Hostname: page-component-cd9895bd7-gvvz8 Total loading time: 0 Render date: 2024-12-28T06:38:27.032Z Has data issue: false hasContentIssue false
  • English
  • Français

Botulinum toxin A injection in the management of shoulder muscle overactivity: A scoping review

Published online by Cambridge University Press:  01 July 2019

Ian James Baguley ,
Hannah Louise Holman Barden ,
Emmanuel Jesulola  and
Melissa Therese Nott
Ian James Baguley*
Affiliation:
Brain Injury Rehabilitation Service, Westmead Hospital, Westmead, NSW, Australia Sydney Medical School, The University of Sydney, Camperdown, NSW, Australia
Hannah Louise Holman Barden
Affiliation:
Brain Injury Rehabilitation Service, Westmead Hospital, Westmead, NSW, Australia School of Community Health, Charles Sturt University, Albury, NSW, Australia
Emmanuel Jesulola
Affiliation:
Brain Injury Rehabilitation Service, Westmead Hospital, Westmead, NSW, Australia Paramedicine Discipline, Charles Sturt University, Bathurst, NSW, Australia
Melissa Therese Nott
Affiliation:
School of Community Health, Charles Sturt University, Albury, NSW, Australia
*
*Corresponding author. Email: ian.baguley@health.nsw.gov.au
Get access

Abstract

The majority of studies examining botulinum toxin A (BTX-A) in the management of upper limb muscle overactivity and pain focus on the distal arm and hand. Research has begun to look at BTX-A efficacy in more proximal upper limb muscles, with literature showing equivocal findings. This scoping review identified 15 studies meeting inclusion criteria whose data were examined against three outcome variables: muscle overactivity, range of movement and pain. Overall, while the majority of injected participants improved on these variables, between-study methodological variability such as research design potentially underpowered studies and arbitrary decision making gave a high likelihood of influencing the interpretation of their results. Future research is warranted, with a robust focus on functional anatomy, a critical appraisal of how BTX-A may help the individual being studied and utilising individualised rather than protocol-driven research paradigms.

Type
Review Article
Information
Brain Impairment , Volume 21 , Issue 1 , March 2020 , pp. 86 - 98
Copyright
© Australasian Society for the Study of Brain Impairment 2019 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ackland, D. C., & Pandy, M. G. (2011). Moment arms of the shoulder muscles during axial rotation. Journal of Orthopaedic Research, 29(5), 658–667.CrossRefGoogle ScholarPubMed
Aoki, K. R., & Francis, J. (2011). Updates on the antinociceptive mechanism hypothesis of botulinum toxin A. Parkinsonism & Related Disorders, 17(Suppl. 1), S28–S33. doi:10.1016/j.parkreldis.2011.06.013.CrossRefGoogle ScholarPubMed
Arksey, H., & O’Malley, L. (2005). Scoping studies: towards a methodological framework. International Journal of Social Research Methodology, 8(1), 19–32. doi:10.1080/1364557032000119616.CrossRefGoogle Scholar
Ashford, S., Jackson, D., & Turner-Stokes, L. (2015). Goal setting, using goal attainment scaling, as a method to identify patient selected items for measuring arm function. Physiotherapy, 101(1), 88–94. doi:10.1016/j.physio.2014.04.001.CrossRefGoogle ScholarPubMed
Ashford, S., & Turner-Stokes, L. (2009). Management of shoulder and proximal upper limb spasticity using botulinum toxin and concurrent therapy interventions: a preliminary analysis of goals and outcomes. Disability & Rehabilitation, 31(3), 220–226.CrossRefGoogle ScholarPubMed
