Effects of prismatic adaptation on balance and postural disorders in patients with chronic right stroke: protocol for a multicentre double-blind randomised sham-controlled trial

Aurélien Hugues, Amandine Guinet-Lacoste, Sylvie Bin, Laurent Villeneuve, Marine Lunven, Dominic Pérennou, Pascal Giraux, Alexandre Foncelle, Yves Rossetti, Sophie Jacquin-Courtois, Jacques Luauté, Gilles Rode, Aurélien Hugues, Amandine Guinet-Lacoste, Sylvie Bin, Laurent Villeneuve, Marine Lunven, Dominic Pérennou, Pascal Giraux, Alexandre Foncelle, Yves Rossetti, Sophie Jacquin-Courtois, Jacques Luauté, Gilles Rode

Abstract

Introduction: Patients with right stroke lesion have postural and balance disorders, including weight-bearing asymmetry, more pronounced than patients with left stroke lesion. Spatial cognition disorders post-stroke, such as misperceptions of subjective straight-ahead and subjective longitudinal body axis, are suspected to be involved in these postural and balance disorders. Prismatic adaptation has showed beneficial effects to reduce visuomotor disorders but also an expansion of effects on cognitive functions, including spatial cognition. Preliminary studies with a low level of evidence have suggested positive effects of prismatic adaptation on weight-bearing asymmetry and balance after stroke. The objective is to investigate the effects of this intervention on balance but also on postural disorders, subjective straight-ahead, longitudinal body axis and autonomy in patients with chronic right stroke lesion.

Methods and analysis: In this multicentre randomised double-blind sham-controlled trial, we will include 28 patients aged from 18 to 80 years, with a first right supratentorial stroke lesion at chronic stage (≥12 months) and having a bearing ≥60% of body weight on the right lower limb. Participants will be randomly assigned to the experimental group (performing pointing tasks while wearing glasses shifting optical axis of 10 degrees towards the right side) or to the control group (performing the same procedure while wearing neutral glasses without optical deviation). All participants will receive a 20 min daily session for 2 weeks in addition to conventional rehabilitation. The primary outcome will be the balance measured using the Berg Balance Scale. Secondary outcomes will include weight-bearing asymmetry and parameters of body sway during static posturographic assessments, as well as lateropulsion (measured using the Scale for Contraversive Pushing), subjective straight-ahead, longitudinal body axis and autonomy (measured using the Barthel Index).

Ethics and dissemination: The study has been approved by the ethical review board in France. Findings will be submitted to peer-reviewed journals relative to rehabilitation or stroke.

Trial registration number: NCT03154138.

Keywords: adult neurology; rehabilitation medicine; stroke.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Procedure from enrolment to the end of study. PA, prismatic adaptation.
Figure 2
Figure 2
Prismatic glasses (A) and sham glasses (B). (A) A pair of prismatic glasses with an optical deviation of 10 degrees towards to the right side; (B) a pair of sham glasses with a neutral optical deviation.
Figure 3
Figure 3
Procedure for prismatic adaptation. The participant will be seated in front of the support set up on a table, with the chin on a part of the support limiting the inclination or rotation of the head and placed in the midline body axis. To limit visuo-feedback during pointing tasks with prism exposure, the support hides the initial position of the patient’s hand but also at the beginning of the movement course (ie, 20%–50%). In addition, the therapist will ensure that the patient perform rapid movements (adapted from Rode et al., 2015).
Figure 4
Figure 4
Subjective straight-ahead assessment. The patient is seated in front of the device set up on a table, with the chin on a part of the device preventing the inclination or rotation of the head. The midline device axis will match the patient sagittal axis. For the manual SSA, the assessor asks the patient, placed in the dark, to point on the horizontal plan of the device with the forefinger of the right hand the ‘straight-ahead’ direction. From a departure position of the right hand closer to navel, the patient spreads the arm without restriction, then returns to the initial position. The pointing is measured by means of an electronic system included in the horizontal plan of the device. The angular deviation from the objective sagittal axis is displayed by the device. For the visual SSA, the patient keeps the initial position of manual SSA and the measurement is still performed in a total darkness. A luminescent red diode will move in front of the patient from the extreme left or right position in the visual field towards the opposite extreme position at a slow speed. The diode is at the same height than the gaze of the patient. The head of the patient is still contained in the chin support limiting its inclination and rotation. The investigator asks the patient to say stop when the red diode reaches the position perceived as being ‘straight-ahead’. The angular deviation from the objective sagittal axis is also displayed by the device. For the open-loop pointing, the patient is still in total darkness and takes the initial position of manual SSA with his/her hand closer to his/her navel. The red luminescent diode is aligned with the objective sagittal axis of the patient. The investigator asks the patient to point in the direction of the red diode on the horizontal plan of the device with the forefinger of the right hand, and then to return to the initial position. For each test, 10 trials will be performed. For visual SSA, five trials will be performed with a departure position of the red diode on the right side of the patient and five others on the left side. SSA, subjective straight-ahead.

