A prospective, randomized, multicenter clinical trial on the safety and efficacy of a ready-to-use fibrin sealant as an adjunct to hemostasis during vascular surgery
Abstract Purpose Anastomotic or “stitch hole” bleeding is common during vascular surgery with synthetic material such as Dacron or polytetrafluoroethylene (PTFE). Hemostatic adjuncts such as fibrin sealant (FS) may reduce blood loss and operating time in such circumstances. We evaluated the safety a...
Gespeichert in:
| Veröffentlicht in: | Annals of vascular surgery 2017-11, Vol.45, p.127-137 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 137 |
|---|---|
| container_issue | |
| container_start_page | 127 |
| container_title | Annals of vascular surgery |
| container_volume | 45 |
| creator | Chetter, Ian Stansby, Gerard Sarralde, José Aurelio Riambau, Vicente Giménez-Gaibar, Antonio MacKenzie, Kent Acín, Francisco Navarro-Puerto, Jordi |
| description | Abstract Purpose Anastomotic or “stitch hole” bleeding is common during vascular surgery with synthetic material such as Dacron or polytetrafluoroethylene (PTFE). Hemostatic adjuncts such as fibrin sealant (FS) may reduce blood loss and operating time in such circumstances. We evaluated the safety and the hemostatic effectiveness of a ready-to-use human plasma-derived FS in vascular surgery. Methods Patients with mild / moderate suture line bleeding during elective, open, vascular surgery using synthetic grafts or patches were studied. In an initial Exploratory Study all patients were treated with FS Grifols, and in a subsequent Primary Study were randomized in a 2:1 ratio to FS Grifols or manual compression (MC). The primary efficacy endpoint was time to hemostasis (TTH), assessed at defined intervals from the start of treatment application, during a 10-minute observational period. Safety endpoints (in Exploratory+Primary Studies) included adverse events (AEs), vital signs, physical assessments, common clinical laboratory tests (coagulation; complete blood count; serum clinical chemistry parameters; microscopic urinalysis), viral markers, and immunogenicity. Results In the Primary Study the proportion of patients who achieved hemostasis at the 3 minute time point was higher in FS Grifols group (46.4%; n=51/110) than in MC group (26.3%; n=15/57) (P |
| doi_str_mv | 10.1016/j.avsg.2017.06.043 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1913831058</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0890509616313061</els_id><sourcerecordid>1913831058</sourcerecordid><originalsourceid>FETCH-LOGICAL-c481t-e4701913c9ca948e73558c4357e562e17ad5611a49e7fc7d65806bb36eca7fea3</originalsourceid><addsrcrecordid>eNp9ks1u1DAUhSMEokPhBVigu2TRBDs_jiMhpKriT6rEAlhbHudm6pDEg689Ungf3hNH07JgwcZe-Jxj-3w3y15yVnDGxZux0Cc6FCXjbcFEwerqUbbjgjd509Xt42zHZMfyhnXiIntGNDLGS1nLp9lFKUXdiorvst_XcPSOjmiCPeEVeL30bra_sL-COU7BGlwCejCTXazREwRv0-oWCHcIpAcMKyQP4DCkc7OCG0CDR92veXB5JITB7r1dgFBPegmgKRlA92NcTIDg4A5nR0GTJehjUh7gpMnESXug6A_o1-fZk0FPhC_u98vs-4f3324-5bdfPn6-ub7NTS15yLFuGe94ZTqju1piWzWNNHXVtNiIEnmr-0ZwrusO28G0vWgkE_t9JdDodkBdXWavz7mpk58RKajZksEpvRtdJLWFy4qzRiZpeZaaVB95HNTR21n7VXGmNjxqVBseteFRTKiEJ5le3efH_Yz9X8sDjyR4exZg-uXJoldkLC4Ge-sTItU7-__8d__YH7j9wBVpdNEvqT_FFZWKqa_bgGzzwbe7meDVH_TxuSk</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1913831058</pqid></control><display><type>article</type><title>A prospective, randomized, multicenter clinical trial on the safety and efficacy of a ready-to-use fibrin sealant as an adjunct to hemostasis during vascular surgery</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Chetter, Ian ; Stansby, Gerard ; Sarralde, José Aurelio ; Riambau, Vicente ; Giménez-Gaibar, Antonio ; MacKenzie, Kent ; Acín, Francisco ; Navarro-Puerto, Jordi</creator><creatorcontrib>Chetter, Ian ; Stansby, Gerard ; Sarralde, José Aurelio ; Riambau, Vicente ; Giménez-Gaibar, Antonio ; MacKenzie, Kent ; Acín, Francisco ; Navarro-Puerto, Jordi ; Investigators of the Fibrin Sealant Grifols Study Group</creatorcontrib><description>Abstract