Baguley, I. J., Nott, M. T., Turner-Stokes, L., De Graaff, S., Katrak, P., McCrory, P., … Hughes, A. (2011). Investigating muscle selection for botulinum toxin-A injections in adults with post-stroke upper limb spasticity. Journal of Rehabilitation Medicine, 43(11), 1032–1037. doi:10.2340/16501977-0885.CrossRefGoogle ScholarPubMed
Baker, J. A., & Pereira, G. (2013). The efficacy of Botulinum Toxin A for spasticity and pain in adults: a systematic review and meta-analysis using the Grades of Recommendation, Assessment, Development and Evaluation approach. Clinical Rehabilitation, 27(12), 1084–1096. doi:10.1177/0269215513491274.CrossRefGoogle ScholarPubMed
Bakheit, A. M., Fedorova, N. V., Skoromets, A. A., Timerbaeva, S. L., Bhakta, B. B., & Coxon, L. (2004). The beneficial antispasticity effect of botulinum toxin type A is maintained after repeated treatment cycles. Journal of Neurology, Neurosurgery & Psychiatry, 75(11), 1558–1561. doi:10.1136/jnnp.2003.035139.CrossRefGoogle ScholarPubMed
Bakheit, A. M., Pittock, S., Moore, A. P., Wurker, M., Otto, S., Erbguth, F., & Coxon, L. (2001). A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke. European Journal of Neurology, 8(6), 559–565. doi:10.1046/j.1468-1331.2001.00277.x.CrossRefGoogle ScholarPubMed
Barnes, M. P. (2008). An overview of the clinical management of spasticity. In Barnes, M. P. & Johnson, G. R. (Eds.), Upper motor neurone syndrome and spasticity: Clinical management and neurophysiology (2nd ed., pp. 1–8). Cambridge: Cambridge University Press.CrossRefGoogle Scholar
Bhakta, B. B., Cozens, J. A., Bamford, J. M., & Chamberlain, M. A. (1996). Use of botulinum toxin in stroke patients with severe upper limb spasticity. Journal of Neurology, Neurosurgery & Psychiatry, 61(1), 30–35.CrossRefGoogle ScholarPubMed
Bhakta, B. B., Cozens, J. A., Chamberlain, M. A., & Bamford, J. M. (2000). Impact of botulinum toxin type A on disability and carer burden due to arm spasticity after stroke: A randomised double blind placebo controlled trial. Journal of Neurology, Neurosurgery & Psychiatry, 69(2), 217–221. doi:10.1136/jnnp.69.2.217.CrossRefGoogle ScholarPubMed
Choi, J. G., Shin, J. H., & Kim, B. R. (2016). Botulinum Toxin A injection into the subscapularis muscle to treat intractable hemiplegic shoulder pain. Annals of Rehabilitation Medicine, 40(4), 592–599. doi:10.5535/arm.2016.40.4.592.CrossRefGoogle ScholarPubMed
Colquhoun, H. L., Levac, D., O’Brien, K. K., Straus, S., Tricco, A. C., Perrier, L., … Moher, D. (2014). Scoping reviews: time for clarity in definition, methods, and reporting. Journal of Clinical Epidemiology, 67(12), 1291–1294. doi:10.1016/j.jclinepi.2014.03.013.CrossRefGoogle ScholarPubMed
Cusick, A., Lannin, N., & Kinnear, B. Z. (2015). Upper limb spasticity management for patients who have received Botulinum Toxin A injection: Australian therapy practice. Australian Occupational Therapy Journal, 62(1), 27–40. doi:10.1111/1440-1630.12142.CrossRefGoogle ScholarPubMed
Davis, E. C., & Barnes, M. P. (2001). The use of botulinum toxin in spasticity. In Barnes, M. P. & Johnson, G. R. (Eds.), Upper motor neurone syndrome and spasticity: Clinical management and neurophysiology (1st ed., pp. 206–222). Cambridge, United Kingdom: Cambridge University Press.Google Scholar
de Boer, K. S., Arwert, H. J., de Groot, J. H., Meskers, C. G., Mishre, A. D., & Arendzen, J. H. (2008). Shoulder pain and external rotation in spastic hemiplegia do not improve by injection of botulinum toxin A into the subscapular muscle. Journal of Neurology, Neurosurgery & Psychiatry, 79(5), 581–583. doi:10.1136/jnnp.2007.128371.CrossRefGoogle Scholar
