Skip to main content
SpringerLink
Log in

Proton pump inhibitors and the risk of colorectal cancer: a systematic review and meta-analysis of observational studies

  • Review
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

The increased risk of colorectal cancer (CRC) associated with long-term use of proton pump inhibitors (PPIs) has attracted considerable attention; however, the conclusions of studies evaluating this correlation are inconsistent or even controversial. Therefore, we conducted a systematic review and meta-analysis to determine the association of PPI use with the risk of CRC.

Methods

A systematic literature search was conducted in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials to identify relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) for the associations between PPI use and the risk of CRC were estimated with a fixed-effects or random-effects model.

Results

We identified and included 9 observational studies (3 cohort studies and 6 case-control studies) comprising 1,036,438 participants. Overall, there was no statistically significant association between PPI use and the risk of CRC (pooled OR 1.26, 95% CI: 0.90–1.73; p = 0.166) when PPI exposure was assessed as a binary variable. However, a weak association between long-term use of PPIs and CRC was demonstrated (pooled OR 1.19, 95% CI: 1.09–1.31; p < 0.001) when the cumulative duration of PPI exposure was confined to > 5 years.

Conclusions

Although the present meta-analysis suggests a weak association between long-term use (> 5 years) of PPIs and CRC, there is not enough statistical power to refute or confirm an association between the use of PPIs and CRC. More high-quality prospective cohort studies are needed to assess this correlation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

All data are available upon request.

References

  1. Mattiuzzi C, Sanchis-Gomar F, Lippi G (2019) Concise update on colorectal cancer epidemiology. Ann Transl Med 7(21):609. https://doi.org/10.21037/atm.2019.07.91

    Article  PubMed  PubMed Central  Google Scholar 

  2. Arnold M, Abnet CC, Neale RE, Vignat J, Giovannucci EL, McGlynn KA, Bray F (2020) Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 159:335–349.e15. https://doi.org/10.1053/j.gastro.2020.02.068

    Article  PubMed  Google Scholar 

  3. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F (2017) Global patterns and trends in colorectal cancer incidence and mortality. Gut 66(4):683–691. https://doi.org/10.1136/gutjnl-2015-310912

    Article  PubMed  Google Scholar 

  4. Stoffel EM, Murphy CC (2020) Epidemiology and mechanisms of the increasing incidence of colon and rectal cancers in young adults. Gastroenterology 158(2):341–353. https://doi.org/10.1053/j.gastro.2019.07.055

    Article  PubMed  Google Scholar 

  5. Murphy N, Ward HA, Jenab M, Rothwell JA, Boutron-Ruault MC, Carbonnel F, Kvaskoff M, Kaaks R, Kuhn T, Boeing H, Aleksandrova K, Weiderpass E, Skeie G, Borch KB, Tjonneland A, Kyro C, Overvad K, Dahm CC, Jakszyn P, Sanchez MJ, Gil L, Huerta JM, Barricarte A, Quiros JR, Khaw KT, Wareham N, Bradbury KE, Trichopoulou A, La Vecchia C, Karakatsani A, Palli D, Grioni S, Tumino R, Fasanelli F, Panico S, Bueno-de-Mesquita B, Peeters PH, Gylling B, Myte R, Jirstrom K, Berntsson J, Xue X, Riboli E, Cross AJ, Gunter MJ (2019) Heterogeneity of colorectal cancer risk factors by anatomical subsite in 10 European countries: a multinational cohort study. Clin Gastroenterol Hepatol 17(7):1323–1331. https://doi.org/10.1016/j.cgh.2018.07.030

    Article  PubMed  PubMed Central  Google Scholar 

  6. Keum N, Giovannucci E (2019) Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol 16(12):713–732. https://doi.org/10.1038/s41575-019-0189-8

    Article  PubMed  Google Scholar 

  7. Bosetti C, Santucci C, Gallus S, Martinetti M, La Vecchia C (2020) Aspirin and the risk of colorectal and other digestive tract cancers: an updated meta-analysis through 2019. Ann Oncol 31(5):558–568. https://doi.org/10.1016/j.annonc.2020.02.012

    Article  CAS  PubMed  Google Scholar 

  8. Lei WY, Wang JH, Yi CH, Liu TT, Hung JS, Wong MW, Bair MJ, Vaezi MF, Orr WC, Chen CL (2020) Association between use of proton pump inhibitors and colorectal cancer: a nationwide population-based study. Clin Res Hepatol Gastroenterol. https://doi.org/10.1016/j.clinre.2020.02.017

