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• W2078266688 abstract "To the Editor:Systemic mastocytosis is a clonal disorder of the mast cell (MC) lineage, with an abnormal proliferation/maturation of this cell type. MCs are biological bombs which, if activated, release in a few seconds a large amount of mediators that are stored in their granules. In systemic mastocytosis (SM), the increased number of MCs provokes a wide variety of clinical pictures, ranging from the pauci-symptomatic form (indolent SM) to near-fatal anaphylaxis or aggressive mastocytosis. The skin is often involved, especially in children, with the typical lesions of urticaria pigmentosa. Diagnosis of SM requires the detection of 1 major and 1 minor criterion or at least 3 minor criteria, according to international guidelines.1Valent P. Akin C. Sperr W.R. Arock M. Lechner K. Bennett J.M. et al.Diagnosis and treatment of systemic mastocytosis.Br J Haematol. 2003; 122: 695-717Crossref PubMed Scopus (182) Google Scholar The major criterion is the finding of multifocal dense MC infiltrates in bone marrow (BM) biopsy or in other extracutaneous organ. The minor criteria are an abnormal morphology of extracutaneous MC (including BM smears), the mutation in the KIT proto-oncogene at codon 816 (D816V mutation) in an extracutaneous organ, the expression of CD2 and/or CD25 on BM MCs, and an increased serum tryptase.It is clear that in SM, any activation of MCs, either IgE-mediated or not, can have serious consequences. This is especially true in subjects with hymenoptera venom allergy (HVA) who are more at risk of severe events than subjects without SM.2Haeberli G. Bronnimann M. Hunziker T. Muller U. Elevated basal serum tryptase and hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy.Clin Exp Allergy. 2003; 33: 1216-1220Crossref PubMed Scopus (202) Google Scholar, 3Kors J.W. van Doormaal J.J. de Monchy J.G. Anaphylactoid shock following Hymenoptera sting as a presenting symptom of systemic mastocytosis.J Intern Med. 1993; 233: 255-258Crossref PubMed Scopus (70) Google Scholar For this reason, although specific immunotherapy (SIT) is recognized as a life-saving treatment, its use in SM remains controversial. Looking at the literature, the general attitude in this regard is that SIT should be avoided in subjects with SM.4Oude Elberink J.N. de Monchy J.G. Kors J.W. van Doormaal J.J. Dubois A.E. Fatal anaphylaxis after a yellow jacket sting, despite venom immunotherapy, in two patients with mastocytosis.J Allergy Clin Immunol. 1997; 99: 153-154Abstract Full Text PDF PubMed Scopus (125) Google Scholar, 5Dubois A.E. Mastocytosis and Hymenoptera allergy.Curr Opin Allergy Clin Immunol. 2004; 4: 291-295Crossref PubMed Scopus (56) Google Scholar By contrast, our clinical observations and a report of a small cohorts of patients with mastocytosis and HVA, treated with SIT without adverse reactions,6Fricker M. Helbling A. Schwartz L. Müller U. Hymenoptera sting anaphylaxis and urticaria pigmentosa: clinical findings and results of venom immunotherapy in ten patients.J Allergy Clin Immunol. 1997; 100: 11-15Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar suggested that the risk-to-benefit ratio of SIT in patients with SM is overall low. To confirm this hypothesis, we systematically collected the clinical data of patients with HVA and SM referred to our unit. After a detailed clinical history and the standard diagnostic workup for HVA (ie, skin prick, intradermal testing, specific IgE CAP-RAST assay),7Bilò M.B. Rueff F. Mosbech H. Bonifazi F. Oude-Elberinck A. et al.Diagnosis of Hymenoptera venom allergy.Allergy. 2005; 60: 1339-1349Crossref PubMed Scopus (474) Google Scholar serum tryptase level was measured (immunofluorimetric CAP assay, Unicap 100; Phadia, Uppsala, Sweden) in all patients with severe HVA. The measurement of tryptase was performed with the patient asymptomatic and no less than 2 weeks after the sting. Patients with serum tryptase level above 11.4 ng/mL (cut-off level in normal subjects) and severe reactions (grade III-IV), after informed consent, underwent BM examination. Those with suspect skin lesions had also skin biopsy. According to international consensus,1Valent P. Akin C. Sperr W.R. Arock M. Lechner K. Bennett J.M. et al.Diagnosis and treatment of systemic mastocytosis.Br J Haematol. 