{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:41:35Z","timestamp":1787020895793,"version":"build-2736575974"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T00:00:00Z","timestamp":1609718400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T00:00:00Z","timestamp":1609718400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Syst Rev"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The growing societal and economic impact of Alzheimer\u2019s disease (AD) is further compounded by the present lack of disease-modifying interventions. Non-pharmacological intervention approaches, such as exercise, have the potential to be powerful approaches to improve or mitigate the symptoms of AD without added side effects or financial burden associated with drug therapies. Various forms and regiments of exercise (i.e., strength, aerobic, multicomponent) have been reported in the literature; however, conflicting evidence obscures clear interpretation of the value and impact of exercise as an intervention for older adults with AD. The primary objective of this review will be to evaluate the effects of exercise interventions for older adults with AD. In addition, this review will evaluate the evidence quality and synthesize the exercise training prescriptions for proper clinical practice guidelines and recommendations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This systematic review and meta-analysis will be carried out by an interdisciplinary collective representing clinical and research stakeholders with diverse expertise related to neurodegenerative diseases and rehabilitation medicine. Literature sources will include the following: Embase, PsychINFO, OVID Medline, and Ovid MEDLINE(R) and Epub Ahead of Print, In-Process &amp; Other Non-Indexed Citations and Daily. Inclusion criteria are participants with late onset AD and structured exercise interventions with prescribed duration, frequency, and intensity. The primary outcome of this study will center on improved or sustained cognitive functioning. Secondary outcomes will include institutionalization-related outcomes, ability in activities of daily living, mood and emotional well-being, quality of life, morbidity, and mortality. Analysis procedures to include measurement of bias, data synthesis, sensitivity analysis, and assessment of heterogeneity are described in this protocol.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This review is anticipated to yield clinically meaningful insight on the specific value of exercise for older adults with AD. Improved understanding of diverse exercise intervention approaches and their specific impact on various health- and function-related outcomes is expected to guide clinicians to more frequently and accurately prescribe meaningful interventions for those affected by AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      PROSPERO\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.crd.york.ac.uk\/prospero\/display_record.php?RecordID=175016\">CRD42020175016<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13643-020-01555-8","type":"journal-article","created":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T02:03:07Z","timestamp":1609725787000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Exercise interventions for older adults with Alzheimer\u2019s disease: a systematic review and meta-analysis protocol"],"prefix":"10.1186","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2032-338X","authenticated-orcid":false,"given":"Julie M.","family":"Faieta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannes","family":"Devos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasanna","family":"Vaduvathiriyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele K.","family":"York","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk I.","family":"Erickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Hirsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian G.","family":"Downer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin E. H.","family":"van Wegen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana C.