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<article 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" xmlns:ali="http://www.niso.org/schemas/ali/1.0/" article-type="research-article" dtd-version="1.2" xml:lang="en"><front><journal-meta><journal-id journal-id-type="publisher-id">Russian Journal of Allergy</journal-id><journal-title-group><journal-title xml:lang="en">Russian Journal of Allergy</journal-title><trans-title-group xml:lang="ru"><trans-title>Российский аллергологический журнал</trans-title></trans-title-group></journal-title-group><issn publication-format="print">2686-682X</issn><issn publication-format="electronic">1810-8830</issn><publisher><publisher-name xml:lang="en">Farmarus Print Media</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">375443</article-id><article-id pub-id-type="doi">10.36691/RJA17063</article-id><article-id pub-id-type="edn">HQKZBA</article-id><article-categories><subj-group subj-group-type="toc-heading" xml:lang="en"><subject>Original studies</subject></subj-group><subj-group subj-group-type="toc-heading" xml:lang="ru"><subject>Оригинальные исследования</subject></subj-group><subj-group subj-group-type="article-type"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title xml:lang="en">Sinonasal symptoms and systemic type 2 inflammation markers in children with concomitant asthma and allergic rhinitis: the impact of polypoid-hyperplastic changes of the sinonasal mucosa</article-title><trans-title-group xml:lang="ru"><trans-title>Синоназальные симптомы и системные маркеры Т2-воспаления у детей с сочетанием бронхиальной астмы и аллергического ринита. Влияние полипозно-гиперпластических изменений синоназальной слизистой оболочки</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-6153-6691</contrib-id><contrib-id contrib-id-type="spin">2581-2539</contrib-id><name-alternatives><name xml:lang="en"><surname>Krasilnikova</surname><given-names>Svetlana V.</given-names></name><name xml:lang="ru"><surname>Красильникова</surname><given-names>Светлана Викторовна</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>MD, Cand. Sci. (Medicine)</p></bio><bio xml:lang="ru"><p>канд. мед. наук</p></bio><email>mashkovasv@mail.ru</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-4985-1546</contrib-id><contrib-id contrib-id-type="spin">3218-6210</contrib-id><name-alternatives><name xml:lang="en"><surname>Gorbunova</surname><given-names>Kseniya V.</given-names></name><name xml:lang="ru"><surname>Горбунова</surname><given-names>Ксения Викторовна</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><email>ksenya.gorbunova@mail.ru</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-4961-384X</contrib-id><contrib-id contrib-id-type="spin">5249-5760</contrib-id><name-alternatives><name xml:lang="en"><surname>Ovsyannikov</surname><given-names>Dmitry Yu.</given-names></name><name xml:lang="ru"><surname>Овсянников</surname><given-names>Дмитрий Юрьевич</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>MD, Dr. Sci. (Medicine), Professor</p></bio><bio xml:lang="ru"><p>д-р мед. наук, профессор</p></bio><email>mdovsyannikov@yahoo.com</email><xref ref-type="aff" rid="aff2"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-3309-4683</contrib-id><contrib-id contrib-id-type="spin">6284-8040</contrib-id><name-alternatives><name xml:lang="en"><surname>Popadyuk</surname><given-names>Valentin I.