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Noninvasive Assessment of Arterial Structure and Function

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Pediatric and Congenital Cardiology, Cardiac Surgery and Intensive Care

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Abstract

Cardiovascular diseases are a leading cause of mortality worldwide. Structural and functional evidence of early vascular disease is present in children and adolescents can be assessed noninvasively, and can inform on the early pathophysiology of both atherosclerosis and hypertension. This chapter details the noninvasive techniques commonly used to assess arterial structure and function, and their research and clinical application in children and adolescents. The use of these techniques in describing the high-risk individual, and the potential for assessing early prevention strategies, are also discussed.

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References

  1. Yusuf S, Hawken S, Ounpuu S et al (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364:937–952

    Article  Google Scholar 

  2. Celermajer DS, Sorensen KE, Gooch VM et al (1992) Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340:1111–1115

    Article  CAS  Google Scholar 

  3. Napoli C, Glass CK, Witztum JL, Deutsch R, D'Armiento FP, Palinski W (1999) Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 354:1234–1241

    Article  CAS  Google Scholar 

  4. McGill HC Jr, McMahan CA, Herderick EE et al (2000) Effects of coronary heart disease risk factors on atherosclerosis of selected regions of the aorta and right coronary artery. PDAY Research Group. Pathobiological Determinants of Atherosclerosis in Youth. Arterioscler Thromb Vasc Biol 20:836–845

    Article  Google Scholar 

  5. Celermajer DS (1997) Endothelial dysfunction: does it matter? Is it reversible? J Am Coll Cardiol 30:325–333

    Article  CAS  Google Scholar 

  6. Lohn M, Dubrovska G, Lauterbach B, Luft FC, Gollasch M, Sharma AM (2002) Periadventitial fat releases a vascular relaxing factor. FASEB J 16:1057–1063

    Article  Google Scholar 

  7. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M (2007) Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 115:459–467

    Article  Google Scholar 

  8. Skilton MR, Sieveking DP, Harmer JA et al (2008) The effects of obesity and non-pharmacological weight loss on vascular and ventricular function and structure. Diabetes Obes Metab 10:874–884

    Article  CAS  Google Scholar 

  9. Skilton MR, Moulin P, Serusclat A, Nony P, Bonnet F (2007) A comparison of the NCEP-ATPIII, IDF and AHA/NHLBI metabolic syndrome definitions with relation to early carotid atherosclerosis in subjects with hypercholesterolemia or at risk of CVD: evidence for sex-specific differences. Atherosclerosis 190:416–422

    Article  CAS  Google Scholar 

  10. Ebrahim S, Papacosta O, Whincup P et al (1999) Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 30:841–850

    Article  CAS  Google Scholar 

  11. Salonen JT, Seppanen K, Rauramaa R, Salonen R (1989) Risk factors for carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study. Ann Med 21:227–229

    Article  CAS  Google Scholar 

  12. Raitakari OT, Juonala M, Kahonen M et al (2003) Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA 290:2277–2283

    Article  CAS  Google Scholar 

  13. Juonala M, Viikari JS, Kahonen M et al (2010) Life-time risk factors and progression of carotid atherosclerosis in young adults: the Cardiovascular Risk in Young Finns study. Eur Heart J 31:1745–1751

    Article  CAS  Google Scholar 

  14. Polak JF, Pencina MJ, Pencina KM, O'Donnell CJ, Wolf PA, D'Agostino RB Sr (2011) Carotid-wall intima-media thickness and cardiovascular events. N Engl J Med 365:213–221

    Article  CAS  Google Scholar 

  15. Skilton MR, Celermajer DS (2006) Endothelial dysfunction and arterial abnormalities in childhood obesity. Int J Obes 30:1041–1049

    Article  CAS  Google Scholar 

  16. Ayer JG, Harmer JA, Nakhla S et al (2009) HDL-cholesterol, blood pressure, and asymmetric dimethylarginine are significantly associated with arterial wall thickness in children. Arterioscler Thromb Vasc Biol 29:943–949

    Article  CAS  Google Scholar 

  17. Wiegman A, de Groot E, Hutten BA et al (2004) Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet 363:369–370

    Article  Google Scholar 

  18. Jarvisalo MJ, Jartti L, Nanto-Salonen K et al (2001) Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children. Circulation 104:2943–2947