Del Mar, C., Hoffman, T., & Glasziou, P. (2017). Information needs, asking questions, and some basics of research studies. In Hoffman, T. (Ed.), Evidence-based practice across the health professions (3rd ed.). Australia: Elsevier.Google Scholar
Demetrios, M., Gorelik, A., Louie, J., Brand, C., Baguley, I., & Khan, F. (2014). Outcomes of ambulatory rehabilitation programmes following boutulinum toxin for spasticity in adults with stroke. Journal of Rehabilitation Medicine, 46, 730–737. doi:10.2340/16501977-1842.CrossRefGoogle ScholarPubMed
Dressler, D., Saberi, F. A., & Barbosa, E. R. (2005). Botulinum Toxin: Mechanisms of action Arquivos de Neuro-Psiquiatria, 63(1), 180–185. doi: S0004-282X20050000100035.CrossRefGoogle ScholarPubMed
Esquenazi, A., Mayer, N. H., Elia, A. E., & Albanese, A. (2009). Botulinum toxin for the management of adult patients with upper motor neuron syndrome. Toxicon, 54(5), 634–638. doi:10.1016/j.toxicon.2009.01.022.CrossRefGoogle ScholarPubMed
Esquenazi, A., Mayer, N., & Garreta, R. (2008). Influence of Botulinum Toxin Type A treatment of elbow flexor spasticity on hemiparetic gait. American Journal of Physical Medicine & Rehabilitation, 87(4), 305–310.CrossRefGoogle ScholarPubMed
Foley, N., Pereira, S., Salter, K., Fernandez, M. M., Speechley, M., Sequeira, K., … Teasell, R. (2013). Treatment with botulinum toxin improves upper-extremity function post stroke: a systematic review and meta-analysis. Archives of Physical Medicine & Rehabilitation, 94(5), 977–989. doi:10.1016/j.apmr.2012.12.006.CrossRefGoogle ScholarPubMed
Gantelius, S., Viklund, A., Hagstromer, M., & Ponten Plum, E. (2013). Botulinum toxin injections in lower extremity changes activity in upper extremity in cerebral palsy - A case report. Gait & Posture, 38(Suppl. 1), S38. doi:10.1016/j.gaitpost.2013.07.077.CrossRefGoogle Scholar
Gopura, R. A. R. C., Kiguchi, K., & Horikawa, E. (2010). A study on human upper-limb muscles activities during daily upper-limb motions. International Journal of Bioelectromagnetism, 12(2), 54–61. doi:https://www.ijbem.org/volume12/number2/ijbem120201.Google Scholar
Hara, T., Abo, M., Hara, H., Kobayashi, K., Shimamoto, Y., Samizo, Y., … Niimi, M. (2017). Effects of botulinum toxin A therapy and multidisciplinary rehabilitation on upper limb and lower limb spasticity in post-stroke patients. International Journal of Neuroscience, 127(6), 469–478. doi: 10.1080/00207454.2016.1196204.CrossRefGoogle ScholarPubMed
Hirsch, M. A., Westhoff, B., Toole, T., Haupenthal, S., Krauspe, R., & Hefter, H. (2005). Association between botulinum toxin injection into the arm and changes in gait in adults after stroke. Movement Disorders, 20(8), 1014–1020. doi:10.1002/mds.20499.CrossRefGoogle ScholarPubMed
Hutin, E., Pradon, D., Barbier, F., Gracies, J.-M., Bussel, B., & Roche, N. (2010). Lower limb coordination in hemiparetic subjects: Impact of Botulinum Toxin injections into rectus femoris. Neurorehabilitation & Neural Repair, 24(5), 442–449. doi:10.1177/1545968309354535.CrossRefGoogle ScholarPubMed
Ivanhoe, C. B., & Reistetter, T. A. (2004). Spasticity: The Misunderstood Part of the Upper Motor Neuron Syndrome. American Journal of Physical Medicine & Rehabilitation, 83(10), S3–S9. doi:10.1097/01.PHM.0000141125.28611.3E CrossRefGoogle ScholarPubMed
Kendall, F. P., McCreary, E. K., Provance, P. G., Rodgers, M. M., & Romani, W. A. (2005). Muscles: Testing and function, with posture and pain (5th ed.). Baltimore, MD: Lippincott Williams & Wilkins.Google Scholar
