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Original research
Hemorrhage rates in patients with acute ischemic stroke treated with intravenous alteplase and thrombectomy versus thrombectomy alone
  1. Katinka R van Kranendonk1,
  2. Manon Kappelhof1,
  3. Agnetha A E Bruggeman1,
  4. Leon A Rinkel2,
  5. Kilian M Treurniet1,3,
  6. Natalie LeCouffe2,
  7. Bart J Emmer1,
  8. Jonathan M Coutinho2,
  9. Lennard Wolff4,
  10. Wim H van Zwam5,
  11. Robert J van Oostenbrugge6,
  12. Aad van der Lugt4,
  13. Diederik W J Dippel7,
  14. Yvo B W E M Roos2,
  15. Henk A Marquering1,8,
  16. Charles B L M Majoie1
  17. MR CLEAN-NO IV Investigators
    1. 1Radiology and Nuclear Medicine, Amsterdam UMC Location AMC, Amsterdam, Noord-Holland, The Netherlands
    2. 2Neurology, Amsterdam UMC Locatie AMC, Amsterdam, North Holland, The Netherlands
    3. 3Radiology, Haaglanden Medical Center Bronovo, Den Haag, Zuid-Holland, The Netherlands
    4. 4Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam, Zuid-Holland, The Netherlands
    5. 5Radiology, Maastricht University Cardiovascular Research Institute Maastricht, Maastricht, Limburg, The Netherlands
    6. 6Neurology, Maastricht University Cardiovascular Research Institute Maastricht, Maastricht, Limburg, The Netherlands
    7. 7Neurology, Erasmus MC, Rotterdam, Zuid-Holland, The Netherlands
    8. 8Biomedical Engineering and Physics, Amsterdam UMC Location AMC, Amsterdam, North Holland, The Netherlands
    1. Correspondence to Katinka R van Kranendonk, Radiology and Nuclear Medicine, Amsterdam UMC Locatie AMC, 1105 AZ Amsterdam, The Netherlands; k.r.vankranendonk{at}amsterdamumc.nl

    Abstract

    Background Intravenous alteplase treatment (IVT) for acute ischemic stroke carries a risk of intracranial hemorrhage (ICH). However, reperfusion of an occluded vessel itself may contribute to the risk of ICH. We determined whether IVT and reperfusion are associated with ICH or its volume in the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN)-NO IV trial.

    Methods The MR CLEAN-NO IV trial randomized patients with acute ischemic stroke due to large vessel occlusion to receive either IVT followed by endovascular treatment (EVT) or EVT alone. ICH was classified according to the Heidelberg bleeding classification on follow-up MRI or CT approximately 8 hours−7 days after stroke. Hemorrhage volume was measured with ITK-snap. Successful reperfusion was defined as extended Thrombolysis In Cerebral Infarction (eTICI) score of 2b-3. Multinomial and binary adjusted logistic regression were used to determine the association of IVT and reperfusion with ICH subtypes.

    Results Of 539 included patients, 173 (32%) developed ICH and 30 suffered from symptomatic ICH (sICH) (6%). Of the patients with ICH, 102 had hemorrhagic infarction, 47 had parenchymal hematoma, 44 had SAH, and six had other ICH. Reperfusion was associated with a decreased risk of SAH, and IVT was not associated with SAH (eTICI 2b-3: adjusted OR 0.45, 95% CI 0.21 to 0.97; EVT without IVT: OR 1.6, 95% CI 0.91 to 2.8). Reperfusion status and IVT were not associated with overall ICH, hemorrhage volume, and sICH (sICH: EVT without IVT, OR 0.96, 95% CI 0.41 to 2.25; eTICI 2b-3, OR 0.49, 95% CI 0.23 to 1.05).

    Conclusion Neither IVT administration before EVT nor successful reperfusion after EVT were associated with ICH, hemorrhage volume, and sICH. SAH occurred more often in patients for whom successful reperfusion was not achieved.

    • Thrombolysis
    • Stroke
    • Thrombectomy
    • Hemorrhage

    Data availability statement

    Data are available upon reasonable request. Data are available upon reasonable request after approval by the CONTRAST data access and writing committee.

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    Data availability statement

    Data are available upon reasonable request. Data are available upon reasonable request after approval by the CONTRAST data access and writing committee.