    Article  CAS  Google Scholar 

  19. Jarvisalo MJ, Raitakari M, Toikka JO et al (2004) Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation 109:1750–1755

    Article  Google Scholar 

  20. Woo KS, Chook P, Yu CW et al (2004) Effects of diet and exercise on obesity-related vascular dysfunction in children. Circulation 109:1981–1986. https://doi.org/10.1161/01.CIR.0000126599.47470.BE

    Article  Google Scholar 

  21. Raiko JR, Magnussen CG, Kahonen M et al (2010) Tracking of noninvasive ultrasound measurements of subclinical atherosclerosis in adulthood: findings from the Cardiovascular Risk in Young Finns Study. Ultrasound Med Biol 36:1237–1244

    Article  Google Scholar 

  22. Skilton MR, Evans N, Griffiths KA, Harmer JA, Celermajer DS (2005) Aortic wall thickness in newborns with intrauterine growth restriction. Lancet 365:1484–1486

    Article  Google Scholar 

  23. Skilton MR (2008) Intrauterine risk factors for precocious atherosclerosis. Pediatrics 121:570–574

    Article  Google Scholar 

  24. Skilton MR, Pahkala K, Viikari JS et al (2015) The association of dietary alpha-linolenic acid with blood pressure and subclinical atherosclerosis in people born small for gestational age: the special Turku coronary risk factor intervention project study. J Pediatr 166:1252–1257

    Article  CAS  Google Scholar 

  25. Kizirian NV, Kong Y, Muirhead R et al (2016) Effects of a low-glycemic index diet during pregnancy on offspring growth, body composition, and vascular health: a pilot randomized controlled trial. Am J Clin Nutr 103(4):1073–1082

    Article  CAS  Google Scholar 

  26. Sarkola T, Abadilla AA, Chahal N, Jaeggi E, McCrindle BW (2011) Feasibility of very-high resolution ultrasound to assess elastic and muscular arterial wall morphology in adolescents attending an outpatient clinic for obesity and lipid abnormalities. Atherosclerosis 219:610–615

    Article  CAS  Google Scholar 

  27. Skilton MR, Serusclat A, Sethu AH et al (2009) Noninvasive measurement of carotid extra-media thickness: associations with cardiovascular risk factors and intima-media thickness. JACC Cardiovasc Imaging 2:176–182

    Article  Google Scholar 

  28. Skilton MR, Viikari JS, Juonala M et al (2011) Fetal growth and preterm birth influence cardiovascular risk factors and arterial health in young adults: the cardiovascular risk in young Finns study. Arterioscler Thromb Vasc Biol 31:2975–2981

    Article  CAS  Google Scholar 

  29. Cai TY, Sullivan TR, Ayer JG et al (2016) Carotid extramedial thickness is associated with local arterial stiffness in children. J Hypertens 34:109–115

    Article  CAS  Google Scholar 

  30. Cai TY, Magnussen C, Haluska B et al (2016) Carotid extra-medial thickness does not predict adverse cardiovascular outcomes in high-risk adults. Diabetes Metab 42:200–203

    Article  CAS  Google Scholar 

  31. Skilton MR, Sullivan TR, Ayer JG et al (2012) Carotid extra-medial thickness in childhood: early life effects on the arterial adventitia. Atherosclerosis 222:478–482

    Article  CAS  Google Scholar 

  32. Skilton MR, Sullivan TR, Ayer JG et al (2014) Weight gain in infancy is associated with carotid extra-medial thickness in later childhood. Atherosclerosis 233:370–374

    Article  CAS  Google Scholar 

  33. Boussel L, Serusclat A, Skilton MR et al (2007) The reliability of high resolution MRI in the measurement of early stage carotid wall thickening. J Cardiovasc Magn Reson 9:771–776

    Article  Google Scholar 

  34. Duivenvoorden R, de Groot E, Elsen BM et al (2009) In vivo quantification of carotid artery wall dimensions: 3.0-Tesla MRI versus B-mode ultrasound imaging. Circ Cardiovasc Imaging 2:235–242