Purpose Anastomotic or “stitch hole” bleeding is common during vascular surgery with synthetic material such as Dacron or polytetrafluoroethylene (PTFE). Hemostatic adjuncts such as fibrin sealant (FS) may reduce blood loss and operating time in such circumstances. We evaluated the safety and the hemostatic effectiveness of a ready-to-use human plasma-derived FS in vascular surgery. Methods Patients with mild / moderate suture line bleeding during elective, open, vascular surgery using synthetic grafts or patches were studied. In an initial Exploratory Study all patients were treated with FS Grifols, and in a subsequent Primary Study were randomized in a 2:1 ratio to FS Grifols or manual compression (MC). The primary efficacy endpoint was time to hemostasis (TTH), assessed at defined intervals from the start of treatment application, during a 10-minute observational period. Safety endpoints (in Exploratory+Primary Studies) included adverse events (AEs), vital signs, physical assessments, common clinical laboratory tests (coagulation; complete blood count; serum clinical chemistry parameters; microscopic urinalysis), viral markers, and immunogenicity. Results In the Primary Study the proportion of patients who achieved hemostasis at the 3 minute time point was higher in FS Grifols group (46.4%; n=51/110) than in MC group (26.3%; n=15/57) (P<0.05). The benefit was maintained at successive time intervals: 69 FS Grifols patients (62.7%) and 18 MC patients (31.6%) at 4 min; 82 FS Grifols patients (74.5%) and 28 MC patients (49.1%) at 5 min. The differences between the groups persisted for TTH ≤7 minutes and TTH ≤10 minutes. Treatment failure was reported for 13 FS Grifols patients (11.8%) and 16 MC patients (28.1%).TTH was shorter after FS Grifols application than after MC application. Differences were statistically significant in favor of FS Grifols for each TTH category and for the overall comparison (p <0.001) as well as for each TTH category (cumulative) and for treatment failure (p =0.016). Overall AE experience and types of AEs reported were those expected in this patient population and were similar between the 2 treatment groups. The most frequently reported AE were procedural pain (59.9% and 69.2% of patients in the FS Grifols [n=72+111] and MC [n=57] groups, respectively) and nausea (23.5% and 19.2% of patients, respectively). Conclusion FS Grifols was efficacious and safe as an adjunct to anastomotic hemostasis in patients undergoing arterial surgery using prosthetic material with mild to moderate bleeding.</description><identifier>ISSN: 0890-5096</identifier><identifier>EISSN: 1615-5947</identifier><identifier>DOI: 10.1016/j.avsg.2017.06.043</identifier><identifier>PMID: 28647631</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>Aged ; Aged, 80 and over ; Blood Loss, Surgical - prevention & control ; Canada ; Female ; Fibrin Tissue Adhesive - adverse effects ; Fibrin Tissue Adhesive - therapeutic use ; Hemostasis - drug effects ; Hemostatic Techniques - adverse effects ; Hemostatics - adverse effects ; Hemostatics - therapeutic use ; Humans ; Male ; Middle Aged ; Prospective Studies ; Single-Blind Method ; Spain ; Surgery ; Time Factors ; Treatment Outcome ; United Kingdom ; Vascular Surgical Procedures - adverse effects</subject><ispartof>Annals of vascular surgery, 2017-11, Vol.45, p.127-137</ispartof><rights>2017 The Authors</rights><rights>Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c481t-e4701913c9ca948e73558c4357e562e17ad5611a49e7fc7d65806bb36eca7fea3</citedby><cites>FETCH-LOGICAL-c481t-e4701913c9ca948e73558c4357e562e17ad5611a49e7fc7d65806bb36eca7fea3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0890509616313061$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28647631$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chetter, Ian</creatorcontrib><creatorcontrib>Stansby, Gerard</creatorcontrib><creatorcontrib>Sarralde, José