Tilman Hackeng

Professor

Prof. Tilman Hackeng studied biochemistry at the University of Utrecht and obtained his PhD at the same University in 1993 on protein C/protein S anticoagulant mechanisms. Shortly after, he left for The Scripps Research Institute, La Jolla, CA, USA, were he worked on translational chemistry in the laboratories of Molecular and Experimental Medicine and Cell Biology.

In 1998, he returned to the Netherlands as a Research Fellow of the Royal Netherlands Academy of Arts and Sciences (KNAW) at the Department of Biochemistry of the University Maastricht. He is past president of the Netherlands Society on Thrombosis and Hemostasis (NVTH), and elected member of the Royal Holland Society of Sciences and Humanities (KHMW). In addition, he is chair of the Scientific Advisory Board of the Netherlands Thrombosis Foundation, acts as reviewer for major journals in the Thrombosis & Haemostasis and Chemistry fields and serves on grant reviewing boards of national and international granting agencies. Currently he is chairman of the Department of Biochemistry of the University Maastricht and Scientific Director of CARIM. He is co-founder of ACS Biomarker BV and Coagulation Profile BV.

His research on chemistry and structure function relationships of blood coagulation proteins explores the involvement of blood coagulation proteins in developing cardiovascular disease. With an emphasis on anticoagulant regulatory pathways, a multidisciplinary approach is used in unraveling functional properties of proteins involved in the regulation of thrombin formation. Functional impairments of coagulation proteins can lead to development of venous and arterial thrombosis, and a fundamental understanding of inter-protein and protein-vessel wall interactions is a prerequisite for understanding how anticoagulant proteins work in preventing thrombosis. A broad technology platform is applied to this programme, from automated thrombin generation, total chemical synthesis of proteins, to NMR protein structural analysis and development of clinical assays. Additional research programmes performed in his laboratory for total chemical protein synthesis comprise several research lines and collaborations in the field of haemostasis and thrombosis, cancer, targeted molecular imaging and synthetic vaccines. Multimodal and multivalent constructs are applied as molecular imaging agents in vitro and in vivo for the targeting and MRI, SPECT, and PET imaging of thrombosis, atherosclerosis and angiogenesis and further developed within Maastricht Imaging Valley under the evolving discipline of translational cardiovascular chemistry.

Department of Biochemistry
Universiteitsingel 50, 6229 ER Maastricht
PO Box 616, 6200 MD Maastricht
Room number: 4.366
T: +31 (0)43 388 1674/1766

  • 2018
    • Richelle, G. J. J., Schmidt, M., Ippel, H., Hackeng, T. M., van Maarseveen, J. H., Nuijens, T., & Timmerman, P. (2018). A One-Pot "Triple-C" Multicyclization Methodology for the Synthesis of Highly Constrained Isomerically Pure Tetracyclic Peptides. Chembiochem, 19(18), 1934-1938. https://doi.org/10.1002/cbic.201800346
    • Vajen, T., Koenen, R. R., Werner, I., Staudt, M., Projahn, D., Curaj, A., Sonmez, T. T., Simsekyilmaz, S., Schumacher, D., Mollmann, J., Hackeng, T. M., von Hundelshausen, P., Weber, C., & Liehn, E. A. (2018). Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis. Scientific Reports, 8, Article 10647. https://doi.org/10.1038/s41598-018-29026-0
