메뉴 건너뛰기




Volumn 55, Issue 11, 2015, Pages 2564-2575

In a canine pneumonia model of exchange transfusion, altering the age but not the volume of older red blood cells markedly alters outcome

Author keywords

[No Author keywords available]

Indexed keywords

HEMOGLOBIN; TRANSFERRIN;

EID: 84947129356     PISSN: 00411132     EISSN: 15372995     Source Type: Journal    
DOI: 10.1111/trf.13275     Document Type: Article
Times cited : (23)

References (50)
  • 1
    • 84947132203 scopus 로고    scopus 로고
    • Requirements for storage, transportation, and expiration. Reference Standard 5.1.8A
    • 27th ed. Bethesda (MD): AABB.
    • Requirements for storage, transportation, and expiration. Reference Standard 5.1.8A. In: Standards for blood banks and transfusion services. 27th ed. Bethesda (MD): AABB; 2011.
    • (2011) Standards for Blood Banks and Transfusion Services
  • 2
    • 80054996933 scopus 로고    scopus 로고
    • [Internet]. Washington (DC): U.S. Department of Health & Human Services [cited 2015 Aug 20]
    • Whitaker BI, Henry RA., The 2011 national blood collection and utilization survey report [Internet]. Washington (DC): U.S. Department of Health & Human Services; 2011 [cited 2015 Aug 20]. Available from: http://www.hhs.gov/ash/bloodsafety/2011-nbcus.pdf
    • (2011) The 2011 National Blood Collection and Utilization Survey Report
    • Whitaker, B.I.1    Henry, R.A.2
  • 3
    • 84925224639 scopus 로고    scopus 로고
    • The pathophysiology and consequences of red blood cell storage
    • e9-12.
    • Orlov D, Karkouti K., The pathophysiology and consequences of red blood cell storage. Anaesthesia 2015; 70 Suppl 1: 29-37, e9-12.
    • (2015) Anaesthesia , vol.70 , pp. 29-37
    • Orlov, D.1    Karkouti, K.2
  • 4
    • 84861773746 scopus 로고    scopus 로고
    • Scientific problems in the regulation of red blood cell products
    • Biomedical Excellence for Safer Transfusion (BEST) Collaborative.
    • Hess JR,; Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Scientific problems in the regulation of red blood cell products. Transfusion 2012; 52: 1827-35.
    • (2012) Transfusion , vol.52 , pp. 1827-1835
    • Hess, J.R.1
  • 6
    • 84876770704 scopus 로고    scopus 로고
    • Decreased erythrocyte deformability after transfusion and the effects of erythrocyte storage duration
    • Frank SM, Abazyan B, Ono M, et al., Decreased erythrocyte deformability after transfusion and the effects of erythrocyte storage duration. Anesth Analg 2013; 116: 975-81.
    • (2013) Anesth Analg , vol.116 , pp. 975-981
    • Frank, S.M.1    Abazyan, B.2    Ono, M.3
  • 7
    • 79961025290 scopus 로고    scopus 로고
    • Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion
    • Donadee C, Raat NJ, Kanias T, et al., Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion. Circulation 2011; 124: 465-76.
    • (2011) Circulation , vol.124 , pp. 465-476
    • Donadee, C.1    Raat, N.J.2    Kanias, T.3
  • 8
    • 84902331787 scopus 로고    scopus 로고
    • Measures of stored red blood cell quality
    • Hess JR., Measures of stored red blood cell quality. Vox Sang 2014; 107: 1-9.
    • (2014) Vox Sang , vol.107 , pp. 1-9
    • Hess, J.R.1
  • 9
    • 84876479056 scopus 로고    scopus 로고
    • Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia
    • Solomon SB, Wang D, Sun J, et al., Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia. Blood 2013; 121: 1663-72.
    • (2013) Blood , vol.121 , pp. 1663-1672
    • Solomon, S.B.1    Wang, D.2    Sun, J.3
  • 10
    • 77953638866 scopus 로고    scopus 로고
    • Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation
    • Hod EA, Zhang N, Sokol SA, et al., Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation. Blood 2010; 115: 4284-92.