</given-names></name><name xml:lang="ru"><surname>Попадюк</surname><given-names>Валентин Иванович</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>MD, Dr. Sci. (Medicine), Professor</p></bio><bio xml:lang="ru"><p>д-р мед. наук, профессор</p></bio><email>popadyuk-vi@rudn.ru</email><xref ref-type="aff" rid="aff2"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0009-0003-5418-0561</contrib-id><contrib-id contrib-id-type="spin">1838-8134</contrib-id><name-alternatives><name xml:lang="en"><surname>Krasilnikova</surname><given-names>Elizaveta V.</given-names></name><name xml:lang="ru"><surname>Красильникова</surname><given-names>Елизавета Валерьевна</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><email>eliz_nova1026@mail.ru</email><xref ref-type="aff" rid="aff3"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-1769-3670</contrib-id><contrib-id contrib-id-type="spin">5036-8467</contrib-id><name-alternatives><name xml:lang="en"><surname>Eliseeva</surname><given-names>Tatyana I.</given-names></name><name xml:lang="ru"><surname>Елисеева</surname><given-names>Татьяна Ивановна</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>MD, Dr. Sci. (Medicine), Professor</p></bio><bio xml:lang="ru"><p>д-р мед. наук, профессор</p></bio><email>eliseevati@yandex.ru</email><xref ref-type="aff" rid="aff1"/></contrib></contrib-group><aff-alternatives id="aff1"><aff><institution xml:lang="en">Privolzhsky Research Medical University</institution></aff><aff><institution xml:lang="ru">Приволжский исследовательский медицинский университет</institution></aff></aff-alternatives><aff-alternatives id="aff2"><aff><institution xml:lang="en">RUDN Universtiy</institution></aff><aff><institution xml:lang="ru">Российский университет дружбы народов имени Патриса Лумумбы</institution></aff></aff-alternatives><aff-alternatives id="aff3"><aff><institution xml:lang="en">National Research Lobachevsky State University of Nizhny Novgorod</institution></aff><aff><institution xml:lang="ru">Национальный исследовательский Нижегородский государственный университет имени Н.И. Лобачевского</institution></aff></aff-alternatives><pub-date date-type="pub" iso-8601-date="2025-12-25" publication-format="electronic"><day>25</day><month>12</month><year>2025</year></pub-date><volume>22</volume><issue>4</issue><fpage>360</fpage><lpage>369</lpage><history><date date-type="received" iso-8601-date="2026-01-23"><day>23</day><month>01</month><year>2026</year></date></history><permissions><copyright-statement xml:lang="en">Copyright ©; 2025, ABV-press</copyright-statement><copyright-statement xml:lang="ru">Copyright ©; 2025, ИД "АБВ-пресс"</copyright-statement><copyright-year>2025</copyright-year><copyright-holder xml:lang="en">ABV-press</copyright-holder><copyright-holder xml:lang="ru">ИД "АБВ-пресс"</copyright-holder><ali:free_to_read xmlns:ali="http://www.niso.org/schemas/ali/1.0/" start_date="2027-12-25"/><license><ali:license_ref xmlns:ali="http://www.niso.org/schemas/ali/1.0/">https://creativecommons.org/licenses/by-nc-nd/4.0/</ali:license_ref></license></permissions><self-uri xlink:href="https://ogarev-online.ru/raj/article/view/375443">https://ogarev-online.ru/raj/article/view/375443</self-uri><abstract xml:lang="en"><p><bold>BACKGROUND: </bold>Bronchial asthma and allergic rhinitis often concomitant to form a single clinical and pathogenetic syndrome based on the activation of T2 inflammation. Important biomarkers of this type of inflammation are eosinophils and total immunoglobulin E. Prolonged course of allergic rhinitis in patients with asthma can lead to the development of chronic rhinosinusitis with polypoid-hyperplastic changes in the sinonasal mucosa. The effect of polypoid-hyperplastic changes on the severity of clinical manifestations and the level of systemic biomarkers of T2 inflammation in patients with a combination of asthma and allergic rhinitis in the pediatric population cannot be considered established.