    Article  CAS  Google Scholar 

  35. Maroules CD, Rosero E, Ayers C, Peshock RM, Khera A (2013) Abdominal aortic atherosclerosis at MR imaging is associated with cardiovascular events: the Dallas heart study. Radiology 269:84–91

    Article  Google Scholar 

  36. Aluquin VP, Albano SA, Chan F, Sandborg C, Pitlick PT (2002) Magnetic resonance imaging in the diagnosis and follow up of Takayasu’s arteritis in children. Ann Rheum Dis 61:526–529

    Article  CAS  Google Scholar 

  37. Mahoney LT, Burns TL, Stanford W et al (1996) Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine study. J Am Coll Cardiol 27:277–284

    Article  CAS  Google Scholar 

  38. Wang L, Jerosch-Herold M, Jacobs DR Jr, Shahar E, Detrano R, Folsom AR (2006) Coronary artery calcification and myocardial perfusion in asymptomatic adults: the MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 48:1018–1026

    Article  CAS  Google Scholar 

  39. Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD (2005) Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol 46:158–165

    Article  CAS  Google Scholar 

  40. Brody AS, Frush DP, Huda W, Brent RL (2007) Radiation risk to children from computed tomography. Pediatrics 120:677–682

    Article  Google Scholar 

  41. Janowitz WR, Agatston AS, Kaplan G, Viamonte M Jr (1993) Differences in prevalence and extent of coronary artery calcium detected by ultrafast computed tomography in asymptomatic men and women. Am J Cardiol 72:247–254

    Article  CAS  Google Scholar 

  42. Gidding SS, Bookstein LC, Chomka EV (1998) Usefulness of electron beam tomography in adolescents and young adults with heterozygous familial hypercholesterolemia. Circulation 98:2580–2583

    Article  CAS  Google Scholar 

  43. Pyke KE, Tschakovsky ME (2005) The relationship between shear stress and flow-mediated dilatation: implications for the assessment of endothelial function. J Physiol 568:357–369

    Article  CAS  Google Scholar 

  44. Anderson TJ, Uehata A, Gerhard MD et al (1995) Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 26:1235–1241

    Article  CAS  Google Scholar 

  45. Black MA, Cable NT, Thijssen DH, Green DJ (2008) Importance of measuring the time course of flow-mediated dilatation in humans. Hypertension 51:203–210

    Article  CAS  Google Scholar 

  46. Donald AE, Halcox JP, Charakida M et al (2008) Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation. J Am Coll Cardiol 51:1959–1964

    Article  Google Scholar 

  47. Joannides R, Haefeli WE, Linder L et al (1995) Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation 91:1314–1319

    Article  CAS  Google Scholar 

  48. Green DJ, Jones H, Thijssen D, Cable NT, Atkinson G (2011) Flow-mediated dilation and cardiovascular event prediction: does nitric oxide matter? Hypertension 57:363–369

    Article  CAS  Google Scholar 

  49. Benjamin EJ, Larson MG, Keyes MJ et al (2004) Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study. Circulation 109:613–619

    Article  Google Scholar 

  50. Juonala M, Kahonen M, Laitinen T et al (2008) Effect of age and sex on carotid intima-media thickness, elasticity and brachial endothelial function in healthy adults: the cardiovascular risk in Young Finns Study. Eur Heart J 29:1198–1206

    Article  Google Scholar 

  51. Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE (1994) Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol 24:1468–1474

    Article  CAS  Google Scholar 

  52. Leeson CPM, Whincup PH, Cook DG et al (1997) Flow-mediated dilation in 9- to 11-year-old children : the influence of intrauterine and childhood factors. Circulation 96:2233–2238

    Article  CAS  Google Scholar 

  53. Hashimoto M, Eto M, Akishita M et al (1999) Correlation between flow-mediated vasodilatation of the brachial artery and intima-media thickness in the carotid artery in men. Arterioscler Thromb Vasc Biol 19:2795–2800

    Article  CAS  Google Scholar 

  54. Halcox JP, Donald AE, Ellins E et al (2009) Endothelial function predicts progression of carotid intima-media thickness. Circulation 119:1005–1012

    Article  Google Scholar 

  55. Sorensen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE (1994) Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level. J Clin Invest 93:50–55

