Inhaled long-acting β2-agonists or long-acting muscarinic antagonists monotherapies are recommended as the first choice of treatment for patients with symptomatic chronic obstructive pulmonary disease. The different but complementary modes of action of these treatments make them suited for use in a fixed-dose combination. Aclidinium bromide 400 µg (a long-acting muscarinic antagonist) twice daily improves patient lung function and health status and reduces breathlessness compared with placebo, and is well tolerated. Combining these effects with the rapid onset of action of formoterol fumarate 12 µg in a twice-daily treatment may provide 24-h relief from chronic obstructive pulmonary disease symptoms. This review discusses the aclidinium/formoterol 400/12 µg combination clinical trial data to date.
{"title":"A twice-daily, fixed-dose combination of aclidinium bromide and formoterol fumarate for the treatment of chronic obstructive pulmonary disease","authors":"J. Beier","doi":"10.4155/CLI.15.34","DOIUrl":"https://doi.org/10.4155/CLI.15.34","url":null,"abstract":"Inhaled long-acting β2-agonists or long-acting muscarinic antagonists monotherapies are recommended as the first choice of treatment for patients with symptomatic chronic obstructive pulmonary disease. The different but complementary modes of action of these treatments make them suited for use in a fixed-dose combination. Aclidinium bromide 400 µg (a long-acting muscarinic antagonist) twice daily improves patient lung function and health status and reduces breathlessness compared with placebo, and is well tolerated. Combining these effects with the rapid onset of action of formoterol fumarate 12 µg in a twice-daily treatment may provide 24-h relief from chronic obstructive pulmonary disease symptoms. This review discusses the aclidinium/formoterol 400/12 µg combination clinical trial data to date.","PeriodicalId":10369,"journal":{"name":"Clinical investigation","volume":"19 1","pages":"691-700"},"PeriodicalIF":0.0,"publicationDate":"2015-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84630703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
D Doherty co-founded 3G Doctor in 2006 as a means of providing patients with a means of private and economical access to the attentions of informed registered doctors. D Doherty’s role involves bringing together feedback from patients and carers, the public, developer communities and technologists to learn how to improve the patient experience, bake in kindness and begin to understand ways in which 3G doctor can deliver and support new care experiences. Interact with D Doherty on Twitter: @mHealth.
{"title":"David Doherty, co-founder of 3G Doctor","authors":"Davis Doherty","doi":"10.4155/CLI.15.29","DOIUrl":"https://doi.org/10.4155/CLI.15.29","url":null,"abstract":"D Doherty co-founded 3G Doctor in 2006 as a means of providing patients with a means of private and economical access to the attentions of informed registered doctors. D Doherty’s role involves bringing together feedback from patients and carers, the public, developer communities and technologists to learn how to improve the patient experience, bake in kindness and begin to understand ways in which 3G doctor can deliver and support new care experiences. Interact with D Doherty on Twitter: @mHealth.","PeriodicalId":10369,"journal":{"name":"Clinical investigation","volume":"36 1","pages":"687-689"},"PeriodicalIF":0.0,"publicationDate":"2015-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88350413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Panettieri, C. Brightling, Ulf Sjobring, AnnaMaria Péterffy, G. Tornling, Sami Z. Daoud, K. Ranade, Sally Hollis, G. Colice
New therapies are being developed to target proinflammatory mediators thought to be involved in the pathophysiology of severe asthma. Tralokinumab is an investigational fully human monoclonal antibody that specifically blocks binding of IL-13 to its receptors. Here, we describe the background leading to the design of two Phase III trials, STRATOS 1 and 2 (NCT02161757 and NCT02194699), which aim to provide confirmatory evidence of the efficacy and safety of tralokinumab in patients with asthma that is uncontrolled despite treatment with inhaled corticosteroids and long-acting β2-agonists. These trials will also confirm the validity of periostin and DPP-4, identified in a prior Phase IIb study (NCT01402986), as predictors of an enhanced response to tralokinumab.
