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<article article-type="research-article" dtd-version="1.3" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xml:lang="ru"><front><journal-meta><journal-id journal-id-type="publisher-id">fcmedicine</journal-id><journal-title-group><journal-title xml:lang="ru">Фундаментальная и клиническая медицина</journal-title><trans-title-group xml:lang="en"><trans-title>Fundamental and Clinical Medicine</trans-title></trans-title-group></journal-title-group><issn pub-type="ppub">2500-0764</issn><issn pub-type="epub">2542-0941</issn><publisher><publisher-name>КемГМУ</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.23946/2500-0764-2021-6-3-25-34</article-id><article-id custom-type="elpub" pub-id-type="custom">fcmedicine-434</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="ru"><subject>ОРИГИНАЛЬНЫЕ СТАТЬИ</subject></subj-group><subj-group subj-group-type="section-heading" xml:lang="en"><subject>ORIGINAL RESEARCH</subject></subj-group></article-categories><title-group><article-title>Морфологическое исследование ксеноперикардиальных биопротезов клапанов сердца с инфекционным эндокардитом</article-title><trans-title-group xml:lang="en"><trans-title>Ultrastructural pathology of bioprosthetic heart valves with infectious endocarditis</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-5558-3229</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Мухамадияров</surname><given-names>Р. А.</given-names></name><name name-style="western" xml:lang="en"><surname>Mukhamadiyarov</surname><given-names>R. A.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Мухамадияров Ринат Авхадиевич, кандидат биологических наук, старший научный сотрудник лаборатории фундаментальных аспектов атеросклероза отдела экспериментальной медицины</p><p>650002, г. Кемерово, б-р Сосновый, д. 6</p></bio><bio xml:lang="en"><p>Rinat A. Mukhamadiyarov, Dr., PhD, Senior Researcher, Laboratory for Vascular Biology, Division of Experimental Medicine</p><p>6, Sosnovy Boulevard, Kemerovo, 650002</p></bio><email xlink:type="simple">rem57@rambler.ru</email><xref ref-type="aff" rid="aff-1"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-9764-4392</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Мильто</surname><given-names>И. В.</given-names></name><name name-style="western" xml:lang="en"><surname>Milto</surname><given-names>I. V.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Мильто Иван Васильевич, доктор медицинских наук, профессор, профессор кафедры морфологии и общей патологии</p><p>634055, г. Томск, Московский тракт, д. 2</p></bio><bio xml:lang="en"><p>Ivan V. Milto, MD, Prof., DSc, Professor, Department of Morphology and General Pathology</p><p>2, Moskovskiy Trakt, Tomsk, 634055</p></bio><xref ref-type="aff" rid="aff-2"/></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-8679-4857</contrib-id><name-alternatives><name name-style="eastern" xml:lang="ru"><surname>Кутихин</surname><given-names>А. Г.</given-names></name><name name-style="western" xml:lang="en"><surname>Kutikhin</surname><given-names>A. G.