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• W2073900288 abstract "Nirvana: release from a state of suffering after an often lengthy period of committed spiritual practice.(Wikipedia)Mucosal healing has recently moved to the fore as an outcome of treatment for patients with Crohn's disease (CD)—no longer an “impossible dream” but a primary goal of care to improve patient outcomes.1Rutgeerts P. Vermeire S. Van Assche G. Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target?.Gut. 2007; 56: 453-455Crossref PubMed Scopus (261) Google Scholar Studies using anti–tumor necrosis factor (anti-TNF) agents have emphasized the overall benefits of mucosal healing for patients.2Baert F. Moortgat L. Van Assche G. et al.Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease.Gastroenterology. 2010; 138: 463-468Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar Over the same period, we have seen data linking mucosal healing to serum drug levels of anti-TNFs, thus supporting the concept of therapeutic drug monitoring in patient management.3Maser E.A. Villela R. Silverberg M.S. et al.Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease.Clin Gastroenterol Hepatol. 2006; 4: 1248-1254Abstract Full Text Full Text PDF PubMed Scopus (537) Google Scholar Combining all these associations would lead the casual observer to an intuitive conclusion: the path to nirvana for our patients with CD requires a commitment to optimizing serum anti-TNF levels and mucosal healing. Two studies in this issue of the journal suggest that this conclusion is not so easily supported.The first, by Colombel et al, reports rates of “deep remission” in patients treated with adalimumab or placebo for 1 year in the EXTEND trial.4Colombel J.F. Rutgeerts P.J. Sandborn W.J. et al.Adalimumab induces deep remission in patients with Crohn's disease.Clin Gastroenterol Hepatol. 2014; 12: 414-422Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar This concept of deep remission has only recently been defined for patients with CD as a state of both clinical remission and mucosal healing.5Colombel J.F. Louis E. Peyrin-Biroulet L. et al.Deep remission: a new concept?.Dig Dis. 2012; 30: 107-111Crossref PubMed Scopus (36) Google Scholar Although not validated as a clinically meaningful outcome, at first glance it seems a logical goal of therapy for patients with CD. In Colombel's study, deep remission rates at weeks 12 and 52 for patients receiving adalimumab were 16% and 19%, respectively, which were higher than those for placebo (10% at week 12 and 0% at week 52). Although deep remission was achieved in only a small group of patients, they had significantly better outcomes for therapy adjustment, hospitalization, surgery, activity impairment, and quality of life when compared with patients who did not achieve deep remission. Notably, however, outcomes for quality of life, productivity, and CD-related hospitalization were similar between patients in deep remission and those who achieved clinical remission alone (no mucosal healing). In fact, patients who achieved mucosal healing only (but had persistent symptoms by Crohn's Disease Activity Index) had numerically lower quality-of-life and productivity scores than those who obtained clinical remission alone. The actual numbers in each group, and their differences, are small in these exploratory analyses and underpowered for the comparison. However, for patients already in clinical remission, obtaining mucosal healing did not lead to substantially better quality-of-life outcomes than clinical remission alone. Outcomes associated with healthcare costs also appeared to be less favorable in those who achieved mucosal healing but were not in clinical remission. Maybe mucosal healing is not the panacea for all the ills of our patients with CD.The high prevalence of functional gastrointestinal disorders in patients with CD may explain this result; symptoms will still make patients go to the emergency department, or miss work, or feel miserable, regardless of how good their mucosa looks.6Farrokhyar F. Marshall J.K. Easterbrook B. et al.Functional gastrointestinal disorders and mood disorders in patients with inactive inflammatory bowel disease: prevalence and impact on health.Inflamm Bowel Dis. 2006; 12: 38-46Crossref PubMed Scopus (220) Google Scholar For clinicians, the prudent conclusion to make from this study is that obtaining mucosal healing in practice is not going to solve all our patients' problems, so a holistic approach to symptom management is still required. For clinical trialists, liberation from both symptoms and endoscopic inflammation may appear to be an admirable goal, but judging anti-inflammatory therapy using a measurement, for example, the Crohn's Disease Activity Index, that is influenced by noninflammatory processes is fraught with problems.7Lahiff C. Safaie