</p> <p><bold>AIM:</bold> Сomparаtive the clinical manifestations (assessed by TNSS and SNOT-22 scales) and the content of systemic biomarkers of T2 inflammation between groups with the presence and absence of polypoid-hyperplastic changes in children and adolescents with combined course of bronchial asthma and allergic rhinitis.</p> <p><bold>METHODS:</bold> The single-stage, single-center observational study included patients with asthma and AR aged 6–17 years. All patients underwent clinical and laboratory examinations, rhino endoscopy and computed tomography of the nose and paranasal sinuses according to indications.</p> <p><bold>RESULTS:</bold> Totally, 268 patients were examined: 203 (75.75 %) boys and 65 (24.25 %) girls. Polypoid-hyperplastic changes in the sinonasal mucosa were detected in 31.84 % of patients. Clinical symptoms (assessed using the TNSS and SNOT-22 scales) were more pronounced in children with polypoid-hyperplastic changes compared to those without polypoid-hyperplastic changes (<italic>p</italic> &lt;0.001), but there was no significant difference between boys and girls in terms of these symptoms. At the same time, TNSS scores were statistically significantly higher for girls than for boys (<italic>p </italic>= 0.045), and SNOT22 scores were significantly higher in both groups (<italic>p </italic>&lt;0.05). Higher levels of eosinophils and total immunoglobulin E were also recorded by children with polypoid-hyperplastic changes (<italic>p</italic> &lt;0.001 and <italic>p = 0,001</italic>respectively), indicating a significant role for systemic T2 inflammation in this.</p> <p><bold>CONCLUSION: </bold>The presence of polypoid-hyperplastic changes in the sinonasal mucosa by children and adolescents with bronchial asthma and allergic rhinitis correlates with increased clinical symptoms and increased levels of eosinophils in blood and total serum immunoglobulin E, especially in girls. The results obtained indicate the potential involvement of systemic T2-inflammation in the processes of pathological remodeling and the formation of structural disorders of polypoid-hyperplastic changes in the sinonasal mucosa.</p></abstract><trans-abstract xml:lang="ru"><p><bold>Обоснование. </bold>Бронхиальная астма и аллергический ринит часто сочетаются, формируя единый клинико-патогенетический синдром, в основе которого лежит активация T2-воспаления. Важными биомаркерами данного типа воспаления являются эозинофилы и общий иммуноглобулин Е. Пролонгированное течение аллергического ринита у пациентов с бронхиальной астмой может приводить к развитию хронического риносинусита с полипозно-гиперпластическими изменениями синоназальной слизистой оболочки. Влияние этих изменений на выраженность клинических проявлений и уровень системных биомаркеров Т2-воспаления у пациентов с сочетанием бронхиальной астмы и аллергического ринита в педиатрической популяции нельзя считать установленным.</p> <p><bold>Цель исследования</bold> — сравнение клинических проявлений (оценка по шкалам TNSS и SNOT-22) и содержания системных биомаркеров Т2-воспаления между группами с наличием и отсутствием полипозно-гиперпластических изменений синоназальной слизистой оболочки у детей и подростков с сочетанным течением бронхиальной астмы и аллергического ринита.</p> <p><bold>Методы.</bold> В одномоментное одноцентровое обсервационное исследование включены пациенты с бронхиальной астмой и аллергическим ринитом в возрасте 6–17 лет. Всем пациентам проведены клинико-лабораторные исследования, по показаниям — риновидеоэндоскопия и компьютерная томография носа и околоносовых пазух.