{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:45:12Z","timestamp":1760147112742,"version":"build-2065373602"},"reference-count":61,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In drug studies, patients are often included when the disease activity is high. This will make any treatment appear to lessen disease activity, although the improvement is biased by selection. This effect is known as regression towards the mean (RTM). We aimed at investigating drug trials in Pulmonary Arterial Hypertension (PAH) using the 6-minute walking distance test (6MWD) as a primary outcome for the phenomenon of RTM. An existing registry of 43 open label studies and 23 randomized controlled trials conducted between 1990 and 2009 was used as the data source. Data analysis was carried out for 18 randomized controlled trials (RCTs) and 24 open label studies out of this registry. Data were analyzed for verum and placebo arms of the RCTs separately, as well as for the open label arms. In the verum arms, the overall effect given as 33.2 m (95% CI: 25.7; 40.6]); 6MWD was slightly lower than the effect in the observational studies, with 44.6 m (95% CI: [25.4; 63.8]). After studying and interpreting the data, we found that regression towards the mean plays only a minor role in PAH studies. In particular, placebo effects in the RCTs were negligibly small, with a mean 6MWD of \u22122.5 m (95% CI: [\u22129.8; 4.7]) in the placebo arm. Therefore, our analysis indicates that results of non-randomized observational studies can be regarded as valid tools for gaining valid clinical effects in patients with PAH.<\/jats:p>","DOI":"10.3390\/ijms24021069","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T01:48:19Z","timestamp":1672969699000},"page":"1069","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["No Placebo Effect beyond Regression to the Mean on the Six Minute Walk Test in Pulmonary Arterial Hypertension Trials"],"prefix":"10.3390","volume":"24","author":[{"given":"Dennis","family":"Anheyer","sequence":"first","affiliation":[{"name":"Department for Psychology and Psychotherapy, Witten\/Herdecke University, 58458 Witten, Germany"},{"name":"Institute for General Practice and Interprofessional Care, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8287-2635","authenticated-orcid":false,"given":"Till Johannes","family":"Bugaj","sequence":"additional","affiliation":[{"name":"Department of General Internal Medicine and Psychosomatics, University of Heidelberg, Medical Hospital, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rainer","family":"L\u00fcdtke","sequence":"additional","affiliation":[{"name":"Stifterverband, 45128 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Appelbaum","sequence":"additional","affiliation":[{"name":"Department for Psychology and Psychotherapy, Witten\/Herdecke University, 58458 Witten, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hubert","family":"Tr\u00fcbel","sequence":"additional","affiliation":[{"name":"Department for Medicine, Witten\/Herdecke University, 58458 Witten, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2695-0701","authenticated-orcid":false,"given":"Thomas","family":"Ostermann","sequence":"additional","affiliation":[{"name":"Department for Psychology and Psychotherapy, Witten\/Herdecke University, 58458 Witten, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1161\/CIRCRESAHA.115.301146","article-title":"Pulmonary arterial hypertension: The clinical syndrome","volume":"115","author":"Lai","year":"2014","journal-title":"Circ. Res."},{"key":"ref_2","first-page":"73","article-title":"Pulmonary Hypertension","volume":"114","author":"Hoeper","year":"2017","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"85S","DOI":"10.1378\/chest.09-2816","article-title":"Worldwide physician education and training in pulmonary hypertension: Pulmonary vascular disease: The global perspective","volume":"137","author":"Elliott","year":"2010","journal-title":"Chest"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1183\/09031936.00107108","article-title":"End-points and clinical trial design in pulmonary arterial hypertension: Have we made progress?","volume":"34","author":"Peacock","year":"2009","journal-title":"Eur. Respir. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.pcad.2011.02.003","article-title":"Exercise testing and training in chronic lung disease and pulmonary arterial hypertension","volume":"53","author":"Arena","year":"2011","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_6","first-page":"246","article-title":"Regression Towards Mediocrity in Hereditary Stature","volume":"15","author":"Galton","year":"1886","journal-title":"J. Anthropol. Inst. Great Br. Irel."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1093\/ije\/dyh299","article-title":"Regression to the mean: What it is and how to deal with it","volume":"34","author":"Barnett","year":"2005","journal-title":"Int. J. Epidemiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1002\/sim.4780020401","article-title":"How much of the placebo \u2018effect\u2019 is really statistical regression?","volume":"2","author":"McDonald","year":"1983","journal-title":"Stat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ejim.2008.03.008","article-title":"Bosentan for patients with chronic thromboembolic pulmonary hypertension","volume":"20","author":"Vassallo","year":"2009","journal-title":"Eur. J. Intern. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"107","DOI":"10.21693\/1933-088X-9.2.107","article-title":"What Can be Learned in 6 Minutes? 6-Minute Walk Test Primer and Role in Pulmonary Arterial Hypertension","volume":"9","author":"Burger","year":"2010","journal-title":"Adv. Pulm. Hypertens."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1164\/ajrccm.161.2.9906015","article-title":"Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing","volume":"161","author":"Miyamoto","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1161\/CIRCULATIONAHA.112.105890","article-title":"Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials","volume":"126","author":"Gabler","year":"2012","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1513\/pats.200802-019SK","article-title":"The ethics of randomized clinical trials in pulmonary arterial hypertension","volume":"5","author":"Halpern","year":"2008","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"217","DOI":"10.4103\/2045-8932.109933","article-title":"Advancing clinical trial design in pulmonary hypertension","volume":"3","author":"Grieve","year":"2013","journal-title":"Pulm. Circ."