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History of fragility fracture is associated with cardiovascular mortality in hemodialysis patients: the Q-Cohort study

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Abstract

Introduction

In patients undergoing dialysis, major bone fracture is associated with a high risk of mortality, including death of cardiovascular (CV) origin. In the present study, we aimed to determine whether a history of fragility fracture is a predictor of CV death in patients undergoing hemodialysis with long-term follow-up.

Materials and methods

In total, 3499 patients undergoing hemodialysis were analyzed for 10 years. We evaluated the history of fragility fracture in each patient at enrollment. The primary outcome was CV death. A Cox proportional hazard model and a competing risk approach were applied to determine the association between a history of fragility fracture and CV death.

Results

A total of 346 patients had a history of fragility fracture at enrollment. During a median follow-up of 8.8 years, 1730 (49.4%) patients died. Among them, 621 patients experienced CV death. Multivariable Cox analyses after adjustment for confounding variables showed that a history of fragility fracture was associated with CV death (hazard ratio, 1.47; 95% confidence interval, 1.16–1.85). In the Fine–Gray regression model, a history of fragility fracture was an independent risk factor for CV death (subdistribution hazard ratio, 1.36; 95% confidence interval, 1.07–1.72).

Conclusion

In a large cohort of patients undergoing hemodialysis, a history of fragility fracture was an independent predictor of CV death.

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References

  1. Ginsberg C, Ix JH (2022) Diagnosis and management of osteoporosis in advanced kidney disease: a review. Am J Kidney Dis 79:427–436

    Article  PubMed  Google Scholar 

  2. Pimentel A, Urena-Torres P, Zillikens MC, Bover J, Cohen-Solal M (2017) Fractures in patients with CKD-diagnosis, treatment, and prevention: a review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis and Transplantation. Kidney Int 92:1343–1355

    Article  PubMed  Google Scholar 

  3. Evenepoel P, Cunningham J, Ferrari S, Haarhaus M, Javaid MK, Lafage-Proust MH, Prieto-Alhambra D, Torres PU, Cannata-Andia J (2021) European Consensus Statement on the diagnosis and management of osteoporosis in chronic kidney disease stages G4–G5D. Nephrol Dial Transplant 36:42–59

    Article  CAS  PubMed  Google Scholar 

  4. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM (2001) Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 38:938–942

    Article  CAS  PubMed  Google Scholar 

  5. Malluche HH, Blomquist G, Monier-Faugere MC, Cantor TL, Davenport DL (2015) High Parathyroid Hormone Level and Osteoporosis Predict Progression of Coronary Artery Calcification in Patients on Dialysis. J Am Soc Nephrol 26:2534–2544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rodriguez-Garcia M, Gomez-Alonso C, Naves-Diaz M, Diaz-Lopez JB, Diaz-Corte C, Cannata-Andia JB (2009) Vascular calcifications, vertebral fractures and mortality in haemodialysis patients. Nephrol Dial Transplant 24:239–246

    Article  PubMed  Google Scholar 

  7. Kazama JJ (2017) Chronic kidney disease and fragility fracture. Clin Exp Nephrol 21:46–52

    Article  CAS  PubMed  Google Scholar 

  8. London GM (2012) Bone-vascular cross-talk. J Nephrol 25:619–625

    Article  PubMed  Google Scholar 

  9. Carrillo-Lopez N, Panizo S, Alonso-Montes C, Roman-Garcia P, Rodriguez I, Martinez-Salgado C, Dusso AS, Naves M, Cannata-Andia JB (2016) Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease. Kidney Int 90:77–89

    Article  CAS  PubMed  Google Scholar 

  10. Iseri K, Dai L, Chen Z, Qureshi AR, Brismar TB, Stenvinkel P, Lindholm B (2020) Bone mineral density and mortality in end-stage renal disease patients. Clin Kidney J 13:307–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Koh GC, Tai BC, Ang LW, Heng D, Yuan JM, Koh WP (2013) All-cause and cause-specific mortality after hip fracture among Chinese women and men: the Singapore Chinese Health Study. Osteoporos Int 24:1981–1989

    Article  PubMed  Google Scholar 

  12. Tsai CH, Lin CL, Hsu HC, Chung WS (2015) Increased risk of stroke among hip fracture patients: a nationwide cohort study. Osteoporos Int 26:645–652