    • van Doorn, P., Rosing, J., Duckers, C., Hackeng, T. M., Simioni, P., & Castoldi, E. (2018). Factor V Has Anticoagulant Activity in Plasma in the Presence of TFPI: Difference between FV1 and FV2. Thrombosis and Haemostasis, 118(7), 1194-1202. https://doi.org/10.1055/s-0038-1656549
    • Thomassen, S., Mastenbroek, T. G., Swieringa, F., Winckers, K., Feijge, M. A. H., Schrijver, R., Cosemans, J. M. E. M., Maroney, S. A., Mast, A. E., Hackeng, T. M., & Heemskerk, J. W. M. (2018). Suppressive Role of Tissue Factor Pathway Inhibitor-alpha in Platelet-Dependent Fibrin Formation under Flow Is Restricted to Low Procoagulant Strength. Thrombosis and Haemostasis, 118(3), 502-513. https://doi.org/10.1055/s-0038-1627453
  • 2017
    • Zhao, Z., Vajen, T., Karshovska, E., Dickhout, A., Schmitt, M. M., Megens, R. T. A., von Hundelshausen, P., Koeppel, T. A., Hackeng, T. M., Weber, C., & Koenen, R. R. (2017). Deletion of junctional adhesion molecule A from platelets increases early-stage neointima formation after wire injury in hyperlipidemic mice. Journal of Cellular and Molecular Medicine, 21(8), 1523-1531. https://doi.org/10.1111/jcmm.13083
    • Doring, Y., Noels, H., van der Vorst, E. P. C., Neideck, C., Egea, V., Drechsler, M., Mandl, M., Pawig, L., Jansen, Y., Schroeder, K., Bidzhekov, K., Megens, R. T. A., Theelen, W., Klinkhammer, B. M., Boor, P., Schurgers, L., van Gorp, R., Ries, C., Kusters, P. J. H., ... Weber, C. (2017). Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity Evidence From Mouse and Human Studies. Circulation, 136(4), 388-403. https://doi.org/10.1161/CIRCULATIONAHA.117.027646
    • ten Cate, H., Hackeng, T. M., & de Frutos, P. G. (2017). Coagulation factor and protease pathways in thrombosis and cardiovascular disease. Thrombosis and Haemostasis, 117(7), 1265-1271. https://doi.org/10.1160/TH17-02-0079
    • Schmidt, M., Toplak, A., Quaedflieg, P. J. L. M., Ippel, H., Richelle, G. J. J., Hackeng, T. M., van Maarseveen, J. H., & Nuijens, T. (2017). Omniligase-1: A Powerful Tool for Peptide Head-to-Tail Cyclization. Advanced Synthesis & Catalysis, 359(12), 2050-2055. https://doi.org/10.1002/adsc.201700314
    • Arts, M., Soons, Z., Ellis, S. R., Pierzchalski, K. A., Balluff, B., Eijkel, G. B., Dubois, L. J., Lieuwes, N. G., Agten, S. M., Hackeng, T. M., van Loon, L. J. C., Heeren, R. M. A., & Damink, S. W. M. O. (2017). Detection of Localized Hepatocellular Amino Acid Kinetics by using Mass Spectrometry Imaging of Stable Isotopes. Angewandte Chemie-International Edition, 56(25), 7146-7150. https://doi.org/10.1002/anie.201702669
    • Alshaikh, N. A., Rosing, J., Thomassen, M. C. L. G. D., Castoldi, E., Simioni, P., & Hackeng, T. M. (2017). New functional assays to selectively quantify the activated protein C- and tissue factor pathway inhibitor-cofactor activities of protein S in plasma. Journal of Thrombosis and Haemostasis, 15(5), 950-960. https://doi.org/10.1111/jth.13657
    • von Hundelshausen, P., Agten, S. M., Eckardt, V., Blanchet, X., Schmitt, M. M., Ippel, H., Neideck, C., Bidzhekov, K., Leberzammer, J., Wichapong, K., Faussner, A., Drechsler, M., Grommes, J., van Geffen, J. P., Li, H., Ortega-Gomez, A., Megens, R. T. A., Naumann, R., Dijkgraaf, I., ... Weber, C. (2017). Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation. Science Translational Medicine, 9(384), Article eaah6650. https://doi.org/10.1126/scitranslmed.aah6650