2003; 122: 695-717Crossref PubMed Scopus (182) Google Scholar we evaluated the BM aspirate, stained by May-Grünwald-Giemsa, and BM biopsies stained with an antitryptase mAb. The presence of atypical MCs on BM aspirate was investigated by using a specific 5-color mAb combination (CD25/CD2/CD45/CD34/CD117). In addition, we assessed the presence of KIT-D816V mutation in BM mononuclear cells by RFLP analysis.Once the diagnosis was established, the patients received SIT according to a regimen involving the weekly administration of the following increasing doses: 4.11, 5, 10, 20, 40, 70, and 100 μg. The maintenance dose, reached in 7 weeks, was then given monthly. All the injections were given by a physician at the clinic, with resuscitation facilities immediately available. The patients were prescribed autoinjectable epinephrine, regularly followed up, and instructed to contact the physicians immediately in the case of new stings. The diagnosis of SM in patients with a strong suspicion and the use of SIT (for which no clear recommendation exists) were considered part of the standard care, and no Institutional Review Board review was therefore required.Between 2004 and 2007, 552 patients were seen. One hundred twenty-one have had a grade IV reaction, and 33 of them had raised tryptase. Sixteen of these patients (12 men; mean age, 49.3 years; range, 19-77 years) with HVA were diagnosed as having SM. In one of them, the clinical diagnosis of SM had been made before. Ten patients fulfilled both major and minor criteria, whereas in 6 patients, 3 minor criteria were found (Table I). SM was an indolent variant in all subjects, and in 2 cases, urticaria pigmentosa was confirmed by skin biopsies. All patients had a clinical history of grade IV reactions after sting, and all had to be treated in an emergency unit. The prescribed SITs were 6 Polistes dominulus (Anallergo, Florence, Italy), 8 Vespula germanica, 1 Polistes spp, and 1 Apis mellifera (Stallergenes, Antony, France).Table IPathologic findings in 16 patients with HVA who fulfilled criteria for diagnosis of SMNo.Age/sexSerum tryptase (ng/mL)>15 MCs/cluster (BM biopsy)Atypical MC (BM smear)MCs CD25/CD2+ (BM)KIT D816V mutation (BM)HVA1∗Histologically confirmed cutaneous mastocytosis.39/M103.0++++Apis m2∗Histologically confirmed cutaneous mastocytosis.33/M56.2++++Polistes d362/M31.6–+–+Polistes d419/M20.0––++Vespula g545/M13.7+++–Polistes d674/M21.2+–+–Polistes spp764/M24.0–+++Polistes d850/M17.6–+++Polistes d939/F18.0–+++Vespula g1037/M20.1++++Vespula g1142/M13.2+++–Vespula g1259/M16.5+++Not doneVespula g1353/F13.4++++Polistes d1477/F30.0+Not doneNot doneNot doneVespula g1568/F28.6–+++Vespula g1628/M26.0++++Vespula gMC, Mast cell; BM, bone marrow; M, male; F, female; Apis m, Apis mellifera; Polistes d, Polistes dominulus; Vespula g, Vespula germanica.∗ Histologically confirmed cutaneous mastocytosis. Open table in a new tab Two patients had reactions during the build-up phase of immunotherapy. One (patient 6) had generalized pruritus without skin lesions or other signs, and one (patient 9) had a grade I urticaria. In both cases, the dose escalation was temporarily stopped by repeating the last tolerated dose, and a premedication with cetirizine 10 mg was given. After 2 weeks, the patients could resume the build-up and reach the maintenance dose without further reactions. Thirteen patients received 1 or more Hymenoptera sting on-field during the maintenance phase, and only 2 of them (patient 3 and patient 14) had a grade IV reaction at the first resting. In these patients, the dose was safely increased to 200 μg, and at subsequent stings they had only a mild local reaction. In the remaining 11 patients, only mild local reactions were seen at re-sting.On the basis of the current literature, SM is considered a high-risk situation for SIT in HVA, because severe events or fatalities can occur.3Kors J.W. van Doormaal J.J. de Monchy J.G. Anaphylactoid shock following Hymenoptera sting as a presenting symptom of systemic mastocytosis.J Intern Med. 1993; 233: 255-258Crossref PubMed Scopus (70) Google Scholar, 5Dubois A.E. Mastocytosis and Hymenoptera allergy.Curr Opin Allergy Clin Immunol. 