    Article  PubMed  Google Scholar 

  13. Alem AM, Sherrard DJ, Gillen DL, Weiss NS, Beresford SA, Heckbert SR, Wong C, Stehman-Breen C (2000) Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int 58:396–399

    Article  CAS  PubMed  Google Scholar 

  14. Wakasugi M, Kazama JJ, Taniguchi M, Wada A, Iseki K, Tsubakihara Y, Narita I (2013) Increased risk of hip fracture among Japanese hemodialysis patients. J Bone Miner Metab 31:315–321

    Article  PubMed  Google Scholar 

  15. Maravic M, Ostertag A, Torres PU, Cohen-Solal M (2014) Incidence and risk factors for hip fractures in dialysis patients. Osteoporos Int 25:159–165

    Article  CAS  PubMed  Google Scholar 

  16. Cameron ID, Chen JS, March LM, Simpson JM, Cumming RG, Seibel MJ, Sambrook PN (2010) Hip fracture causes excess mortality owing to cardiovascular and infectious disease in institutionalized older people: a prospective 5-year study. J Bone Miner Res 25:866–872

    Article  PubMed  Google Scholar 

  17. Hsu WWQ, Sing CW, Li GHY, Tan KCB, Cheung BMY, Wong JSH, Wong IC, Cheung CL (2021) Immediate risk for cardiovascular events in hip fracture patients: a population-based cohort study. J Gerontol A Biol Sci Med Sci 77:1923–1929

    Article  Google Scholar 

  18. Laroche M, Pecourneau V, Blain H, Breuil V, Chapurlat R, Cortet B, Sutter B, Degboe Y (2017) Osteoporosis and ischemic cardiovascular disease. Joint Bone Spine 84:427–432

    Article  CAS  PubMed  Google Scholar 

  19. von der Recke P, Hansen MA, Hassager C (1999) The association between low bone mass at the menopause and cardiovascular mortality. Am J Med 106:273–278

    Article  PubMed  Google Scholar 

  20. Iseri K, Carrero JJ, Evans M, Fellander-Tsai L, Berg H, Runesson B, Stenvinkel P, Lindholm B, Qureshi AR (2020) Major fractures after initiation of dialysis: incidence, predictors and association with mortality. Bone 133:115242

    Article  PubMed  Google Scholar 

  21. Mittalhenkle A, Gillen DL, Stehman-Breen CO (2004) Increased risk of mortality associated with hip fracture in the dialysis population. Am J Kidney Dis 44:672–679

    Article  PubMed  Google Scholar 

  22. Xie L, Hu X, Li W, Ouyang Z (2021) A retrospective study of end-stage kidney disease patients on maintenance hemodialysis with renal osteodystrophy-associated fragility fractures. BMC Nephrol 22:23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yamada S, Taniguchi M, Tokumoto M, Yoshitomi R, Yoshida H, Tatsumoto N, Hirakata H, Fujimi S, Kitazono T, Tsuruya K (2017) Modified creatinine index and the risk of bone fracture in patients undergoing hemodialysis: the Q-Cohort study. Am J Kidney Dis 70:270–280

    Article  CAS  PubMed  Google Scholar 

  24. Brown JP, Josse RG (2002) 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 167:S1-34

    PubMed  PubMed Central  Google Scholar 

  25. Kazama JJ (2007) Japanese society of Dialysis Tapy treatment guidelines for secondary hyperparathyroidism. Ther Apher Dial 11:S44-47

    Article  CAS  PubMed  Google Scholar 

  26. Pincus D, Ravi B, Wasserstein D, Huang A, Paterson JM, Nathens AB, Kreder HJ, Jenkinson RJ, Wodchis WP (2017) Association between wait time and 30-Day mortality in adults undergoing Hip Fracture Surgery. JAMA 318:1994–2003

    Article  PubMed  PubMed Central  Google Scholar 

  27. Lofling L, Sundstrom A, Kieler H, Bahmanyar S, Linder M (2019) Exposure to antimuscarinic medications for treatment of overactive bladder and risk of lung cancer and colon cancer. Clin Epidemiol 11:133–143

    Article  PubMed  PubMed Central  Google Scholar 

  28. Andrew NE, Kim J, Thrift AG, Kilkenny MF, Lannin NA, Anderson CS, Donnan GA, Hill K, Middleton S, Levi C, Faux S, Grimley R, Gange N, Geraghty R, Ermel S, Cadilhac DA (2018) Prescription of antihypertensive medication at discharge influences survival following stroke. Neurology 90:e745–e753