</p> <p><bold>Результаты.</bold> Обследованы 268 пациентов с бронхиальной астмой и аллергическим ринитом: 203 (75,75 %) мальчика и 65 (24,25 %) девочек. У 31,84 % пациентов выявлены полипозно-гиперпластические изменения синоназальной слизистой оболочки. У детей с данными изменениями клинические симптомы (по шкалам TNSS и SNOT-22) более выражены, чем у пациентов без морфологических изменений (<italic>р </italic>&lt;0,001). При этом у девочек с полипозно-гиперпластическими изменениями синоназальной слизистой оболочки показатели по TNSS и SNOT-22 были статистически значимо выше, чем у мальчиков (<italic>р </italic>= 0,045 и <italic>р </italic>&lt;0,001 соответственно). У детей с полипозно-гиперпластическими изменениями синоназальной слизистой оболочки зафиксированы более высокие уровни эозинофилов в периферической крови и общего иммуноглобулина Е в сыворотке крови, что свидетельствует о значимой роли системного Т2-воспаления в развитии данного состояния (<italic>p </italic>&lt;0,001 и <italic>p </italic>= 0,001 соответственно).</p> <p><bold>Заключение. </bold>У детей и подростков с бронхиальной астмой и аллергическим ринитом наличие полипозно-гиперпластических изменений синоназальной слизистой оболочки коррелирует с усилением клинических симптомов и повышением уровней эозинофилов в периферической крови и сывороточного общего иммуноглобулина E, особенно у девочек. Полученные результаты свидетельствуют о потенциальной вовлеченности системного T2-воспаления в процессы патологического ремоделирования и формирования структурных нарушений синоназальной слизистой оболочки у данной категории пациентов.</p></trans-abstract><kwd-group xml:lang="en"><kwd>bronchial asthma</kwd><kwd>allergic rhinitis</kwd><kwd>polypoid rhinosinusitis</kwd><kwd>biomarker</kwd><kwd>children</kwd><kwd>adolescents</kwd></kwd-group><kwd-group xml:lang="ru"><kwd>бронхиальная астма</kwd><kwd>аллергический ринит</kwd><kwd>полипозный риносинусит</kwd><kwd>биомаркер</kwd><kwd>дети</kwd><kwd>подростки</kwd></kwd-group></article-meta></front><body></body><back><ref-list><ref id="B1"><label>1.</label><mixed-citation>Brożek JL, Bousquet J, Agache I, et al. Allergic rhinitis and its impact on asthma (ARIA) guidelines — 2016 revision. J Allergy Clin Immunol. 2017;140(4):950–958. doi: 10.1016/j.jaci.2017.03.050 EDN: YDTHOX</mixed-citation></ref><ref id="B2"><label>2.</label><mixed-citation>Rabe APJ, Loke WJ, Gurjar K, et al. Global burden of asthma, and its impact on specific subgroups: nasal polyps, allergic rhinitis, severe asthma, eosinophilic asthma. J Asthma Allergy. 2023;16:1097–1113. doi: 10.2147/JAA.S418145 EDN: BEBLGE</mixed-citation></ref><ref id="B3"><label>3.</label><mixed-citation>Paiva Ferreira LKD, Paiva Ferreira LAM, Monteiro TM, et al. Combined allergic rhinitis and asthma syndrome (CARAS). Int Immunopharmacol. 2019;74:105718. doi: 10.1016/j.intimp.2019.105718 EDN: JJHSVQ</mixed-citation></ref><ref id="B4"><label>4.</label><mixed-citation>Kang N, Kim TB. Eosinophilic-associated disease overlap: what do we know about it? Allergy Asthma Immunol Res. 2023;15(5):539–542. doi: 10.4168/aair.2023.15.5.539 EDN: OMXPQU</mixed-citation></ref><ref id="B5"><label>5.</label><mixed-citation>Krasilnikova SV, Krestova EI, Eliseeva TI, et al. Inflammatory mediators in nasal secretion in patients with bronchial asthma and allergic rhinitis with or without polyposis and hypertrophic sinonasal mucosa. Explor Med. 2025;6:1001306. doi: 10.37349/emed.2025.1001306</mixed-citation></ref><ref id="B6"><label>6.