FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2149244937> ?p ?o ?g. }

• W2149244937 endingPage "1568" @default.
• W2149244937 startingPage "1564" @default.
• W2149244937 abstract "Critical limb ischemia (CLI) continues to form a substantial burden on Western healthcare. Many patients still face amputation as a last treatment option. Autologous bone marrow (BM)-derived cell administration has emerged as a potential new treatment, but proof for sustainable clinical effects of BM-derived cell therapy in CLI is still lacking. The JUVENTAS (reJUVenating ENdothelial progenitor cells via Transcutaneous intra-Arterial Supplementation) trial is the first randomized, placebo-controlled, double-blinded clinical trial on repeated intra-arterial BM mononuclear cell (MNC) infusion in 110 to 160 CLI patients, designed to provide definite proof for the efficacy of stem cell therapy. Primary outcome is the incidence of major amputation at 6 months. Inclusion of patients is well underway. If BM-MNC cells therapy is beneficial, it could become a novel treatment to prevent amputation in patients with CLI. Critical limb ischemia (CLI) continues to form a substantial burden on Western healthcare. Many patients still face amputation as a last treatment option. Autologous bone marrow (BM)-derived cell administration has emerged as a potential new treatment, but proof for sustainable clinical effects of BM-derived cell therapy in CLI is still lacking. The JUVENTAS (reJUVenating ENdothelial progenitor cells via Transcutaneous intra-Arterial Supplementation) trial is the first randomized, placebo-controlled, double-blinded clinical trial on repeated intra-arterial BM mononuclear cell (MNC) infusion in 110 to 160 CLI patients, designed to provide definite proof for the efficacy of stem cell therapy. Primary outcome is the incidence of major amputation at 6 months. Inclusion of patients is well underway. If BM-MNC cells therapy is beneficial, it could become a novel treatment to prevent amputation in patients with CLI. Critical limb ischemia (CLI) imposes a large burden on Western healthcare, as a considerable number of patients with CLI (∼40%) are ineligible for surgical or radiological revascularization. The prognosis is poor,1Norgren L. Hiatt W.R. Dormandy J.A. Nehler M.R. Harris K.A. Fowkes F.G. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).J Vasc Surg. 2007; 45: S5-S67Abstract Full Text Full Text PDF PubMed Scopus (3859) Google Scholar and with the lack of pharmacological treatments and other effective therapies, amputation is often the only treatment option left. Consequently, development of new revascularization therapies for CLI is of great importance. Bone marrow (BM)-derived endothelial progenitor cells (EPC) have been identified as a potential new therapeutic tool in the treatment of CLI. Since the first observation of their presence in peripheral blood in the 1990s, increasing evidence indicates that EPC contribute to postnatal neovascularization by homing and incorporation into sites of new vessel formation.2Asahara T. Masuda H. Takahashi T. Kalka C. Pastore C. Silver M. et al.Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization.Circ Res. 1999; 85: 221-228Crossref PubMed Scopus (2829) Google Scholar, 3Crosby J.R. Kaminski W.E. Schatteman G. Martin P.J. Raines E.W. Seifert R.A. Bowen-Pope D.F. Endothelial cells of hematopoietic origin make a significant contribution to adult blood vessel formation.Circ Res. 2000; 87: 728-730Crossref PubMed Scopus (447) Google Scholar Encouraging results of small clinical studies on progenitor cell-based therapy have been reported in patients with CLI. Thus far, over 30 clinical studies have reported on the use of BM or peripheral blood (PB)-derived progenitor cells in patients with peripheral arterial occlusive disease (PAOD) or CLI (for an overview of design, patient number, route of administration, and outcome of these studies, see Sprengers et al4Sprengers R.W. Lips D.J. Moll F.L. Verhaar M.C. Progenitor cell therapy in patients with critical limb ischemia without surgical options.Ann Surg. 2008; 247: 411-420Crossref PubMed Scopus (59) Google Scholar). Almost all studies reported beneficial results