P. Awais A. et al.The Crohn's disease activity index (CDAI) is similarly elevated in patients with Crohn's disease and in patients with irritable bowel syndrome.Aliment Pharmacol Ther. 2013; 37: 786-794Crossref PubMed Scopus (83) Google Scholar Until we better understand the mechanisms of persistent intestinal symptoms in patients who have achieved mucosal healing, combining symptoms and mucosal healing into 1 end-point should be reconsidered as a measure of response to anti-inflammatory therapies.The second paper in this issue, also by Colombel et al, examines whether mucosal healing in patients with CD correlated with serum drug levels of certolizumab pegol (CZP) in the MUSIC (endoscopic MUcoSal Improvement in patients with active Crohn's disease treated with certolizumab pegol) trial.8Colombel J.F. Sandborn W.J. Allez M. et al.Association between plasma concentrations of certolizumab pegol and endoscopic outcomes of patients with Crohn's disease.Clin Gastroenterol Hepatol. 2014; 12: 423-431Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar In the MUSIC trial, patients with active CD and endoscopic ulcers at baseline received CZP every 4 weeks to week 54.9Hebuterne X. Lemann M. Bouhnik Y. et al.Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol.Gut. 2013; 62: 201-208Crossref PubMed Scopus (138) Google Scholar Of the initial patients enrolled in the MUSIC trial, 45 patients had both CZP levels and endoscopic scores available at week 10; these make up the population of interest in the Colombel paper. These patients' mean CZP levels at week 8 were significantly associated with their probability of endoscopic remission at week 10, and patients with the highest quartile of CZP levels at week 8 were more likely to be in endoscopic remission at week 10, when compared to the lowest quartile levels. The authors' conclusion was that endoscopic improvements are associated with higher plasma CZP concentrations in patients with CD.If mucosal healing is a final step on the path to nirvana, is optimization of serum anti-TNF levels an important first step? Prospective trials of therapeutic drug monitoring of anti-TNFs to achieve mucosal healing have not been published yet, and there are challenges in interpreting the existing literature on this topic.10Moore C. Vaughn B. Moss A.C. Analysis of reporting standards of serum anti-TNF levels in patients with IBD.Inflamm Bowel Dis. 2013; 19: P080Google Scholar From a conceptual stand-point, it is unclear whether inflammation is the cause, or the effect, of lower serum anti-TNF levels. It has been reported that nonresponders to infliximab exhibit higher levels of infliximab in their feces than responders, suggesting that patients with ongoing inflammation leak infliximab into their intestinal lumen.11Brandse J. Wildenberg M. de Bruyn J. et al.Fecal loss of infliximab as a cause of lack of response in severe inflammatory bowel disease.Gastroenterology. 2013; 142: S-36Google Scholar Similarly, other markers of the inflammatory state, such as baseline C-reactive protein (CRP), fecal calprotectin, and albumin, have also been associated with lower serum infliximab levels.12Fasanmade A.A. Adedokun O.J. Blank M. et al.Pharmacokinetic properties of infliximab in children and adults with Crohn's disease: a retrospective analysis of data from 2 phase III clinical trials.Clin Ther. 2011; 33: 946-964Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 13Hamalainen A. Sipponen T. Kolho K.L. Serum infliximab concentrations in pediatric inflammatory bowel disease.Scand J Gastroenterol. 2013; 48: 35-41Crossref PubMed Scopus (38) Google Scholar Studies associating low serum infliximab levels with high serum CRP levels are often cited to support therapeutic drug monitoring, but snap-shot associations from a single time point may make incorrect assumptions that lower drug levels, not more inflammation, is the causative process.14Feagan B.G. Novel infliximab and antibody-to-infliximab assays are predictive of disease activity in patients with Crohn's disease.Gastroenterology. 2012; 142: A565Google Scholar In the Colombel study, baseline CRP was inversely proportional to CZP plasma concentration at week 8, and patients with an elevated CRP at week 8 were less likely to obtain endoscopic remission at week 10. Interestingly, in this study, baseline CRP was able to predict future endoscopic outcomes as well as serum CZP was.For clinicians, there is also a disconnect between the implications of published studies and their access to serum anti-TNF assays in practice. No commercially available test for CZP is currently available, and access to infliximab or adalimumab levels on a global basis is limited to academic centers. A range of different infliximab assays are used in European centers, with only modest correlations between them, and none of these research kits