    • Kapustin, A. N., Schoppet, M., Schurgers, L. J., Reynolds, J. L., McNair, R., Heiss, A., Jahnen-Dechent, W., Hackeng, T. M., Schlieper, G., Harrison, P., & Shanahan, C. M. (2017). Prothrombin Loading of Vascular Smooth Muscle Cell-Derived Exosomes Regulates Coagulation and Calcification. Arteriosclerosis Thrombosis and Vascular Biology, 37(3), E22-E32. https://doi.org/10.1161/ATVBAHA.116.308886
    • Winckers, K., Thomassen, S., ten Cate, H., & Hackeng, T. M. (2017). Platelet full length TFPI-alpha in healthy volunteers is not affected by sex or hormonal use. PLOS ONE, 12(2), Article 0168273. https://doi.org/10.1371/journal.pone.0168273
    • van Doorn, P., Rosing, J., Wielders, S. J., Hackeng, T. M., & Castoldi, E. (2017). The C-terminus of tissue factor pathway inhibitor-alpha inhibits factor V activation by protecting the Arg(1545) cleavage site. Journal of Thrombosis and Haemostasis, 15(1), 140-149. https://doi.org/10.1111/jth.13559
    • Hendrikx, G., Hackeng, T. M., van Gorp, R., Bauwens, M., Schurgers, L. J., Mottaghy, F. M., Post, M. J., & Dijkgraaf, I. (2017). Use of Cyclic Backbone NGR-Based SPECT to Increase Efficacy of Postmyocardial Infarction Angiogenesis Imaging. Contrast Media & Molecular Imaging, 2017, Article 8638549. https://doi.org/10.1155/2017/8638549
    • Arts, M., Soons, Z., Dubois, L. J., Pierzchalski, K. A., Ellis, S. R., Balluff, B., Eijkel, G. B., Cramer, T., Lieuwes, N., Agten, S. M., Hackeng, T. M., Van Loon, L. J., Heeren, R. M., & Damink, S. W. O. (2017). Visualizing hepatocellular amino acid kinetics through mass spectrometry imaging of stable isotopes. Journal of Hepatology, 66(1), S43-S44. https://doi.org/10.1016/S0168-8278(17)30349-5
  • 2016
    • Agten, S. M., Koenen, R. R., Ippel, H., Eckardt, V., von Hundelshausen, P., Mayo, K. H., Weber, C., & Hackeng, T. M. (2016). Probing Functional Heteromeric Chemokine Protein-Protein Interactions through Conformation-Assisted Oxime Ligation. Angewandte Chemie-International Edition, 55(48), 14963-14966. https://doi.org/10.1002/anie.201607036
    • Wentink, M. Q., Hackeng, T. M., Tabruyn, S. P., Puijk, W. C., Schwamborn, K., Altschuh, D., Meloen, R. H., Schuurman, T., Griffioen, A. W., & Timmerman, P. (2016). Targeted vaccination against the bevacizumab binding site on VEGF using 3D-structured peptides elicits efficient antitumor activity. Proceedings of the National Academy of Sciences of the United States of America, 113(44), 12532-12537. https://doi.org/10.1073/pnas.1610258113
    • Caolo, V., Vries, M., Zupancich, J., Houben, M., Mihov, G., Wagenaar, A., Swennen, G., Nossent, Y., Quax, P., Suylen, D., Dijkgraaf, I., Molin, D., Hackeng, T., & Post, M. (2016). CXCL1 microspheres: a novel tool to stimulate arteriogenesis. Drug Delivery, 23(8), 2919-2926. https://doi.org/10.3109/10717544.2015.1120366
    • Ippel, H., Miller, M. C., Vertesy, S., Zheng, Y., Javier Canada, F., Suylen, D., Umemoto, K., Romano, C., Hackeng, T., Tai, G., Leffler, H., Kopitz, J., Andre, S., Kuebler, D., Jimenez-Barbero, J., Oscarson, S., Gabius, H.-J., & Mayo, K. H. (2016). Intra- and intermolecular interactions of human galectin-3: assessment by full-assignment-based NMR. Glycobiology, 26(8), 888-903. https://doi.org/10.1093/glycob/cww021