Kong, K.-H., Neo, J.-J., & Chua, K. S. G. (2007). A randomized controlled study of botulinum toxin A in the treatment of hemiplegic shoulder pain associated with spasticity. Clinical Rehabilitation, 21(1), 28–35. doi:10.1177/0269215506072082.CrossRefGoogle ScholarPubMed
Lam, K., Lau, K. K., So, K. K., Tam, C. K., Wu, Y. M., Cheung, G., … Leung, C. (2012). Can botulinum toxin decrease carer burden in long term care residents with upper limb spasticity? A randomized controlled study. Journal of the American Medical Directors Association, 13(5), 477–484. doi:10.1016/j.jamda.2012.03.005.CrossRefGoogle ScholarPubMed
Lang, C. E., & Schieber, M. H. (2004). Reduced muscle selectivity during individuated finger movements in humans after damage to the motor cortex or corticospinal tract. Journal of Neurophysiology, 91(4), 1722–1733. doi:10.1152/jn.00805.2003.CrossRefGoogle ScholarPubMed
Lang, C. E., Bland, M. D., Bailey, R. R., Schaefer, S. Y., & Birkenmeier, R. L. (2013). Assessment of upper extremity impairment, function, and activity after stroke: foundations for clinical decision making. Journal of Hand Therapy, 26(2), 104–115. doi: 10.1016/j.jht.2012.06.005.CrossRefGoogle ScholarPubMed
Levac, D., Colquhoun, H., & O’Brien, K. K. (2010). Scoping studies: advancing the methodology. Implementation Science, 5(1), 69. doi:10.1186/1748-5908-5-69.CrossRefGoogle ScholarPubMed
Lim, J. Y., Koh, J. H., & Paik, N. J. (2008). Intramuscular botulinum toxin-A reduces hemiplegic shoulder pain: a randomized, double-blind, comparative study versus intraarticular triamcinolone acetonide. Stroke, 39(1), 126–131. doi:10.1161/STROKEAHA.107.484048 CrossRefGoogle ScholarPubMed
Marciniak, C. M. (2011). Poststroke hypertonicity: upper limb assessment and treatment. Topics in Stroke Rehabilitation, 18(3), 179–194. doi:10.1310/tsr1803-179.CrossRefGoogle ScholarPubMed
Marciniak, C. M., Harvey, R. L., Gagnon, C. M., Duraski, S. A., Denby, F. A., McCarty, S., … Fierstein, K. M. (2012). Does botulinum toxin type A decrease pain and lessen disability in hemiplegic survivors of stroke with shoulder pain and spasticity?: a randomized, double-blind, placebo-controlled trial. American Journal of Physical Medicine & Rehabilitation, 91(12), 1007–1019. doi:10.1097/PHM.0b013e31826ecb02.CrossRefGoogle ScholarPubMed
Marco, E., Duarte, E., Vila, J., Tejero, M., Guillen, A., Boza, R., … Espadaler, J. M. (2007). Is botulinum toxin type A effective in the treatment of spastic shoulder pain in patients after stroke? A double-blind randomized clinical trial. Journal of Rehabilitation Medicine, 39(6), 440–447. doi:10.2340/16501977-0066.CrossRefGoogle ScholarPubMed
Mayer, N. H. (2004). Choosing upper limb muscles for focal intervention after traumatic brain injury. Journal of Head Trauma Rehabilitation, 19(2), 119–142.CrossRefGoogle ScholarPubMed
McCrory, P., Turner-Stokes, L., Baguley, I. J., De Graaff, S., Katrak, P., Sandanam, J., … Hughes, A. (2009). Botulinum toxin A for treatment of upper limb spasticity following stroke: a multi-centre randomized placebo-controlled study of the effects on quality of life and other person-centred outcomes. Journal of Rehabilitation Medicine, 41(7), 536–544. doi: 10.2340/16501977-0366.CrossRefGoogle ScholarPubMed
McMinn, R. M. H. (1990). Last’s Anatomy: Regional and Applied (8th ed.). Edinburgh, UK: Churchill Livingstone.Google Scholar
National Health and Medical Research Council. (2009). NHMRC additional levels of evidence and grades for recommendations for developers of guidelines. Retrieved from https://www.mja.com.au/sites/default/files/NHMRC.levels.of.evidence.2008-09.pdf Google Scholar