</given-names></name></name-alternatives><bio xml:lang="ru"><p>Кутихин Антон Геннадьевич, кандидат медицинских наук, заведующий лабораторией фундаментальных аспектов атеросклероза отдела экспериментальной медицины</p><p>650002, г. Кемерово, б-р Сосновый, д. 6</p></bio><bio xml:lang="en"><p>Anton G. Kutikhin, MD, PhD, Head of the Laboratory for Vascular Biology, Division of Experimental Medicine</p><p>6, Sosnovy Boulevard, Kemerovo, 650002</p></bio><xref ref-type="aff" rid="aff-1"/></contrib></contrib-group><aff-alternatives id="aff-1"><aff xml:lang="ru"><institution>ФГБНУ «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний»</institution><country>Россия</country></aff><aff xml:lang="en"><institution>Research Institute for Complex Issues of Cardiovascular Diseases</institution><country>Russian Federation</country></aff></aff-alternatives><aff-alternatives id="aff-2"><aff xml:lang="ru"><institution>ФГБОУ ВО «Сибирский государственный медицинский университет» Министерства здравоохранения Российской Федерации</institution><country>Россия</country></aff><aff xml:lang="en"><institution>Siberian State Medical University</institution><country>Russian Federation</country></aff></aff-alternatives><pub-date pub-type="collection"><year>2021</year></pub-date><pub-date pub-type="epub"><day>26</day><month>09</month><year>2021</year></pub-date><volume>6</volume><issue>3</issue><fpage>25</fpage><lpage>34</lpage><permissions><copyright-statement>Copyright &amp;#x00A9; Мухамадияров Р.А., Мильто И.В., Кутихин А.Г., 2021</copyright-statement><copyright-year>2021</copyright-year><copyright-holder xml:lang="ru">Мухамадияров Р.А., Мильто И.В., Кутихин А.Г.</copyright-holder><copyright-holder xml:lang="en">Mukhamadiyarov R.A., Milto I.V., Kutikhin A.G.</copyright-holder><license xml:lang="ru" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>Данная работа распространяется под лицензией Creative Commons Attribution 4.0.</license-p></license><license xml:lang="en" license-type="creative-commons-attribution" xlink:href="https://creativecommons.org/licenses/by/4.0/" xlink:type="simple"><license-p>This work is licensed under a Creative Commons Attribution 4.0 License.</license-p></license></permissions><self-uri xlink:href="https://fcm.kemsmu.ru/jour/article/view/434">https://fcm.kemsmu.ru/jour/article/view/434</self-uri><abstract><sec><title>Цель</title><p>Цель. Описание морфологического строения створок ксеноперикардиальных биопротезов (БП) клапанов сердца, извлеченных из митральной позиции при замене протеза по причине эндокардита.</p></sec><sec><title>Материалы и методы</title><p>Материалы и методы. Исследовано 7 эпоксиобработанных ксеноперикардиальных БП модели «ЮниЛайн» (ЗАО «Неокор», г. Кемерово), извлеченных из митральной позиции при повторных хирургических вмешательствах в связи с развитием позднего протезного эндокардита. Образцы фиксировали в забуференном параформальдегиде с постфиксацией в тетраоксиде осмия. После обезвоживания в спиртах возрастающей концентрации и ацетоне образцы заключали в эпоксидную смолу. После полимеризации смолы образцы шлифовали, а затем полировали до нужной глубины образца. Для повышения электронного контраста образцы обрабатывали спиртовым раствором уранилацетата в процессе обезвоживания и цитратом свинца по Рейнольдсу после полировки эпоксидных блоков. Образцы визуализировали посредством сканирующей электронной микроскопии в обратно-рассеянных электронах при ускоряющем напряжении 15 кВ.</p></sec><sec><title>Результаты</title><p>Результаты. В изученных образцах створок БП отмечали деградацию и дезинтеграцию внеклеточного матрикса, что проявлялось в разрыхлении, фрагментации и снижении электронной плотности коллагеновых и эластиновых волокон. В структуре створок наблюдали появление клеток реципиента, среди которых идентифицировали макрофаги, гигантские клетки инородных тел, нейтрофилы, эндотелиальные клетки и гладкие миоциты. Наибольшее количество клеток находилось на поверхностях створок. Несмотря на сходство клеточного состава, локализация клеток на желудочковой и предсердной поверхностях была различной. В центральной части створок отмечали присутствие единичных клеток, преимущественно макрофагов.