Aurelio</creatorcontrib><creatorcontrib>Riambau, Vicente</creatorcontrib><creatorcontrib>Giménez-Gaibar, Antonio</creatorcontrib><creatorcontrib>MacKenzie, Kent</creatorcontrib><creatorcontrib>Acín, Francisco</creatorcontrib><creatorcontrib>Navarro-Puerto, Jordi</creatorcontrib><creatorcontrib>Investigators of the Fibrin Sealant Grifols Study Group</creatorcontrib><title>A prospective, randomized, multicenter clinical trial on the safety and efficacy of a ready-to-use fibrin sealant as an adjunct to hemostasis during vascular surgery</title><title>Annals of vascular surgery</title><addtitle>Ann Vasc Surg</addtitle><description>Abstract Purpose Anastomotic or “stitch hole” bleeding is common during vascular surgery with synthetic material such as Dacron or polytetrafluoroethylene (PTFE). Hemostatic adjuncts such as fibrin sealant (FS) may reduce blood loss and operating time in such circumstances. We evaluated the safety and the hemostatic effectiveness of a ready-to-use human plasma-derived FS in vascular surgery. Methods Patients with mild / moderate suture line bleeding during elective, open, vascular surgery using synthetic grafts or patches were studied. In an initial Exploratory Study all patients were treated with FS Grifols, and in a subsequent Primary Study were randomized in a 2:1 ratio to FS Grifols or manual compression (MC). The primary efficacy endpoint was time to hemostasis (TTH), assessed at defined intervals from the start of treatment application, during a 10-minute observational period. Safety endpoints (in Exploratory+Primary Studies) included adverse events (AEs), vital signs, physical assessments, common clinical laboratory tests (coagulation; complete blood count; serum clinical chemistry parameters; microscopic urinalysis), viral markers, and immunogenicity. Results In the Primary Study the proportion of patients who achieved hemostasis at the 3 minute time point was higher in FS Grifols group (46.4%; n=51/110) than in MC group (26.3%; n=15/57) (P<0.05). The benefit was maintained at successive time intervals: 69 FS Grifols patients (62.7%) and 18 MC patients (31.6%) at 4 min; 82 FS Grifols patients (74.5%) and 28 MC patients (49.1%) at 5 min. The differences between the groups persisted for TTH ≤7 minutes and TTH ≤10 minutes. Treatment failure was reported for 13 FS Grifols patients (11.8%) and 16 MC patients (28.1%).TTH was shorter after FS Grifols application than after MC application. Differences were statistically significant in favor of FS Grifols for each TTH category and for the overall comparison (p <0.001) as well as for each TTH category (cumulative) and for treatment failure (p =0.016). Overall AE experience and types of AEs reported were those expected in this patient population and were similar between the 2 treatment groups. The most frequently reported AE were procedural pain (59.9% and 69.2% of patients in the FS Grifols [n=72+111] and MC [n=57] groups, respectively) and nausea (23.5% and 19.2% of patients, respectively). Conclusion FS Grifols was efficacious and safe as an adjunct to anastomotic hemostasis in patients undergoing arterial surgery using prosthetic material with mild to moderate bleeding.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Blood Loss, Surgical - prevention & control</subject><subject>Canada</subject><subject>Female</subject><subject>Fibrin Tissue Adhesive - adverse effects</subject><subject>Fibrin Tissue Adhesive - therapeutic use</subject><subject>Hemostasis - drug effects</subject><subject>Hemostatic Techniques - adverse effects</subject><subject>Hemostatics - adverse effects</subject><subject>Hemostatics - therapeutic use</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Prospective Studies</subject><subject>Single-Blind Method</subject><subject>Spain</subject><subject>Surgery</subject><subject>Time Factors</subject><subject>Treatment Outcome</subject><subject>United Kingdom</subject><subject>Vascular Surgical Procedures - adverse