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Philippou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Negm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedram","family":"Ahmadnezhad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilpa","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melike","family":"Kahya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pallavi","family":"Sood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia C.","family":"Heyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,4]]},"reference":[{"issue":"2","key":"1555_CR1","first-page":"A34","volume":"3","author":"DP Chapman","year":"2006","unstructured":"Chapman DP, Williams SM, Strine TW, Anda RF, Moore MJ. Dementia and its implications for public health. Prev Chronic Dis. 2006;3(2):A34.","journal-title":"Prev Chronic Dis"},{"issue":"1","key":"1555_CR2","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jalz.2012.11.007","volume":"9","author":"M Prince","year":"2013","unstructured":"Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9(1):63\u201375.e2. https:\/\/doi.org\/10.1016\/j.jalz.2012.11.007.","journal-title":"Alzheimers Dement"},{"key":"1555_CR3","doi-asserted-by":"crossref","unstructured":"Barker WW, Luis CA, Kashuba A, et al. Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord. 2002;16(4):203\u201312.","DOI":"10.1097\/00002093-200210000-00001"},{"issue":"3","key":"1555_CR4","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/j.jalz.2019.01.010","volume":"15","author":"J Gaugler","year":"2019","unstructured":"Gaugler J, James B, Johnson T, Marin A, Weuve J. 2019 Alzheimer\u2019s disease facts and figures. Alzheimers Dement. 2019;15(3):321\u201387.","journal-title":"Alzheimers Dement"},{"issue":"19","key":"1555_CR5","doi-asserted-by":"publisher","first-page":"1778","DOI":"10.1212\/WNL.0b013e31828726f5","volume":"80","author":"LE Hebert","year":"2013","unstructured":"Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010\u20132050) estimated using the 2010 census. Neurology. 2013;80(19):1778\u201383. https:\/\/doi.org\/10.1212\/WNL.0b013e31828726f5.","journal-title":"Neurology."},{"issue":"3","key":"1555_CR6","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","volume":"7","author":"GM McKhann","year":"2011","unstructured":"McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease. Alzheimers Dement. 2011;7(3):263.","journal-title":"Alzheimers Dement"},{"issue":"1","key":"1555_CR7","doi-asserted-by":"publisher","first-page":"69","DOI":"10.2174\/157015910790909520","volume":"8","author":"F Massoud","year":"2010","unstructured":"Massoud F, Gauthier S. Update on the pharmacological treatment of Alzheimer\u2019s disease. Curr Neuropharmacol. 2010;8(1):69\u201380. https:\/\/doi.org\/10.2174\/157015910790909520.","journal-title":"Curr Neuropharmacol"},{"key":"1555_CR8","unstructured":"Benefits of exercise. https:\/\/medlineplus.gov\/benefitsofexercise.html. Accessed 27 Feb 2020."},{"issue":"4","key":"1555_CR9","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1136\/bjsports-2013-093184","volume":"49","author":"LF ten Brinke","year":"2015","unstructured":"ten Brinke LF, Bolandzadeh N, Nagamatsu LS, et al. Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: a 6-month randomised controlled trial. Br J Sports Med. 2015;49(4):248\u201354. https:\/\/doi.org\/10.1136\/bjsports-2013-093184.","journal-title":"Br J Sports Med"},{"key":"1555_CR10","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1186\/1745-6215-15-394","volume":"15","author":"F Yu","year":"2014","unstructured":"Yu F, Bronas UG, Konety S, et al. Effects of aerobic exercise on cognition and hippocampal volume in Alzheimer\u2019s disease: study protocol of a randomized controlled trial (The FIT-AD trial). Trials. 2014;15:394. https:\/\/doi.org\/10.1186\/1745-6215-15-394.","journal-title":"Trials."},{"issue":"2","key":"1555_CR11","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/1467-9280.t01-1-01430","volume":"14","author":"S Colcombe","year":"2003","unstructured":"Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci. 2003;14(2):125\u201330. https:\/\/doi.org\/10.1111\/1467-9280.t01-1-01430.","journal-title":"Psychol Sci"},{"issue":"4","key":"1555_CR12","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1177\/153331750301800409","volume":"18","author":"P Heyn","year":"2003","unstructured":"Heyn P. The effect of a multisensory exercise program on engagement, behavior, and selected physiological indexes in persons with dementia. Am J Alzheimers Dis Other Demen. 2003;18(4):247\u201351. https:\/\/doi.org\/10.1177\/153331750301800409.","journal-title":"Am J Alzheimers Dis Other Demen"},{"issue":"10","key":"1555_CR13","doi-asserted-by":"publisher","first-page":"1694","DOI":"10.1016\/j.apmr.2004.03.019","volume":"85","author":"P Heyn","year":"2004","unstructured":"Heyn P, Abreu BC, Ottenbacher KJ. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil. 2004;85(10):1694\u2013704. https:\/\/doi.org\/10.1016\/j.apmr.2004.03.019.","journal-title":"Arch Phys Med Rehabil"},{"issue":"6","key":"1555_CR14","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1007\/bf02982674","volume":"12","author":"PC Heyn","year":"2008","unstructured":"Heyn PC, Johnson KE, Kramer AF. Endurance and strength training outcomes on cognitively impaired and cognitively intact older adults: a meta-analysis. J Nutr Health Aging. 2008;12(6):401\u20139. https:\/\/doi.org\/10.1007\/bf02982674.","journal-title":"J Nutr Health Aging"},{"key":"1555_CR15","doi-asserted-by":"publisher","first-page":"626","DOI":"10.3389\/fnhum.2016.00626","volume":"10","author":"CM Stillman","year":"2016","unstructured":"Stillman CM, Cohen J, Lehman ME, Erickson KI. Mediators of physical activity on neurocognitive function: a review at multiple levels of analysis. Front Hum Neurosci. 2016;10:626. https:\/\/doi.org\/10.3389\/fnhum.2016.00626.","journal-title":"Front Hum Neurosci"},{"issue":"3","key":"1555_CR16","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/oby.2006.46","volume":"14","author":"RK Dishman","year":"2006","unstructured":"Dishman RK, Berthoud H-R, Booth FW, et al. Neurobiology of exercise. Obesity (Silver Spring). 2006;14(3):345\u201356. https:\/\/doi.org\/10.1038\/oby.2006.46.","journal-title":"Obesity (Silver Spring)"},{"key":"1555_CR17","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.2147\/CIA.S163067","volume":"13","author":"Y Zhu","year":"2018","unstructured":"Zhu Y, Wu H, Qi M, et al. Effects of a specially designed aerobic dance routine on mild cognitive impairment. Clin Interv Aging. 2018;13:1691\u2013700. https:\/\/doi.org\/10.2147\/CIA.S163067.","journal-title":"Clin Interv Aging"},{"issue":"6","key":"1555_CR18","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1097\/JSM.0000000000000476","volume":"28","author":"S-G Hong","year":"2018","unstructured":"Hong S-G, Kim J-H, Jun T-W. Effects of 12-week resistance exercise on electroencephalogram patterns and cognitive function in the elderly with mild cognitive impairment: a randomized controlled trial. Clin J Sport Med. 2018;28(6):500\u20138. https:\/\/doi.org\/10.1097\/JSM.0000000000000476.","journal-title":"Clin J Sport Med"},{"key":"1555_CR19","volume-title":"Exercise is Medicine","author":"American College of Sports Medicine","year":"2014","unstructured":"American College of Sports Medicine. Exercise is medicine: healthcare providers\u2019 action guide. In: Exercise is Medicine. Indianopolis: American College of Sports Medicine; 2014. https:\/\/www.exerciseismedicine.org\/support_page.php\/health-care-providers\/. Accessed 2 Nov 2020."},{"key":"1555_CR20","doi-asserted-by":"publisher","unstructured":"Sabia S, Dugravot A, Dartigues J-F, et al. Physical activity, cognitive decline, and risk of dementia: 28\u2009year follow-up of Whitehall II cohort study. BMJ. 2017;357. https:\/\/doi.org\/10.1136\/bmj.j2709.","DOI":"10.1136\/bmj.j2709"},{"key":"1555_CR21","doi-asserted-by":"publisher","first-page":"9234105","DOI":"10.1155\/2018\/9234105","volume":"2018","author":"MY Cui","year":"2018","unstructured":"Cui MY, Lin Y, Sheng JY, Zhang X, Cui RJ. Exercise intervention associated with cognitive improvement in Alzheimer\u2019s disease. Neural Plast. 2018;2018:9234105. https:\/\/doi.org\/10.1155\/2018\/9234105.","journal-title":"Neural Plast"},{"issue":"1","key":"1555_CR22","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1111\/j.1532-5415.2011.03761.x","volume":"60","author":"SB Hindin","year":"2012","unstructured":"Hindin SB, Zelinski EM. Extended practice and aerobic exercise interventions benefit untrained cognitive outcomes in older adults: a meta-analysis. J Am Geriatr Soc. 2012;60(1):136\u201341. https:\/\/doi.org\/10.1111\/j.1532-5415.2011.03761.x.","journal-title":"J Am Geriatr Soc"},{"issue":"1","key":"1555_CR23","doi-asserted-by":"publisher","first-page":"30","DOI":"10.7326\/M17-1528","volume":"168","author":"M Brasure","year":"2018","unstructured":"Brasure M, Desai P, Davila H, et al. Physical activity interventions in preventing cognitive decline and Alzheimer-type dementia: a systematic review. Ann Intern Med. 2018;168(1):30\u20138. https:\/\/doi.org\/10.7326\/M17-1528.","journal-title":"Ann Intern Med"},{"key":"1555_CR24","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.arr.2018.07.009","volume":"47","author":"NA Guitar","year":"2018","unstructured":"Guitar NA, Connelly DM, Nagamatsu LS, Orange JB, Muir-Hunter SW. The effects of physical exercise on executive function in community-dwelling older adults living with