on clinical parameters. However, most of the studies have been small and lacked double-blind controls. Large, randomized, placebo-controlled trials are needed to evaluate the effects of cell-based therapy in CLI. The JUVENTAS (reJUVenating ENdothelial progenitor cells via Transcutaneous intra-Arterial Supplementation) trial is an investigator-driven trial that examines the potential clinical effects of repeated intra-arterial infusion of BM-MNC in CLI patients. In addition, it studies the functional characteristics of BM-MNC obtained from CLI patients and will relate BM-MNC dysfunction to clinical outcome. This translational approach may lead to the identification of predictive assays or markers for therapeutic efficacy and may eventually yield strategies to improve therapeutic efficacy. To our knowledge, this is the first translational trial of its size that will investigate the clinical effects of intra-arterial infusion of BM-MNC in patients with CLI. This clinical update will cover the design of the JUVENTAS trial and discuss its decisions regarding unsolved issues on cell therapy in CLI patients. The JUVENTAS trial has a randomized, double-blind, placebo-controlled design. A total number of 110 to 160 patients with proven chronic CLI or selected patients with severely invalidating intermittent claudication (claudicants on the verge of rest pain), who are not candidates for surgical or radiological revascularization (as decided by a multidisciplinary team of vascular surgeons and radiologists) will be included in the trial. Risk factors for cardiovascular disease are treated according to Dutch practice guidelines. Patients are screened for eligibility according to the criteria listed in Table. After obtaining written informed consent, patients are randomized by the Data Safety Monitoring Committee by means of a computerized randomization table to either repeated intra-arterial infusion of BM-MNC or placebo (a flow chart of the study design is shown in the Fig). The Gene and Cell Therapy Facility of the University Medical Center Utrecht is informed about the randomization result after BM aspiration. The steering committee and clinical staff remain blinded to the treatment allocation.TableInclusion and exclusion criteria of the JUVENTAS trialInclusion criteriaExclusion criteria•Age > 18 years•Severe PAOD (Fontaine class IIb, III, and/or IV)•Invalidating intermittent claudication•Persistent recurring rest pain requiring analgesia•Non-healing ulcers present for >4 weeks without evidence of improvement in response to conventional therapies•Ankle brachial index < 0.6 or unreliable (non-compressible or not in proportion to the Fontaine classification)•Not eligible for surgical or radiological revascularization•Written informed consent•History of neoplasm or malignancy in the past 10 years•Serious known concomitant disease with life expectancy of less than one year•(Anticipated) inability to obtain 100 ml of bone marrow aspirate•Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C virus•Follow-up impossible Open table in a new tab BM aspirates are obtained in all patients. A total volume of 100 ml BM is aspirated from the iliac crest under local anesthetic and conscious sedation according to local routine. Seven ml of BM aspirate is kept separately for fundamental research purposes. The remaining BM aspirate is used for purification of BM-MNC by density gradient centrifugation. After washing, the MNC is resuspended in a physiological salt solution containing 10% human serum albumin (HSA). For the study group, one-third of the remaining cells is prepared for direct infusion, while two-thirds of the cells are cryopreserved using 10% dimethylsulfoxide (DMSO) and stored for later infusions. For the control group, a placebo is prepared using autologous erythrocytes to match the color of the BM-derived cellular product in order to guarantee the double blinding procedure at the time of infusion. One-third of the placebo is prepared for direct infusion, while two-thirds of the placebo are cryopreserved and stored in the same manner as performed for the study group. Patients are scheduled for three visits at the clinical research unit for intra-arterial