{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:18:36Z","timestamp":1792426716689,"version":"4.5.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,11,2]],"date-time":"2018-11-02T00:00:00Z","timestamp":1541116800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,11,2]],"date-time":"2018-11-02T00:00:00Z","timestamp":1541116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009633","name":"U.S. Department of Health &amp; Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD070647"],"award-info":[{"award-number":["HD070647"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"U.S. Department of Health &amp; Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD080755"],"award-info":[{"award-number":["HD080755"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We performed whole exome sequencing to identify an unknown genetic cause of azoospermia and male infertility in a large Pakistani family. Three infertile males were subjected to semen analysis, hormone testing, testicular histology, ultrasonography, karyotyping, Y-chromosome microdeletion and <jats:italic>CFTR<\/jats:italic> testing. The clinical testing suggested a diagnosis of obstructive azoospermia (OA). To identify the cause, we performed whole exome sequencing (WES) for 2 infertile brothers and 2 fertile family members. For segregation analysis and variant confirmation, we performed Sanger sequencing. WES data analysis of the family revealed segregated variants in 3 candidate genes. We considered novel nonsense variant c.2440C\u2009&gt;\u2009T(p.Arg814*) in X-linked gene <jats:italic>ADGRG2<\/jats:italic> as biologically most plausible. It is predicted to truncate the protein by 204 amino acids (aa) at a key transmembrane domain. <jats:italic>Adgrg2<\/jats:italic>-knockout male mice show sperm loss due to obstructive fluid stasis, while <jats:italic>ADGRG2<\/jats:italic> mutations cause OA in the infertile male patients. Our analysis of testicular histology reveals secondary severe reduction of spermatogenesis, consistent with human and knockout mouse phenotypes. The <jats:italic>ADGRG2<\/jats:italic> nonsense mutation is absent in the largest population databases, ExAC and gnomAD. Analysis of the novel nonsense mutation in extended family members confirmed co-segregation of the mutation with OA in all affected males. The likely pathogenic nature of the mutation is supported by its truncation effect on the transmembrane domain and distinctive ultrasound results. The study demonstrates effectiveness of WES in discovering a genetic cause of azoospermia.<\/jats:p>","DOI":"10.1038\/s41598-018-34262-5","type":"journal-article","created":{"date-parts":[[2018,10,29]],"date-time":"2018-10-29T15:38:01Z","timestamp":1540827481000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["X-linked ADGRG2 mutation and obstructive azoospermia in a large Pakistani family"],"prefix":"10.1038","volume":"8","author":[{"given":"Muhammad Jaseem","family":"Khan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nijole","family":"Pollock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaiyang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Castro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubina","family":"Nazli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jawad","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulman","family":"Basit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandar","family":"Rajkovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander N.","family":"Yatsenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,11,2]]},"reference":[{"key":"34262_CR1","doi-asserted-by":"publisher","unstructured":"Agarwal, A., Mulgund, A., Hamada, A. & Chyatte, M. R. A unique view on male infertility around the globe. Reprod Biol Endocrinol 13, 37, https:\/\/doi.org\/10.1186\/s12958-015-0032-1 (2015).","DOI":"10.1186\/s12958-015-0032-1"},{"issue":"6","key":"34262_CR2","doi-asserted-by":"publisher","first-page":"2466","DOI":"10.1016\/j.fertnstert.2008.03.022","volume":"91","author":"John E. Anderson","year":"2009","unstructured":"Anderson, J. E., Farr, S. L., Jamieson, D. J., Warner, L. & Macaluso, M. Infertility services reported by men in the United States: national survey data. Fertil Steril 91, 2466\u20132470, S0015-0282(08)00593-1 (2009).","journal-title":"Fertility and Sterility"},{"key":"34262_CR3","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1111\/j.1365-2605.2010.01087.x","volume":"34","author":"F Tuttelmann","year":"2011","unstructured":"Tuttelmann, F. et al. Clinical experience with azoospermia: aetiology and chances for spermatozoa detection upon biopsy. International journal of andrology 34, 291\u2013298 (2011).","journal-title":"International journal of andrology"},{"key":"34262_CR4","unstructured":"AUA. The Evaluation of the Azoospermic Male: Best Practice Statement. Revised. Male Infertility, 4\u201325 (2011)."