  9. Qu G, Sun C, Sharma M, Uy JP, Song EJ, Bhan C, Shu L (2020) Is antibiotics use really associated with increased risk of colorectal cancer? An updated systematic review and meta-analysis of observational studies. Int J Colorectal Dis 35:1397–1412. https://doi.org/10.1007/s00384-020-03658-z

    Article  PubMed  Google Scholar 

  10. Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL (2015) Trends in prescription drug use among adults in the United States from 1999-2012. JAMA 314(17):1818–1831. https://doi.org/10.1001/jama.2015.13766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Savarino V, Marabotto E, Zentilin P, Furnari M, Bodini G, De Maria C, Pellegatta G, Coppo C, Savarino E (2018) Proton pump inhibitors: use and misuse in the clinical setting. Expert Rev Clin Pharmacol 11(11):1123–1134. https://doi.org/10.1080/17512433.2018.1531703

    Article  CAS  PubMed  Google Scholar 

  12. Yu LY, Sun LN, Zhang XH, Li YQ, Yu L, Yuan ZQ, Meng L, Zhang HW, Wang YQ (2017) A review of the novel application and potential adverse effects of proton pump inhibitors. Adv Ther 34(5):1070–1086. https://doi.org/10.1007/s12325-017-0532-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Savarino V, Dulbecco P, de Bortoli N, Ottonello A, Savarino E (2017) The appropriate use of proton pump inhibitors (PPIs): need for a reappraisal. Eur J Intern Med 37:19–24. https://doi.org/10.1016/j.ejim.2016.10.007

    Article  CAS  PubMed  Google Scholar 

  14. Ghosh G, Schnoll-Sussman F, Mathews S, Katz PO (2020) Reported proton pump inhibitor side effects: what are physician and patient perspectives and behaviour patterns? Aliment Pharmacol Ther 51(1):121–128. https://doi.org/10.1111/apt.15522

    Article  CAS  PubMed  Google Scholar 

  15. Elias E, Targownik LE (2019) The clinician’s guide to proton pump inhibitor related adverse events. Drugs 79(7):715–731. https://doi.org/10.1007/s40265-019-01110-3

    Article  PubMed  Google Scholar 

  16. Alkhushaym N, Almutairi AR, Althagafi A, Fallatah SB, Oh M, Martin JR, Babiker HM, McBride A, Abraham I (2020) Exposure to proton pump inhibitors and risk of pancreatic cancer: a meta-analysis. Expert Opin Drug Saf 19(3):327–334. https://doi.org/10.1080/14740338.2020.1715939

    Article  CAS  PubMed  Google Scholar 

  17. Song HJ, Jiang X, Henry L, Nguyen MH, Park H (2020) Proton pump inhibitors and risk of liver cancer and mortality in patients with chronic liver disease: a systematic review and meta-analysis. Eur J Clin Pharmacol 76(6):851–866. https://doi.org/10.1007/s00228-020-02854-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lai SW, Liao KF, Lai HC, Lin CL, Sung FC (2013) Use of proton pump inhibitors correlates with increased risk of colorectal cancer in Taiwan. Asia Pac J Clin Oncol 9(2):192–193. https://doi.org/10.1111/ajco.12054

    Article  PubMed  Google Scholar 

  19. Yang YX, Hennessy S, Propert K, Hwang WT, Sedarat A, Lewis JD (2007) Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology 133(3):748–754. https://doi.org/10.1053/j.gastro.2007.06.022

    Article  CAS  PubMed  Google Scholar 

  20. Lee JK, Merchant SA, Schneider JL, Jensen CD, Fireman BH, Quesenberry CP, Corley DA (2020) Proton pump inhibitor use and risk of gastric, colorectal, liver, and pancreatic cancers in a community-based population. Am J Gastroenterol 115(5):706–715. https://doi.org/10.14309/ajg.0000000000000591

    Article  PubMed  Google Scholar 

  21. Ahn JS, Park SM, Eom CS, Kim S, Myung SK (2012) Use of proton pump inhibitor and risk of colorectal cancer: a meta-analysis of observational studies. Korean J Fam Med 33(5):272–279. https://doi.org/10.4082/kjfm.2012.33.5.272

