{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T04:27:06Z","timestamp":1772166426776,"version":"3.50.1"},"reference-count":0,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Donatio Intensivistam","award":["DI-21-4-0003A"],"award-info":[{"award-number":["DI-21-4-0003A"]}]},{"name":"Czech Clinical Research Infrastructure Network CZECRIN","award":["LM 2018128"],"award-info":[{"award-number":["LM 2018128"]}]},{"name":"University Hospital Brno","award":["65269705"],"award-info":[{"award-number":["65269705"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2021,12]]},"abstract":"Abstract<\/jats:title>\n \n Objectives<\/jats:title>\n The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days.<\/jats:p>\n <\/jats:sec>\n \n Trial design<\/jats:title>\n REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice.<\/jats:p>\n <\/jats:sec>\n \n Participants<\/jats:title>\n The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic.<\/jats:p>\n <\/jats:sec>\n \n Inclusion criteria<\/jats:title>\n Subjects will be eligible for the trial if they meet all of the following criteria:<\/jats:p>\n 1. Adult (\u226518 years of age) at time of enrolment;<\/jats:p>\n 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing);<\/jats:p>\n 3. Intubation\/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy;<\/jats:p>\n 4. Moderate or severe ARDS according to Berlin criteria:<\/jats:p>\n \n \u2003\u2022 Moderate \u2013 PaO\n 2<\/jats:sub>\n \/FiO\n 2<\/jats:sub>\n 100\u2013200 mmHg;\n <\/jats:p>\n \n \u2003\u2022 Severe \u2013 PaO\n 2<\/jats:sub>\n \/FiO\n 2<\/jats:sub>\n < 100 mmHg;\n <\/jats:p>\n 5. Admission to ICU in the last 24 hours.<\/jats:p>\n <\/jats:sec>\n \n Exclusion criteria<\/jats:title>\n Subjects will not be eligible for the trial if they meet any of the following criteria:<\/jats:p>\n 1. Known allergy\/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol);<\/jats:p>\n 2. Fulfilled criteria for ARDS for \u226514 days at enrolment;<\/jats:p>\n 3. Pregnancy or breastfeeding;<\/jats:p>\n 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method);<\/jats:p>\n 5. End-of-life decision or patient is expected to die within next 24 hours;<\/jats:p>\n 6. Decision not to intubate or ceilings of care in place;<\/jats:p>\n 7. Immunosuppression and\/or immunosuppressive drugs in medical history:<\/jats:p>\n \u2003a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days;<\/jats:p>\n \u2003b) Systemic corticosteroid use before hospitalization;<\/jats:p>\n \u2003c) Any dose of dexamethasone during the present hospital stay for COVID-19 for \u22655 days before enrolment;<\/jats:p>\n \u2003d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock);<\/jats:p>\n 8. Current haematological or generalized solid malignancy;<\/jats:p>\n 9. Any contraindication for corticosteroid administration, e.g.<\/jats:p>\n \u2003\u2022 intractable hyperglycaemia;<\/jats:p>\n \u2003\u2022 active gastrointestinal bleeding;<\/jats:p>\n \u2003\u2022 adrenal gland disorders;<\/jats:p>\n \u2003\u2022 presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment;<\/jats:p>\n 10. Cardiac arrest before ICU admission;<\/jats:p>\n 11. Participation in another interventional trial in the last 30 days.<\/jats:p>\n <\/jats:sec>\n \n Intervention and comparator<\/jats:title>\n Dexamethasone solution for injection\/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1\u20135, followed by dexamethasone 10 mg intravenously once daily on day 6\u201310. Patients in the control group will receive dexamethasone 6 mg day 1\u201310. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection\/infusion can be used.<\/jats:p>\n <\/jats:sec>\n \n Main outcomes<\/jats:title>\n Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation.<\/jats:p>\n <\/jats:sec>\n \n Secondary endpoints<\/jats:title>\n a) Mortality from any cause at 60 days after randomisation;<\/jats:p>\n b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14;<\/jats:p>\n c) WHO Clinical Progression Scale at Day 14;<\/jats:p>\n d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge;<\/jats:p>\n e) Independence at 90 days after randomisation assessed by Barthel Index.<\/jats:p>\n The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index.<\/jats:p>\n <\/jats:sec>\n \n Randomisation<\/jats:title>\n Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied:<\/jats:p>\n \u2022 Age <65 and \u2265 65;<\/jats:p>\n \u2022 Charlson Comorbidity index (CCI) <3 and \u22653;<\/jats:p>\n \u2022 CRP <150 mg\/L and \u2265150 mg\/L<\/jats:p>\n \u2022 Trial centre.<\/jats:p>\n Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day.<\/jats:p>\n <\/jats:sec>\n \n Blinding (masking)<\/jats:title>\n This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed.<\/jats:p>\n <\/jats:sec>\n \n Numbers to be randomised (sample size)<\/jats:title>\n The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled.<\/jats:p>\n <\/jats:sec>\n \n Trial Status<\/jats:title>\n This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021.<\/jats:p>\n <\/jats:sec>\n \n Trial registration<\/jats:title>\n \n The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier:\n NCT04663555<\/jats:ext-link>\n with a last update posted on February 1, 2021.\n <\/jats:p>\n <\/jats:sec>\n \n Full protocol<\/jats:title>\n The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.<\/jats:p>\n <\/jats:sec>","DOI":"10.1186\/s13063-021-05116-9","type":"journal-article","created":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T04:03:11Z","timestamp":1614571391000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Effect of dexamethasone in patients with ARDS and COVID-19 \u2013 prospective, multi-centre, open-label, parallel-group, randomised controlled trial (REMED trial): A structured summary of a study protocol for a randomised controlled trial"],"prefix":"10.1186","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6911-2575","authenticated-orcid":false,"given":"Jan","family":"Mal\u00e1ska","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Sta\u0161ek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franti\u0161ek","family":"Du\u0161ka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Bal\u00edk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"M\u00e1ca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Hruda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Vymazal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olga","family":"Klementov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Zatloukal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Gabrhel\u00edk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel","family":"Novotn\u00fd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Regina","family":"Demlov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Kub\u00e1tov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Vinklerov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Svobodn\u00edk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milan","family":"Kratochv\u00edl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jozef","family":"Klu\u010dka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roman","family":"G\u00e1l","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mervyn","family":"Singer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"on behalf of the