    Article  PubMed  Google Scholar 

  29. Baena-Diez JM, Penafiel J, Subirana I et al (2016) Risk of cause-specific death in individuals with diabetes: a competing risks analysis. Diabetes Care 39:1987–1995

    Article  PubMed  Google Scholar 

  30. Schulz E, Arfai K, Liu X, Sayre J, Gilsanz V (2004) Aortic calcification and the risk of osteoporosis and fractures. J Clin Endocrinol Metab 89:4246–4253

    Article  CAS  PubMed  Google Scholar 

  31. Carrillo-Lopez N, Martinez-Arias L, Fernandez-Villabrille S, Ruiz-Torres MP, Dusso A, Cannata-Andia JB, Naves-Diaz M, Panizo S, W European Renal Osteodystrophy (2021) Role of the RANK/RANKL/OPG and Wnt/beta-Catenin systems in CKD bone and cardiovascular disorders. Calcif Tissue Int 108:439–451

    Article  CAS  PubMed  Google Scholar 

  32. Simpson EL, Martyn-St James M, Hamilton J, Wong R, Gittoes N, Selby P, Davis S (2020) Clinical effectiveness of denosumab, raloxifene, romosozumab, and teriparatide for the prevention of osteoporotic fragility fractures: a systematic review and network meta-analysis. Bone 130:115081

    Article  CAS  PubMed  Google Scholar 

  33. Corallini F, Rimondi E, Secchiero P (2008) TRAIL and osteoprotegerin: a role in endothelial physiopathology? Front Biosci 13:135–147

    Article  CAS  PubMed  Google Scholar 

  34. De Mare A, Maudsley S, Azmi A, Hendrickx JO, Opdebeeck B, Neven E, D’Haese PC, Verhulst A (2019) Sclerostin as regulatory molecule in vascular media calcification and the bone-vascular axis. Toxins (Basel) 11:428. https://doi.org/10.3390/toxins11070428

    Article  CAS  PubMed  Google Scholar 

  35. Li R, Mittelstein D, Lee J, Fang K, Majumdar R, Tintut Y, Demer LL, Hsiai TK (2012) A dynamic model of calcific nodule destabilization in response to monocyte- and oxidized lipid-induced matrix metalloproteinases. Am J Physiol Cell Physiol 302:C658-665

    Article  CAS  PubMed  Google Scholar 

  36. Zhang Y, Ge C, Wang L, Liu X, Chen Y, Li M, Zhang M (2015) Induction of DKK1 by ox-LDL negatively regulates intracellular lipid accumulation in macrophages. FEBS Lett 589:52–58

    Article  CAS  PubMed  Google Scholar 

  37. Moldovan D, Rusu C, Potra A, Moldovan I, Patiu IM, Gherman-Caprioara M, Kacso IM (2017) Osteoprotegerin and uremic osteoporosis in chronic hemodialysis patients. Int Urol Nephrol 49:895–901

    Article  CAS  PubMed  Google Scholar 

  38. De Mare A, Opdebeeck B, Neven E, D’Haese PC, Verhulst A (2022) Sclerostin protects against vascular calcification development in mice. J Bone Miner Res 37:687–699

    Article  PubMed  Google Scholar 

  39. Mace ML, Gravesen E, Nordholm A, Egstrand S, Morevati M, Nielsen C, Kjaer A, Behets G, D’Haese P, Olgaard K, Lewin E (2021) Chronic kidney disease-induced vascular calcification impairs bone metabolism. J Bone Miner Res 36:510–522

    Article  CAS  PubMed  Google Scholar 

  40. Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM (2007) Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 71:438–441

    Article  CAS  PubMed  Google Scholar 

  41. Chen Z, Qureshi AR, Ripsweden J, Wennberg L, Heimburger O, Lindholm B, Barany P, Haarhaus M, Brismar TB, Stenvinkel P (2016) Vertebral bone density associates with coronary artery calcification and is an independent predictor of poor outcome in end-stage renal disease patients. Bone 92:50–57

    Article  PubMed  Google Scholar 

  42. Yahagi K, Kolodgie FD, Otsuka F, Finn AV, Davis HR, Joner M, Virmani R (2016) Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat Rev Cardiol 13:79–98