Nott, M. T., Barden, H. L., & Baguley, I. J. (2014). Goal attainment following upper-limb botulinum toxin-A injections: Are we facilitating achievement of client-centred goals? Journal of Rehabilitation Medicine, 46(9), 864–868. doi:10.2340/16501977-1853.CrossRefGoogle ScholarPubMed
Nudo, R. J. (2013). Recovery after brain injury: mechanisms and principles. Frontiers in Human Neuroscience, 7, 887. doi:10.3389/fnhum.2013.00887.CrossRefGoogle ScholarPubMed
Ozcakir, S., & Sivrioglu, K. (2007). Botulinum toxin in poststroke spasticity. Clinical Medicine & Research, 5(2), 132–138. doi:10.3121/cmr.2007.716.CrossRefGoogle ScholarPubMed
Patel, A. T. (2011). Successful treatment of long-term, poststroke, upper-limb spasticity with onaotulinumtoxinA. Physical Therapy, 91(11), 1636–1641. doi:10.2522/ptj.20100370.CrossRefGoogle Scholar
Pedreira, G., Cardoso, E., & Melo, E. (2008). Botulinum toxin type A for refractory post-stroke shoulder pain. Arquivos de Neuro-Psiquiatria, 66(2-A), 213–215. doi:10.1590/S0004-282X2008000200014.CrossRefGoogle ScholarPubMed
Rosales, R. L., Arimura, K., Takenaga, S., & Osame, M. (1996). Extrafusal and intrafusal muscle effects in experimental botulinum toxin-A injection. Muscle & nerve, 19(4), 488–496.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
Rosales, R. L., & Chua-Yap, A. S. (2008). Evidence-based systematic review on the efficacy and safety of botulinum toxin-A therapy in post-stroke spasticity. Journal of Neural Transmission, 115(4), 617–623. doi:10.1007/s00702-007-0869-3.CrossRefGoogle ScholarPubMed
Rousseaux, M., Kozlowski, O., & Froger, J. (2002). Efficacy of botulinum toxin A in upper limb function of hemiplegic patients. Journal of Neurology, 249(1), 76–84.CrossRefGoogle ScholarPubMed
Royal College of Physicians, British Society of Rehabilitation Medicine, Chartered Society of Physiotherapy, Association of Chartered Physiotherapists Interested in Neurology (2018). Spasticity in adults: management using botulinum toxin - National guidelines. London, UK: Royal College of Physicians.Google Scholar
Sedgwick, P. (2014). What is an open label trial? British Medical Journal, 348, 1–2. doi:10.1136/bmj.g3434.Google ScholarPubMed
Shaw, L. C., Price, C. I. M., van Wijck, F. M. J., Shackley, P., Steen, N., Barnes, M. P., … Rodgers, H. (2011). Botulinum toxin for the upper limb after stroke (BoTULS) trial: Effect on impairment, activity limitation, and pain. Stroke, 42(5), 1371–1379. doi:10.1161/strokeaha.110.582197.CrossRefGoogle ScholarPubMed
Sheean, G., Lannin, N. A., Turner-Stokes, L., Rawicki, B., & Snow, B. J. (2010). Botulinum toxin assessment, intervention and after-care for upper limb hypertonicity in adults: international consensus statement. European Journal of Neurology, 17(Suppl. 2), 74–93. doi:10.1111/j.1468-1331.2010.03129.x.CrossRefGoogle ScholarPubMed
Simpson, D. M., Hallett, M., Ashman, E. J., Comella, C. L., Green, M. W., Gronseth, G. S., … Yablon, S. A. (2016). Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology, 86(19), 1818–1826. doi:10.1212/wnl.0000000000002560.CrossRefGoogle ScholarPubMed
Slawek, J., Bogucki, A., & Reclawowicz, D. (2005). Botulinum toxin type A for upper limb spasticity following stroke: an open-label study with individualised, flexible injection regimens. Neurological Sciences, 26(1), 32–39. doi:10.1007/s10072-005-0379-8.CrossRefGoogle ScholarPubMed
Smith, S. J., Ellis, E., White, S., & Moore, A. P. (2000). A double-blind placebo-controlled study of botulinum toxin in upper limb spasticity after stroke or head injury. Clinical Rehabilitation, 14(1), 5–13. doi:10.1191/026921500666642221.CrossRefGoogle ScholarPubMed