have been independently compared to the commercially available assays in the United States (Prometheus, LabCorp).15Vande C.N. Buurman D.J. Sturkenboom M.G. et al.Detection of infliximab levels and anti-infliximab antibodies: a comparison of three different assays.Aliment Pharmacol Ther. 2012; 36: 765-771Crossref PubMed Scopus (180) Google Scholar Thus, the practical implications of these study results for a gastroenterologist in Boston, Berlin, or Brasilia may be very different.What does all this mean when managing CD with anti-TNFs? Whatever the doubts about drug levels and inflammation causation from observational studies, preliminary data does suggest that optimization of serum anti-TNF levels may lead to improvement in mucosal healing outcomes.16Bouguen G. Levesque B.G. Pola S. et al.Endoscopic assessment and treating to target increase the likelihood of mucosal healing in patients with Crohn's disease.Clin Gastroenterol Hepatol. 2013 Nov 15; ([Epub ahead of print])Google Scholar Where serum anti-TNF levels are not available, or economical, CRP levels are an alternative means of identifying patients at higher risk of therapeutic failure.17Reinisch W. Colombel J.F. Sandborn W.J. et al.Infliximab serum trough level and CRP change are associated with corticosteroid-free remission in Crohn's disease: a post-hoc analysis of the sonic trial.Gut. 2012; 61: A170PubMed Google Scholar Deep remission as an outcome appears hampered by the fact that the Crohn's Disease Activity Index also measures noninflammatory symptoms. If a commitment to regular therapeutic drug monitoring and endoscopic assessments will lead to higher mucosal healing rates, this pathway will still need to prove its overall impact on patient well-being and healthcare costs. Nirvana: release from a state of suffering after an often lengthy period of committed spiritual practice.(Wikipedia) Mucosal healing has recently moved to the fore as an outcome of treatment for patients with Crohn's disease (CD)—no longer an “impossible dream” but a primary goal of care to improve patient outcomes.1Rutgeerts P. Vermeire S. Van Assche G. Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target?.Gut. 2007; 56: 453-455Crossref PubMed Scopus (261) Google Scholar Studies using anti–tumor necrosis factor (anti-TNF) agents have emphasized the overall benefits of mucosal healing for patients.2Baert F. Moortgat L. Van Assche G. et al.Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease.Gastroenterology. 2010; 138: 463-468Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar Over the same period, we have seen data linking mucosal healing to serum drug levels of anti-TNFs, thus supporting the concept of therapeutic drug monitoring in patient management.3Maser E.A. Villela R. Silverberg M.S. et al.Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease.Clin Gastroenterol Hepatol. 2006; 4: 1248-1254Abstract Full Text Full Text PDF PubMed Scopus (537) Google Scholar Combining all these associations would lead the casual observer to an intuitive conclusion: the path to nirvana for our patients with CD requires a commitment to optimizing serum anti-TNF levels and mucosal healing. Two studies in this issue of the journal suggest that this conclusion is not so easily supported. The first, by Colombel et al, reports rates of “deep remission” in patients treated with adalimumab or placebo for 1 year in the EXTEND trial.4Colombel J.F. Rutgeerts P.J. Sandborn W.J. et al.Adalimumab induces deep remission in patients with Crohn's disease.Clin Gastroenterol Hepatol. 2014; 12: 414-422Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar This concept of deep remission has only recently been defined for patients with CD as a state of both clinical remission and mucosal healing.5Colombel J.F. Louis E. Peyrin-Biroulet L. et al.Deep remission: a new concept?.Dig Dis. 2012; 30: 107-111Crossref PubMed Scopus (36) Google Scholar Although not validated as a clinically meaningful outcome, at first glance it seems a logical goal of therapy for patients with CD. In Colombel's study, deep remission rates at weeks 12 and 52 for patients receiving adalimumab were 16% and 19%, respectively, which were higher than those for placebo (10% at week 12 and 0% at week 52). Although deep remission was achieved in only a small group of patients, they had significantly better outcomes for therapy adjustment, hospitalization, surgery, activity impairment, and quality of life when compared with patients who did not achieve deep remission. Notably, however, outcomes for quality of life, productivity, and CD-related hospitalization were similar between patients in deep remission and those who achieved clinical remission alone (no mucosal healing). In fact, patients who achieved mucosal healing only (but had persistent symptoms by Crohn's Disease Activity Index) had numerically