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    Footnotes

    • Collaborators List of MR CLEAN-NO IV Investigators, Collaborators, and Affiliations. Principal investigators: Yvo Roos (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Charles Majoie (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Study coordinators Kilian Treurniet (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Jonathan Coutinho (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Bart Emmer (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Natalie LeCouffe (MD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Manon Kappelhof (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Leon Rinkel (MD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Agnetha Bruggeman (MD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Local principal investigators: Bob Roozenbeek (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Adriaan van Es (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Inger de Ridder (MD, PhD) (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), Wim van Zwam (MD, PhD) (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), Bart van der Worp (MD, PhD) (University Medical Center Utrecht, Brain Center, Utrecht, the Netherlands), Rob Lo (MD, PhD) (University Medical Center Utrecht, Brain Center, Utrecht, the Netherlands), Koos Keizer (MD, PhD) (Catharina Hospital, Eindhoven, the Netherlands), Rob Gons (MD), Lonneke Yo (MD, PhD) (Catharina Hospital, Eindhoven, the Netherlands), Jelis Boiten (MD, PhD) (Haaglanden Medical Center, the Hague, the Netherlands), Ido van den Wijngaard (MD, PhD) (Haaglanden Medical Center, the Hague, the Netherlands), Geert Lycklama à Nijeholt (MD, PhD) (Haaglanden Medical Center, the Hague, the Netherlands), Jeannette Hofmeijer (MD, PhD) (Rijnstate Hospital, Arnhem, the Netherlands), Jasper Martens (MD) (Rijnstate Hospital, Arnhem, the Netherlands), Wouter Schonewille (MD, PhD) (St Antonius Hospital, Nieuwegein, the Netherlands), Jan Albert Vos (MD, PhD) (St Antonius Hospital, Nieuwegein, the Netherlands), Anil Tuladhar (MD, PhD) (Radboud University Medical Center, Nijmegen, the Netherlands), Floris Schreuder (MD, PhD) (Radboud University Medical Center, Nijmegen, the Netherlands), Jeroen Boogaarts (MD, PhD) (Radboud University Medical Center, Nijmegen, the Netherlands), Sjoerd Jenniskens (MD) (Radboud University Medical Center, Nijmegen, the Netherlands), Karlijn de Laat (MD, PhD) (HagaZiekenhuis, the Hague, the Netherlands), Lukas van Dijk (MD, PhD) (HagaZiekenhuis, the Hague, the Netherlands), Heleen den Hertog (MD, PhD) (Isala Klinieken, Zwolle, the Netherlands), Boudewijn van Hasselt (MD) (Isala Klinieken, Zwolle, the Netherlands), Paul Brouwers (MD, PhD) (Medisch Spectrum Twente, Enschede, the Netherlands), Emiel Sturm (MD) (Medisch Spectrum Twente, Enschede, the Netherlands), Tomas Bulut (MD) (Medisch Spectrum Twente, Enschede, the Netherlands), Michel Remmers (MD) (Amphia Hospital, Breda, the Netherlands), Anouk van Norden (MD) (Amphia Hospital, Breda, the Netherlands), Thijs de Jong (MD) (Amphia Hospital, Breda, the Netherlands), Anouk Rozeman (MD) (Albert Schweitzer Hospital, Dordrecht, the Netherlands), Otto Elgersma (MD, PhD) (Albert Schweitzer Hospital, Dordrecht, the Netherlands), Maarten Uyttenboogaart (MD, PhD) (University Medical Center Groningen, the Netherlands), Reinoud Bokkers (MD, PhD) (University Medical Center Groningen, the Netherlands), Julia van Tuijl (MD) (Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands), Issam Boukrab (MD) (Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands), Hans Kortman (MD) (Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands), Vincent Costalat (MD, PhD) (Centre Hospitalier Universitaire de Montpellier, Montpellier, France), Caroline Arquizan (MD, PhD) (Centre Hospitalier Universitaire de Montpellier, Montpellier, France), Robin Lemmens (MD, PhD) (Universitair Ziekenhuis Leuven, Leuven, Belgium), Jelle Demeestere (MD, PhD) (Universitair Ziekenhuis Leuven, Leuven, Belgium), Philippe Desfontaines (MD, PhD) (Centre Hospitalier Chrétien, Liège, Belgium), Denis Brisbois (MD, PhD) (Centre Hospitalier Chrétien, Liège, Belgium), Frédéric Clarençon (MD, PhD) (Pitié-Salpêtrière Hospital, Paris, France), Yves Samson (MD, PhD) (Pitié-Salpêtrière Hospital, Paris, France), Local trial collaborators: Executive and writing committee Yvo Roos (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Charles Majoie (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Adriaan van Es (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Wim van Zwam (MD, PhD) (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), Jelis Boiten (MD, PhD) (Haaglanden Medical Center, the Hague, the Netherlands), Geert Lycklama à Nijeholt (MD, PhD) (Haaglanden Medical Center, the Hague, the Netherlands), Lonneke Yo (MD, PhD) (Catharina Hospital, Eindhoven, the Netherlands), Koos Keizer (MD, PhD) (Catharina Hospital, Eindhoven, the Netherlands), Jonathan Coutinho (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Bart Emmer (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Kilian Treurniet (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Natalie LeCouffe (MD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Manon Kappelhof (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Data Safety Monitoring Board: Martin Brown (MD) – Chair (National Hospital for Neurology and Neurosurgery, London, UK), Phil White (MD, PhD) (Institute of Neuroscience and Newcastle University Institute for Ageing, Newcastle University, Newcastle, UK), John Gregson (MD, PhD) (London School of Hygiene and Tropical Medicine, London, UK), Independent trial statistician Daan Nieboer (MSc) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), CONTRAST clinical trial collaborators: Research leaders: Diederik Dippel (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Charles Majoie (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Consortium coordinator: Rick van Nuland (PhD) (Lygature, Utrecht, the Netherlands), Imaging assessment committee: Charles Majoie (MD, PhD) – Chair (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Aad van der Lugt (MD, PhD) – Chair (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Wim van Zwam (MD, PhD) (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), Linda Jacobi (MD, PhD) (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), René van den Berg (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Ludo Beenen (MD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Bart Emmer (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Adriaan van Es (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Pieter-Jan van Doormaal (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Geert Lycklama (MD, PhD) (Haaglanden Medical Center, the Hague, the Netherlands), Ido van den Wijngaard (MD, PhD) (Haaglanden Medical Center, the Hague, the Netherlands), Albert Yoo (MD, PhD) (Texas Stroke Institute, Plano, Texas, USA), Lonneke Yo (MD, PhD) (Catharina Hospital, Eindhoven, the Netherlands), Jasper Martens (MD, PhD) (Rijnstate Hospital, Arnhem, the Netherlands), Bas Hammer (MD, PhD) (HagaZiekenhuis, the Hague, the Netherlands), Stefan Roosendaal (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Anton Meijer (MD, PhD) (Radboud University Medical Center, Nijmegen, the Netherlands), Menno Krietemeijer (MD) (Catharina Hospital, Eindhoven, the Netherlands), Reinoud Bokkers (MD, PhD) (University Medical Center Groningen, the Netherlands), Anouk van der Hoorn (MD, PhD) (University Medical Center Groningen, the Netherlands), Dick Gerrits (MD) (Medisch Spectrum Twente, Enschede, the Netherlands), Adverse event committee: Robert van Oostenbrugge (MD, PhD) – Chair (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), Bart Emmer (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Jonathan Coutinho (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Ben Jansen (MD, PhD) (Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands), Outcome assessment committee: Yvo Roos (MD, PhD) – Chair (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Sanne Manschot (MD, PhD) (Haaglanden Medical Center, the Hague, the Netherlands), Diederik Dippel (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Henk Kerkhof (MD, PhD) (University Medical Center Utrecht, Brain Center, Utrecht, the Netherlands), Ido van den Wijngaard (MD, PhD) (Haaglanden Medical Center, the Hague, the Netherlands), Jonathan Coutinho (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Peter Koudstaal (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Koos Keizer (MD, PhD) (Catharina Hospital, Eindhoven, the Netherlands), Data management group Hester Lingsma (PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Diederik Dippel (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Vicky Chalos (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Olvert Berkhemer (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Imaging data management Aad van der Lugt (MD, PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Charles Majoie (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Adriaan Versteeg (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Lennard Wolff (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Jiahang Su (MSc) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Manon Tolhuisen (MSc) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Henk van Voorst (MD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Biomaterials and translational group: Hugo ten Cate (MD, PhD) (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), Moniek de Maat (PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Samantha Donse-Donkel (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Heleen van Beusekom (PhD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Aladdin Taha (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Local collaborators: Vicky Chalos (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Kilian Treurniet (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Sophie van den Berg (MD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Natalie LeCouffe (MD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Rob van de Graaf (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Robert-Jan Goldhoorn (MD) (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), Aladdin Taha (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Samantha Donse-Donkel (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Wouter Hinsenveld (MD) (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), Anne Pirson (MD) (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), Lotte Sondag (MD) (Radboud University Medical Center, Nijmegen, the Netherlands), Manon Kappelhof (MD, PhD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Rik Reinink (MD) (University Medical Center Utrecht, Brain Center, Utrecht, the Netherlands), Manon Tolhuisen (MSc) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Josje Brouwer (MD) (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Lennard Wolff (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Sabine Collette (University Medical Center Groningen, the Netherlands), Wouter van der Steen (MD) (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Research nurses: Rita Sprengers (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands), Martin Sterrenberg (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Naziha El Ghannouti (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Sabrina Verheesen (Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands), Wilma Pellikaan (St Antonius Hospital, Nieuwegein, the Netherlands), Kitty Blauwendraat (St Antonius Hospital, Nieuwegein, the Netherlands), Yvonne Drabbe (HagaZiekenhuis, the Hague, the Netherlands), Joke de Meris (Haaglanden Medical Center, the Hague, the Netherlands), Michelle Simons (Rijnstate Hospital, Arnhem, the Netherlands), Hester Bongenaar (Catharina Hospital, Eindhoven, the Netherlands), Anja van Loon (Amphia Hospital, Breda, the Netherlands), Eva Ponjee (Isala Klinieken, Zwolle, the Netherlands), Rieke Eilander (Isala Klinieken, Zwolle, the Netherlands), Suze Kooij (Albert Schweitzer Hospital, Dordrecht, the Netherlands), Marieke de Jong (University Medical Center Groningen, the Netherlands), Esther Santegoets (Elisabeth-TweeSteden Hospital, Tilburg, the Netherlands), Suze Roodenburg (Albert Schweitzer Hospital, Dordrecht, the Netherlands), Ayla van Ahee (Amsterdam UMC location, University of Amsterdam, Amsterdam the Netherlands),5 Marinette Moynier (Centre Hospitalier Universitaire de Montpellier, Montpellier, France), Annemie Devroye (Universitair Ziekenhuis Leuven, Leuven, Belgium), Evelyn Marcis (Universitair Ziekenhuis Leuven, Leuven, Belgium), Ingrid Iezzi (Centre Hospitalier Chrétien, Liège, Belgium), Annie David (Centre Hospitalier Chrétien, Liège, Belgium), Atika Talbi (Pitié-Salpêtrière Hospital, Paris, France), Study monitors: Leontien Heiligers (Erasmus MC University Medical Center, Rotterdam, the Netherlands), Yvonne Martens (Erasmus MC University Medical Center, Rotterdam, the Netherlands).