infusion of BM-MNC or placebo. The first infusion is performed within 4 hours after BM aspiration. The subsequent two infusions take place at 3-week intervals. Syringes without information about the containing product (BM-MNC or placebo) are provided by the local Gene and Cell Therapy Facility to the clinical staff at the time of cell or placebo infusion. An experienced operator will slowly administer 10 ml of BM-MNC or placebo into the common femoral artery of the affected leg by hand injection. Clinical evaluation is performed by the same investigator at baseline and at 2- and 6-month follow up. The primary outcome is incidence of major amputation (defined as being sited through or above the ankle joint) at 6 months. Secondary outcomes are the incidence of minor amputations (sited more distal than the ankle joint), changes in the number and extent of leg ulcers, resolvement of rest pain or improvement of pain-free walking distance, improvement of ankle-brachial index and transcutaneous oxygen pressure, and changes in quality of life. Standardized magnetic resonance imaging/angiography (MRI/MRA) imaging is performed at the time of inclusion and after 6-month follow up to allow for objective measures for neovascularization (eg, collateral vessel formation, flow measurements, perfusion measurements). The sample size for the JUVENTAS trial is based on a 6-month risk of major amputation in patients with unreconstructed chronic critical leg ischemia of 42%5Lepantalo M. Matzke S. Outcome of unreconstructed chronic critical leg ischaemia.Eur J Vasc Endovasc Surg. 1996; 11: 153-157Abstract Full Text PDF PubMed Scopus (169) Google Scholar and an estimated reduction of the risk of major amputation by BM-MNC infusion of 50%. Previously, predominantly Asian studies reported marked beneficial effects of BM-MNC therapy, claiming prevention of limb amputation in 73% and 91%.6Kawamura A. Horie T. Tsuda I. Ikeda A. Egawa H. Imamura E. et al.Prevention of limb amputation in patients with limbs ulcers by autologous peripheral blood mononuclear cell implantation.Ther Apher Dial. 2005; 9: 59-63Crossref PubMed Scopus (75) Google Scholar, 7Kawamura A. Horie T. Tsuda I. Abe Y. Yamada M. Egawa H. et al.Clinical study of therapeutic angiogenesis by autologous peripheral blood stem cell (PBSC) transplantation in 92 patients with critically ischemic limbs.J Artif Organs. 2006; 9: 226-233Crossref PubMed Scopus (90) Google Scholar For Western patients, who often have multiple risk factors, fewer data are available, but results seem more modest. A recent Dutch study showed relevant and sustained improvement in 15 out of 27 CLI patients.8van Tongeren R.B. Hamming J.F. Fibbe W.E. Van W.V. Frerichs S.J. Stiggelbout A.M. et al.Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia.J Cardiovasc Surg (Torino). 2008; 49: 51-58PubMed Google Scholar One uncontrolled Belgian study, in a similar population of 16 CLI patients with many cardiovascular risk factors, suggested that in these patients results are modest and restricted to the least affected patients.9de Vriese A.S. Billiet J. van D.J. Ghekiere J. de Letter J.A. Autologous transplantation of bone marrow mononuclear cells for limb ischemia in a caucasian population with atherosclerosis obliterans.J Intern Med. 2008; 263: 395-403Crossref PubMed Scopus (29) Google Scholar The estimated 50% reduction in risk of major amputations is a conservative estimate and takes into account that the effects in a Western, older population with multiple risk factors may be less than in the Asian population. To allow for definite conclusions on the efficacy of cell administration in CLI patients, group sequential interim analysis will be performed. This statistical method allows for a varying number of patients to be included in a trial, depending on the difference in outcome between two groups. On average, fewer patients are needed in a trial if the expected difference in the primary outcome variable appears to be real.10Whitehead J. The design and analysis of sequential clinical trials. John Wiley & Sons, Chichester1997Crossref Google Scholar Assuming that BM-MNC infusion will reduce the risk of major amputation by 50%, it has been