    Article  CAS  Google Scholar 

  56. Woo KS, Chook P, Yu CW et al (2004) Overweight in children is associated with arterial endothelial dysfunction and intima-media thickening. Int J Obes Relat Metab Disord 28:852–857

    Article  CAS  Google Scholar 

  57. Celermajer DS, Adams MR, Clarkson P et al (1996) Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med 334:150–154

    Article  CAS  Google Scholar 

  58. Hingorani AD, Cross J, Kharbanda RK et al (2000) Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation 102:994–999

    Article  CAS  Google Scholar 

  59. Clarkson P, Adams MR, Powe AJ et al (1996) Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 97:1989–1994

    Article  CAS  Google Scholar 

  60. Raitakari OT, Adams MR, McCredie RJ, Griffiths KA, Celermajer DS (1999) Arterial endothelial dysfunction related to passive smoking is potentially reversible in healthy young adults. Ann Intern Med 130:578–581

    Article  CAS  Google Scholar 

  61. Santangelo K, Falkner B, Kushner H (1989) Forearm hemodynamics at rest and stress in borderline hypertensive adolescents. Am J Hypertens 2:52–56

    Article  CAS  Google Scholar 

  62. Selamet Tierney ES, Newburger JW, Gauvreau K et al (2009) Endothelial pulse amplitude testing: feasibility and reproducibility in adolescents. J Pediatr 154:901–905

    Article  Google Scholar 

  63. Tagawa T, Imaizumi T, Endo T, Shiramoto M, Harasawa Y, Takeshita A (1994) Role of nitric oxide in reactive hyperemia in human forearm vessels. Circulation 90:2285–2290

    Article  CAS  Google Scholar 

  64. Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, Ganz P (2006) Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. J Appl Physiol 101:545–548

    Article  CAS  Google Scholar 

  65. Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Kajiyama G, Oshima T (2001) A noninvasive measurement of reactive hyperemia that can be used to assess resistance artery endothelial function in humans. Am J Cardiol 87:121–125

    Article  CAS  Google Scholar 

  66. Kuvin JT, Patel AR, Sliney KA et al (2003) Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J 146:168–174

    Article  Google Scholar 

  67. Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A (2004) Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 44:2137–2141

    Article  Google Scholar 

  68. Rubinshtein R, Kuvin JT, Soffler M et al (2010) Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 31:1142–1148

    Article  Google Scholar 

  69. de Berrazueta JR, Guerra-Ruiz A, García-Unzueta MT et al (2010) Endothelial dysfunction, measured by reactive hyperaemia using strain-gauge plethysmography, is an independent predictor of adverse outcome in heart failure. Eur J Heart Fail 12:477–483

    Article  CAS  Google Scholar 

  70. Mahmud FH, Earing MG, Lee RA, Lteif AN, Driscoll DJ, Lerman A (2006) Altered endothelial function in asymptomatic male adolescents with type 1 diabetes. Congenit Heart Dis 1:98–103

    Article  Google Scholar 

  71. Duck MM, Hoffman RP (2007) Impaired endothelial function in healthy African-American adolescents compared with caucasians. J Pediatr 150:400–406

    Article  CAS  Google Scholar 

  72. Laurent S, Cockcroft J, Van Bortel L et al (2006) Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 27:2588–2605

    Article  Google Scholar 

  73. Hansen TW, Li Y, Staessen JA et al (2008) Independent prognostic value of the ambulatory arterial stiffness index and aortic pulse wave velocity in a general population. J Hum Hypertens 22:214–216

    Article  CAS  Google Scholar 

  74. Laurent S, Boutouyrie P, Asmar R et al (2001) Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 37:1236–1241

    Article  CAS  Google Scholar 

  75. Im JA, Lee JW, Shim JY, Lee HR, Lee DC (2007) Association between brachial-ankle pulse wave velocity and cardiovascular risk factors in healthy adolescents. J Pediatr 150:247–251

    Article  Google Scholar 

  76. Niboshi A, Hamaoka K, Sakata K, Inoue F (2006) Characteristics of brachial-ankle pulse wave velocity in Japanese children. Eur J Pediatr 165:625–629

    Article  Google Scholar 

  77. Pillsbury HC 3rd, Hung W, Kyle MC, Freis ED (1974) Arterial pulse waves and velocity and systolic time intervals in diabetic children. Am Heart J 87:783–790