},{"key":"34262_CR5","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1038\/nm.f.1895","volume":"14","author":"MM Matzuk","year":"2008","unstructured":"Matzuk, M. M. & Lamb, D. J. The biology of infertility: research advances and clinical challenges. Nat Med 14, 1197\u20131213 (2008).","journal-title":"Nat Med"},{"key":"34262_CR6","doi-asserted-by":"crossref","unstructured":"O\u2019Flynn O\u2019Brien, K. L., Varghese, A. C. & Agarwal, A. The genetic causes of male factor infertility: a review. Fertil Steril 93, 1\u201312, (2010).","DOI":"10.1016\/j.fertnstert.2009.10.045"},{"issue":"S1","key":"34262_CR7","doi-asserted-by":"publisher","first-page":"27","DOI":"10.6061\/clinics\/2013(Sup01)04","volume":"68","author":"A Gudeloglu","year":"2013","unstructured":"Gudeloglu, A. & Parekattil, S. J. Update in the evaluation of the azoospermic male. Clinics (Sao Paulo) 68 Suppl 1, 27\u201334, (2013).","journal-title":"Clinics"},{"key":"34262_CR8","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.urology.2010.10.001","volume":"77","author":"JY Lee","year":"2011","unstructured":"Lee, J. Y., Dada, R., Sabanegh, E., Carpi, A. & Agarwal, A. Role of genetics in azoospermia. Urology 77, 598\u2013601, https:\/\/doi.org\/10.1016\/j.urology.2010.10.001 (2011).","journal-title":"Urology"},{"key":"34262_CR9","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1038\/ncpuro0166","volume":"2","author":"PJ Turek","year":"2005","unstructured":"Turek, P. J. Practical approaches to the diagnosis and management of male infertility. Nat Clin Pract Urol 2, 226\u2013238 (2005).","journal-title":"Nat Clin Pract Urol"},{"issue":"9","key":"34262_CR10","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1038\/ejhg.2012.290","volume":"21","author":"Albrecht R\u00f6pke","year":"2013","unstructured":"Ropke, A. et al. Comprehensive sequence analysis of the NR5A1 gene encoding steroidogenic factor 1 in a large group of infertile males. Eur J Hum Genet, https:\/\/doi.org\/10.1038\/ejhg.2012.290 (2013).","journal-title":"European Journal of Human Genetics"},{"key":"34262_CR11","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s00439-012-1234-7","volume":"132","author":"L Mou","year":"2013","unstructured":"Mou, L. et al. A dominant-negative mutation of HSF2 associated with idiopathic azoospermia. Hum Genet 132, 159\u2013165, https:\/\/doi.org\/10.1007\/s00439-012-1234-7 (2013).","journal-title":"Hum Genet"},{"key":"34262_CR12","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1016\/S0140-6736(03)14845-3","volume":"362","author":"T Miyamoto","year":"2003","unstructured":"Miyamoto, T. et al. Azoospermia in patients heterozygous for a mutation in SYCP3. Lancet 362, 1714\u20131719 (2003).","journal-title":"Lancet"},{"key":"34262_CR13","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1002\/humu.21264","volume":"31","author":"Y Choi","year":"2010","unstructured":"Choi, Y. et al. Mutations in SOHLH1 gene associate with nonobstructive azoospermia. Hum Mutat 31, 788\u2013793, https:\/\/doi.org\/10.1002\/humu.21264 (2010).","journal-title":"Hum Mutat"},{"key":"34262_CR14","doi-asserted-by":"publisher","first-page":"2097","DOI":"10.1056\/NEJMoa1406192","volume":"372","author":"AN Yatsenko","year":"2015","unstructured":"Yatsenko, A. N. et al. X-linked TEX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med 372, 2097\u20132107, https:\/\/doi.org\/10.1056\/NEJMoa1406192 (2015).","journal-title":"N Engl J Med"},{"key":"34262_CR15","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1056\/NEJM199506013322204","volume":"332","author":"M Chillon","year":"1995","unstructured":"Chillon, M. et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med 332, 1475\u20131480 (1995).","journal-title":"N Engl J Med"},{"key":"34262_CR16","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.ajhg.2016.06.012","volume":"99","author":"O Patat","year":"2016","unstructured":"Patat, O. et al. Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens. Am J Hum Genet 99, 437\u2013442, https:\/\/doi.org\/10.1016\/j.ajhg.2016.06.012 (2016).","journal-title":"Am J Hum Genet"},{"key":"34262_CR17","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1111\/andr.12407","volume":"5","author":"B Yang","year":"2017","unstructured":"Yang, B. et al. Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population. Andrology 5, 954\u2013957, https:\/\/doi.org\/10.1111\/andr.12407 (2017).","journal-title":"Andrology"},{"key":"34262_CR18","doi-asserted-by":"publisher","first-page":"8642","DOI":"10.1128\/MCB.24.19.8642-8648.2004","volume":"24","author":"B Davies","year":"2004","unstructured":"Davies, B. et al. Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility. Mol Cell Biol 24, 8642\u20138648 (2004).","journal-title":"Mol Cell Biol"},{"key":"34262_CR19","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1124\/mol.115.098749","volume":"88","author":"KR Monk","year":"2015","unstructured":"Monk, K. R. et al. Adhesion G Protein-Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms. Mol Pharmacol 88, 617\u2013623, https:\/\/doi.org\/10.1124\/mol.115.098749 (2015).","journal-title":"Mol Pharmacol"},{"key":"34262_CR20","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1002\/mrd.10220","volume":"64","author":"H Obermann","year":"2003","unstructured":"Obermann, H. et al. HE6, a two-subunit heptahelical receptor associated with apical membranes of efferent and epididymal duct epithelia. Molecular reproduction and development 64, 13\u201326, https:\/\/doi.org\/10.1002\/mrd.10220 (2003).","journal-title":"Molecular reproduction and development"},{"key":"34262_CR21","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1136\/jmedgenet-2014-102921","volume":"52","author":"Y Tenenbaum-Rakover","year":"2015","unstructured":"Tenenbaum-Rakover, Y. et al. Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure. J Med Genet 52, 391\u2013399, https:\/\/doi.org\/10.1136\/jmedgenet-2014-102921 (2015).","journal-title":"J Med Genet"},{"key":"34262_CR22","unstructured":"WHO. WHO laboratory manual for examination and processing of human semen. Fifth Edition. 56\u2013102 (2010)."},{"key":"34262_CR23","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1515\/CCLM.2006.160","volume":"44","author":"R Stricker","year":"2006","unstructured":"Stricker, R., Eberhart, R., Chevailler, M. C., Quinn, F. A. & Bischof, P. Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer. Clin Chem Lab Med 44, 883\u2013887, https:\/\/doi.org\/10.1515\/CCLM.2006.160 (2006).","journal-title":"Clin Chem Lab Med"},{"key":"34262_CR24","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1093\/humrep\/del279","volume":"22","author":"RI McLachlan","year":"2007","unstructured":"McLachlan, R. I., Rajpert-De Meyts, E., Hoei-Hansen, C. E., de Kretser, D. M. & Skakkebaek, N. E. Histological evaluation of the human testis\u2013approaches to optimizing the clinical value of the assessment: mini review. Hum Reprod 22, 2\u201316, https:\/\/doi.org\/10.1093\/humrep\/del279 (2007).","journal-title":"Hum Reprod"},{"key":"34262_CR25","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1111\/j.1464-410X.2012.11203.x","volume":"111","author":"A Abdel Raheem","year":"2013","unstructured":"Abdel Raheem, A. et al. Testicular histopathology as a predictor of a positive sperm retrieval in men with non-obstructive azoospermia. BJU Int 111, 492\u2013499, https:\/\/doi.org\/10.1111\/j.1464-410X.2012.11203.x (2013).","journal-title":"BJU Int"},{"key":"34262_CR26","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1043\/2009-0379-RA.1","volume":"134","author":"LA Cerilli","year":"2010","unstructured":"Cerilli, L. A., Kuang, W. & Rogers, D. A practical approach to testicular biopsy interpretation for male infertility. Arch Pathol Lab Med 134, 1197\u20131204, https:\/\/doi.org\/10.1043\/2009-0379-RA.1 (2010).","journal-title":"Arch Pathol Lab Med"},{"key":"34262_CR27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000353118","volume":"141","author":"A Simons","year":"2013","unstructured":"Simons, A., Shaffer, L. G. & Hastings, R. J. Cytogenetic Nomenclature: Changes in the ISCN 2013 Compared to the 2009 Edition. Cytogenet Genome Res 141, 1\u20136, https:\/\/doi.org\/10.1159\/000353118 (2013).","journal-title":"Cytogenet Genome Res"},{"key":"34262_CR28","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1111\/j.2047-2927.2013.00173.x","volume":"2","author":"C Krausz","year":"2014","unstructured":"Krausz, C., Hoefsloot, L., Simoni, M. & Tuttelmann, F. EAA\/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions: state-of-the-art 2013. Andrology 2, 5\u201319, https:\/\/doi.org\/10.1111\/j.2047-2927.2013.00173.x (2014).","journal-title":"Andrology"},{"key":"34262_CR29","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1101\/pdb.prot083659","volume":"2015","author":"R