2004; 4: 291-295Crossref PubMed Scopus (56) Google Scholar Nonetheless, these patients are also at very high risk when they are stung by the sensitizing Hymenoptera.2Haeberli G. Bronnimann M. Hunziker T. Muller U. Elevated basal serum tryptase and hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy.Clin Exp Allergy. 2003; 33: 1216-1220Crossref PubMed Scopus (202) Google Scholar, 3Kors J.W. van Doormaal J.J. de Monchy J.G. Anaphylactoid shock following Hymenoptera sting as a presenting symptom of systemic mastocytosis.J Intern Med. 1993; 233: 255-258Crossref PubMed Scopus (70) Google Scholar and SIT can confer a satisfactory protection. On the basis of these considerations and previous clinical observations,6Fricker M. Helbling A. Schwartz L. Müller U. Hymenoptera sting anaphylaxis and urticaria pigmentosa: clinical findings and results of venom immunotherapy in ten patients.J Allergy Clin Immunol. 1997; 100: 11-15Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar we vaccinated several patients with SM without observing important side effects. Moreover, almost all of them achieved a relevant protection and decreased their grade of reaction from IV to I. The 2 patients who maintained a grade IV reaction on maintenance SIT could achieve a benefit by increasing the maintenance dose.8Rueff F, Wenderoth A, Przybilla B. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses.Google Scholar We are aware that the population evaluated in our study is small, but if we take into account the rarity of SM and the low frequency of severe HVA, this study includes the largest cohorts of patients with HVA and SM treated with SIT. An accessory observation is that SM was indeed diagnosed in 16 of 121 patients with severe HVA. Thus it can be supposed that severe HVA could be a clinical manifestation of underlying SM, as reported with idiopathic anaphylaxis.9Akin C. Scott L.M. Kocabas C.N. Kushnir-Sukhov N. Brittain E. Noel P. et al.Demonstration of an aberrant mast cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis.Blood. 2007; 110: 2331-2333Crossref PubMed Scopus (188) Google Scholar This would support the usefulness of tryptase assay screening in patients with Hymenoptera-induced anaphylaxis. On the basis of the observed risk/benefit ratio, we suggest that patients with ascertained SM and HVA receive a specific vaccination with a very slow increase of the dose, carefully respecting the recommendations for a safe administration. To the Editor: Systemic mastocytosis is a clonal disorder of the mast cell (MC) lineage, with an abnormal proliferation/maturation of this cell type. MCs are biological bombs which, if activated, release in a few seconds a large amount of mediators that are stored in their granules. In systemic mastocytosis (SM), the increased number of MCs provokes a wide variety of clinical pictures, ranging from the pauci-symptomatic form (indolent SM) to near-fatal anaphylaxis or aggressive mastocytosis. The skin is often involved, especially in children, with the typical lesions of urticaria pigmentosa. Diagnosis of SM requires the detection of 1 major and 1 minor criterion or at least 3 minor criteria, according to international guidelines.1Valent P. Akin C. Sperr W.R. Arock M. Lechner K. Bennett J.M. et al.Diagnosis and treatment of systemic mastocytosis.Br J Haematol. 2003; 122: 695-717Crossref PubMed Scopus (182) Google Scholar The major criterion is the finding of multifocal dense MC infiltrates in bone marrow (BM) biopsy or in other extracutaneous organ. The minor criteria are an abnormal morphology of extracutaneous MC (including BM smears), the mutation in the KIT proto-oncogene at codon 816 (D816V mutation) in an extracutaneous organ, the expression of CD2 and/or CD25 on BM MCs, and an increased serum tryptase. It is clear that in SM, any activation of MCs, either IgE-mediated or not, can have serious consequences. This is especially true in subjects with hymenoptera venom allergy (HVA) who are more at risk of severe events than subjects without SM.2Haeberli G. Bronnimann M. Hunziker T. Muller U. Elevated basal serum tryptase and hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy.Clin Exp Allergy. 