    Article  Google Scholar 

  78. Mattace-Raso FU, van der Cammen TJ, Hofman A et al (2006) Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 113:657–663

    Article  Google Scholar 

  79. Paini A, Boutouyrie P, Calvet D, Tropeano AI, Laloux B, Laurent S (2006) Carotid and aortic stiffness: determinants of discrepancies. Hypertension 47:371–376

    Article  CAS  Google Scholar 

  80. Whincup PH, Gilg JA, Donald AE et al (2005) Arterial distensibility in adolescents: the influence of adiposity, the metabolic syndrome, and classic risk factors. Circulation 112:1789–1797

    Article  CAS  Google Scholar 

  81. Leeson CP, Whincup PH, Cook DG et al (2000) Cholesterol and arterial distensibility in the first decade of life: a population-based study. Circulation 101:1533–1538

    Article  CAS  Google Scholar 

  82. Mori A, Uchida N, Inomo A, Izumi S (2006) Stiffness of systemic arteries in appropriate- and small-for-gestational-age newborn infants. Pediatrics 118:1035–1041

    Article  Google Scholar 

  83. Touboul PJ, Hennerici MG, Meairs S et al (2007) Mannheim carotid intima-media thickness consensus (2004–2006). Cerebrovasc Dis 23:75–80

    Article  Google Scholar 

  84. Urbina EM, Williams RV, Alpert BS et al (2009) Noninvasive assessment of subclinical atherosclerosis in children and adolescents: recommendations for standard assessment for clinical research: a scientific statement from the American Heart Association. Hypertension 54:919–950

    Article  CAS  Google Scholar 

  85. Crowe LA, Ariff B, Keegan J et al (2005) Comparison between three-dimensional volume-selective turbo spin-echo imaging and two-dimensional ultrasound for assessing carotid artery structure and function. J Magn Reson Imaging 21:282–289

    Article  Google Scholar 

  86. Corretti MC, Anderson TJ, Benjamin EJ et al (2002) Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 39:257–265

    Article  Google Scholar 

  87. Higashi Y, Yoshizumi M (2003) New methods to evaluate endothelial function: method for assessing endothelial function in humans using a strain-gauge plethysmography: nitric oxide-dependent and -independent vasodilation. J Pharmacol Sci 93:399–404

    Article  CAS  Google Scholar 

  88. Axtell AL, Gomari FA, Cooke JP (2010) Assessing endothelial vasodilator function with the endo-PAT 2000. J Vis Exp 44:e2167

    Google Scholar 

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Authors and Affiliations

  1. Boden Collaboration for Obesity, Nutrition, Exercise and Eating Disorders, University of Sydney School of Medicine, The University of Sydney, Sydney, NSW, Australia

    Michael R. Skilton

  2. University of Sydney School of Medicine, The University of Sydney, Sydney, NSW, Australia

    David S. Celermajer

  3. The Heart Research Institute, Sydney, NSW, Australia

    David S. Celermajer

Authors
  1. Michael R. Skilton
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  2. David S. Celermajer
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Correspondence to Michael R. Skilton .

Editor information

Editors and Affiliations

  1. Children’s Hospital Colorado University of Colorado Denver, School of, Aurora, CO, USA

    Eduardo M. da Cruz

  2. Children's Hospital Colorado University of Colorado School of Medicin, Aurora, CO, USA

    Dunbar Ivy

  3. Department of Cardiac Surgery, German Pediatric Heart Center, Sankt Augustin, Germany

    Viktor Hraska

  4. Pediatric Cardiac Surgery, Children's Hospital Colorado University of Colorado, Aurora, CO, USA

    James Jaggers

Section Editor information

  1. Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO, USA

    Stephen R. Daniels MD, PhD

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Skilton, M.R., Celermajer, D.S. (2020). Noninvasive Assessment of Arterial Structure and Function. In: da Cruz, E.M., Ivy, D., Hraska, V., Jaggers, J. (eds) Pediatric and Congenital Cardiology, Cardiac Surgery and Intensive Care. Springer, London. https://doi.org/10.1007/978-1-4471-4999-6_56-2

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  • DOI: https://doi.org/10.1007/978-1-4471-4999-6_56-2

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