{"title":"STRATOS 1 and 2: considerations in clinical trial design for a fully human monoclonal antibody in severe asthma","authors":"R. Panettieri, C. Brightling, Ulf Sjobring, AnnaMaria Péterffy, G. Tornling, Sami Z. Daoud, K. Ranade, Sally Hollis, G. Colice","doi":"10.4155/CLI.15.38","DOIUrl":"https://doi.org/10.4155/CLI.15.38","url":null,"abstract":"New therapies are being developed to target proinflammatory mediators thought to be involved in the pathophysiology of severe asthma. Tralokinumab is an investigational fully human monoclonal antibody that specifically blocks binding of IL-13 to its receptors. Here, we describe the background leading to the design of two Phase III trials, STRATOS 1 and 2 (NCT02161757 and NCT02194699), which aim to provide confirmatory evidence of the efficacy and safety of tralokinumab in patients with asthma that is uncontrolled despite treatment with inhaled corticosteroids and long-acting β2-agonists. These trials will also confirm the validity of periostin and DPP-4, identified in a prior Phase IIb study (NCT01402986), as predictors of an enhanced response to tralokinumab.","PeriodicalId":10369,"journal":{"name":"Clinical investigation","volume":"42 1","pages":"701-711"},"PeriodicalIF":0.0,"publicationDate":"2015-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75115126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Brightling, Millie Wang, M. Braddock, L. Nordenmark, Mattis Gottlow, G. Colice
Eosinophils are key effector cells in asthma-associated airway inflammation and remodeling; IL-13 is involved in regulating eosinophil activity. Tralokinumab, currently in Phase III clinical development for patients with severe uncontrolled asthma, is an investigational fully human monoclonal antibody designed to inhibit IL-13. In Phase II studies, tralokinumab improved lung function and had other clinical benefits in those patients with asthma who had an upregulated IL-13 axis. In a subgroup of patients that underwent quantitative computed tomography, there were improvements in airway morphometry, suggestive of a possible effect upon remodeling. The Phase II MESOS study (NCT02449473) aims to better understand the mechanism of action of tralokinumab in improving asthma control, by investigating tralokinumab effects on eosinophil-driven inflammation and airway remodeling.
{"title":"MESOS: considerations in designing a mechanistic study for a biologic used to treat asthma","authors":"C. Brightling, Millie Wang, M. Braddock, L. Nordenmark, Mattis Gottlow, G. Colice","doi":"10.4155/CLI.15.36","DOIUrl":"https://doi.org/10.4155/CLI.15.36","url":null,"abstract":"Eosinophils are key effector cells in asthma-associated airway inflammation and remodeling; IL-13 is involved in regulating eosinophil activity. Tralokinumab, currently in Phase III clinical development for patients with severe uncontrolled asthma, is an investigational fully human monoclonal antibody designed to inhibit IL-13. In Phase II studies, tralokinumab improved lung function and had other clinical benefits in those patients with asthma who had an upregulated IL-13 axis. In a subgroup of patients that underwent quantitative computed tomography, there were improvements in airway morphometry, suggestive of a possible effect upon remodeling. The Phase II MESOS study (NCT02449473) aims to better understand the mechanism of action of tralokinumab in improving asthma control, by investigating tralokinumab effects on eosinophil-driven inflammation and airway remodeling.","PeriodicalId":10369,"journal":{"name":"Clinical investigation","volume":"22 1","pages":"713-722"},"PeriodicalIF":0.0,"publicationDate":"2015-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90433859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
W. Busse, Millie Wang, J. Gibson, Mattis Gottlow, M. Braddock, G. Colice
In a Phase IIb study, administration of tralokinumab, an anti-IL-13, fully human monoclonal antibody, to patients with severe uncontrolled asthma treated with high-dose inhaled corticosteroid (ICS) and long-acting β2-agonists (LABA) significantly improved lung function. Since many patients with severe asthma using ICS-LABA only achieve symptom control with add-on oral corticosteroids (OCS), an unmet need for OCS-sparing treatment strategies exists. This Phase III, randomized, double-blind, parallel-group, placebo-controlled TROPOS (NCT02281357) study will evaluate the OCS-sparing potential of tralokinumab in patients with severe asthma requiring continuous ICS-LABA and chronic maintenance OCS. After an initial screening/assessment period, patients will be randomized to tralokinumab or placebo for 40 weeks (12-week induction, 20-week OCS reduction and 8-week maintenance phases); patients will be followed-up for 14 weeks.