2003; 33: 1216-1220Crossref PubMed Scopus (202) Google Scholar, 3Kors J.W. van Doormaal J.J. de Monchy J.G. Anaphylactoid shock following Hymenoptera sting as a presenting symptom of systemic mastocytosis.J Intern Med. 1993; 233: 255-258Crossref PubMed Scopus (70) Google Scholar For this reason, although specific immunotherapy (SIT) is recognized as a life-saving treatment, its use in SM remains controversial. Looking at the literature, the general attitude in this regard is that SIT should be avoided in subjects with SM.4Oude Elberink J.N. de Monchy J.G. Kors J.W. van Doormaal J.J. Dubois A.E. Fatal anaphylaxis after a yellow jacket sting, despite venom immunotherapy, in two patients with mastocytosis.J Allergy Clin Immunol. 1997; 99: 153-154Abstract Full Text PDF PubMed Scopus (125) Google Scholar, 5Dubois A.E. Mastocytosis and Hymenoptera allergy.Curr Opin Allergy Clin Immunol. 2004; 4: 291-295Crossref PubMed Scopus (56) Google Scholar By contrast, our clinical observations and a report of a small cohorts of patients with mastocytosis and HVA, treated with SIT without adverse reactions,6Fricker M. Helbling A. Schwartz L. Müller U. Hymenoptera sting anaphylaxis and urticaria pigmentosa: clinical findings and results of venom immunotherapy in ten patients.J Allergy Clin Immunol. 1997; 100: 11-15Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar suggested that the risk-to-benefit ratio of SIT in patients with SM is overall low. To confirm this hypothesis, we systematically collected the clinical data of patients with HVA and SM referred to our unit. After a detailed clinical history and the standard diagnostic workup for HVA (ie, skin prick, intradermal testing, specific IgE CAP-RAST assay),7Bilò M.B. Rueff F. Mosbech H. Bonifazi F. Oude-Elberinck A. et al.Diagnosis of Hymenoptera venom allergy.Allergy. 2005; 60: 1339-1349Crossref PubMed Scopus (474) Google Scholar serum tryptase level was measured (immunofluorimetric CAP assay, Unicap 100; Phadia, Uppsala, Sweden) in all patients with severe HVA. The measurement of tryptase was performed with the patient asymptomatic and no less than 2 weeks after the sting. Patients with serum tryptase level above 11.4 ng/mL (cut-off level in normal subjects) and severe reactions (grade III-IV), after informed consent, underwent BM examination. Those with suspect skin lesions had also skin biopsy. According to international consensus,1Valent P. Akin C. Sperr W.R. Arock M. Lechner K. Bennett J.M. et al.Diagnosis and treatment of systemic mastocytosis.Br J Haematol. 2003; 122: 695-717Crossref PubMed Scopus (182) Google Scholar we evaluated the BM aspirate, stained by May-Grünwald-Giemsa, and BM biopsies stained with an antitryptase mAb. The presence of atypical MCs on BM aspirate was investigated by using a specific 5-color mAb combination (CD25/CD2/CD45/CD34/CD117). In addition, we assessed the presence of KIT-D816V mutation in BM mononuclear cells by RFLP analysis. Once the diagnosis was established, the patients received SIT according to a regimen involving the weekly administration of the following increasing doses: 4.11, 5, 10, 20, 40, 70, and 100 μg. The maintenance dose, reached in 7 weeks, was then given monthly. All the injections were given by a physician at the clinic, with resuscitation facilities immediately available. The patients were prescribed autoinjectable epinephrine, regularly followed up, and instructed to contact the physicians immediately in the case of new stings. The diagnosis of SM in patients with a strong suspicion and the use of SIT (for which no clear recommendation exists) were considered part of the standard care, and no Institutional Review Board review was therefore required. Between 2004 and 2007, 552 patients were seen. One hundred twenty-one have had a grade IV reaction, and 33 of them had raised tryptase. Sixteen of these patients (12 men; mean age, 49.3 years; range, 19-77 years) with HVA were diagnosed as having SM. In one of them, the clinical diagnosis of SM had been made before. Ten patients fulfilled both major and minor criteria, whereas in 6 patients, 3 minor criteria were found (Table I). SM was an indolent variant in all subjects, and in 2 cases, urticaria pigmentosa was confirmed by skin biopsies. All patients had a clinical history of grade IV reactions after sting, and all had to be treated in an emergency unit. The prescribed SITs were 6 Polistes dominulus (Anallergo, Florence, Italy), 8 