    • (2010) Blood , vol.115 , pp. 4284-4292
    • Hod, E.A.1    Zhang, N.2    Sokol, S.A.3
  • 11
    • 83555165250 scopus 로고    scopus 로고
    • Transfusion of fresh murine red blood cells reverses adverse effects of older stored red blood cells
    • Hendrickson JE, Hod EA, Hudson KE, et al., Transfusion of fresh murine red blood cells reverses adverse effects of older stored red blood cells. Transfusion 2011; 51: 2695-702.
    • (2011) Transfusion , vol.51 , pp. 2695-2702
    • Hendrickson, J.E.1    Hod, E.A.2    Hudson, K.E.3
  • 12
    • 84859712543 scopus 로고    scopus 로고
    • Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in Guinea pigs by haptoglobin therapy
    • Baek JH, D'Agnillo F, Vallelian F, et al., Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy. J Clin Invest 2012; 122: 1444-58.
    • (2012) J Clin Invest , vol.122 , pp. 1444-1458
    • Baek, J.H.1    D'Agnillo, F.2    Vallelian, F.3
  • 13
    • 84887074284 scopus 로고    scopus 로고
    • Adverse effects of hemorrhagic shock resuscitation with stored blood are ameliorated by inhaled nitric oxide in lambs
    • Baron DM, Beloiartsev A, Nakagawa A, et al., Adverse effects of hemorrhagic shock resuscitation with stored blood are ameliorated by inhaled nitric oxide in lambs. Crit Care Med 2013; 41: 2492-501.
    • (2013) Crit Care Med , vol.41 , pp. 2492-2501
    • Baron, D.M.1    Beloiartsev, A.2    Nakagawa, A.3
  • 14
    • 84912522924 scopus 로고    scopus 로고
    • Transfusion of stored blood impairs host defenses against Gram-negative pathogens in mice
    • Prestia K, Bandyopadhyay S, Slate A, et al., Transfusion of stored blood impairs host defenses against Gram-negative pathogens in mice. Transfusion 2014; 54: 2842-51.
    • (2014) Transfusion , vol.54 , pp. 2842-2851
    • Prestia, K.1    Bandyopadhyay, S.2    Slate, A.3
  • 15
    • 40949102607 scopus 로고    scopus 로고
    • Duration of red-cell storage and complications after cardiac surgery
    • Koch CG, Li L, Sessler DI, et al., Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008; 358: 1229-39.
    • (2008) N Engl J Med , vol.358 , pp. 1229-1239
    • Koch, C.G.1    Li, L.2    Sessler, D.I.3
  • 16
    • 67650594229 scopus 로고    scopus 로고
    • Transfusions in the less severely injured: Does age of transfused blood affect outcomes?
    • Weinberg JA, McGwin, G Jr, Marques MB, et al., Transfusions in the less severely injured: does age of transfused blood affect outcomes?. J Trauma 2008; 65: 794-8.
    • (2008) J Trauma , vol.65 , pp. 794-798
    • Weinberg, J.A.1    McGwin, G.2    Marques, M.B.3
  • 17
    • 79955115053 scopus 로고    scopus 로고
    • Age of red blood cells and mortality in the critically ill
    • Pettilä V, Westbrook AJ, Nichol AD, et al., Age of red blood cells and mortality in the critically ill. Crit Care 2011; 15: R116 -
    • (2011) Crit Care , vol.15 , pp. R116
    • Pettilä, V.1    Westbrook, A.J.2    Nichol, A.D.3
  • 18
    • 84884939805 scopus 로고    scopus 로고
    • Age of red blood cells and outcome in acute kidney injury
    • Kaukonen KM, Vaara ST, Pettilä V, et al., Age of red blood cells and outcome in acute kidney injury. Crit Care 2013; 17: R222.