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chen S, Song X, Gao X, Li M, Chen Z, He Y, Zhan W (2011) Proton pump inhibitors and the risk of colorectal cancer: a meta-analysis. J Clin Gastroenterol 45(2):177. https://doi.org/10.1097/MCG.0b013e3181ea181e

    Article  PubMed  Google Scholar 

  23. Hwang IC, Chang J, Park SM (2017) Emerging hazard effects of proton pump inhibitor on the risk of colorectal cancer in low-risk populations: a Korean nationwide prospective cohort study. PLoS One 12(12):e0189114. https://doi.org/10.1371/journal.pone.0189114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Babic A, Zhang X, Morales-Oyarvide V, Yuan C, Khalaf N, Khalili H, Lochhead P, Chan AT, Ogino S, Wolpin BM, Wu K, Fuchs CS, Giovannucci EL, Stampfer MJ, Ng K (2020) Acid-suppressive medications and risk of colorectal cancer: results from three large prospective cohort studies. Br J Cancer. https://doi.org/10.1038/s41416-020-0939-y

  25. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4(1):1. https://doi.org/10.1186/2046-4053-4-1

    Article  PubMed  PubMed Central  Google Scholar 

  26. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605. https://doi.org/10.1007/s10654-010-9491-z

    Article  PubMed  Google Scholar 

  27. Sedgwick P (2014) Relative risks versus odds ratios. BMJ 348:g1407. https://doi.org/10.1136/bmj.g1407

    Article  Google Scholar 

  28. Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560. https://doi.org/10.1136/bmj.327.7414.557

    Article  PubMed  PubMed Central  Google Scholar 

  29. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188. https://doi.org/10.1016/0197-2456(86)90046-2

    Article  CAS  PubMed  Google Scholar 

  30. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634. https://doi.org/10.1136/bmj.315.7109.629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Robertson DJ, Larsson H, Friis S, Pedersen L, Baron JA, Sørensen HT (2007) Proton pump inhibitor use and risk of colorectal cancer: a population-based, case–control study. Gastroenterology 133(3):755–760. https://doi.org/10.1053/j.gastro.2007.06.014

    Article  PubMed  Google Scholar 

  32. van Soest EM, van Rossum LG, Dieleman JP, van Oijen MG, Siersema PD, Sturkenboom MC, Kuipers EJ (2008) Proton pump inhibitors and the risk of colorectal cancer. Am J Gastroenterol 103(4):966–973. https://doi.org/10.1111/j.1572-0241.2007.01665.x

    Article  PubMed  Google Scholar 

  33. Chubak J, Boudreau DM, Rulyak SJ, Mandelson MT (2009) Colorectal cancer risk in relation to use of acid suppressive medications. Pharmacoepidemiol Drug Saf 18(7):540–544. https://doi.org/10.1002/pds.1749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sedgwick P, Marston L (2015) How to read a funnel plot in a meta-analysis. BMJ 351:h4718. https://doi.org/10.1136/bmj.h4718

    Article  PubMed  Google Scholar 

  35. Zeng X, Liu L, Zheng M, Sun H, Xiao J, Lu T, Huang G, Chen P, Zhang J, Zhu F, Li H, Duan Q (2016) Pantoprazole, an FDA-approved proton-pump inhibitor, suppresses colorectal cancer growth by targeting T-cell-originated protein kinase. Oncotarget 7(16):22460–22473. https://doi.org/10.18632/oncotarget.7984

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zheng M, Luan S, Gao S, Cheng L, Hao B, Li J, Chen Y, Hou X, Chen L, Li H (2017) Proton pump inhibitor ilaprazole suppresses cancer growth by targeting T-cell-originated protein kinase. Oncotarget 8(24):39143–39153. https://doi.org/10.18632/oncotarget.16609

    Article  PubMed  PubMed Central  Google Scholar 

  37. Patlolla JMR, Zhang Y, Li Q, Steele VE, Rao CV (2012) Anti-carcinogenic properties of omeprazole against human colon cancer cells and azoxymethane-induced colonic aberrant crypt foci formation in rats. Int J Oncol 40(1):170–175. https://doi.org/10.3892/ijo.2011.1214

    Article  CAS  PubMed  Google Scholar 

  38. Lundell L, Vieth M, Gibson F, Nagy P, Kahrilas PJ (2015) Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology. Aliment Pharmacol Ther 42(6):649–663. https://doi.org/10.1111/apt.13324