</p></sec><sec><title>Заключение</title><p>Заключение. Развитие протезного эндокардита сопровождается миграцией клеток реципиента в структуру БП. Заселение клетками является следствием развития структурных нарушений поверхностей створок и приводит к дезинтеграции внеклеточного матрикса в центральной части створок.</p></sec></abstract><trans-abstract xml:lang="en"><sec><title>Aim</title><p>Aim. To study the ultrastructure of mitral bioprosthetic heart valves (BHVs) which failed due to infective endocarditis.</p></sec><sec><title>Materials and Methods</title><p>Materials and Methods. Here we examined 7 ethylene glycol diglycidyl ether-treated xenopericardial BHVs excised during repeated BHV replacement because of prosthetic endocarditis. After being fixed in formalin and postfixed in osmium tetroxide, BHVs were dehydrated and stained in uranyl acetate with the subsequent embedding into epoxy resin, grinding, polishing, and lead citrate counterstaining. Upon the sputter coating with carbon, we visualised the BHV microanatomy by means of backscattered scanning electron microscopy at 15 kV voltage.</p></sec><sec><title>Results</title><p>Results. The extracellular matrix underwent degradation and disintegration resulting in loosening, fragmentation, and reduction in the electron density of collagen and elastin fibers. We observed a number of recipient cells (macrophages, multinucleated giant cells, neutrophils, endothelial cells and smooth muscle cells) within the BHVs. The highest number of cells was localized on the valve surfaces. The localization of the recipient cells on the ventricular and atrial surfaces was different. The central part of the valves was abundantly populated by macrophages.</p></sec><sec><title>Conclusion</title><p>Conclusion. Prosthetic endocarditis is accompanied by the migration of recipient cells into the BHV structure, which is the consequence of surface and extracellular matrix disintegration.</p></sec></trans-abstract><kwd-group xml:lang="ru"><kwd>макрофаги</kwd><kwd>воспаление</kwd><kwd>биопротезы клапанов сердца</kwd><kwd>протезный эндокардит</kwd><kwd>сканирующая электронная микроскопия</kwd><kwd>внеклеточный матрикс</kwd></kwd-group><kwd-group xml:lang="en"><kwd>macrophages</kwd><kwd>inflammation</kwd><kwd>bioprosthetic heart valves</kwd><kwd>infective endocarditis</kwd><kwd>scanning electron microscopy</kwd><kwd>extracellular matrix. Conflict of Interest None declared</kwd></kwd-group><funding-group><funding-statement xml:lang="ru">Работа выполнена при поддержке комплексной программы фундаментальных научных исследований СО РАН в рамках фундаментальной темы НИИ КПССЗ № 0546-2019-0002 «Патогенетическое обоснование разработки имплантатов для сердечно-сосудистой хирургии на основе биосовместимых материалов, с реализацией пациент-ориентированного подхода с использованием математического моделирования, тканевой инженерии и геномных предикторов»</funding-statement><funding-statement xml:lang="en">This study was supported by the Complex Program of Basic Research under the Siberian Branch of the Russian Academy of Sciences within the Basic Research Topic of Research Institute for Complex Issues of Cardiovascular Diseases № 0546- 2019-0002 «Pathogenetic basis for the development of cardiovascular implants from biocompatible materials using patient-oriented approach, mathematical