</label><mixed-citation>Mormile M, Mormile I, Fuschillo S, et al. Eosinophilic airway diseases: from pathophysiological mechanisms to clinical practice. Int J Mol Sci. 2023;24(8):7254. doi: 10.3390/ijms24087254 EDN: JWECPF</mixed-citation></ref><ref id="B7"><label>7.</label><mixed-citation>Samitas K, Carter A, Kariyawasam HH, Xanthou G. Upper and lower airway remodelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: the one airway concept revisited. Allergy. 2018;73(5):993–1002. doi: 10.1111/all.13373 EDN: YEZTPF</mixed-citation></ref><ref id="B8"><label>8.</label><mixed-citation>Fokkens WJ, Lund VJ, Hopkins C, et al. European position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020;58(Suppl S29):1–464. doi: 10.4193/Rhin20.600 EDN: THMJZZ</mixed-citation></ref><ref id="B9"><label>9.</label><mixed-citation>Murtomäki A, Heleva A, Torkki P, et al. Comorbidities of chronic rhinosinusitis in children and adults. Clinical Transl Allergy. 2024;14(4):e12354. doi: 10.1002/clt2.12354 EDN: SRQBIX</mixed-citation></ref><ref id="B10"><label>10.</label><mixed-citation>Khan A, Huynh TMT, Vandeplas G, et al. The GALEN rhinosinusitis cohort: chronic rhinosinusitis with nasal polyps affects health-related quality of life. Rhinology. 2019;57(5):343–351. doi: 10.4193/Rhin19.158</mixed-citation></ref><ref id="B11"><label>11.</label><mixed-citation>Kurbacheva OM, Dyneva ME, Shilovskii IP, et al. Polypous rhinosinusitis in combination with bronchial asthma: clinical features and cellular characteristics of local and systemic inflammation. Russian Journal of Allergy. 2020;17(1):32–49. (In Russ.) doi: 10.36691/RAJ.2020.17.1.003 EDN: NBSLED</mixed-citation></ref><ref id="B12"><label>12.</label><mixed-citation>De Corso E, Corbò M, Montuori C, et al. Blood and local nasal eosinophilia in chronic rhinosinusitis with nasal polyps: prevalence and correlation with severity of disease. Acta Otorhinolaryngol Ital. 2025;45(1):39–46. doi: 10.14639/0392-100x-n2877 EDN: NBYKDC</mixed-citation></ref><ref id="B13"><label>13.</label><mixed-citation>Miyasaka T, Dobashi-Okuyama K, Kawakami K, et al. Sex plays a multifaceted role in asthma pathogenesis. Biomolecules. 2022;12(5). doi: 10.3390/biom12050650 EDN: UVLMVF</mixed-citation></ref><ref id="B14"><label>14.</label><mixed-citation>Gorbunova KV, Khramova RN, Eliseeva TI, et al. Impact of age and gender on spirometric parameters in adolescents with bronchial asthma. Pediatria n.a. G.N. Speransky. 2023;102(5):8–13. (In Russ.) doi: 10.24110/0031-403X-2023-102-5-8-13 EDN: FUJBXO</mixed-citation></ref><ref id="B15"><label>15.</label><mixed-citation>Аллергический ринит. Клинические рекомендации. Российская ассоциация аллергологов и клинических иммунологов; Союз педиатров России; Национальная медицинская ассоциация оториноларингологов. 2024. Режим доступа: https://cr.minzdrav.gov.ru/view-cr/261_2</mixed-citation></ref><ref id="B16"><label>16.</label><mixed-citation>Di Cicco ME, Bizzoco F, Morelli E, et al. Nasal polyps in children: the early origins of a challenging adulthood condition. Children (Basel). 2021;8(11):997. doi: 10.3390/children8110997 EDN: PORLGY</mixed-citation></ref><ref id="B17"><label>17.</label><mixed-citation>Ryazantsev SV, Kirichenko IM, Savlevich EL, et al. Acute and chronic rhinosinusitis age characteristics. Russian Bulletin of Otorhinolaryngology. 2024;89(1):64–72. (In Russ.) doi: 10.17116/otorino20248901164 EDN: GBTQIV</mixed-citation></ref><ref id="B18"><label>18.</label><mixed-citation>Savlevich EL, Zurochka AV, Kurbacheva OM, et al. Pleiomorphism of the cytokine profile in nasal polyp tissue depending on the phenotype of chronic rhinosinusitis with nasal polyps. Russian Bulletin of Otorhinolaryngology. 