effects</subject><issn>0890-5096</issn><issn>1615-5947</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9ks1u1DAUhSMEokPhBVigu2TRBDs_jiMhpKriT6rEAlhbHudm6pDEg689Ungf3hNH07JgwcZe-Jxj-3w3y15yVnDGxZux0Cc6FCXjbcFEwerqUbbjgjd509Xt42zHZMfyhnXiIntGNDLGS1nLp9lFKUXdiorvst_XcPSOjmiCPeEVeL30bra_sL-COU7BGlwCejCTXazREwRv0-oWCHcIpAcMKyQP4DCkc7OCG0CDR92veXB5JITB7r1dgFBPegmgKRlA92NcTIDg4A5nR0GTJehjUh7gpMnESXug6A_o1-fZk0FPhC_u98vs-4f3324-5bdfPn6-ub7NTS15yLFuGe94ZTqju1piWzWNNHXVtNiIEnmr-0ZwrusO28G0vWgkE_t9JdDodkBdXWavz7mpk58RKajZksEpvRtdJLWFy4qzRiZpeZaaVB95HNTR21n7VXGmNjxqVBseteFRTKiEJ5le3efH_Yz9X8sDjyR4exZg-uXJoldkLC4Ge-sTItU7-__8d__YH7j9wBVpdNEvqT_FFZWKqa_bgGzzwbe7meDVH_TxuSk</recordid><startdate>20171101</startdate><enddate>20171101</enddate><creator>Chetter, Ian</creator><creator>Stansby, Gerard</creator><creator>Sarralde, José Aurelio</creator><creator>Riambau, Vicente</creator><creator>Giménez-Gaibar, Antonio</creator><creator>MacKenzie, Kent</creator><creator>Acín, Francisco</creator><creator>Navarro-Puerto, Jordi</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20171101</creationdate><title>A prospective, randomized, multicenter clinical trial on the safety and efficacy of a ready-to-use fibrin sealant as an adjunct to hemostasis during vascular surgery</title><author>Chetter, Ian ; Stansby, Gerard ; Sarralde, José Aurelio ; Riambau, Vicente ; Giménez-Gaibar, Antonio ; MacKenzie, Kent ; Acín, Francisco ; Navarro-Puerto, Jordi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c481t-e4701913c9ca948e73558c4357e562e17ad5611a49e7fc7d65806bb36eca7fea3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Blood Loss, Surgical - prevention & control</topic><topic>Canada</topic><topic>Female</topic><topic>Fibrin Tissue Adhesive - adverse effects</topic><topic>Fibrin Tissue Adhesive - therapeutic use</topic><topic>Hemostasis - drug effects</topic><topic>Hemostatic Techniques - adverse effects</topic><topic>Hemostatics - adverse effects</topic><topic>Hemostatics - therapeutic use</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Prospective Studies</topic><topic>Single-Blind Method</topic><topic>Spain</topic><topic>Surgery</topic><topic>Time Factors</topic><topic>Treatment Outcome</topic><topic>United Kingdom</topic><topic>Vascular Surgical Procedures - adverse effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chetter, Ian</creatorcontrib><creatorcontrib>Stansby, Gerard</creatorcontrib><creatorcontrib>Sarralde, José Aurelio</creatorcontrib><creatorcontrib>Riambau, Vicente</creatorcontrib><creatorcontrib>Giménez-Gaibar, Antonio</creatorcontrib><creatorcontrib>MacKenzie, Kent</creatorcontrib><creatorcontrib>Acín, Francisco</creatorcontrib><creatorcontrib>Navarro-Puerto, Jordi</creatorcontrib><creatorcontrib>Investigators of the Fibrin Sealant Grifols Study Group</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Annals of vascular surgery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chetter, Ian</au><au>Stansby, Gerard</au><au>Sarralde, José Aurelio</au><au>Riambau, Vicente</au><au>Giménez-Gaibar, Antonio</au><au>MacKenzie, Kent</au><au>Acín, Francisco</au><au>Navarro-Puerto, Jordi</au><aucorp>Investigators of the Fibrin Sealant Grifols Study Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A prospective, randomized, multicenter clinical trial on the safety and efficacy of a ready-to-use fibrin sealant as an adjunct to hemostasis during vascular surgery</atitle><jtitle>Annals of vascular surgery</jtitle><addtitle>Ann Vasc Surg</addtitle><date>2017-11-01</date><risdate>2017</risdate><volume>45</volume><spage>127</spage><epage>137</epage><pages>127-137</pages><issn>0890-5096</issn><eissn>1615-5947</eissn><abstract>Abstract Purpose Anastomotic or “stitch hole” bleeding is common during vascular surgery with synthetic material such as Dacron or polytetrafluoroethylene (PTFE). Hemostatic adjuncts such as fibrin sealant (FS) may reduce blood loss and operating time in such circumstances. We evaluated the safety and the hemostatic effectiveness of a ready-to-use human plasma-derived FS in vascular