{"title":"TROPOS: designing a clinical trial to evaluate the oral corticosteroid-sparing effect of a biologic in severe asthma","authors":"W. Busse, Millie Wang, J. Gibson, Mattis Gottlow, M. Braddock, G. Colice","doi":"10.4155/CLI.15.37","DOIUrl":"https://doi.org/10.4155/CLI.15.37","url":null,"abstract":"In a Phase IIb study, administration of tralokinumab, an anti-IL-13, fully human monoclonal antibody, to patients with severe uncontrolled asthma treated with high-dose inhaled corticosteroid (ICS) and long-acting β2-agonists (LABA) significantly improved lung function. Since many patients with severe asthma using ICS-LABA only achieve symptom control with add-on oral corticosteroids (OCS), an unmet need for OCS-sparing treatment strategies exists. This Phase III, randomized, double-blind, parallel-group, placebo-controlled TROPOS (NCT02281357) study will evaluate the OCS-sparing potential of tralokinumab in patients with severe asthma requiring continuous ICS-LABA and chronic maintenance OCS. After an initial screening/assessment period, patients will be randomized to tralokinumab or placebo for 40 weeks (12-week induction, 20-week OCS reduction and 8-week maintenance phases); patients will be followed-up for 14 weeks.","PeriodicalId":10369,"journal":{"name":"Clinical investigation","volume":"125 1","pages":"723-730"},"PeriodicalIF":0.0,"publicationDate":"2015-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74628355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Seremetis, R. Kulkarni, A. Regnault, E. Santagostino
Hemophilia A is an X-linked recessive hereditary bleeding disorder resulting from a deficiency in coagulation factor VIII. Difficulties due to hemophilia and its management present challenges for patient's quality of life. Turoctocog alfa, a recombinant, B-domain truncated factor VIII, is a recent US FDA- and EMA-approved replacement therapy shown to be an effective and safe option for the treatment of individuals with hemophilia A. Data collected throughout two Phase 3, multinational, open-label, non-randomized, non-comparative trials demonstrated that individuals with hemophilia A, particularly young adults experienced improvements in health-related quality of life when switched from an on-demand to a prophylactic regimen of turoctocog alfa.
{"title":"Turoctocog alfa in the treatment of individuals with hemophilia A: review of quality of life data collected in Phase III trials","authors":"S. Seremetis, R. Kulkarni, A. Regnault, E. Santagostino","doi":"10.4155/CLI.15.43","DOIUrl":"https://doi.org/10.4155/CLI.15.43","url":null,"abstract":"Hemophilia A is an X-linked recessive hereditary bleeding disorder resulting from a deficiency in coagulation factor VIII. Difficulties due to hemophilia and its management present challenges for patient's quality of life. Turoctocog alfa, a recombinant, B-domain truncated factor VIII, is a recent US FDA- and EMA-approved replacement therapy shown to be an effective and safe option for the treatment of individuals with hemophilia A. Data collected throughout two Phase 3, multinational, open-label, non-randomized, non-comparative trials demonstrated that individuals with hemophilia A, particularly young adults experienced improvements in health-related quality of life when switched from an on-demand to a prophylactic regimen of turoctocog alfa.","PeriodicalId":10369,"journal":{"name":"Clinical investigation","volume":"5 1","pages":"755-765"},"PeriodicalIF":0.0,"publicationDate":"2015-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78598464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
What is the problem all about? Clinical trials are sometimes described as being rather ‘blunt’ instruments, and that often may be true: we use them to find answers to very broad questions such as ‘does this drug work better than a control drug?’ But they are also very important and delicate instruments: we use them to find answers to questions such as ‘how much does this drug work?’ ‘what is the safety profile of this drug?’ and so on. And in the nature of research, we do not know what the right answer is and we have to rely on the clinical trial to give us the right answer. If anything is broken in the trial, it might give us the wrong answer – but we might have no way of know whether answer is right or wrong (unless we can see a break, or maybe just a dent, in the trial). Bias is one of the big concerns in any trial and it is why we typically use the key building blocks of blinding and randomization. It is also why we typically do not look at the data every week or two and see how one treatment is doing compared with another. We set up an experiment, we allow it to run unhindered, and then we look at the results. The problem (of course) is what should we do if something in the trial is going in a very different direction to where we thought it was? This might be that the new treatment is far better than the control treatment – even to the extent that it is far better than we initially expected. Patients are potentially being disadvantaged by being randomized to the control arm; something needs to be done. Or it might be that our new treatment, while backed by some of the greatest investors and optimists the world has produced, actually is not working. We are wasting a lot of time, resource, patients’ goodwill and, not to forget ... quite a lot of money. Something surely needs to be done! So we are in the dilemma of wanting to run a trial, without external interference, maintaining blinding and randomization, but we also want to know what the results look like. Enter the independent data monitoring committee (DMC).