lower quality-of-life and productivity scores than those who obtained clinical remission alone. The actual numbers in each group, and their differences, are small in these exploratory analyses and underpowered for the comparison. However, for patients already in clinical remission, obtaining mucosal healing did not lead to substantially better quality-of-life outcomes than clinical remission alone. Outcomes associated with healthcare costs also appeared to be less favorable in those who achieved mucosal healing but were not in clinical remission. Maybe mucosal healing is not the panacea for all the ills of our patients with CD. The high prevalence of functional gastrointestinal disorders in patients with CD may explain this result; symptoms will still make patients go to the emergency department, or miss work, or feel miserable, regardless of how good their mucosa looks.6Farrokhyar F. Marshall J.K. Easterbrook B. et al.Functional gastrointestinal disorders and mood disorders in patients with inactive inflammatory bowel disease: prevalence and impact on health.Inflamm Bowel Dis. 2006; 12: 38-46Crossref PubMed Scopus (220) Google Scholar For clinicians, the prudent conclusion to make from this study is that obtaining mucosal healing in practice is not going to solve all our patients' problems, so a holistic approach to symptom management is still required. For clinical trialists, liberation from both symptoms and endoscopic inflammation may appear to be an admirable goal, but judging anti-inflammatory therapy using a measurement, for example, the Crohn's Disease Activity Index, that is influenced by noninflammatory processes is fraught with problems.7Lahiff C. Safaie P. Awais A. et al.The Crohn's disease activity index (CDAI) is similarly elevated in patients with Crohn's disease and in patients with irritable bowel syndrome.Aliment Pharmacol Ther. 2013; 37: 786-794Crossref PubMed Scopus (83) Google Scholar Until we better understand the mechanisms of persistent intestinal symptoms in patients who have achieved mucosal healing, combining symptoms and mucosal healing into 1 end-point should be reconsidered as a measure of response to anti-inflammatory therapies. The second paper in this issue, also by Colombel et al, examines whether mucosal healing in patients with CD correlated with serum drug levels of certolizumab pegol (CZP) in the MUSIC (endoscopic MUcoSal Improvement in patients with active Crohn's disease treated with certolizumab pegol) trial.8Colombel J.F. Sandborn W.J. Allez M. et al.Association between plasma concentrations of certolizumab pegol and endoscopic outcomes of patients with Crohn's disease.Clin Gastroenterol Hepatol. 2014; 12: 423-431Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar In the MUSIC trial, patients with active CD and endoscopic ulcers at baseline received CZP every 4 weeks to week 54.9Hebuterne X. Lemann M. Bouhnik Y. et al.Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol.Gut. 2013; 62: 201-208Crossref PubMed Scopus (138) Google Scholar Of the initial patients enrolled in the MUSIC trial, 45 patients had both CZP levels and endoscopic scores available at week 10; these make up the population of interest in the Colombel paper. These patients' mean CZP levels at week 8 were significantly associated with their probability of endoscopic remission at week 10, and patients with the highest quartile of CZP levels at week 8 were more likely to be in endoscopic remission at week 10, when compared to the lowest quartile levels. The authors' conclusion was that endoscopic improvements are associated with higher plasma CZP concentrations in patients with CD. If mucosal healing is a final step on the path to nirvana, is optimization of serum anti-TNF levels an important first step? Prospective trials of therapeutic drug monitoring of anti-TNFs to achieve mucosal healing have not been published yet, and there are challenges in interpreting the existing literature on this topic.10Moore C. Vaughn B. Moss A.C. Analysis of reporting standards of serum anti-TNF levels in patients with IBD.Inflamm Bowel Dis. 2013; 19: P080Google Scholar From a conceptual stand-point, it is unclear whether inflammation is the cause, or the effect, of lower serum anti-TNF levels. It has been reported that nonresponders to infliximab exhibit higher levels of infliximab in their feces than responders, suggesting that patients with ongoing inflammation leak infliximab into their intestinal lumen.11Brandse J. Wildenberg M. de Bruyn J. et al.Fecal loss of infliximab as a cause of lack of response in severe inflammatory bowel disease.Gastroenterology. 