    Article  CAS  PubMed  Google Scholar 

  39. Thorburn CM, Friedman GD, Dickinson CJ, Vogelman JH, Orentreich N, Parsonnet J (1998) Gastrin and colorectal cancer: a prospective study. Gastroenterology 115(2):275–280. https://doi.org/10.1016/s0016-5085(98)70193-3

    Article  CAS  PubMed  Google Scholar 

  40. Georgopoulos SD, Polymeros D, Triantafyllou K, Spiliadi C, Mentis A, Karamanolis DG, Ladas SD (2006) Hypergastrinemia is associated with increased risk of distal colon adenomas. Digestion 74(1):42–46. https://doi.org/10.1159/000096593

    Article  PubMed  Google Scholar 

  41. Koh TJ, Dockray GJ, Varro A, Cahill RJ, Dangler CA, Fox JG, Wang TC (1999) Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation. J Clin Invest 103(8):1119–1126. https://doi.org/10.1172/jci4910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Han YM, Park JM, Park SH, Hahm KB, Hong SP, Kim EH (2013) Gastrin promotes intestinal polyposis through cholecystokinin-B receptor-mediated proliferative signaling and fostering tumor microenvironment. J Physiol Pharmacol 64(4):429–437

    CAS  PubMed  Google Scholar 

  43. Sasaki T, Mori S, Kishi S, Fujiwara-Tani R, Ohmori H, Nishiguchi Y, Hojo Y, Kawahara I, Nakashima C, Fujii K, Luo Y, Kuniyasu H (2020) Effect of proton pump inhibitors on colorectal cancer. Int J Mol Sci 21(11):3877. https://doi.org/10.3390/ijms21113877

    Article  CAS  PubMed Central  Google Scholar 

  44. Han YM, Baik Hahm K, Park J-M, Hong SP, Kim E-H (2014) Paradoxically augmented anti-tumorigenic action of proton pump inhibitor and gastrin in APCMin/+ intestinal polyposis model. Neoplasia 16(1):73–83. https://doi.org/10.1593/neo.131510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Han YM, Park JM, Kangwan N, Jeong M, Lee S, Cho JY, Ko WJ, Hahm KB (2015) Role of proton pump inhibitors in preventing hypergastrinemia-associated carcinogenesis and in antagonizing the trophic effect of gastrin. J Physiol Pharmacol 66(2):159–167

    CAS  PubMed  Google Scholar 

  46. Song LJ, Liu RJ, Zeng Z, Alper SL, Cui HJ, Lu Y, Zheng L, Yan ZW, Fu GH (2012) Gastrin inhibits a novel, pathological colon cancer signaling pathway involving EGR1, AE2, and P-ERK. J Mol Med (Berl) 90(6):707–718. https://doi.org/10.1007/s00109-011-0851-2

    Article  CAS  Google Scholar 

  47. Jackson MA, Goodrich JK, Maxan ME, Freedberg DE, Abrams JA, Poole AC, Sutter JL, Welter D, Ley RE, Bell JT, Spector TD, Steves CJ (2016) Proton pump inhibitors alter the composition of the gut microbiota. Gut 65(5):749–756. https://doi.org/10.1136/gutjnl-2015-310861

    Article  CAS  PubMed  Google Scholar 

  48. Wong SH, Yu J (2019) Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat Rev Gastroenterol Hepatol 16(11):690–704. https://doi.org/10.1038/s41575-019-0209-8

    Article  CAS  PubMed  Google Scholar 

  49. Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, Tigchelaar EF, Jankipersadsing SA, Cenit MC, Harmsen HJ, Dijkstra G, Franke L, Xavier RJ, Jonkers D, Wijmenga C, Weersma RK, Zhernakova A (2016) Proton pump inhibitors affect the gut microbiome. Gut 65(5):740–748. https://doi.org/10.1136/gutjnl-2015-310376

    Article  CAS  PubMed  Google Scholar 

  50. Si H, Yang Q, Hu H, Ding C, Wang H, Lin X (2020) Colorectal cancer occurrence and treatment based on changes in intestinal flora. Semin Cancer Biol. https://doi.org/10.1016/j.semcancer.2020.05.004

  51. Montalban-Arques A, Scharl M (2019) Intestinal microbiota and colorectal carcinoma: implications for pathogenesis, diagnosis, and therapy. EBioMedicine 48:648–655. https://doi.org/10.1016/j.ebiom.2019.09.050