{"title":"Data monitoring committees in clinical trials: best practice, complexities and considerations","authors":"S. Day","doi":"10.4155/CLI.15.31","DOIUrl":"https://doi.org/10.4155/CLI.15.31","url":null,"abstract":"What is the problem all about? Clinical trials are sometimes described as being rather ‘blunt’ instruments, and that often may be true: we use them to find answers to very broad questions such as ‘does this drug work better than a control drug?’ But they are also very important and delicate instruments: we use them to find answers to questions such as ‘how much does this drug work?’ ‘what is the safety profile of this drug?’ and so on. And in the nature of research, we do not know what the right answer is and we have to rely on the clinical trial to give us the right answer. If anything is broken in the trial, it might give us the wrong answer – but we might have no way of know whether answer is right or wrong (unless we can see a break, or maybe just a dent, in the trial). Bias is one of the big concerns in any trial and it is why we typically use the key building blocks of blinding and randomization. It is also why we typically do not look at the data every week or two and see how one treatment is doing compared with another. We set up an experiment, we allow it to run unhindered, and then we look at the results. The problem (of course) is what should we do if something in the trial is going in a very different direction to where we thought it was? This might be that the new treatment is far better than the control treatment – even to the extent that it is far better than we initially expected. Patients are potentially being disadvantaged by being randomized to the control arm; something needs to be done. Or it might be that our new treatment, while backed by some of the greatest investors and optimists the world has produced, actually is not working. We are wasting a lot of time, resource, patients’ goodwill and, not to forget ... quite a lot of money. Something surely needs to be done! So we are in the dilemma of wanting to run a trial, without external interference, maintaining blinding and randomization, but we also want to know what the results look like. Enter the independent data monitoring committee (DMC).","PeriodicalId":10369,"journal":{"name":"Clinical investigation","volume":"15 1","pages":"615-617"},"PeriodicalIF":0.0,"publicationDate":"2015-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86175439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tyrosine kinase inhibitors (TKIs) are the mainstay of the management of advanced gastrointestinal stromal tumors (GISTs). Currently, imatinib, sunitinib and regorafenib are approved treatments for advanced GISTs. However, most standard therapies eventually stop working due to polyclonal evolution of the disease, which results in TKI resistance and overall disease progression. For patients with refractory GISTs after progression on all approved TKIs, resumption of previously effective TKIs may have clinical benefit. However, no randomized trial had been performed to support TKI reuse in patients with advanced GISTs. Recently, a placebo-controlled randomized Phase III trial (RIGHT) found that imatinib resumption significantly prolonged progression-free survival in patients with TKI-refractory GISTs versus placebo. The details of the RIGHT trial and its clinical implications are reviewed here.