2013; 142: S-36Google Scholar Similarly, other markers of the inflammatory state, such as baseline C-reactive protein (CRP), fecal calprotectin, and albumin, have also been associated with lower serum infliximab levels.12Fasanmade A.A. Adedokun O.J. Blank M. et al.Pharmacokinetic properties of infliximab in children and adults with Crohn's disease: a retrospective analysis of data from 2 phase III clinical trials.Clin Ther. 2011; 33: 946-964Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 13Hamalainen A. Sipponen T. Kolho K.L. Serum infliximab concentrations in pediatric inflammatory bowel disease.Scand J Gastroenterol. 2013; 48: 35-41Crossref PubMed Scopus (38) Google Scholar Studies associating low serum infliximab levels with high serum CRP levels are often cited to support therapeutic drug monitoring, but snap-shot associations from a single time point may make incorrect assumptions that lower drug levels, not more inflammation, is the causative process.14Feagan B.G. Novel infliximab and antibody-to-infliximab assays are predictive of disease activity in patients with Crohn's disease.Gastroenterology. 2012; 142: A565Google Scholar In the Colombel study, baseline CRP was inversely proportional to CZP plasma concentration at week 8, and patients with an elevated CRP at week 8 were less likely to obtain endoscopic remission at week 10. Interestingly, in this study, baseline CRP was able to predict future endoscopic outcomes as well as serum CZP was. For clinicians, there is also a disconnect between the implications of published studies and their access to serum anti-TNF assays in practice. No commercially available test for CZP is currently available, and access to infliximab or adalimumab levels on a global basis is limited to academic centers. A range of different infliximab assays are used in European centers, with only modest correlations between them, and none of these research kits have been independently compared to the commercially available assays in the United States (Prometheus, LabCorp).15Vande C.N. Buurman D.J. Sturkenboom M.G. et al.Detection of infliximab levels and anti-infliximab antibodies: a comparison of three different assays.Aliment Pharmacol Ther. 2012; 36: 765-771Crossref PubMed Scopus (180) Google Scholar Thus, the practical implications of these study results for a gastroenterologist in Boston, Berlin, or Brasilia may be very different. What does all this mean when managing CD with anti-TNFs? Whatever the doubts about drug levels and inflammation causation from observational studies, preliminary data does suggest that optimization of serum anti-TNF levels may lead to improvement in mucosal healing outcomes.16Bouguen G. Levesque B.G. Pola S. et al.Endoscopic assessment and treating to target increase the likelihood of mucosal healing in patients with Crohn's disease.Clin Gastroenterol Hepatol. 2013 Nov 15; ([Epub ahead of print])Google Scholar Where serum anti-TNF levels are not available, or economical, CRP levels are an alternative means of identifying patients at higher risk of therapeutic failure.17Reinisch W. Colombel J.F. Sandborn W.J. et al.Infliximab serum trough level and CRP change are associated with corticosteroid-free remission in Crohn's disease: a post-hoc analysis of the sonic trial.Gut. 2012; 61: A170PubMed Google Scholar Deep remission as an outcome appears hampered by the fact that the Crohn's Disease Activity Index also measures noninflammatory symptoms. If a commitment to regular therapeutic drug monitoring and endoscopic assessments will lead to higher mucosal healing rates, this pathway will still need to prove its overall impact on patient well-being and healthcare costs. Association Between Plasma Concentrations of Certolizumab Pegol and Endoscopic Outcomes of Patients With Crohn's DiseaseClinical Gastroenterology and HepatologyVol. 12Issue 3PreviewMonitoring plasma concentrations of anti–tumor necrosis factor agents could optimize treatment of patients with Crohn's Disease (CD). In a post hoc analysis of data from a clinical trial, we compared the relationship between plasma concentrations of certolizumab pegol (CZP) and endoscopic and clinical responses and remission with CZP therapy in patients with moderate to severe ileocolonic CD. Full-Text PDF Adalimumab Induces Deep Remission in Patients With Crohn's DiseaseClinical Gastroenterology and HepatologyVol. 12Issue 3PreviewPatients with moderate to severe ileocolonic Crohn's disease (CD) who received adalimumab induction and maintenance therapy had greater rates of mucosal healing than patients who received placebo after adalimumab induction therapy in a 52-week trial (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing). We investigated whether this treatment also induced deep remission—a composite clinical and endoscopic end point. Full-Text PDF" @default.
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• W2073900288 title "Therapeutic Drug Monitoring, Mucosal Healing, Deep Remission: The Path to Nirvana in Crohn's Disease?" @default.
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