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ostermann, T., Willich, S.N., and L\u00fcdtke, R. (2008). Regression toward the mean\u2014A detection method for unknown population mean based on Mee and Chua\u2019s algorithm. BMC Med. Res. Methodol., 8.","DOI":"10.1186\/1471-2288-8-52"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1164\/rccm.200510-1668OC","article-title":"Pulmonary arterial hypertension in France: Results from a national registry","volume":"173","author":"Humbert","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1183\/09031936.00194909","article-title":"The 6-min walk distance in healthy subjects: Reference standards from seven countries","volume":"37","author":"Casanova","year":"2011","journal-title":"Eur. Respir. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1164\/rccm.200410-1411OC","article-title":"Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study","volume":"171","author":"Wilkins","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1378\/chest.07-2681","article-title":"Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension","volume":"134","author":"Suntharalingam","year":"2008","journal-title":"Chest"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1183\/09031936.00011308","article-title":"A randomised, controlled trial of bosentan in severe COPD","volume":"32","author":"Stolz","year":"2008","journal-title":"Eur. Respir. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"521","DOI":"10.7326\/0003-4819-149-8-200810210-00004","article-title":"Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: A randomized trial","volume":"149","author":"Simonneau","year":"2008","journal-title":"Ann. Intern. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1056\/NEJMoa012212","article-title":"Bosentan therapy for pulmonary arterial hypertension","volume":"346","author":"Rubin","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1378\/chest.07-0592","article-title":"Sildenafil improves health-related quality of life in patients with pulmonary arterial hypertension","volume":"133","author":"Gilbert","year":"2008","journal-title":"Chest"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1378\/chest.126.2.420","article-title":"Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease","volume":"126","author":"Oudiz","year":"2004","journal-title":"Chest"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1056\/NEJMoa020204","article-title":"Inhaled iloprost for severe pulmonary hypertension","volume":"347","author":"Olschewski","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1164\/rccm.200603-358OC","article-title":"Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension","volume":"174","author":"McLaughlin","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1161\/CIRCULATIONAHA.107.716373","article-title":"Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension","volume":"116","author":"Lewis","year":"2007","journal-title":"Circulation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1016\/j.jacc.2008.08.059","article-title":"Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial","volume":"52","author":"Jansa","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1161\/CIRCULATIONAHA.107.742510","article-title":"Ambrisentan for the treatment of pulmonary arterial hypertension: Results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2","volume":"117","author":"Olschewski","year":"2008","journal-title":"Circulation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1016\/S0735-1097(02)01786-2","article-title":"Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: A randomized, double-blind, placebo-controlled trial","volume":"39","author":"Humbert","year":"2002","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1056\/NEJMc051946","article-title":"Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension","volume":"353","author":"Ghofrani","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.jacc.2005.04.050","article-title":"Ambrisentan therapy for pulmonary arterial hypertension","volume":"46","author":"Badesch","year":"2005","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/S0140-6736(01)06250-X","article-title":"Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebocontrolled study","volume":"358","author":"Channick","year":"2001","journal-title":"Lancet"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1016\/S0735-1097(03)00463-7","article-title":"Beraprost therapy for pulmonary arterial hypertension","volume":"41","author":"Barst","year":"2003","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1164\/rccm.200307-957OC","article-title":"Sitaxsentan therapy for pulmonary arterial hypertension","volume":"169","author":"Barst","year":"2004","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1111\/j.1399-3046.2007.00863.x","article-title":"Safety and efficacy of autologous endothelial progenitor cells transplantation in children with idiopathic pulmonary arterial hypertension: Open-label pilot study","volume":"12","author":"Zhu","year":"2008","journal-title":"Pediatr. Transplant."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/hr.2009.113","article-title":"The efficacy and safety of sildenafil in Chinese patients with pulmonary arterial hypertension","volume":"32","author":"Xu","year":"2009","journal-title":"Hypertens. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1378\/chest.129.3.683","article-title":"Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: A prospective, multicenter, open-label, 12-week trial","volume":"129","author":"Tapson","year":"2006","journal-title":"Chest"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1177\/112972980600700304","article-title":"Delivery of intravenous treprostinil at low infusion rates using a miniaturized infusion pump in patients with pulmonary arterial hypertension","volume":"7","author":"Tapson","year":"2006","journal-title":"J. Vasc. Access"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/FJC.0b013e31802b3184","article-title":"Rapid switch from intravenous epoprostenol to intravenous treprostinil in patients with pulmonary arterial hypertension","volume":"49","author":"Sitbon","year":"2007","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1183\/09031936.00039007","article-title":"Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension","volume":"30","author":"Reichenberger","year":"2007","journal-title":"Eur. Respir. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1161\/CIRCULATIONAHA.105.603001","article-title":"Phosphodiesterase-5 inhibitor in Eisenmenger syndrome: A preliminary observational study","volume":"114","author":"Mukhopadhyay","year":"2006","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1177\/0961203307076509","article-title":"Bosentan use in systemic lupus erythematosus patients with pulmonary arterial hypertension","volume":"16","author":"Mok","year":"2007","journal-title":"Lupus"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1161\/01.CIR.0000099502.17776.C2","article-title":"Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension","volume":"108","author":"Michelakis","year":"2003","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1536\/ihj.50.513","article-title":"Effects of long-acting beraprost sodium (TRK-100STP) in Japanese patients with pulmonary arterial hypertension","volume":"50","author":"Kunieda","year":"2009","journal-title":"Int. Heart J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.healun.2007.07.040","article-title":"Safety and efficacy of transition from subcutaneous treprostinil to oral sildenafil in patients with pulmonary arterial hypertension","volume":"26","author":"Keogh","year":"2007","journal-title":"J. Heart Lung Transplant."},{"key":"ref_47","first-page":"1829","article-title":"Pilot study of short-term effects of a novel long-acting oral beraprost in patients with pulmonary arterial hypertension","volume":"71","author":"Ikeda","year":"2007","journal-title":"Circ. J. Off. J. Jpn. Circ. Soc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1155\/2006\/746176","article-title":"An open-label, multicentre pilot study of bosentan in pulmonary arterial hypertension related to congenital heart disease","volume":"13","author":"Ibrahim","year":"2006","journal-title":"Can. Respir. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3274","DOI":"10.1161\/CIRCULATIONAHA.104.473371","article-title":"Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: Twelve-month clinical trial of a single-drug, open-label, pilot study","volume":"111","author":"Humpl","year":"2005","journal-title":"Circulation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1378\/chest.128.4.2363","article-title":"Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension","volume":"128","author":"Hoeper","year":"2005","journal-title":"Chest"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1183\/09031936.03.00008003","article-title":"Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids","volume":"22","author":"Hoeper","year":"2003","journal-title":"Eur. Respir. J."},{"key":"ref_52","first-page":"342","article-title":"Sildenafil for pulmonary hypertension secondary to congenital heart diseases","volume":"59","author":"Gupta","year":"2007","journal-title":"Indian Heart J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1164\/rccm.200505-766OC","article-title":"Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension","volume":"172","author":"Tapson","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.healun.2007.04.013","article-title":"Creation of a model comparing 6-minute walk test to metabolic equivalent in evaluating treatment effects in pulmonary arterial hypertension","volume":"26","author":"Huo","year":"2007","journal-title":"J. Heart Lung Transplant."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1378\/chest.121.6.1860","article-title":"Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: Open-label pilot study","volume":"121","author":"Barst","year":"2002","journal-title":"Chest"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1136\/hrt.2006.100388","article-title":"Long-term oral bosentan treatment in patients with pulmonary arterial hypertension related to congenital heart disease: A 2-year study","volume":"93","author":"Apostolopoulou","year":"2007","journal-title":"Heart"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1136\/hrt.2004.051961","article-title":"Effect of the oral endothelin antagonist bosentan on the clinical, exercise, and haemodynamic status of patients with pulmonary arterial hypertension related to congenital heart disease","volume":"91","author":"Apostolopoulou","year":"2005","journal-title":"Heart"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.pupt.2005.09.006","article-title":"Sildenafil improves hemodynamic parameters in COPD\u2014An investigation of six patients","volume":"19","author":"Alp","year":"2006","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_59","first-page":"15","article-title":"Methodological Contribution to the Analysis of Election Results in Party Strongholds","volume":"3","author":"Ostermann","year":"2009","journal-title":"Methods Data Anal."},{"key":"ref_60","first-page":"39","article-title":"Regression Toward the Mean and the Paired Sample t Test","volume":"45","author":"Mee","year":"1991","journal-title":"Am. Stat."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1136\/ebmental-2019-300117","article-title":"How to perform a meta-analysis with R: A practical tutorial","volume":"22","author":"Balduzzi","year":"2019","journal-title":"Evid. Based Ment. Health"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1069\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:00:33Z","timestamp":1760119233000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1069"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,5]]},"references-count":61,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24021069"],"URL":"https:\/\/doi.org\/10.3390\/ijms24021069","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,1,5]]}}}