    • Contributors CBLM, HAM, YB, DWJD, AvdL, RJvO, WHvZ, LW, JMC, BJE, NL, KMT, LAR, AAEB and MK designed the MR CLEAN NO IV trial. MK, AAEB, LAR, KMT, NL, LW collected and prepared the data for the trial. KRvK, MK, AAEB, LAR and KMT prepared data for this study. KRvK performed the statistical analysis, interpreted the results and drafted the paper with assistance from MK, KMT, HAM and CBLM. The article was critically revised by AAEB, LAR, NL, BJE, JMC, LW, WHvZ, RJvO, AvdL, DWJD, YBWR, HAM and CBLM. CBLM acts as guarantor for the article. All authors contributed to the submitted version.

    • Funding MR CLEAN NO_IV was funded through the CONTRAST consortium, which acknowledges the support from the Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation (CVON2015-01: CONTRAST), and from the Brain Foundation Netherlands (HA2015.01.06). The collaboration project is additionally financed by the Ministry of Economic Affairs by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships (LSHM17016). This work was funded in part through unrestricted funding by Stryker, Medtronic and Cerenovus.

    • Disclaimer The funding sources were not involved in study design, monitoring, data collection, statistical analyses, interpretation of results, or manuscript writing.

    • Competing interests CBLM reports grants from CVON/Dutch Heart Foundation and Stryker (related and paid to institution), and TWIN Foundation, European Commission, Health Evaluation Netherlands (outside the submitted work and paid to institution); and is shareholder of Nico.lab. HAM is cofounder and shareholder of Nico.lab. DWJD and Van der Lugt report grants from Dutch Heart Foundation, Dutch Brain Foundation, Health Holland, Stryker, Medtronic Penumbra, Cerenovus and Thrombolytic Science Inc, all paid to the institution. YDWR is shareholder of Nico.lab. JMC reports research support from Medtronic (paid to institution). All other authors have nothing to disclose.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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