REMED Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Antoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petr","family":"Suk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Korbi\u010dka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Hudec","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Fric","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V\u00e1clav","family":"Zvon\u00ed\u010dek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Tencer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Kol\u00e1\u0159","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petr","family":"Kafka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Ot\u00e1hal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Rul\u00ed\u0161ek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marek","family":"Flaksa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Svobodov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Sklienka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filip","family":"Bur\u0161a","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcela","family":"K\u00e1\u0148ov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Varady","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filip","family":"Haiduk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladim\u00edr","family":"\u0160r\u00e1mek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel","family":"Suk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marek","family":"Fencl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"\u010cundrle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel","family":"\u0160t\u011btka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marek","family":"Luke\u0161","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milo\u0161","family":"Chobola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Berou\u0161ek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuzana","family":"P\u0159ikrylov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji\u0159\u00ed","family":"Bure\u0161","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jarom\u00edr","family":"Vajter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vlasta","family":"Vlas\u00e1kov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Garaj","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lenka","family":"Doubravsk\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji\u0159\u00ed","family":"Pouska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakub","family":"Klete\u010dka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Graus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tereza","family":"\u0160ob\u00e1\u0148ov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radovan","family":"Turek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Tyll","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ale\u0161","family":"R\u00e1ra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,1]]},"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-021-05116-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-021-05116-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-021-05116-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,15]],"date-time":"2022-01-15T02:11:46Z","timestamp":1642212706000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-021-05116-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,1]]},"references-count":0,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["5116"],"URL":"https:\/\/doi.org\/10.1186\/s13063-021-05116-9","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-210774\/v1","asserted-by":"object"}]},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,1]]},"assertion":[{"value":"4 February 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The trial was approved by the Ethics Committee for Multi-Centric Clinical Trials University Hospital Brno on January 28, 2021 Identifier: 11\/21-MEK.This trial will be conducted following the applicable legislation and requirements for good clinical practice according to ICH E6(R2). Compliance with this standard provides public assurance that the rights, safety and well-being of trial participants are protected and that the clinical trial data are credible. All potential amendments will be submitted to the relevant Ethics committee and Regulatory authority for approval.Informed consent procedure<\/b>The investigator assesses the patient\u2019s ability to decide, and the extent of potential consciousness impairment based on Glasgow Coma Score and other appropriate clinical measures (at the discretion of the trial centre).Fully conscious and oriented patients (GCS 15)<\/b>Patient with decision-making capacity will go through the standard procedure (informative interview with the investigator, written information for the patient, the possibility to ask questions, and adequate time to discuss with family and decide). If the patient wishes to participate, he\/she will provide written prospective informed consent.Patients with limited ability to decide (GCS 13 or 14)<\/b>Some patients may be limited in their decisional capacity due to their acute health status and\/or medication. Generally, if a patient understands simplified information and can communicate verbally, the simplified procedure of obtaining informed consent will be applied. The shortened (one-page) information sheet and consent form for signature will be used.As soon as the patient regains full decisional capacity, he\/she will be approached to provide consent for continuation of his\/her participation in the trial. Patients will be informed about the option to withdraw from the trial. Patients who decide to terminate their involvement can permit the sponsor to use the data collected, or they can ask for deletion of all data collected. Both options will be presented to them.If the patient does not regain decisional capacity, the initial consent will remain valid.Patients lacking the capacity to decide (GCS 12 or less)<\/b>It is expected that a significant proportion of screened patients will lack capacity to provide informed consent due to severely altered consciousness, severe respiratory distress, or sedation necessary to facilitate mechanical ventilation. In this situation, the deferred consent policy will be applied. Such a patient will be enrolled after an independent physician witnesses (in writing) that the patient cannot give his\/her consent and fulfils eligibility criteria.A patient\u2019s close person (spouse\/partner, close relative, caregiver) will be informed about the patient's enrolment and the nature of the study. If possible, and compliant with the epidemiological restrictions by the government, the patient's close person will meet the investigator for an informative interview, to obtain the information leaflet, and to sign a confirmation that he\/she was informed about the patient\u2019s participation in the trial.As soon as the patient regains decisional capacity, he\/she will be approached to provide consent for continuation of his\/her participation in the trial. Patients will be informed about the option to withdraw from the trial. Patients who decide to terminate their involvement can permit the sponsor to use data collected, or can ask for deletion of all data collected to date. Both options will be presented to them.If the patient does not regain decisional capacity, the initial consent by an independent physician will remain valid.Vulnerable population<\/b>Beside patients with diminished decision capacity, other specifically vulnerable participants (children, pregnant women, prisoners, refugees, institutionalized patients, patients with severe mental illnesses, etc.) will not be enrolled in this clinical trial.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Investigators declare no financial or non-financial competing interest regarding the focus of this trial.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"172"}}