Vespula germanica, 1 Polistes spp, and 1 Apis mellifera (Stallergenes, Antony, France). MC, Mast cell; BM, bone marrow; M, male; F, female; Apis m, Apis mellifera; Polistes d, Polistes dominulus; Vespula g, Vespula germanica. Two patients had reactions during the build-up phase of immunotherapy. One (patient 6) had generalized pruritus without skin lesions or other signs, and one (patient 9) had a grade I urticaria. In both cases, the dose escalation was temporarily stopped by repeating the last tolerated dose, and a premedication with cetirizine 10 mg was given. After 2 weeks, the patients could resume the build-up and reach the maintenance dose without further reactions. Thirteen patients received 1 or more Hymenoptera sting on-field during the maintenance phase, and only 2 of them (patient 3 and patient 14) had a grade IV reaction at the first resting. In these patients, the dose was safely increased to 200 μg, and at subsequent stings they had only a mild local reaction. In the remaining 11 patients, only mild local reactions were seen at re-sting. On the basis of the current literature, SM is considered a high-risk situation for SIT in HVA, because severe events or fatalities can occur.3Kors J.W. van Doormaal J.J. de Monchy J.G. Anaphylactoid shock following Hymenoptera sting as a presenting symptom of systemic mastocytosis.J Intern Med. 1993; 233: 255-258Crossref PubMed Scopus (70) Google Scholar, 5Dubois A.E. Mastocytosis and Hymenoptera allergy.Curr Opin Allergy Clin Immunol. 2004; 4: 291-295Crossref PubMed Scopus (56) Google Scholar Nonetheless, these patients are also at very high risk when they are stung by the sensitizing Hymenoptera.2Haeberli G. Bronnimann M. Hunziker T. Muller U. Elevated basal serum tryptase and hymenoptera venom allergy: relation to severity of sting reactions and to safety and efficacy of venom immunotherapy.Clin Exp Allergy. 2003; 33: 1216-1220Crossref PubMed Scopus (202) Google Scholar, 3Kors J.W. van Doormaal J.J. de Monchy J.G. Anaphylactoid shock following Hymenoptera sting as a presenting symptom of systemic mastocytosis.J Intern Med. 1993; 233: 255-258Crossref PubMed Scopus (70) Google Scholar and SIT can confer a satisfactory protection. On the basis of these considerations and previous clinical observations,6Fricker M. Helbling A. Schwartz L. Müller U. Hymenoptera sting anaphylaxis and urticaria pigmentosa: clinical findings and results of venom immunotherapy in ten patients.J Allergy Clin Immunol. 1997; 100: 11-15Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar we vaccinated several patients with SM without observing important side effects. Moreover, almost all of them achieved a relevant protection and decreased their grade of reaction from IV to I. The 2 patients who maintained a grade IV reaction on maintenance SIT could achieve a benefit by increasing the maintenance dose.8Rueff F, Wenderoth A, Przybilla B. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses.Google Scholar We are aware that the population evaluated in our study is small, but if we take into account the rarity of SM and the low frequency of severe HVA, this study includes the largest cohorts of patients with HVA and SM treated with SIT. An accessory observation is that SM was indeed diagnosed in 16 of 121 patients with severe HVA. Thus it can be supposed that severe HVA could be a clinical manifestation of underlying SM, as reported with idiopathic anaphylaxis.9Akin C. Scott L.M. Kocabas C.N. Kushnir-Sukhov N. Brittain E. Noel P. et al.Demonstration of an aberrant mast cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis.Blood. 2007; 110: 2331-2333Crossref PubMed Scopus (188) Google Scholar This would support the usefulness of tryptase assay screening in patients with Hymenoptera-induced anaphylaxis. On the basis of the observed risk/benefit ratio, we suggest that patients with ascertained SM and HVA receive a specific vaccination with a very slow increase of the dose, carefully respecting the recommendations for a safe administration." @default.
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• W2078266688 title "Allergen specific immunotherapy is safe and effective in patients with systemic mastocytosis and Hymenoptera allergy" @default.
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