{"title":"Rechallenge with imatinib in advanced gastrointestinal stromal tumors: clinical implications of the RIGHT trial","authors":"C. Yoo, Yoon-Koo Kang","doi":"10.4155/CLI.15.26","DOIUrl":"https://doi.org/10.4155/CLI.15.26","url":null,"abstract":"Tyrosine kinase inhibitors (TKIs) are the mainstay of the management of advanced gastrointestinal stromal tumors (GISTs). Currently, imatinib, sunitinib and regorafenib are approved treatments for advanced GISTs. However, most standard therapies eventually stop working due to polyclonal evolution of the disease, which results in TKI resistance and overall disease progression. For patients with refractory GISTs after progression on all approved TKIs, resumption of previously effective TKIs may have clinical benefit. However, no randomized trial had been performed to support TKI reuse in patients with advanced GISTs. Recently, a placebo-controlled randomized Phase III trial (RIGHT) found that imatinib resumption significantly prolonged progression-free survival in patients with TKI-refractory GISTs versus placebo. The details of the RIGHT trial and its clinical implications are reviewed here.","PeriodicalId":10369,"journal":{"name":"Clinical investigation","volume":"24 1","pages":"665-675"},"PeriodicalIF":0.0,"publicationDate":"2015-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82270815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
2015 Elin H Davies speaks to Stella Bennett, Commissioning Editor: Elin qualified as a children’s nurse at Great Ormond St Children’s Hospital, pursuing a BSc, MSc and receiving a PhD from University College London. Elin has over a decade of clinical and academic experience of research and drug development, working at an international level. She also worked at the EMA for 6 years as part of the team responsible for implementing the Paediatric Regulation in Europe. In January 2015, Elin launched a social enterprise using wearable technology and mobile phone apps to monitor disease progression. She also has a personal interest in empowering children to become involved in the health/research agenda. Her personal passion is for extreme challenges and adventures.
{"title":"Nursing to regulator, rowing to digital health","authors":"E. Davies","doi":"10.4155/cli.15.28","DOIUrl":"https://doi.org/10.4155/cli.15.28","url":null,"abstract":"2015 Elin H Davies speaks to Stella Bennett, Commissioning Editor: Elin qualified as a children’s nurse at Great Ormond St Children’s Hospital, pursuing a BSc, MSc and receiving a PhD from University College London. Elin has over a decade of clinical and academic experience of research and drug development, working at an international level. She also worked at the EMA for 6 years as part of the team responsible for implementing the Paediatric Regulation in Europe. In January 2015, Elin launched a social enterprise using wearable technology and mobile phone apps to monitor disease progression. She also has a personal interest in empowering children to become involved in the health/research agenda. Her personal passion is for extreme challenges and adventures.","PeriodicalId":10369,"journal":{"name":"Clinical investigation","volume":"4 1","pages":"619-620"},"PeriodicalIF":0.0,"publicationDate":"2015-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87250264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The goal of this review is to critically analyze data supporting the use of ruxolitinib in polycythemia vera patients resistant or intolerant to hydroxyurea. We analyzed the randomized Phase III study (RESPONSE) and we applied the Grading of Evidence, Assessment, Development and Evaluation approach by evaluating five dimensions of evidence: overall risk of bias, imprecision, inconsistency, indirectness and publication bias. We upgraded the quality of evidence because of large effect size on splenomegaly, hematocrit and symptoms but we downgraded it for performance bias and for indirectness of the comparator. In conclusion, by identifying factors affecting the quality of evidence, we rated the outcomes of ruxolitinib in polycythemia vera patients resistant or intolerant to hydroxyurea as having moderate level of evidence.
{"title":"Ruxolitinib for patients with polycythemia vera who have had an inadequate response or are intolerant to hydroxyurea: a critical appraisal","authors":"G. Barosi","doi":"10.4155/CLI.15.33","DOIUrl":"https://doi.org/10.4155/CLI.15.33","url":null,"abstract":"The goal of this review is to critically analyze data supporting the use of ruxolitinib in polycythemia vera patients resistant or intolerant to hydroxyurea. We analyzed the randomized Phase III study (RESPONSE) and we applied the Grading of Evidence, Assessment, Development and Evaluation approach by evaluating five dimensions of evidence: overall risk of bias, imprecision, inconsistency, indirectness and publication bias. We upgraded the quality of evidence because of large effect size on splenomegaly, hematocrit and symptoms but we downgraded it for performance bias and for indirectness of the comparator. In conclusion, by identifying factors affecting the quality of evidence, we rated the outcomes of ruxolitinib in polycythemia vera patients resistant or intolerant to hydroxyurea as having moderate level of evidence.","PeriodicalId":10369,"journal":{"name":"Clinical investigation","volume":"53 1","pages":"643-651"},"PeriodicalIF":0.0,"publicationDate":"2015-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87448446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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