estimated that with a two-sided alpha of 0.05 and a power of 80%, approximately 110 to 160 patients need to be enrolled in the JUVENAS Trial and followed for 6 months. If important clinical differences between groups become evident during an interim analysis, the trial will be stopped, and patients will be offered the best treatment available. If the observed benefit is ‘clearly’ larger, or if placebo treatment appears to be better than BM-MNC infusion, early termination of the trial may be recommended. Recruitment of patients for the JUVENTAS Trial commenced in September 2006, and to date over 60 patients have been included in the trial. After a start-up phase, the speed of inclusion increased steadily, and recruitment of the 110th patient is currently expected by the end of 2011. If inclusion is prolonged to 160 patients, inclusion is expected to close by the end of 2012. Analysis and reporting is expected to be completed a half year after inclusion has ended. The trial has been submitted to the ClinicalTrials.gov trial register under number NCT00371371. Although progenitor cell-based therapy has emerged as a promising new tool in the treatment of CLI, no definite proof about its efficacy is yet available, since the clinical studies thus far have been small and lacked double-blinded controls. The JUVENTAS trial has been designed to investigate the effects of intra-arterial infusion of BM-MNC in patients with CLI in a randomized, double-blind, placebo-controlled manner, and to provide additional evidence for efficacy and safety of cell-based therapeutic neovascularization. With regard to cell therapy, many questions are still unanswered: for example, concerning the optimal cell population to be administered, the optimal route of administration, the optimal dose, the need for multiple treatments, and the impact of BM cell dysfunction. Several uncontrolled studies, often in Asian populations, have showed that intramuscular (IM) administration of BM-MNC is feasible and safe and has potential beneficial clinical effects.4Sprengers R.W. Lips D.J. Moll F.L. Verhaar M.C. Progenitor cell therapy in patients with critical limb ischemia without surgical options.Ann Surg. 2008; 247: 411-420Crossref PubMed Scopus (59) Google Scholar Of the 10 studies (190 patients) in Western populations, five applied intra-arterial (IA) injection, either alone11Lenk K. Adams V. Lurz P. Erbs S. Linke A. Gielen S. et al.Therapeutical potential of blood-derived progenitor cells in patients with peripheral arterial occlusive disease and critical limb ischaemia.Eur Heart J. 2005; 26: 1903-1909Crossref PubMed Scopus (118) Google Scholar, 12Chochola M. Pytlik R. Kobylka P. Skalicka L. Kideryova L. Beran S. et al.Autologous intra-arterial infusion of bone marrow mononuclear cells in patients with critical leg ischemia.Int Angiol. 2008; 27: 281-290PubMed Google Scholar, 13Napoli C. Farzati B. Sica V. Iannuzzi E. Coppola G. Silvestroni A. et al.Beneficial effects of autologous bone marrow cell infusion and antioxidants/L-arginine in patients with chronic critical limb ischemia.Eur J Cardiovasc Prev Rehabil. 2008; 15: 709-718Crossref PubMed Scopus (39) Google Scholar or in combination with IM injections.8van Tongeren R.B. Hamming J.F. Fibbe W.E. Van W.V. Frerichs S.J. Stiggelbout A.M. et al.Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia.J Cardiovasc Surg (Torino). 2008; 49: 51-58PubMed Google Scholar, 14Bartsch T. Brehm M. Zeus T. Kogler G. Wernet P. Strauer B.E. Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (the TAM-PAD study).Clin Res Cardiol. 2007; 96: 891-899Crossref PubMed Scopus (108) Google Scholar Several reasons for choosing IA administration over IM administration as the optimal delivery route can be identified: (a) preclinical data suggest that IA injection leads to improved survival of injected cells;4Sprengers R.W. Lips D.J. Moll F.L. Verhaar M.C. Progenitor cell therapy in patients with critical limb ischemia without surgical options.Ann Surg. 2008; 247: 411-420Crossref PubMed Scopus (59) Google Scholar (b) most CLI patients have multi-level disease, including the femoropopliteal tract and pedal arteries. These zones may be better reached by IA as compared with IM calf injections;4Sprengers R.W. Lips D.J. Moll F.L. Verhaar M.C. Progenitor cell therapy in patients with critical limb ischemia without surgical options.Ann Surg. 2008; 247: 411-420Crossref PubMed Scopus (59) Google Scholar (c) extensive experience exists and positive results have been reported on intra- (coronary) artery administration of BM-MNC in patients with myocardial ischemia (see meta analyses15Lipinski M.J. Biondi-Zoccai G.G. Abbate A. Khianey R. Sheiban I. Bartunek J. et al.Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials.J Am Coll Cardiol. 2007; 50: 1761-1767Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar, 16Abdel-Latif A. Bolli R. Tleyjeh I.M. Montori V.M. Perin E.C. Hornung C.A. et al.Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis.Arch Intern Med. 2007; 167: 989-997Crossref PubMed Scopus (792) Google Scholar); (d) in preclinical studies similar results for intra-arterial versus intramuscular injection on angiogenic activity were observed.17Yoshida M. Horimoto H. Mieno S. Nomura Y. Okawa H. Nakahara K. Sasaki S. Intra-arterial bone marrow cell transplantation induces angiogenesis in rat hindlimb ischemia.Eur Surg Res. 2003; 35: 86-91Crossref PubMed Scopus (29) Google Scholar With regard to dosing, the JUVENTAS Trial chose to administer progenitor cells obtained from 100 ml BM, which can be aspirated under local anesthesia with a low risk of adverse events (none thus far) in a repeated infusion scheme. No criteria such as a minimal cell number, CD34+ cell number, and/or percentage have been defined. This strategy maximizes the amount of BM that is administered to the patient. In other clinical trials thus far, varying doses of injected MNC, with varying concentrations of CD34+ cells have been used. In studies on BM-MNC administration in CLI patients, amounts of aspirated BM ranging from 80 to 1000 ml have been reported, from which varying amounts of MNC and different fractions of CD34+ cells retrieved.4Sprengers R.W. Lips D.J. Moll F.L. Verhaar M.C. Progenitor cell therapy in patients with critical limb ischemia without surgical options.Ann Surg. 2008; 247: 411-420Crossref PubMed Scopus (59) Google Scholar All of those studies have reported beneficial effects on clinical outcome, and no consistent evidence of a dose-response in humans has been reported. In the JUVENTAS trial, all data on numbers of infused BM-MNC, CD34+ cells, etc. are documented and will be related to study outcome. Studies in myocardial ischemia have shown that only a limited number of cells are retained in the injured tissue. It was assumed that repeated administration of cells would lead to enhanced retainment of cells, and, therefore, a three times intra-arterial infusion scheme was chosen. No previous studies have reported on BM-MNC dose escalations or comparisons of different time points and frequencies of injection. A recent small dose-escalating study was unable to demonstrate differences between various dosages of intramuscularly transplanted GCSF-mobilized CD34+ cells, but encouraged larger randomized controlled trials on this topic.18Kawamoto A. Katayama M. Handa N. Kinoshita M. Takano H. Horii M. et al.Intramuscular transplantation of granulocyte colony stimulating factor-mobilized CD34-positive cells in patients with critical limb ischemia: a phase I/IIa, multi-center, single-blind and dose-escalation clinical trial.Stem Cells. 2009; 27: 2857-2864Crossref PubMed Scopus (169) Google Scholar Several studies have demonstrated that circulating EPC are reduced and dysfunctional in the presence of risk factors for cardiovascular disease.19Vasa M. Fichtlscherer S. Aicher A. Adler K. Urbich C. Martin H. et al.Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease.Circ Res. 2001; 89: E1-E7Crossref PubMed Scopus (2032) Google Scholar Such functional impairment has been shown to extend to BM-MNC. BM-MNC obtained from patients with chronic ischemic heart disease has profoundly reduced neovascularization capacity.20Heeschen C. Lehmann R. Honold J. Assmus B. Aicher A. Walter D.H. et al.Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease.Circulation. 