    • Wichapong, K., Alard, J. .-E., Ortega-Gomez, A., Weber, C., Hackeng, T. M., Soehnlein, O., & Nicolaes, G. A. F. (2016). Structure-Based Design of Peptidic Inhibitors of the Interaction between CC Chemokine Ligand 5 (CCL5) and Human Neutrophil Peptides 1 (HNP1). Journal of Medicinal Chemistry, 59(9), 4289-4301. https://doi.org/10.1021/acs.jmedchem.5b01952
    • Agten, S. M., Dawson, P. E., & Hackeng, T. M. (2016). Oxime conjugation in protein chemistry: from carbonyl incorporation to nucleophilic catalysis. Journal of Peptide Science, 22(5), 271-279. https://doi.org/10.1002/psc.2874
    • Mattheij, N. J. A., Swieringa, F., Mastenbroek, T. G., Berny-Lang, M. A., May, F., Baaten, C. C. F. M. J., van der Meijden, P. E. J., Henskens, Y. M. C., Beckers, E. A. M., Suylen, D. P. L., Nolte, M. W., Hackeng, T. M., McCarty, O. J. T., Heemskerk, J. W. M., & Cosemans, J. M. E. M. (2016). Coated platelets function in platelet-dependent fibrin formation via integrin alpha(IIb)beta(3) and transglutaminase factor XIII. Haematologica-the Hematology Journal, 101(4), 427-436. https://doi.org/10.3324/haematol.2015.131441
    • Peraramelli, S., Thomassen, S., Heinzmann, A., Hackeng, T. M., Hartmann, R., Scheiflinger, F., Dockal, M., & Rosing, J. (2016). Role of exosite binding modulators in the inhibition of Fxa by TFPI. Thrombosis and Haemostasis, 115(3), 580-590. https://doi.org/10.1160/TH15-04-0354
    • Miller, M. C., Ippel, H., Suylen, D., Klyosov, A. A., Traber, P. G., Hackeng, T., & Mayo, K. H. (2016). Binding of polysaccharides to human galectin-3 at a noncanonical site in its carbohydrate recognition domain. Glycobiology, 26(1), 88-99. https://doi.org/10.1093/glycob/cwv073
    • Agten, S. M., Suylen, D. P. L., & Hackeng, T. M. (2016). Oxime Catalysis by Freezing. Bioconjugate Chemistry, 27(1), 42-46. https://doi.org/10.1021/acs.bioconjchem.5b00611
  • 2015
    • Alard, J.-E., Ortega-Gomez, A., Wichapong, K., Bongiovanni, D., Horckmans, M., Megens, R. T. A., Leoni, G., Ferraro, B., Rossaint, J., Paulin, N., Ng, J., Ippel, H., Suylen, D., Hinkel, R., Blanchet, X., Gaillard, F., D'Amico, M., von Hundelshausen, P., Zarbock, A., ... Soehnlein, O. (2015). Recruitment of classical monocytes can be inhibited by disturbing heteromers of neutrophil HNP1 and platelet CCL5. Science Translational Medicine, 7(317), Article 317ra196. https://doi.org/10.1126/scitranslmed.aad5330
    • Spronk, H. M. H., Cannegieter, S., Morange, P., Hackeng, T., Huisman, M., Nagler, M., Posthuma, J., Ninivaggi, M., Zwaveling, S., van der Hulle, T., Scheres, L. J. J., van Mens, T. E., & Mackman, N. (2015). Theme 2: Epidemiology, Biomarkers, and Imaging of Venous Thromboembolism (and postthrombotic syndrome). Thrombosis Research, 136, S8-S12. https://doi.org/10.1016/j.thromres.2015.07.035
    • Hu, Q., van Gaal, E. V. B., Brundel, P., Ippel, H., Hackeng, T., Rijcken, C. J. F., Storm, G., Hennink, W. E., & Prakash, J. (2015). A novel approach for the intravenous delivery of leuprolide using core-cross-linked polymeric micelles. Journal of Controlled Release, 205, 98-108. https://doi.org/10.1016/j.jconrel.2014.12.023
    • Vries, M. H. M., Wagenaar, A., Verbruggen, S. E. L., Molin, D. G. M., Dijkgraaf, I., Hackeng, T., & Post, M. J. (2015). CXCL1 promotes arteriogenesis through enhanced monocyte recruitment into the peri-collateral space. Angiogenesis, 18(2), 163-171. https://doi.org/10.1007/s10456-014-9454-1