    Article  PubMed  PubMed Central  Google Scholar 

  52. Bonderup OK, Nielsen GL, Dall M, Pottegard A, Hallas J (2018) Significant association between the use of different proton pump inhibitors and microscopic colitis: a nationwide Danish case-control study. Aliment Pharmacol Ther 48(6):618–625. https://doi.org/10.1111/apt.14916

    Article  CAS  PubMed  Google Scholar 

  53. Tontini GE, Pastorelli L, Spina L, Fabris F, Bruni B, Clemente C, de Nucci G, Cavallaro F, Marconi S, Neurath MF, Neumann H, Tacconi M, Vecchi M (2014) Microscopic colitis and colorectal neoplastic lesion rate in chronic nonbloody diarrhea. Inflamm Bowel Dis 20(5):882–891. https://doi.org/10.1097/mib.0000000000000030

    Article  PubMed  Google Scholar 

  54. Sonnenberg A, Genta RM (2015) Low prevalence of colon polyps in chronic inflammatory conditions of the colon. Am J Gastroenterol 110(7):1056–1061. https://doi.org/10.1038/ajg.2015.130

    Article  CAS  PubMed  Google Scholar 

  55. Lasry A, Zinger A, Ben-Neriah Y (2016) Inflammatory networks underlying colorectal cancer. Nat Immunol 17(3):230–240. https://doi.org/10.1038/ni.3384

    Article  CAS  PubMed  Google Scholar 

  56. Izano M, Wei EK, Tai C, Swede H, Gregorich S, Harris TB, Klepin H, Satterfield S, Murphy R, Newman AB, Rubin SM, Braithwaite D, Health ABCs (2016) Chronic inflammation and risk of colorectal and other obesity-related cancers: the health, aging and body composition study. Int J Cancer 138(5):1118–1128. https://doi.org/10.1002/ijc.29868

    Article  CAS  PubMed  Google Scholar 

  57. Lundgren D, Eklöf V, Palmqvist R, Hultdin J, Karling P (2019) Proton pump inhibitor use is associated with elevated faecal calprotectin levels. A cross-sectional study on subjects referred for colonoscopy. Scand J Gastroenterol 54(2):152–157. https://doi.org/10.1080/00365521.2019.1566493

    Article  CAS  PubMed  Google Scholar 

  58. Turvill J, Aghahoseini A, Sivarajasingham N, Abbas K, Choudhry M, Polyzois K, Lasithiotakis K, Volanaki D, Kim B, Langlands F, Andrew H, Roos J, Mellen S, Turnock D, Jones A (2016) Faecal calprotectin in patients with suspected colorectal cancer: a diagnostic accuracy study. Br J Gen Pract 66(648):e499–e506. https://doi.org/10.3399/bjgp16X685645

    Article  PubMed  PubMed Central  Google Scholar 

  59. Schneider JL, Kolitsopoulos F, Corley DA (2016) Risk of gastric cancer, gastrointestinal cancers and other cancers: a comparison of treatment with pantoprazole and other proton pump inhibitors. Aliment Pharmacol Ther 43(1):73–82. https://doi.org/10.1111/apt.13450

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all authors of the studies included in our meta-analysis.

Author information

Authors and Affiliations

  1. Department of Hepatopancreatobiliary Medicine, The Second Hospital of Jilin University, No. 218 Ziqiang Road, Changchun, Jilin, 130000, China

    Tianyi Ma, Meng Wu, Shengnan Jia & Lanlan Yang

Authors
  1. Tianyi Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shengnan Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lanlan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Tianyi Ma contributed to the study design, statistical analysis, and manuscript writing; Meng Wu and Shengnan Jia conducted literature retrieval and data collection; and Lanlan Yang viewed and revised the manuscript. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Lanlan Yang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethics approval

This systematic review and meta-analysis used previously published data and did not use any unpublished data. Therefore, ethical approval for the analysis was not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Code availability

Not applicable.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, T., Wu, M., Jia, S. et al. Proton pump inhibitors and the risk of colorectal cancer: a systematic review and meta-analysis of observational studies. Int J Colorectal Dis 35, 2157–2169 (2020). https://doi.org/10.1007/s00384-020-03717-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-020-03717-5

Keywords

Search

Navigation