2004; 109: 1615-1622Crossref PubMed Scopus (564) Google Scholar In PAOD, particularly in diabetes, reduced circulating EPC numbers and function have been reported.21Fadini G.P. Sartore S. Albiero M. Baesso I. Murphy E. Menegolo M. et al.Number and function of endothelial progenitor cells as a marker of severity for diabetic vasculopathy.Arterioscler Thromb Vasc Biol. 2006; 26: 2140-2146Crossref PubMed Scopus (351) Google Scholar One small study showed lower circulating and BM EPC levels in patients with limb ischemia compared with controls, with a significant reduction in the mRNA expression level of EPC markers in BM-MNC, suggesting lower angiogenic potential.22Yamamoto K. Kondo T. Suzuki S. Izawa H. Kobayashi M. Emi N. et al.Molecular evaluation of endothelial progenitor cells in patients with ischemic limbs: therapeutic effect by stem cell transplantation.Arterioscler Thromb Vasc Biol. 2004; 24: e192-e196Crossref PubMed Google Scholar It has been suggested that the more modest response to BM-MNC therapy observed in Caucasian as compared with Asian patients may be related to the higher prevalence of cardiovascular risk factors and associated EPC dysfunction.8van Tongeren R.B. Hamming J.F. Fibbe W.E. Van W.V. Frerichs S.J. Stiggelbout A.M. et al.Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia.J Cardiovasc Surg (Torino). 2008; 49: 51-58PubMed Google Scholar, 9de Vriese A.S. Billiet J. van D.J. Ghekiere J. de Letter J.A. Autologous transplantation of bone marrow mononuclear cells for limb ischemia in a caucasian population with atherosclerosis obliterans.J Intern Med. 2008; 263: 395-403Crossref PubMed Scopus (29) Google Scholar A functional impairment of BM-MNC may limit the therapeutic potential of autologous BM cell therapy. The JUVENTAS Trial therefore includes a preclinical part that focuses on the functional characterization of the BM-MNC obtained from CLI patients. Functional characteristics of the BM-MNC will be related to clinical outcome. Such a translational approach may lead to the identification of predictive assays or markers for therapeutic efficacy and may eventually yield strategies to improve therapeutic efficacy. The JUVENTAS Trial will be the largest randomized, double-blind, placebo-controlled clinical trial yet conducted to evaluate the clinical effects of intra-arterial infusion of BM-MNC in patients with CLI. The results from this trial will further strengthen the evidence on the efficacy of cell-based therapy for CLI. If repeated intra-arterial infusion of autologous BM-MNC is beneficial, it could become a novel treatment to prevent amputation in patients with CLI." @default.
• W2149244937 created "2016-06-24" @default.
• W2149244937 creator A5021597876 @default.
• W2149244937 creator A5045826001 @default.
• W2149244937 creator A5053633093 @default.
• W2149244937 creator A5058643964 @default.
• W2149244937 date "2010-06-01" @default.
• W2149244937 modified "2023-10-11" @default.
• W2149244937 title "Rationale and design of the JUVENTAS trial for repeated intra-arterial infusion of autologous bone marrow-derived mononuclear cells in patients with critical limb ischemia" @default.
• W2149244937 cites W197648304 @default.
• W2149244937 cites W1996642397 @default.
• W2149244937 cites W2009485059 @default.
• W2149244937 cites W2011011711 @default.
• W2149244937 cites W2021573874 @default.
• W2149244937 cites W2023447789 @default.
• W2149244937 cites W2060548737 @default.
• W2149244937 cites W2068481509 @default.
• W2149244937 cites W2071746224 @default.
• W2149244937 cites W2085778192 @default.
• W2149244937 cites W2113436661 @default.
• W2149244937 cites W2124421653 @default.
• W2149244937 cites W2124774771 @default.
• W2149244937 cites W2130761693 @default.
• W2149244937 cites W2132418620 @default.
• W2149244937 cites W2144875367 @default.
• W2149244937 cites W2144985796 @default.
• W2149244937 cites W2145639716 @default.
• W2149244937 cites W2150097253 @default.
• W2149244937 doi "https://doi.org/10.1016/j.jvs.2010.02.020" @default.
• W2149244937 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20488328" @default.
• W2149244937 hasPublicationYear "2010" @default.
• W2149244937 type Work @default.
• W2149244937 sameAs 2149244937 @default.
• W2149244937 citedByCount "46" @default.