modeling, tissue engineering, and genomic predictors»</funding-statement></funding-group></article-meta></front><back><ref-list><title>References</title><ref id="cit1"><label>1</label><citation-alternatives><mixed-citation xml:lang="ru">Lepidi H, Casalta J-P, Fournier P-E, Habib G, Collart F, Raoul D. Quantitative Histological Examination of Bioprosthetic Heart Valves. Clin Infect Dis. 2006;42(5):590-596. https://doi.org/10.1086/500135</mixed-citation><mixed-citation xml:lang="en">Lepidi H, Casalta J-P, Fournier P-E, Habib G, Collart F, Raoul D. Quantitative Histological Examination of Bioprosthetic Heart Valves. Clin Infect Dis. 2006;42(5):590-596. https://doi.org/10.1086/500135</mixed-citation></citation-alternatives></ref><ref id="cit2"><label>2</label><citation-alternatives><mixed-citation xml:lang="ru">Johnston DR, Soltesz EG, Vakil N, Rajeswaran J, Rosell EE, Sabik JF, Smedira NG, Svensson LG, Lytle BW, Blackstone EH. Longterm durability of bioprosthetic aortic valves: implications from 12,569 implants. Ann Thorac Surg. 2015;99(4):1239-1247. https://doi.org/10.1016/j.athoracsur.2014.10.070</mixed-citation><mixed-citation xml:lang="en">Johnston DR, Soltesz EG, Vakil N, Rajeswaran J, Rosell EE, Sabik JF, Smedira NG, Svensson LG, Lytle BW, Blackstone EH. Longterm durability of bioprosthetic aortic valves: implications from 12,569 implants. Ann Thorac Surg. 2015;99(4):1239-1247. https://doi.org/10.1016/j.athoracsur.2014.10.070</mixed-citation></citation-alternatives></ref><ref id="cit3"><label>3</label><citation-alternatives><mixed-citation xml:lang="ru">Kossar AP, George I, Gordon R, Ferrari G. Bacterial infiltration and bioprosthetic valve failure: Emerging diagnostics for emerging therapies. J Thorac Cardiovasc Surg. 2020;159(4):1279-1282. https://doi.org/10.1016/j.jtcvs.2019.07.149</mixed-citation><mixed-citation xml:lang="en">Kossar AP, George I, Gordon R, Ferrari G. Bacterial infiltration and bioprosthetic valve failure: Emerging diagnostics for emerging therapies. J Thorac Cardiovasc Surg. 2020;159(4):1279-1282. https://doi.org/10.1016/j.jtcvs.2019.07.149</mixed-citation></citation-alternatives></ref><ref id="cit4"><label>4</label><citation-alternatives><mixed-citation xml:lang="ru">Skowasch D, Steinmetz M, Nickenig G, Bauriedel G. Is the degeneration of aortic valve bioprostheses similar to that of native aortic valves? Insights into valvular pathology. Expert Rev Med Devices. 2006;3(4):453-462. https://doi.org/10.1586/17434440.3.4.453</mixed-citation><mixed-citation xml:lang="en">Skowasch D, Steinmetz M, Nickenig G, Bauriedel G. Is the degeneration of aortic valve bioprostheses similar to that of native aortic valves? Insights into valvular pathology. Expert Rev Med Devices. 2006;3(4):453-462. https://doi.org/10.1586/17434440.3.4.453</mixed-citation></citation-alternatives></ref><ref id="cit5"><label>5</label><citation-alternatives><mixed-citation xml:lang="ru">Синицкий М.Ю., Асанов М.А., Тхоренко Б.А., Одаренко Ю.Н., Понасенко А.В. Микрофлора периферической крови пациентов с инфекционным эндокардитом. Клиническая лабораторная диагностика. 2018;63(10): 636-640. https://doi.org/10.18821/0869-2084-2018-63-10-636-640</mixed-citation><mixed-citation xml:lang="en">Sinitsky MYu, Asanov МА, Tkhorenko BА, Odarenko YuN, Ponasenko AV. Microflora of peripheral blood obtained from patients with infective endocarditis. Russian Clinical Laboratory Diagnostics. 