    • Ippel, H., Miller, M. C., Berbis, M. A., Suylen, D., Andre, S., Hackeng, T. M., Canada, F. J., Weber, C., Gabius, H.-J., Jimenez-Barbero, J., & Mayo, K. H. (2015). H-1, C-13, and N-15 backbone and side-chain chemical shift assignments for the 36 proline-containing, full length 29 kDa human chimera-type galectin-3. Biomolecular Nmr Assignments, 9(1), 59-63. https://doi.org/10.1007/s12104-014-9545-3
    • Dargaud, Y., Scoazec, J. Y., Wielders, S. J. H., Trzeciak, C., Hackeng, T. M., Negrier, C., Hemker, H. C., Lindhout, T., & Castoldi, E. (2015). Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation. Blood, 125(9), 1497-1501. https://doi.org/10.1182/blood-2014-10-604553
    • Karshovska, E., Zhao, Z., Blanchet, X., Schmitt, M. M. N., Bidzhekov, K., Soehnlein, O., von Hundelshausen, P., Mattheij, N. J., Cosemans, J. M. E. M., Megens, R. T. A., Koeppel, T. A., Schober, A., Hackeng, T. M., Weber, C., & Koenen, R. R. (2015). Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice. Circulation Research, 116(4), 587-599. https://doi.org/10.1161/CIRCRESAHA.116.304035
    • Zarzycka, B., Seijkens, T., Nabuurs, S. B., Ritschel, T., Grommes, J., Soehnlein, O., Schrijver, R., van Tiel, C. M., Hackeng, T. M., Weber, C., Giehler, F., Kieser, A., Lutgens, E., Vriend, G., & Nicolaes, G. A. F. (2015). Discovery of Small Molecule CD40-TRAF6 Inhibitors. Journal of Chemical Information and Modeling, 55(2), 294-307. https://doi.org/10.1021/ci500631e
    • Du, J., Wichapong, K., Hackeng, T. M., & Nicolaes, G. A. F. (2015). Molecular simulation studies of human coagulation factor VIII C domain-mediated membrane binding. Thrombosis and Haemostasis, 113(2), 373-384. https://doi.org/10.1160/TH14-02-0180
    • Hendrikx, G., De Saint-Hubert, M., Dijkgraaf, I., Bauwens, M., Douma, K., Wierts, R., Pooters, I., van den Akker, N. M., Hackeng, T. M., Post, M. J., & Mottaghy, F. M. (2015). Molecular imaging of angiogenesis after myocardial infarction by (111)In-DTPA-cNGR and (99m)Tc-sestamibi dual-isotope myocardial SPECT. EJNMMI Research, 5, 13-22. Article 2. https://doi.org/10.1186/s13550-015-0081-7
    • Thomassen, M. C. L. G. D., Heinzmann, A. C. A., Herfs, L., Hartmann, R., Dockal, M., Scheiflinger, F., Hackeng, T. M., & Rosing, J. (2015). Tissue factor-independent inhibition of thrombin generation by tissue factor pathway inhibitor-alpha. Journal of Thrombosis and Haemostasis, 13(1), 92-100. https://doi.org/10.1111/jth.12766
  • 2014
    • Peraramelli, S., Thomassen, S., Heinzmann, A., Rosing, J., Hackeng, T. M., Hartmann, R., Scheiflinger, F., & Dockal, M. (2014). Inhibition of tissue factor: factor VIIa-catalyzed factor IX and factor X activation by TFPI and TFPI constructs. Journal of Thrombosis and Haemostasis, 12(11), 1826-1837. https://doi.org/10.1111/jth.12713
    • Kapsokalyvas, D., Schiffers, P. M. H., Maij, N., Suylen, D. P., Hackeng, T. M., van Zandvoort, M. A. M. J., & De Mey, J. G. R. (2014). Imaging evidence for endothelin ETA/ETB receptor heterodimers in isolated rat mesenteric resistance arteries. Life Sciences, 111(1-2), 36-41. https://doi.org/10.1016/j.lfs.2014.07.007
    • Schmitt, M. M. N., Fraemohs, L., Hackeng, T. M., Weber, C., & Koenen, R. R. (2014). Atherogenic mononuclear cell recruitment is facilitated by oxidized lipoprotein-induced endothelial junctional adhesion molecule-A redistribution. Atherosclerosis, 234(2), 254-264. https://doi.org/10.1016/j.atherosclerosis.2014.03.014