    • (2013) Crit Care , vol.17 , pp. R222
    • Kaukonen, K.M.1    Vaara, S.T.2    Pettilä, V.3
  • 19
    • 84886802022 scopus 로고    scopus 로고
    • Transfusion of older red blood cells is associated with decreased graft survival after orthotopic liver transplantation
    • Cywinski JB, You J, Argalious M, et al., Transfusion of older red blood cells is associated with decreased graft survival after orthotopic liver transplantation. Liver Transpl 2013; 19: 1181-8.
    • (2013) Liver Transpl , vol.19 , pp. 1181-1188
    • Cywinski, J.B.1    You, J.2    Argalious, M.3
  • 20
    • 78650813289 scopus 로고    scopus 로고
    • Duration of red cell storage influences mortality after trauma
    • discussion 1431-2.
    • Weinberg JA, McGwin G Jr, Vandromme MJ, et al., Duration of red cell storage influences mortality after trauma. J Trauma 2010; 69: 1427-31; discussion 1431-2.
    • (2010) J Trauma , vol.69 , pp. 1427-1431
    • Weinberg, J.A.1    McGwin, G.2    Vandromme, M.J.3
  • 21
    • 84861782317 scopus 로고    scopus 로고
    • Transfusion of older stored blood and risk of death: A meta-analysis
    • Wang D, Sun J, Solomon SB, et al., Transfusion of older stored blood and risk of death: a meta-analysis. Transfusion 2012; 52: 1184-95.
    • (2012) Transfusion , vol.52 , pp. 1184-1195
    • Wang, D.1    Sun, J.2    Solomon, S.B.3
  • 22
    • 84927153742 scopus 로고    scopus 로고
    • Effects of red-cell storage duration on patients undergoing cardiac surgery
    • Steiner ME, Ness PM, Assmann SF, et al., Effects of red-cell storage duration on patients undergoing cardiac surgery. N Engl J Med 2015; 372: 1419-29.
    • (2015) N Engl J Med , vol.372 , pp. 1419-1429
    • Steiner, M.E.1    Ness, P.M.2    Assmann, S.F.3
  • 23
    • 84927168718 scopus 로고    scopus 로고
    • Age of transfused blood in critically ill adults
    • Lacroix J, Hébert PC, Fergusson DA, et al., Age of transfused blood in critically ill adults. N Engl J Med 2015; 372: 1410-8.
    • (2015) N Engl J Med , vol.372 , pp. 1410-1418
    • Lacroix, J.1    Hébert, P.C.2    Fergusson, D.A.3
  • 24
    • 84862776674 scopus 로고    scopus 로고
    • The effect of blood storage duration on in-hospital mortality: A randomized controlled pilot feasibility trial
    • Heddle NM, Cook RJ, Arnold DM, et al., The effect of blood storage duration on in-hospital mortality: a randomized controlled pilot feasibility trial. Transfusion 2012; 52: 1203-12.
    • (2012) Transfusion , vol.52 , pp. 1203-1212
    • Heddle, N.M.1    Cook, R.J.2    Arnold, D.M.3
  • 25
    • 84922319331 scopus 로고    scopus 로고
    • A randomised controlled trial of standard transfusion versus fresher red blood cell use in intensive care (TRANSFUSE): Protocol and statistical analysis plan
    • Kaukonen KM, Bailey M, Ady B, et al., A randomised controlled trial of standard transfusion versus fresher red blood cell use in intensive care (TRANSFUSE): protocol and statistical analysis plan. Crit Care Resusc 2014; 16: 255-61.
    • (2014) Crit Care Resusc , vol.16 , pp. 255-261
    • Kaukonen, K.M.1    Bailey, M.2    Ady, B.3
  • 26
    • 85041670120 scopus 로고    scopus 로고
    • [Internet]. Bethesda (MD): National Library of Medicine (US); 2013- [cited 2015 Aug 20] NLM Identifier: NCT01977547
    • Washington University School of Medicine. Age of blood in children in pediatric intensive care units (ABC PICU). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2013- [cited 2015 Aug 20]. Available from: https://clinicaltrials.gov/ct2/show/NCT01977547. NLM Identifier: NCT01977547.