Strobl, W., Theologis, T., Brunner, R., Kocer, S., Viehweger, E., Pascual-Pascual, I., & Placzek, R. (2015). Best clinical practice in Botulinum Toxin treatment for children with Cerebral Palsy. Toxins, 7(5), 1629–16848. doi:10.3390/toxins7051629.CrossRefGoogle ScholarPubMed
Suenaga, N., Minami, A., & Fujisawa, H. (2003). Electromyographic analysis of internal rotational motion of the shoulder in various positions. Journal of Shoulder & Elbow Surgery, 12(5), 501–505. doi:10.1016/S1058274603001691.CrossRefGoogle Scholar
Sunnerhagen, K. S., Olver, J., & Francisco, G. E. (2013). Assessing and treating functional impairment in poststroke spasticity. Neurology, 80(2), S35–S44. doi: 10.1212/WNL.0b013e3182764aa2.CrossRefGoogle ScholarPubMed
Terry, G. C., & Chopp, T. M. (2000). Functional anatomy of the shoulder. Journal of Athletic Training, 35(3), 248–255.Google Scholar
Turner-Stokes, L., Ashford, S., Esquenazi, A., Wissel, J., Ward, A. B., Francisco, G., … Simpson, D. M. (2018). A comprehensive patient-centred approach to adult spastic paresis: a consensus-based framework. European Journal of Physical and Rehabilitation Medicine, 54(4), 605–617.Google Scholar
Turner-Stokes, L., & Jackson, D. (2002). Shoulder pain after stroke: a review of the evidence base to inform the development of an integrated care pathway. Clinical Rehabilitation, 16(3), 276–298. doi:10.1191/0269215502cr491.CrossRefGoogle ScholarPubMed
Ward, A. B., Aguilar, M., De Beyl, Z., Gedin, S., Kanovsky, P., Molteni, F., … Yakovleff, A. (2003). Use of botulinum toxin type A in management of adult spasticity - A European consensus statement. Journal of Rehabilitation Medicine, 35(2), 98–99.CrossRefGoogle ScholarPubMed
Winstein, C., Wing, A. M., & Whitall, J. (2003). Motor control and learning principles for rehabilitation of upper limb movements after brain injury. In Grafman, J. & Robertson, I. H. (Eds.), Handbook of neuropsychology (2nd ed., Vol. 9, pp. 79–138). New York: Elsevier Science B. V.Google Scholar
Wissel, J., Muller, J., Dressnandt, J., Heinen, F., Naumann, M., Topka, H., & Poewe, W. (2000). Management of spasticity associated pain with botulinum toxin A. Journal of Pain & Symptom Management, 20(1), 44–49.CrossRefGoogle ScholarPubMed
Wissel, J., Ward, A. B., Erztgaard, P., Bensmail, D., Hecht, M. J., Lejeune, T. M., & Schnider, P. (2009). European consensus table on the use of botulinum toxin type A in adult spasticity. Journal of Rehabilitation Medicine, 41(1), 13–25. doi: 10.2340/16501977-0303 CrossRefGoogle ScholarPubMed
World Health Organisation. (2001). International Classification of functioning, disability and health: ICF. Geneva: WHO.Google Scholar
Yablon, S. A., Brin, M. F., VanDenburgh, A. M., Zhou, J., Garabedian-Ruffalo, S. M., Abu-Shakra, S., & Beddingfield, F. C. 3rd. (2011). Dose response with onabotulinumtoxinA for post-stroke spasticity: a pooled data analysis. Movement Disorders, 26(2), 209–215. doi:10.1002/mds.23426.CrossRefGoogle ScholarPubMed
Yelnik, A. P., Colle, F. M., Bonan, I. V., & Vicaut, E. (2007). Treatment of shoulder pain in spastic hemiplegia by reducing spasticity of the subscapular muscle: a randomised, double blind, placebo controlled study of botulinum toxin A. Journal of Neurology, Neurosurgery & Psychiatry, 78(8), 845–848. doi:10.1136/jnnp.2006.103341.CrossRefGoogle ScholarPubMed
Zeferino, S. I., & Aycock, A. (2010). Poststroke shoulder pain: Inevitable or preventable. Rehabilitation Nursing, 35(4), 147–151.CrossRefGoogle ScholarPubMed