    • Projahn, D., Simsekyilmaz, S., Singh, S., Kanzler, I., Kramp, B. K., Langer, M., Burlacu, A., Bernhagen, J., Klee, D., Zernecke, A., Hackeng, T. M., Groll, J., Weber, C., Liehn, E. A., & Koenen, R. R. (2014). Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction. Journal of Cellular and Molecular Medicine, 18(5), 790-800. https://doi.org/10.1111/jcmm.12225
    • Chatzigeorgiou, A., Seijkens, T., Zarzycka, B., Engel, D., Poggi, M., van den Berg, S., van den Berg, S., Soehnlein, O., Winkels, H., Beckers, L., Lievens, D., Driessen, A., Kusters, P., Biessen, E., Garcia-Martin, R., Klotzsche-von Ameln, A., Gijbels, M., Noelle, R., Boon, L., ... Lutgens, E. (2014). Correction for Chatzigeorgiou et al., Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance (vol 111, pg 2686, 2014). Proceedings of the National Academy of Sciences of the United States of America, 111(12), 4644-4644. https://doi.org/10.1073/pnas.1403231111
    • Chatzigeorgioua, A., Seijkens, T., Zarzycka, B., Engel, D., Poggi, M., van den Berg, S., van den Berg, S., Soehnlein, O., Winkels, H., Beckers, L., Lievens, D., Driessen, A., Kusters, P., Biessen, E., Garcia-Martin, R., Ameln, A. K., Gijbels, M., Noelle, R., Boon, L., ... Lutgens, E. (2014). Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proceedings of the National Academy of Sciences of the United States of America, 111(7), 2686-2691. https://doi.org/10.1073/pnas.1400419111
    • Schmitt, M. M. N., Megens, R. T. A., Zernecke, A., Bidzhekov, K., van den Akker, N. M., Rademakers, T., van Zandvoort, M. A., Hackeng, T. M., Koenen, R. R., & Weber, C. (2014). Endothelial Junctional Adhesion Molecule-A Guides Monocytes Into Flow-Dependent Predilection Sites of Atherosclerosis. Circulation, 129(1), 66–76. https://doi.org/10.1161/CIRCULATIONAHA.113.004149
  • 2013
    • Agten, S. M., Suylen, D., Ippel, H., Kokozidou, M., Tans, G., van de Vijver, P., Koenen, R. R., & Hackeng, T. M. (2013). Chemoselective Oxime Reactions in Proteins and Peptides by Using an Optimized Oxime Strategy: The Demise of Levulinic Acid. Chembiochem, 14(18), 2431-2434. https://doi.org/10.1002/cbic.201300598
    • Nuzzo, F., Radu, C., Baralle, M., Spiezia, L., Hackeng, T. M., Simioni, P., & Castoldi, E. (2013). Antisense-based RNA therapy of factor V deficiency: in vitro and ex vivo rescue of a F5 deep-intronic splicing mutation. Blood, 122(23), 3825-3831. https://doi.org/10.1182/blood-2013-04-499657
    • Heeb, M. J., Mesters, R. M., Fernandez, J. A., Hackeng, T. M., Nakasone, R. K., & Griffin, J. H. (2013). Plasma protein S residues 37-50 mediate its binding to factor Va and inhibition of blood coagulation. Thrombosis and Haemostasis, 110(2), 275-282. https://doi.org/10.1160/TH12-12-0953
    • Dijkgraaf, I., Van de Vijver, P., Dirksen, A., & Hackeng, T. M. (2013). Synthesis and application of cNGR-containing imaging agents for detection of angiogenesis. Bioorganic & Medicinal Chemistry, 21(12), 3555-3564. https://doi.org/10.1016/j.bmc.2013.04.002
    • Winckers, K., ten Cate, H., & Hackeng, T. M. (2013). The role of tissue factor pathway inhibitor in atherosclerosis and arterial thrombosis. Blood Reviews, 27(3), 119-132. https://doi.org/10.1016/j.blre.2013.03.001
    • Peraramelli, S., Thomassen, S., Heinzmann, A., Rosing, J., Hackeng, T. M., Hartmann, R., Scheiflinger, F., & Dockal, M. (2013). Direct inhibition of factor VIIa by TFPI and TFPI constructs. Journal of Thrombosis and Haemostasis, 11(4), 704-714. https://doi.org/10.1111/jth.12152