    • Age of Blood in Children in Pediatric Intensive Care Units (ABC PICU)
    • Washington University School of Medicine1
  • 27
    • 84055177595 scopus 로고    scopus 로고
    • Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non-transferrin-bound iron
    • Hod EA, Brittenham GM, Billote GB, et al., Transfusion of human volunteers with older, stored red blood cells produces extravascular hemolysis and circulating non-transferrin-bound iron. Blood 2011; 118: 6675-82.
    • (2011) Blood , vol.118 , pp. 6675-6682
    • Hod, E.A.1    Brittenham, G.M.2    Billote, G.B.3
  • 28
    • 84857648196 scopus 로고    scopus 로고
    • Fresh and stored red blood cell transfusion equivalently induce subclinical pulmonary gas exchange deficit in normal humans
    • Weiskopf RB, Feiner J, Toy P, et al., Fresh and stored red blood cell transfusion equivalently induce subclinical pulmonary gas exchange deficit in normal humans. Anesth Analg 2012; 114: 511-9.
    • (2012) Anesth Analg , vol.114 , pp. 511-519
    • Weiskopf, R.B.1    Feiner, J.2    Toy, P.3
  • 29
    • 33646788018 scopus 로고    scopus 로고
    • Fresh blood and aged stored blood are equally efficacious in immediately reversing anemia-induced brain oxygenation deficits in humans
    • Weiskopf RB, Feiner J, Hopf H, et al., Fresh blood and aged stored blood are equally efficacious in immediately reversing anemia-induced brain oxygenation deficits in humans. Anesthesiology 2006; 104: 911-20.
    • (2006) Anesthesiology , vol.104 , pp. 911-920
    • Weiskopf, R.B.1    Feiner, J.2    Hopf, H.3
  • 30
    • 84904466361 scopus 로고    scopus 로고
    • Transfusion of older stored blood worsens outcomes in canines depending on the presence and severity of pneumonia
    • Wang D, Cortés-Puch I, Sun J, et al., Transfusion of older stored blood worsens outcomes in canines depending on the presence and severity of pneumonia. Transfusion 2014; 54: 1712-24.
    • (2014) Transfusion , vol.54 , pp. 1712-1724
    • Wang, D.1    Cortés-Puch, I.2    Sun, J.3
  • 31
    • 84896057236 scopus 로고    scopus 로고
    • Washing older blood units before transfusion reduces plasma iron and improves outcomes in experimental canine pneumonia
    • Cortés-Puch I, Wang D, Sun J, et al., Washing older blood units before transfusion reduces plasma iron and improves outcomes in experimental canine pneumonia. Blood 2014; 123: 1403-11.
    • (2014) Blood , vol.123 , pp. 1403-1411
    • Cortés-Puch, I.1    Wang, D.2    Sun, J.3
  • 32
    • 0034220455 scopus 로고    scopus 로고
    • Use of a prestorage leukoreduction filter effectively removes leukocytes from canine whole blood while preserving red blood cell viability
    • Brownlee L, Wardrop KJ, Sellon RK, et al., Use of a prestorage leukoreduction filter effectively removes leukocytes from canine whole blood while preserving red blood cell viability. J Vet Intern Med 2000; 14: 412-7.
    • (2000) J Vet Intern Med , vol.14 , pp. 412-417
    • Brownlee, L.1    Wardrop, K.J.2    Sellon, R.K.3
  • 33
    • 0029398188 scopus 로고
    • Selection of anticoagulant-preservatives for canine and feline blood storage
    • Wardrop KJ., Selection of anticoagulant-preservatives for canine and feline blood storage. Vet Clin North Am Small Anim Pract 1995; 25: 1263-76.
    • (1995) Vet Clin North Am Small Anim Pract , vol.25 , pp. 1263-1276
    • Wardrop, K.J.1
  • 34
    • 35348973516 scopus 로고    scopus 로고
    • A canine model of septic shock: Balancing animal welfare and scientific relevance
    • Minneci PC, Deans KJ, Hansen B, et al., A canine model of septic shock: balancing animal welfare and scientific relevance. Am J Physiol Heart Circ Physiol 2007; 293: H2487-500.