Chen","year":"2015","unstructured":"Chen, R., Im, H. & Snyder, M. Whole-Exome Enrichment with the Agilent SureSelect Human All Exon Platform. Cold Spring Harb Protoc 2015, 626\u2013633, https:\/\/doi.org\/10.1101\/pdb.prot083659 (2015).","journal-title":"Cold Spring Harb Protoc"},{"key":"34262_CR30","doi-asserted-by":"publisher","first-page":"e164","DOI":"10.1093\/nar\/gkq603","volume":"38","author":"K Wang","year":"2010","unstructured":"Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38, e164, https:\/\/doi.org\/10.1093\/nar\/gkq603 (2010).","journal-title":"Nucleic Acids Res"},{"key":"34262_CR31","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1038\/msb.2011.75","volume":"7","author":"F Sievers","year":"2011","unstructured":"Sievers, F. et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7, 539, https:\/\/doi.org\/10.1038\/msb.2011.75 (2011).","journal-title":"Mol Syst Biol"},{"key":"34262_CR32","doi-asserted-by":"publisher","first-page":"e115","DOI":"10.1093\/nar\/gks596","volume":"40","author":"A Untergasser","year":"2012","unstructured":"Untergasser, A. et al. Primer3\u2013new capabilities and interfaces. Nucleic Acids Res 40, e115, https:\/\/doi.org\/10.1093\/nar\/gks596 (2012).","journal-title":"Nucleic Acids Res"},{"key":"34262_CR33","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","volume":"347","author":"M Uhlen","year":"2015","unstructured":"Uhlen, M. et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419, https:\/\/doi.org\/10.1126\/science.1260419 (2015).","journal-title":"Science"},{"key":"34262_CR34","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","volume":"536","author":"M Lek","year":"2016","unstructured":"Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285\u2013291, https:\/\/doi.org\/10.1038\/nature19057 (2016).","journal-title":"Nature"},{"key":"34262_CR35","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1111\/andr.12450","volume":"6","author":"DAS de Souza","year":"2018","unstructured":"de Souza, D. A. S., Faucz, F. R., Pereira-Ferrari, L., Sotomaior, V. S. & Raskin, S. Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: reproductive implications and genetic counseling. Andrology 6, 127\u2013135, https:\/\/doi.org\/10.1111\/andr.12450 (2018).","journal-title":"Andrology"},{"key":"34262_CR36","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1111\/j.1439-0272.1998.tb01164.x","volume":"30","author":"C Kirchhoff","year":"1998","unstructured":"Kirchhoff, C., Osterhoff, C., Pera, I. & Schroter, S. Function of human epididymal proteins in sperm maturation. Andrologia 30, 225\u2013232 (1998).","journal-title":"Andrologia"},{"key":"34262_CR37","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1093\/humrep\/16.3.529","volume":"16","author":"MV Meng","year":"2001","unstructured":"Meng, M. V. et al. Impaired spermatogenesis in men with congenital absence of the vas deferens. Hum Reprod 16, 529\u2013533 (2001).","journal-title":"Hum Reprod"},{"key":"34262_CR38","unstructured":"Sommers, D. & Winter, T. In Diagnostic Ultrasound (eds Rumack, C. M. & Levine, D.) 818\u2013855 (Elsevier, 2018)."},{"key":"34262_CR39","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1006\/geno.2001.6630","volume":"77","author":"A Manson","year":"2001","unstructured":"Manson, A. & Huxley, C. Skipping of exon 9 of human CFTR in YAC-transgenic mice. Genomics 77, 127\u2013134, https:\/\/doi.org\/10.1006\/geno.2001.6630 (2001).","journal-title":"Genomics"},{"key":"34262_CR40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1165\/rcmb.2006-0184TR","volume":"36","author":"C Guilbault","year":"2007","unstructured":"Guilbault, C., Saeed, Z., Downey, G. P. & Radzioch, D. Cystic fibrosis mouse models. Am J Respir Cell Mol Biol 36, 1\u20137, https:\/\/doi.org\/10.1165\/rcmb.2006-0184TR (2007).","journal-title":"Am J Respir Cell Mol Biol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-34262-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-34262-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-34262-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T11:06:50Z","timestamp":1671620810000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-34262-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,2]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["34262"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-34262-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,2]]},"assertion":[{"value":"1 June 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 November 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"16280"}}