    Article  CAS  PubMed  Google Scholar 

  43. Nakamura N, Torii S, Tsuchiya H, Nakano A, Oikawa Y, Yajima J, Nakamura S, Nakano M, Masuda N, Ohta H, Yumoto K, Natsumeda M, Ijichi T, Ikari Y, Nakazawa G (2020) Formation of calcified nodule as a cause of early in-stent restenosis in patients undergoing dialysis. J Am Heart Assoc 9:e016595

    Article  PubMed  PubMed Central  Google Scholar 

  44. Solbu MD, Mjoen G, Mark PB, Holdaas H, Fellstrom B, Schmieder RE, Zannad F, Herrington WG, Jardine AG (2018) Predictors of atherosclerotic events in patients on haemodialysis: post hoc analyses from the AURORA study. Nephrol Dial Transplant 33:102–112

    CAS  PubMed  Google Scholar 

  45. Raggi P, Bellasi A, Ferramosca E, Islam T, Muntner P, Block GA (2007) Association of pulse wave velocity with vascular and valvular calcification in hemodialysis patients. Kidney Int 71:802–807

    Article  CAS  PubMed  Google Scholar 

  46. Lindman BR, Bonow RO, Otto CM (2013) Current management of calcific aortic stenosis. Circ Res 113:223–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Notarnicola A, Maccagnano G, Moretti L, Tafuri S, Moretti B (2017) Cardiopathy and osteoporosis: the epidemiology in a region of Italy. J Biol Regul Homeost Agents 31:251–255

    CAS  PubMed  Google Scholar 

  48. Pfister R, Michels G, Sharp SJ, Luben R, Wareham NJ, Khaw KT (2014) Low bone mineral density predicts incident heart failure in men and women: the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk prospective study. JACC Heart Fail 2:380–389

    Article  PubMed  Google Scholar 

  49. Dutka M, Bobinski R, Wojakowski W, Francuz T, Pajak C, Zimmer K (2022) Osteoprotegerin and RANKL-RANK-OPG-TRAIL signalling axis in heart failure and other cardiovascular diseases. Heart Fail Rev 27:1395–1411

    Article  PubMed  Google Scholar 

  50. Akoumianakis I, Polkinghorne M, Antoniades C (2022) Non-canonical WNT signalling in cardiovascular disease: mechanisms and therapeutic implications. Nat Rev Cardiol 19:783–797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chiang CH, Liu CJ, Chen PJ, Huang CC, Hsu CY, Chen ZY, Chan WL, Huang PH, Chen TJ, Chung CM, Lin SJ, Chen JW, Leu HB (2013) Hip fracture and risk of acute myocardial infarction: a nationwide study. J Bone Miner Res 28:404–411

    Article  PubMed  Google Scholar 

  52. Tanko LB, Christiansen C, Cox DA, Geiger MJ, McNabb MA, Cummings SR (2005) Relationship between osteoporosis and cardiovascular disease in postmenopausal women. J Bone Miner Res 20:1912–1920

    Article  PubMed  Google Scholar 

  53. Lunyera J, Scialla JJ (2018) Update on chronic kidney disease mineral and bone disorder in cardiovascular disease. Semin Nephrol 38:542–558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Komaba H, Ketteler M, Cunningham J, Fukagawa M (2021) Old and new drugs for the management of bone disorders in CKD. Calcif Tissue Int 108:486–495

    Article  CAS  PubMed  Google Scholar 

  55. Bover J, Urena P, Brandenburg V, Goldsmith D, Ruiz C, DaSilva I, Bosch RJ (2014) Adynamic bone disease: from bone to vessels in chronic kidney disease. Semin Nephrol 34:626–640

    Article  PubMed  Google Scholar 

  56. Andress DL (2008) Adynamic bone in patients with chronic kidney disease. Kidney Int 73:1345–1354

    Article  CAS  PubMed  Google Scholar 

  57. Sato H, Nagasawa T, Saito A, Miyazaki M (2018) Risk of cardiovascular mortality predicted by the serum calcium level and calcification score at the initiation of dialysis. Clin Exp Nephrol 22:957–966

    Article  CAS  PubMed  Google Scholar 

  58. Nakagawa Y, Komaba H, Hamano N, Wada T, Hida M, Suga T, Kakuta T, Fukagawa M (2020) Metacarpal bone mineral density by radiographic absorptiometry predicts fracture risk in patients undergoing maintenance hemodialysis. Kidney Int 98:970–978