    • (2007) Am J Physiol Heart Circ Physiol , vol.293 , pp. H2487-H2500
    • Minneci, P.C.1    Deans, K.J.2    Hansen, B.3
  • 35
    • 84857373097 scopus 로고    scopus 로고
    • Non-transferrin bound iron: A key role in iron overload and iron toxicity
    • Brissot P, Ropert M, Le Lan C, et al., Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta 2012; 1820: 403-10.
    • (2012) Biochim Biophys Acta , vol.1820 , pp. 403-410
    • Brissot, P.1    Ropert, M.2    Le Lan, C.3
  • 36
    • 0036275173 scopus 로고    scopus 로고
    • Transferrin binding in Staphylococcus aureus: Involvement of a cell wall-anchored protein
    • Taylor JM, Heinrichs DE., Transferrin binding in Staphylococcus aureus: involvement of a cell wall-anchored protein. Mol Microbiol 2002; 43: 1603-14.
    • (2002) Mol Microbiol , vol.43 , pp. 1603-1614
    • Taylor, J.M.1    Heinrichs, D.E.2
  • 37
    • 0034193246 scopus 로고    scopus 로고
    • The staphylococcal transferrin receptor: A glycolytic enzyme with novel functions
    • Modun B, Morrissey J, Williams P., The staphylococcal transferrin receptor: a glycolytic enzyme with novel functions. Trends Microbiol 2000; 8: 231-7.
    • (2000) Trends Microbiol , vol.8 , pp. 231-237
    • Modun, B.1    Morrissey, J.2    Williams, P.3
  • 38
    • 0030969403 scopus 로고    scopus 로고
    • Siderophore production by Staphylococcus aureus and identification of iron-regulated proteins
    • Courcol RJ, Trivier D, Bissinger MC, et al., Siderophore production by Staphylococcus aureus and identification of iron-regulated proteins. Infect Immun 1997; 65: 1944-8.
    • (1997) Infect Immun , vol.65 , pp. 1944-1948
    • Courcol, R.J.1    Trivier, D.2    Bissinger, M.C.3
  • 39
    • 0348141912 scopus 로고    scopus 로고
    • Role of siderophore biosynthesis in virulence of Staphylococcus aureus: Identification and characterization of genes involved in production of a siderophore
    • Dale SE, Doherty-Kirby A, Lajoie G, et al., Role of siderophore biosynthesis in virulence of Staphylococcus aureus: identification and characterization of genes involved in production of a siderophore. Infect Immun 2004; 72: 29-37.
    • (2004) Infect Immun , vol.72 , pp. 29-37
    • Dale, S.E.1    Doherty-Kirby, A.2    Lajoie, G.3
  • 40
    • 0025122629 scopus 로고
    • The effect of parenteral iron administration on the development of Staphylococcus aureus-induced experimental pyelonephritis in rats
    • Ang O, Gungor M, Aricioglu F, et al., The effect of parenteral iron administration on the development of Staphylococcus aureus-induced experimental pyelonephritis in rats. Int J Exp Pathol 1990; 71: 507-11.
    • (1990) Int J Exp Pathol , vol.71 , pp. 507-511
    • Ang, O.1    Gungor, M.2    Aricioglu, F.3
  • 41
    • 78650767132 scopus 로고    scopus 로고
    • The association between the transfusion of older blood and outcomes after trauma
    • Hassan M, Pham TN, Cuschieri J, et al., The association between the transfusion of older blood and outcomes after trauma. Shock 2011; 35: 3-8.
    • (2011) Shock , vol.35 , pp. 3-8
    • Hassan, M.1    Pham, T.N.2    Cuschieri, J.3
  • 42
    • 0017671012 scopus 로고
    • Increased incidence of gram-negative neonatal sepsis with intramuscular iron administration
    • Barry DM, Reeve AW., Increased incidence of gram-negative neonatal sepsis with intramuscular iron administration. Pediatrics 1977; 60: 908-12.
