplasia. Dig Dis Sci. 2009;54:862–8.

    Article  CAS  PubMed  Google Scholar 

  37. Nakajima TE, Yamada Y, Hamano T, Furuta K, Matsuda T, Fujita S, et al. Adipocytokines as new promising markers of colorectal tumors: adiponectin for colorectal adenoma, and resistin and visfatin for colorectal cancer. Cancer Sci. 2010;101:1286–91.

    Article  CAS  PubMed  Google Scholar 

  38. Kemik O, Sumer A, Kemik AS, Hasirci I, Purisa S, Dulger AC, et al. The relationship among acute-phase response proteins, cytokines and hormones in cachectic patients with colon cancer. World J Surg Oncol. 2010;8:85.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Gonullu G, Kahraman H, Bedir A, Bektas A, Yücel I. Association between adiponectin, resistin, insulin resistance, and colorectal tumors. Int J Colorectal Dis. 2010;25:205–12.

    Article  PubMed  Google Scholar 

  40. Svobodova S, Topolcan O, Holubec L Jr, Levy M, Pecen L, Svacina S. Parameters of biological activity in colorectal cancer. Anticancer Res. 2011;31:373–8.

    CAS  PubMed  Google Scholar 

  41. Gialamas SP, Petridou ET, Tseleni-Balafouta S, Spyridopoulos TN, Matsoukis IL, Kondi-Pafiti A, et al. Serum adiponectin levels and tissue expression of adiponectin receptors are associated with risk, stage, and grade of colorectal cancer. Metabolism. 2011;60:1530–8.

    Article  CAS  PubMed  Google Scholar 

  42. Al Khaldi RM, Al Mulla F, Al Awadhi S, Kapila K, Mojiminiyi OA. Associations of single nucleotide polymorphisms in the adiponectin gene with adiponectin levels and cardio-metabolic risk factors in patients with cancer. Dis Markers. 2011;30:197–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Catalán V, Gómez-Ambrosi J, Rodríguez A, Ramírez B, Silva C, Rotellar F, et al. Up-regulation of the novel proinflammatory adipokines lipocalin-2, chitinase-3 like-1 and osteopontin as well as angiogenic-related factors in visceral adipose tissue of patients with colon cancer. J Nutr Biochem. 2011;22:634–41.

    Article  PubMed  Google Scholar 

  44. Touvier M, Fezeu L, Ahluwalia N, Julia C, Charnaux N, Sutton A, et al. Pre-diagnostic levels of adiponectin and soluble vascular cell adhesion molecule-1 are associated with colorectal cancer risk. World J Gastroenterol. 2012;18:2805–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kemik O, Kemik AS, Begenik H, Erdur FM, Emre H, Sumer A, et al. The relationship among acute-phase responce proteins, cytokines, and hormones in various gastrointestinal cancer types patients with cachectic. Hum Exp Toxicol. 2012;31:117–25.

    Article  CAS  PubMed  Google Scholar 

  46. Ho GY, Wang T, Gunter MJ, Strickler HD, Cushman M, Kaplan RC, et al. Adipokines linking obesity with colorectal cancer risk in postmenopausal women. Cancer Res. 2012;72:3029–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hillenbrand A, Fassler J, Huber N, Xu P, Henne-Bruns D, Templin M, et al. Changed adipocytokine concentrations in colorectal tumor patients and morbidly obese patients compared to healthy controls. BMC Cancer. 2012;12:545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gulcelik MA, Colakoglu K, Dincer H, Dogan L, Yenidogan E, Gulcelik NE. Associations between adiponectin and two different cancers: breast and colon. Asian Pac J Cancer Prev. 2012;13:395–8.

    Article  PubMed  Google Scholar 

  49. Chen MW, Ye S, Zhao LL, Wang SY, Li YX, Yu CJ, et al. Association of plasma total and high-molecular-weight adiponectin with risk of colorectal cancer: an observational study in Chinese male. Med Oncol. 2012;29:3129–35.

    Article  CAS  PubMed  Google Scholar 

  50. Song M, Zhang X, Wu K, Ogino S, Fuchs CS, Giovannucci EL, et al. Plasma adiponectin and soluble leptin receptor and risk of colorectal cancer: a prospective study. Cancer Prev Res (Phila). 2013;6:875–85.

    Article  CAS  PubMed  Google Scholar 

  51. Aleksandrova K, Jenab M, Bueno-de-Mesquita HB, Fedirko V, Kaaks R, Lukanova A, et al. Biomarker patterns of inflammatory and metabolic pathways are associated with risk of colorectal cancer: results from the European Prospective Investigation into Cancer and Nutrition (EPIC). Eur J Epidemiol. 2014;29:261–75.

    Article  CAS  PubMed  Google Scholar 

  52. Aleksandrova K, Drogan D, Boeing H, Jenab M, Bas Bueno-de-Mesquita H, Jansen E, et al. Adiposity, mediating biomarkers and risk of colon cancer in the European prospective investigation into cancer and nutrition study. Int J Cancer. 2014;134:612–21.

    Article  CAS  PubMed  Google Scholar 

  53. Abe Vicente M, Donizetti Silva T, Barão K, Vitor Felipe A, Oyama Missae L, Manoukian Forones N. The influence of nutritional status and disease on adiponectin and TNF-α; levels in colorectal cancer patients. Nutr Hosp. 2014;30:140–6.

    PubMed  Google Scholar 

  54. Erdogan S, Yilmaz FM, Yazici O, Yozgat A, Sezer S, Ozdemir N, et al. Inflammation and chemerin in colorectal cancer. Tumour Biol. 2016;37:6337–42.