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We appreciate the contributions of the participants in the Q-Cohort Study, members of the Society for the Study of Kidney Disease. The personnel (institutions) who participated in the study are as follows: Takashi Ando (Hakozaki Park Internal Medicine Clinic), Takashi Ariyoshi (Ariyoshi Clinic), Koichiro Goto (Goto Clinic), Fumitada Hattori (Nagao Hospital), Harumichi Higashi (St. Mary’s Hospital), Tadashi Hirano (Hakujyuji Hospital), Kei Hori (Munakata Medical Association Hospital), Takashi Inenaga (Ekisaikai Moji Hospital), Hidetoshi Kanai (Kokura Memorial Hospital), Shigemi Kiyama (Kiyama Naika), Tetsuo Komota (Komota Clinic), Hiromasa Kuma (Kuma Clinic), Toshiro Maeda (Kozenkai-Maeda Hospital), Junichi Makino (Makino Clinic), Dai Matsuo (Hirao Clinic), Chiaki Miishima (Miishima Naika Clinic), Koji Mitsuiki (Japanese Red Cross Fukuoka Hospital), Kenichi Motomura (Motomura Naika Clinic), Sadatoshi Nakamura and Hidetoshi Nakamura (Kokura Daiichi Hospital), Koichi Nakashima (Ohashi Internal Circulatory Clinic), Nobumitsu Okita (Shiroishi Kyoritsu Hospital), Shinichiro Osato (Osato Jin Clinic), Sakura Sakamoto (Fujiyamato Spa Hospital), Keiko Shigematsu (Shigematsu Clinic), Kazumasa Shimamatsu (Shimamatsu Naika Iin), Yoshito Shogakiuchi (Shin-Ai Clinic), Hiroaki Takamura (Hara Hospital), Kazuhito Takeda (Iizuka Hospital), Asuka Terai (Chidoribashi Hospital), Hideyoshi Tanaka (Mojiko-Jin Clinic), Suguru Tomooka (Hakozaki Park Internal Medicine Clinic), Jiro Toyonaga (Fukuoka Renal Clinic), Hiroshi Tsuruta (Steel Memorial Yawata Hospital), Ryutaro Yamaguchi (Shiseikai Hospital), Taihei Yanagida (Saiseikai Yahata General Hospital), Tetsuro Yanase (Yanase Internal Medicine Clinic), Tetsuhiko Yoshida (Hamanomachi Hospital), Takahiro Yoshimitsu (Gofukumachi Kidney Clinic, Harasanshin Hospital), and Koji Yoshitomi (Yoshitomi Medical Clinic).

We also thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, NHO Kyushu Medical Center, Fukuoka, Japan

    Naoki Haruyama & Masaru Nakayama

  2. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shunsuke Yamada, Shigeru Tanaka, Takanari Kitazono & Toshiaki Nakano

  3. Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan

    Hiroto Hiyamuta

  4. Fukuoka Renal Clinic, Fukuoka, Japan

    Masatomo Taniguchi

  5. Division of Nephrology and Dialysis Center, Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan

    Masanori Tokumoto

  6. Department of Nephrology, Nara Medical University, Kashihara, Nara, Japan

    Kazuhiko Tsuruya

Authors
  1. Naoki Haruyama
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  2. Masaru Nakayama
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  3. Shunsuke Yamada
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  4. Shigeru Tanaka
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  5. Hiroto Hiyamuta
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  6. Masatomo Taniguchi
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  7. Masanori Tokumoto
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  8. Kazuhiko Tsuruya
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  9. Takanari Kitazono
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  10. Toshiaki Nakano
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Contributions

N.H. contributed to the study conception, study design, and data interpretation and wrote the manuscript. M.N. and S.Y. contributed to the data acquisition and interpretation. S.T. and H.H. contributed to the data collection and interpretation. M.T., M.T., K.T., T.N., and T.K. contributed to the data interpretation and reviewed and revised the manuscript. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Toshiaki Nakano.

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Conflict of interest

Naoki Haruyama, Masaru Nakayama, Shunsuke Yamada, Shigeru Tanaka, Hiroto Hiyamuta, Masatomo Taniguchi, and Masanori Tokumoto declare that they have no conflict of interest. Dr. Tsuruya reports receiving honoraria from Astellas Pharma Inc.

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Haruyama, N., Nakayama, M., Yamada, S. et al. History of fragility fracture is associated with cardiovascular mortality in hemodialysis patients: the Q-Cohort study. J Bone Miner Metab 42, 253–263 (2024). https://doi.org/10.1007/s00774-024-01501-x

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