    • (1977) Pediatrics , vol.60 , pp. 908-912
    • Barry, D.M.1    Reeve, A.W.2
  • 43
    • 84897537450 scopus 로고    scopus 로고
    • Health care-associated infection after red blood cell transfusion: A systematic review and meta-analysis
    • Rohde JM, Dimcheff DE, Blumberg N, et al., Health care-associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA 2014; 311: 1317-26.
    • (2014) JAMA , vol.311 , pp. 1317-1326
    • Rohde, J.M.1    Dimcheff, D.E.2    Blumberg, N.3
  • 44
    • 84874930219 scopus 로고    scopus 로고
    • Association between cell-free hemoglobin, acetaminophen, and mortality in patients with sepsis: An observational study
    • Janz DR, Bastarache JA, Peterson JF, et al., Association between cell-free hemoglobin, acetaminophen, and mortality in patients with sepsis: an observational study. Crit Care Med 2013; 41: 784-90.
    • (2013) Crit Care Med , vol.41 , pp. 784-790
    • Janz, D.R.1    Bastarache, J.A.2    Peterson, J.F.3
  • 45
    • 84893178871 scopus 로고    scopus 로고
    • Mechanism of faster NO scavenging by older stored red blood cells
    • Liu C, Liu X, Janes J, et al., Mechanism of faster NO scavenging by older stored red blood cells. Redox Biol 2014; 2: 211-9.
    • (2014) Redox Biol , vol.2 , pp. 211-219
    • Liu, C.1    Liu, X.2    Janes, J.3
  • 46
    • 53249085811 scopus 로고    scopus 로고
    • The reaction of hydrogen peroxide with hemoglobin induces extensive alpha-globin crosslinking and impairs the interaction of hemoglobin with endogenous scavenger pathways
    • Vallelian F, Pimenova T, Pereira CP, et al., The reaction of hydrogen peroxide with hemoglobin induces extensive alpha-globin crosslinking and impairs the interaction of hemoglobin with endogenous scavenger pathways. Free Radic Biol Med 2008; 45: 1150-8.
    • (2008) Free Radic Biol Med , vol.45 , pp. 1150-1158
    • Vallelian, F.1    Pimenova, T.2    Pereira, C.P.3
  • 47
    • 77953098749 scopus 로고    scopus 로고
    • Duration of red blood cell storage and survival of transfused patients (CME)
    • Edgren G, Kamper-Jørgensen M, Eloranta S, et al., Duration of red blood cell storage and survival of transfused patients (CME). Transfusion 2010; 50: 1185-95.
    • (2010) Transfusion , vol.50 , pp. 1185-1195
    • Edgren, G.1    Kamper-Jørgensen, M.2    Eloranta, S.3
  • 48
    • 77951551894 scopus 로고    scopus 로고
    • Duration of red cell storage before transfusion and in-hospital mortality
    • e1.
    • Eikelboom JW, Cook RJ, Liu Y, et al., Duration of red cell storage before transfusion and in-hospital mortality. Am Heart J 2010; 159: 737-43 e1.
    • (2010) Am Heart J , vol.159 , pp. 737-743
    • Eikelboom, J.W.1    Cook, R.J.2    Liu, Y.3
  • 49
    • 77956335153 scopus 로고    scopus 로고
    • Association between length of storage of transfused red blood cells and multiple organ dysfunction syndrome in pediatric intensive care patients
    • Gauvin F, Spinella PC, Lacroix J, et al., Association between length of storage of transfused red blood cells and multiple organ dysfunction syndrome in pediatric intensive care patients. Transfusion 2010; 50: 1902-13.
    • (2010) Transfusion , vol.50 , pp. 1902-1913
    • Gauvin, F.1    Spinella, P.C.2    Lacroix, J.3
  • 50
    • 44849109612 scopus 로고    scopus 로고
    • Evaluation of proposed FDA criteria for the evaluation of radiolabeled red cell recovery trials
    • Dumont LJ, AuBuchon JP., Evaluation of proposed FDA criteria for the evaluation of radiolabeled red cell recovery trials. Transfusion 2008; 48: 1053-60.
    • (2008) Transfusion , vol.48 , pp. 1053-1060
    • Dumont, L.J.1    AuBuchon, J.P.2


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.