2018;63(10):636-640. (In Russ). https://doi.org/10.18821/0869-2084-2018-63-10-636-640</mixed-citation></citation-alternatives></ref><ref id="cit6"><label>6</label><citation-alternatives><mixed-citation xml:lang="ru">Butany J, Zhou T, Leong SW, Cunningham KS, Thangaroopan M, Jegatheeswaran A, Feindel C, David TE. Inflammation and infection in nine surgically explanted Medtronic Freestyle stentless aortic valves. Cardiovasc Pathol. 2007;16(5):258-267. https://doi.org/10.1016/j.carpath.2007.01.009</mixed-citation><mixed-citation xml:lang="en">Butany J, Zhou T, Leong SW, Cunningham KS, Thangaroopan M, Jegatheeswaran A, Feindel C, David TE. Inflammation and infection in nine surgically explanted Medtronic Freestyle stentless aortic valves. Cardiovasc Pathol. 2007;16(5):258-267. https://doi.org/10.1016/j.carpath.2007.01.009</mixed-citation></citation-alternatives></ref><ref id="cit7"><label>7</label><citation-alternatives><mixed-citation xml:lang="ru">Мухамадияров Р.А., Рутковская Н.В., Мильто И.В., Сидорова О.Д., Барбараш Л.С. Клеточный состав эксплантированных биопротезов клапанов сердца при инфекционном эндокардите. Архив патологии. 2019;81(6):16-23. https://doi.org/10.17116/patol20198106116</mixed-citation><mixed-citation xml:lang="en">Mukhamadiyarov RA, Rutkovskaya NV, Mil’to IV, Sidorova OD, Barbarash LS. The cellular composition of explanted bioprosthetic heart valves in infective endocarditis. Arkhiv Patologii. 2019;81(6):16-23. (In Russ). https://doi.org/10.17116/patol20198106116</mixed-citation></citation-alternatives></ref><ref id="cit8"><label>8</label><citation-alternatives><mixed-citation xml:lang="ru">Bourguignon T, Bouquiaux-Stablo AL, Candolfi P, Mirza A, Loardi C, May MA, El-Khoury R, Marchand M, Aupart, M. Very long-term outcomes of the Carpentier-Edwards Perimount valve in aortic position. Ann Thorac Surg. 2015;99(3):831-837. https://doi.org/10.1016/j.athoracsur.2014.09.030</mixed-citation><mixed-citation xml:lang="en">Bourguignon T, Bouquiaux-Stablo AL, Candolfi P, Mirza A, Loardi C, May MA, El-Khoury R, Marchand M, Aupart, M. Very long-term outcomes of the Carpentier-Edwards Perimount valve in aortic position. Ann Thorac Surg. 2015;99(3):831-837. https://doi.org/10.1016/j.athoracsur.2014.09.030</mixed-citation></citation-alternatives></ref><ref id="cit9"><label>9</label><citation-alternatives><mixed-citation xml:lang="ru">Bosio S, Leekha S, Gamb SI, Wright AJ, Terrell CL, Miller DV. Mycobacterium fortuitum prosthetic valve endocarditis: a case for the pathogenetic role of biofilms. Cardiovasc Pathol. 2012;21(4):361-364. https://doi.org/10.1016/j.carpath.2011.11.001</mixed-citation><mixed-citation xml:lang="en">Bosio S, Leekha S, Gamb SI, Wright AJ, Terrell CL, Miller DV. Mycobacterium fortuitum prosthetic valve endocarditis: a case for the pathogenetic role of biofilms. Cardiovasc Pathol. 2012;21(4):361-364. https://doi.org/10.1016/j.carpath.2011.11.001</mixed-citation></citation-alternatives></ref><ref id="cit10"><label>10</label><citation-alternatives><mixed-citation xml:lang="ru">Oberbach A, Friedrich M, Lehmann S, Schlichting N, Kullnick Y, Gräber S, Buschmann T, Hagl C, Bagaev E; CardiOmics group; Clinical Microbiology group; Bioinformatics group. Bacterial infiltration in structural heart valve disease. J Thorac Cardiovasc Surg. 2019:S0022- 5223(19)30451-9. https://doi.org/10.1016/j.jtcvs.2019.02.019</mixed-citation><mixed-citation xml:lang="en">Oberbach A, Friedrich M, Lehmann S, Schlichting N, Kullnick Y, Gräber S, Buschmann T, Hagl C, Bagaev E; CardiOmics group; Clinical Microbiology group; Bioinformatics group. Bacterial infiltration in structural heart valve disease. J Thorac Cardiovasc Surg. 2019:S0022- 5223(19)30451-9. https://doi.org/10.1016/j.jtcvs.2019.02.019</mixed-citation></citation-alternatives></ref><ref id="cit11"><label>11</label><citation-alternatives><mixed-citation xml:lang="ru">Côté N, Pibarot P, Clavel MA. Incidence, risk factors, clinical impact, and management of bioprosthesis structural valve degeneration. Curr Opin Cardiol. 