    Article  CAS  PubMed  Google Scholar 

  55. Chandler PD, Buring JE, Manson JE, Moorthy MV, Zhang S, Lee IM, et al. Association between plasma adiponectin levels and colorectal cancer risk in women. Cancer Causes Control. 2015;26:1047–52.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Inamura K, Song M, Jung S, Nishihara R, Yamauchi M, Lochhead P, et al. Prediagnosis plasma adiponectin in relation to colorectal cancer risk according to KRAS mutation status. J Natl Cancer Inst. 2016;108:djv363.

    Article  PubMed  Google Scholar 

  57. Florescu A, Branisteanu D, Bilha S, Scripcariu D, Florescu I, Scripcariu V, et al. Leptin and adiponectin dynamics at patients with rectal neoplasm—gender differences. PLoS One. 2019;14:e0212471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhao X, Zhang Y, Deng L, Wang Y, Li Y, Chen M. The association between Chinese patients' elevated omentin-1 levels, their clinicopathological features, and the risk of colorectal cancer. Int J Clin Exp Pathol. 2019;12:2264–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Polito R, Nigro E, Fei L, L DEM, Monaco ML, D'Amico R, et al. Adiponectin is inversely associated with tumour grade in colorectal cancer patients. Anticancer Res. 2020;40:3751–7.

    Article  CAS  PubMed  Google Scholar 

  60. Myte R, Harlid S, Sundkvist A, Gylling B, Häggström J, Zingmark C, et al. A longitudinal study of prediagnostic metabolic biomarkers and the risk of molecular subtypes of colorectal cancer. Sci Rep. 2020;10:5336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mhaidat NM, Alzoubi KH, Kubas MA, Banihani MN, Hamdan N, Al-Jaberi TM. High levels of leptin and non-high molecular weight-adiponectin in patients with colorectal cancer: Association with chemotherapy and common genetic polymorphisms. Biomed Rep. 2021;14:13.

    CAS  PubMed  Google Scholar 

  62. Otake S, Takeda H, Suzuki Y, Fukui T, Watanabe S, Ishihama K, et al. Association of visceral fat accumulation and plasma adiponectin with colorectal adenoma: evidence for participation of insulin resistance. Clin Cancer Res. 2005;11:3642–6.

    Article  CAS  PubMed  Google Scholar 

  63. Fukumoto J, Otake T, Tajima O, Tabata S, Abe H, Mizoue T, et al. Adiponectin and colorectal adenomas: self defense forces health study. Cancer Sci. 2008;99:781–6.

    Article  CAS  PubMed  Google Scholar 

  64. Yamaji T, Iwasaki M, Sasazuki S, Tsugane S. Interaction between adiponectin and leptin influences the risk of colorectal adenoma. Cancer Res. 2010;70:5430–7.

    Article  CAS  PubMed  Google Scholar 

  65. Bobe G, Murphy G, Rogers CJ, Hance KW, Albert PS, Laiyemo AO, et al. Serum adiponectin, leptin, C-peptide, homocysteine, and colorectal adenoma recurrence in the Polyp Prevention Trial. Cancer Epidemiol Biomarkers Prev. 2010;19:1441–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chronis A, Thomopoulos K, Sapountzis A, Triantos C, Kalafateli M, Kalofonos C, et al. Adiposity factors are not related to the presence of colorectal adenomas. Clin Exp Gastroenterol. 2011;4:257–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. An W, Bai Y, Deng SX, Gao J, Ben QW, Cai QC, et al. Adiponectin levels in patients with colorectal cancer and adenoma: a meta-analysis. Eur J Cancer Prev. 2012;21:126–33.

    Article  CAS  PubMed  Google Scholar 

  68. Wang Y, Li J, Fu X, Li J, Liu L, Alkohlani A, et al. Association of circulating leptin and adiponectin levels with colorectal cancer risk: a systematic review and meta-analysis of case-control studies. Cancer Epidemiol. 2021;73:101958.

    Article  PubMed  Google Scholar 

Download references

Funding

This work is supported indirectly by the John W. Price and Barbara Thruston Atwood Price Trust. Funding source had no role in the design and conduct of the study or the collection, analysis and interpretation of the data.

Author information

Authors and Affiliations

  1. Price Institute of Surgical Research, Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA

    Anne Macleod, Katharina M. Scheurlen, James F. Burton, Mary Alex Parks & Susan Galandiuk

  2. Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, USA

    Mst Sharmin Akter Sumy & Jeremy T. Gaskins

  3. Hiram C. Polk Jr. MD Department of Surgery, University of Louisville, Louisville, KY, USA

    Susan Galandiuk

Authors
  1. Anne Macleod
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katharina M. Scheurlen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James F. Burton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mary Alex Parks
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mst Sharmin Akter Sumy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeremy T. Gaskins
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Susan Galandiuk
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AM contributed to design; data acquisition, analysis, and interpretation; manuscript writing. KMS contributed conception and design, data interpretation and manuscript revision. JFB and MAP contributed to data acquisition, analysis, and manuscript revision. SS contributed to data acquisition, analysis, and interpretation. JTG contributed to data analysis and interpretation, and manuscript revision. SG contributed to conception and design, data interpretation, and manuscript revision.

Corresponding author

Correspondence to Susan Galandiuk.

Ethics declarations

Competing interests

SG is the Editor-in-Chief of the journal Diseases of the Colon and Rectum, is the Director of the Price Institute of Surgical Research, and receives support from AbbVie for clinical research not related to this work. All other authors have no competing interests or conflicts of interest to declare.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Macleod, A., Scheurlen, K.M., Burton, J.F. et al. Systemic adiponectin levels in colorectal cancer and adenoma: a systematic review and meta-analysis. Int J Obes 47, 911–921 (2023). https://doi.org/10.1038/s41366-023-01358-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-023-01358-6

Search

Advanced search

Quick links