• W2149244937 countsByYear W21492449372012 @default.
• W2149244937 countsByYear W21492449372013 @default.
• W2149244937 countsByYear W21492449372014 @default.
• W2149244937 countsByYear W21492449372015 @default.
• W2149244937 countsByYear W21492449372016 @default.
• W2149244937 countsByYear W21492449372017 @default.
• W2149244937 countsByYear W21492449372018 @default.
• W2149244937 countsByYear W21492449372019 @default.
• W2149244937 countsByYear W21492449372020 @default.
• W2149244937 countsByYear W21492449372021 @default.
• W2149244937 countsByYear W21492449372022 @default.
• W2149244937 crossrefType "journal-article" @default.
• W2149244937 hasAuthorship W2149244937A5021597876 @default.
• W2149244937 hasAuthorship W2149244937A5045826001 @default.
• W2149244937 hasAuthorship W2149244937A5053633093 @default.
• W2149244937 hasAuthorship W2149244937A5058643964 @default.
• W2149244937 hasBestOaLocation W21492449371 @default.
• W2149244937 hasConcept C10882517 @default.
• W2149244937 hasConcept C126322002 @default.
• W2149244937 hasConcept C137061746 @default.
• W2149244937 hasConcept C141071460 @default.
• W2149244937 hasConcept C142724271 @default.
• W2149244937 hasConcept C185592680 @default.
• W2149244937 hasConcept C201750760 @default.
• W2149244937 hasConcept C202751555 @default.
• W2149244937 hasConcept C204787440 @default.
• W2149244937 hasConcept C27081682 @default.
• W2149244937 hasConcept C2776204877 @default.
• W2149244937 hasConcept C2777466421 @default.
• W2149244937 hasConcept C2779389132 @default.
• W2149244937 hasConcept C2780007613 @default.
• W2149244937 hasConcept C2781099653 @default.
• W2149244937 hasConcept C28328180 @default.
• W2149244937 hasConcept C2911091166 @default.
• W2149244937 hasConcept C3018348675 @default.
• W2149244937 hasConcept C535046627 @default.
• W2149244937 hasConcept C541997718 @default.
• W2149244937 hasConcept C54355233 @default.
• W2149244937 hasConcept C55493867 @default.
• W2149244937 hasConcept C71924100 @default.
• W2149244937 hasConcept C86803240 @default.
• W2149244937 hasConceptScore W2149244937C10882517 @default.
• W2149244937 hasConceptScore W2149244937C126322002 @default.
• W2149244937 hasConceptScore W2149244937C137061746 @default.
• W2149244937 hasConceptScore W2149244937C141071460 @default.
• W2149244937 hasConceptScore W2149244937C142724271 @default.
• W2149244937 hasConceptScore W2149244937C185592680 @default.
• W2149244937 hasConceptScore W2149244937C201750760 @default.
• W2149244937 hasConceptScore W2149244937C202751555 @default.
• W2149244937 hasConceptScore W2149244937C204787440 @default.
• W2149244937 hasConceptScore W2149244937C27081682 @default.
• W2149244937 hasConceptScore W2149244937C2776204877 @default.
• W2149244937 hasConceptScore W2149244937C2777466421 @default.
• W2149244937 hasConceptScore W2149244937C2779389132 @default.
• W2149244937 hasConceptScore W2149244937C2780007613 @default.
• W2149244937 hasConceptScore W2149244937C2781099653 @default.
• W2149244937 hasConceptScore W2149244937C28328180 @default.
• W2149244937 hasConceptScore W2149244937C2911091166 @default.
• W2149244937 hasConceptScore W2149244937C3018348675 @default.
• W2149244937 hasConceptScore W2149244937C535046627 @default.
• W2149244937 hasConceptScore W2149244937C541997718 @default.
• W2149244937 hasConceptScore W2149244937C54355233 @default.
• W2149244937 hasConceptScore W2149244937C55493867 @default.
• W2149244937 hasConceptScore W2149244937C71924100 @default.

• next