2017;32(2):123-129. https://doi.org/10.1097/HCO.0000000000000372</mixed-citation><mixed-citation xml:lang="en">Côté N, Pibarot P, Clavel MA. Incidence, risk factors, clinical impact, and management of bioprosthesis structural valve degeneration. Curr Opin Cardiol. 2017;32(2):123-129. https://doi.org/10.1097/HCO.0000000000000372</mixed-citation></citation-alternatives></ref><ref id="cit12"><label>12</label><citation-alternatives><mixed-citation xml:lang="ru">Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F, Dulgheru R, El Khoury G, Erba PA, Iung B, Miro JM, Mulder BJ, Plonska-Gosciniak E, Price S, Roos-Hesselink J, Snygg-Martin U, Thuny F, Tornos Mas P, Vilacosta I, Zamorano JL; ESC Scientific Document Group. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015;36(44):3075-3128. https://doi.org/10.1093/eurheartj/ehv319</mixed-citation><mixed-citation xml:lang="en">Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Del Zotti F, Dulgheru R, El Khoury G, Erba PA, Iung B, Miro JM, Mulder BJ, Plonska-Gosciniak E, Price S, Roos-Hesselink J, Snygg-Martin U, Thuny F, Tornos Mas P, Vilacosta I, Zamorano JL; ESC Scientific Document Group. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015;36(44):3075-3128. https://doi.org/10.1093/eurheartj/ehv319</mixed-citation></citation-alternatives></ref><ref id="cit13"><label>13</label><citation-alternatives><mixed-citation xml:lang="ru">Cahill TJ, Prendergast BD. Infective endocarditis. Lancet. 2016;387(10021):882-893. https://doi.org/10.1016/S0140-6736(15)00067-7</mixed-citation><mixed-citation xml:lang="en">Cahill TJ, Prendergast BD. Infective endocarditis. Lancet. 2016;387(10021):882-893. https://doi.org/10.1016/S0140-6736(15)00067-7</mixed-citation></citation-alternatives></ref><ref id="cit14"><label>14</label><citation-alternatives><mixed-citation xml:lang="ru">Pibarot P, Dumesnil JG. Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation. 2009;119(7):1034- 1048. https://doi.org/10.1161/CIRCULATIONAHA.108.778886</mixed-citation><mixed-citation xml:lang="en">Pibarot P, Dumesnil JG. Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation. 2009;119(7):1034- 1048. https://doi.org/10.1161/CIRCULATIONAHA.108.778886</mixed-citation></citation-alternatives></ref><ref id="cit15"><label>15</label><citation-alternatives><mixed-citation xml:lang="ru">Skowasch D, Schrempf S, Wernert N, Steinmetz M, Jabs A, Tuleta I, Welsch U, Preusse CJ, Likungu JA, Welz A, Lüderitz B, Bauriedel G. Cells of primarily extra-valvular origin in degenerative aortic valves and bioprostheses. Eur Heart J. 2005;26(23):2576-2580. https://doi.org/10.1093/eurheartj/ehi458</mixed-citation><mixed-citation xml:lang="en">Skowasch D, Schrempf S, Wernert N, Steinmetz M, Jabs A, Tuleta I, Welsch U, Preusse CJ, Likungu JA, Welz A, Lüderitz B, Bauriedel G. Cells of primarily extra-valvular origin in degenerative aortic valves and bioprostheses. Eur Heart J. 2005;26(23):2576-2580. https://doi.org/10.1093/eurheartj/ehi458</mixed-citation></citation-alternatives></ref></ref-list><fn-group><fn fn-type="conflict"><p>The authors declare that there are no conflicts of interest present.</p></fn></fn-group></back></article>