Alzheimer\u2019s-type dementia: a systematic review. Ageing Res Rev. 2018;47:159\u201367. https:\/\/doi.org\/10.1016\/j.arr.2018.07.009.","journal-title":"Ageing Res Rev"},{"issue":"1","key":"1555_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/2046-4053-4-1","volume":"4","author":"D Moher","year":"2015","unstructured":"Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4(1):1. https:\/\/doi.org\/10.1186\/2046-4053-4-1.","journal-title":"Syst Rev"},{"issue":"2","key":"1555_CR26","first-page":"126","volume":"100","author":"CJ Caspersen","year":"1985","unstructured":"Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep. 1985;100(2):126\u201331.","journal-title":"Public Health Rep"},{"key":"1555_CR27","unstructured":"2018 Physical Activity Guidelines Advisory Committee. US Department of Health and Human Services. Published online 2018:779."},{"key":"1555_CR28","unstructured":"Cochrane Handbook for Systematic Reviews of Interventions. https:\/\/training.cochrane.org\/handbook\/archive\/v5.1\/. Accessed 27 Feb 2020."},{"key":"1555_CR29","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","volume":"366","author":"JAC Sterne","year":"2019","unstructured":"Sterne JAC, Savovi\u0107 J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. https:\/\/doi.org\/10.1136\/bmj.l4898.","journal-title":"BMJ."},{"issue":"11","key":"1555_CR30","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1002\/sim.1186","volume":"21","author":"JPT Higgins","year":"2002","unstructured":"Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539\u201358. https:\/\/doi.org\/10.1002\/sim.1186.","journal-title":"Stat Med"},{"issue":"8","key":"1555_CR31","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1016\/j.jagp.2013.05.004","volume":"22","author":"H Brodaty","year":"2014","unstructured":"Brodaty H, Woodward M, Boundy K, Ames D, Balshaw R. Prevalence and predictors of burden in caregivers of people with dementia. Am J Geriatr Psychiatry. 2014;22(8):756\u201365. https:\/\/doi.org\/10.1016\/j.jagp.2013.05.004.","journal-title":"Am J Geriatr Psychiatry"},{"issue":"8","key":"1555_CR32","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1017\/S1041610215000460","volume":"27","author":"M Park","year":"2015","unstructured":"Park M, Sung M, Kim SK, Kim S, Lee DY. Multidimensional determinants of family caregiver burden in Alzheimer\u2019s disease. Int Psychogeriatr. 2015;27(8):1355\u201364. https:\/\/doi.org\/10.1017\/S1041610215000460.","journal-title":"Int Psychogeriatr"},{"issue":"9-10","key":"1555_CR33","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1111\/jocn.13601","volume":"26","author":"S Liu","year":"2017","unstructured":"Liu S, Li C, Shi Z, et al. Caregiver burden and prevalence of depression, anxiety and sleep disturbances in Alzheimer\u2019s disease caregivers in China. J Clin Nurs. 2017;26(9-10):1291\u2013300. https:\/\/doi.org\/10.1111\/jocn.13601.","journal-title":"J Clin Nurs"}],"container-title":["Systematic Reviews"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13643-020-01555-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13643-020-01555-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13643-020-01555-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T02:05:11Z","timestamp":1609725911000},"score":1,"resource":{"primary":{"URL":"https:\/\/systematicreviewsjournal.biomedcentral.com\/articles\/10.1186\/s13643-020-01555-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,4]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1555"],"URL":"https:\/\/doi.org\/10.1186\/s13643-020-01555-8","relation":{},"ISSN":["2046-4053"],"issn-type":[{"value":"2046-4053","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,4]]},"assertion":[{"value":"4 May 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 December 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 January 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable. Due to the study design, no human data was collected; therefore, consent for publication was not attained from any persons.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"MH declares the following interests: MAH, grant funding from Merz Neurosciences, Dutch Brain Foundation, Dutch Parkinson Patient Association. Editorial Board, Parkinsonism and Related Disorders, speaker honoraria from International Association of Parkinsonism and Related Disorders. Non-financial: American Congress of Rehabilitation Medicine\u2014Neurodegenerative Diseases Networking Group. All remaining authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6"}}