surgery. Methods Patients with mild / moderate suture line bleeding during elective, open, vascular surgery using synthetic grafts or patches were studied. In an initial Exploratory Study all patients were treated with FS Grifols, and in a subsequent Primary Study were randomized in a 2:1 ratio to FS Grifols or manual compression (MC). The primary efficacy endpoint was time to hemostasis (TTH), assessed at defined intervals from the start of treatment application, during a 10-minute observational period. Safety endpoints (in Exploratory+Primary Studies) included adverse events (AEs), vital signs, physical assessments, common clinical laboratory tests (coagulation; complete blood count; serum clinical chemistry parameters; microscopic urinalysis), viral markers, and immunogenicity. Results In the Primary Study the proportion of patients who achieved hemostasis at the 3 minute time point was higher in FS Grifols group (46.4%; n=51/110) than in MC group (26.3%; n=15/57) (P<0.05). The benefit was maintained at successive time intervals: 69 FS Grifols patients (62.7%) and 18 MC patients (31.6%) at 4 min; 82 FS Grifols patients (74.5%) and 28 MC patients (49.1%) at 5 min. The differences between the groups persisted for TTH ≤7 minutes and TTH ≤10 minutes. Treatment failure was reported for 13 FS Grifols patients (11.8%) and 16 MC patients (28.1%).TTH was shorter after FS Grifols application than after MC application. Differences were statistically significant in favor of FS Grifols for each TTH category and for the overall comparison (p <0.001) as well as for each TTH category (cumulative) and for treatment failure (p =0.016). Overall AE experience and types of AEs reported were those expected in this patient population and were similar between the 2 treatment groups. The most frequently reported AE were procedural pain (59.9% and 69.2% of patients in the FS Grifols [n=72+111] and MC [n=57] groups, respectively) and nausea (23.5% and 19.2% of patients, respectively). Conclusion FS Grifols was efficacious and safe as an adjunct to anastomotic hemostasis in patients undergoing arterial surgery using prosthetic material with mild to moderate bleeding.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>28647631</pmid><doi>10.1016/j.avsg.2017.06.043</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0890-5096 |
| ispartof | Annals of vascular surgery, 2017-11, Vol.45, p.127-137 |
| issn | 0890-5096 1615-5947 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1913831058 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Aged Aged, 80 and over Blood Loss, Surgical - prevention & control Canada Female Fibrin Tissue Adhesive - adverse effects Fibrin Tissue Adhesive - therapeutic use Hemostasis - drug effects Hemostatic Techniques - adverse effects Hemostatics - adverse effects Hemostatics - therapeutic use Humans Male Middle Aged Prospective Studies Single-Blind Method Spain Surgery Time Factors Treatment Outcome United Kingdom Vascular Surgical Procedures - adverse effects |
| title | A prospective, randomized, multicenter clinical trial on the safety and efficacy of a ready-to-use fibrin sealant as an adjunct to hemostasis during vascular surgery |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T07%3A23%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20prospective,%20randomized,%20multicenter%20clinical%20trial%20on%20the%20safety%20and%20efficacy%20of%20a%20ready-to-use%20fibrin%20sealant%20as%20an%20adjunct%20to%20hemostasis%20during%20vascular%20surgery&rft.jtitle=Annals%20of%20vascular%20surgery&rft.au=Chetter,%20Ian&rft.aucorp=Investigators%20of%20the%20Fibrin%20Sealant%20Grifols%20Study%20Group&rft.date=2017-11-01&rft.volume=45&rft.spage=127&rft.epage=137&rft.pages=127-137&rft.issn=0890-5096&rft.eissn=1615-5947&rft_id=info:doi/10.1016/j.avsg.2017.06.043&rft_dat=%3Cproquest_cross%3E1913831058%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1913831058&rft_id=info:pmid/28647631&rft_els_id=S0890509616313061&rfr_iscdi=true |