2023;88(1):50–56. (In Russ.) doi: 10.17116/otorino20228801150 EDN: YRQNQC</mixed-citation></ref><ref id="B19"><label>19.</label><mixed-citation>Sreeparvathi A, Kalyanikuttyamma LK, Kumar M, et al. Significance of blood eosinophil count in patients with chronic rhinosinusitis with nasal polyposis. J Clin Diagn Res. 2017;11(2):MC08–MC11. doi: 10.7860/JCDR/2017/25320.9445</mixed-citation></ref><ref id="B20"><label>20.</label><mixed-citation>Brunet A, Milara J, Frias S, et al. Molecular and clinical predictors of quality of life in chronic rhinosinusitis with nasal polyps. J Clin Med. 2023;12(4):1391. doi: 10.3390/jcm12041391 EDN: LIIDNY</mixed-citation></ref><ref id="B21"><label>21.</label><mixed-citation>Aslan F, Altun E, Paksoy S, Turan G. Could Eosinophilia predict clinical severity in nasal polyps? Multidiscip Respir Med. 2017;12:21. doi: 10.1186/s40248-017-0102-7</mixed-citation></ref><ref id="B22"><label>22.</label><mixed-citation>Hong SN, Won JY, Nam EC, et al. Clinical manifestations of allergic rhinitis by age and gender: a 12-year single-center study. Ann Otol Rhinol Laryngol. 2020;129(9):910–917. doi: 10.1177/0003489420921197 EDN: EOAAOF</mixed-citation></ref><ref id="B23"><label>23.</label><mixed-citation>Dundervill C, Al-Asadi Z, Behnke J, et al. Gender differences in quality of life of adolescent patients with chronic rhinosinusitis. Ann Otol Rhinol Laryngol. 2024;133(2):169–173. doi: 10.1177/00034894231195662 EDN: LJMKFU</mixed-citation></ref><ref id="B24"><label>24.</label><mixed-citation>Ference EH, Tan BK, Hulse KE, et al. Commentary on gender differences in prevalence, treatment, and quality of life of patients with chronic rhinosinusitis. Allergy Rhinol (Providence). 2015;6(2):82–88. doi: 10.2500/ar.2015.6.0120</mixed-citation></ref><ref id="B25"><label>25.</label><mixed-citation>Lal D, Rounds AB, Divekar R. Gender-specific differences in chronic rhinosinusitis patients electing endoscopic sinus surgery. Int Forum Allergy Rhinol. 2016;6(3):278–286. doi: 10.1002/alr.21667</mixed-citation></ref><ref id="B26"><label>26.</label><mixed-citation>Cai Y, Zhou J, Webb DC. Estrogen stimulates Th2 cytokine production and regulates the compartmentalisation of eosinophils during allergen challenge in a mouse model of asthma. Int Arch Allergy Immunol. 2012;158(3):252–260. doi: 10.1159/000331437</mixed-citation></ref><ref id="B27"><label>27.</label><mixed-citation>Laffont S, Blanquart E, Guery JC. Sex differences in asthma: a key role of androgen-signaling in group 2 innate lymphoid cells. Front Immunol. 2017;8:1069. doi: 10.3389/fimmu.2017.01069</mixed-citation></ref><ref id="B28"><label>28.</label><mixed-citation>Reddy KD, Oliver BGG. Sexual dimorphism in chronic respiratory diseases. Cell Biosci. 2023;13(1):47. doi: 10.1186/s13578-023-00998-5 EDN: XUFWLY</mixed-citation></ref><ref id="B29"><label>29.</label><mixed-citation>Krasilnikova SV, Kolesnik AS, Gorbunova KV, et al. Influence of age and sex on values of SNOT-22 sinonasal test domains in children and adolescents with bronchial asthma. Russian Rhinology. 2025;33(3):197–204. (In Russ.) doi: 10.17116/rosrino202533031197 EDN: IOZKUK</mixed-citation></ref><ref id="B30"><label>30.</label><mixed-citation>Chen Z, Shang Y, Duan W, et al. Androgens have therapeutic potential in T2 asthma by mediating METTL3 in bronchial epithelial cells. Int Immunopharmacol. 2024;143(Pt 1):113322. doi: 10.1016/j.intimp.2024.113322 EDN: YAMOGT</mixed-citation></ref></ref-list></back></article>