References

    1. Sackley CM. The relationships between weight-bearing asymmetry after stroke, motor function and activities of daily living. Physiother Theory Pract 1990;6:179–85. 10.3109/09593989009048293
    1. Rode G, Tiliket C, Boisson D. Predominance of postural imbalance in left hemiparetic patients. Scand J Rehabil Med 1997;29:11–16.
    1. Geurts ACH, de Haart M, van Nes IJW, et al. . A review of standing balance recovery from stroke. Gait Posture 2005;22:267–81. 10.1016/j.gaitpost.2004.10.002
    1. Genthon N, Rougier P, Gissot A-S, et al. . Contribution of each lower limb to upright standing in stroke patients. Stroke 2008;39:1793–9. 10.1161/STROKEAHA.107.497701
    1. Ishii F, Matsukawa N, Horiba M, et al. . Impaired ability to shift weight onto the non-paretic leg in right-cortical brain-damaged patients. Clin Neurol Neurosurg 2010;112:406–12. 10.1016/j.clineuro.2010.02.006
    1. Cheng PT, Liaw MY, Wong MK, et al. . The sit-to-stand movement in stroke patients and its correlation with falling. Arch Phys Med Rehabil 1998;79:1043–6. 10.1016/S0003-9993(98)90168-X
    1. Pérennou D, Pélissier J, Amblard B. La posture et Le contrôle postural Du patient cérébrolésé vasculaire: une revue de la littérature. Annales de Réadaptation et de Médecine Physique 1996;39:497–513. 10.1016/S0168-6054(97)84233-X
    1. Dickstein R, Abulaffio N. Postural sway of the affected and nonaffected pelvis and leg in stance of hemiparetic patients. Arch Phys Med Rehabil 2000;81:364–7. 10.1016/s0003-9993(00)90085-6
    1. Portnoy S, Reif S, Mendelboim T, et al. . Postural control of individuals with chronic stroke compared to healthy participants: Timed-Up-and-Go, functional reach test and center of pressure movement. Eur J Phys Rehabil Med 2017;53:685–93. 10.23736/S1973-9087.17.04522-1
    1. Pérennou DA, Mazibrada G, Chauvineau V, et al. . Lateropulsion, pushing and verticality perception in hemisphere stroke: a causal relationship? Brain 2008;131:2401–13. 10.1093/brain/awn170
    1. Dai S, Piscicelli C, Clarac E, et al. . Balance, lateropulsion, and gait disorders in subacute stroke. Neurology 2021;96:e2147–59. 10.1212/WNL.0000000000011152
    1. Dai S, Piscicelli C, Clarac E, et al. . Lateropulsion after hemispheric stroke: a form of spatial neglect involving Graviception. Neurology 2021;96:e2160–71. 10.1212/WNL.0000000000011826
    1. Tyson SF, Hanley M, Chillala J, et al. . Balance disability after stroke. Phys Ther 2006;86:30–8. 10.1093/ptj/86.1.30
    1. Pérennou D, Bénaïm C, Rouget E, et al. . [Postural balance following stroke: towards a disadvantage of the right brain-damaged hemisphere]. Rev Neurol 1999;155:281–90.
    1. Schmid AA, Van Puymbroeck M, Altenburger PA, et al. . Balance and balance self-efficacy are associated with activity and participation after stroke: a cross-sectional study in people with chronic stroke. Arch Phys Med Rehabil 2012;93:1101–7. 10.1016/j.apmr.2012.01.020
    1. van der Kooi E, Schiemanck SK, Nollet F, et al. . Falls are associated with lower self-reported functional status in patients after stroke. Arch Phys Med Rehabil 2017;98:2393–8. 10.1016/j.apmr.2017.05.003
    1. Wesselhoff S, Hanke TA, Evans CC. Community mobility after stroke: a systematic review. Top Stroke Rehabil 2018;25:224–38. 10.1080/10749357.2017.1419617
    1. Kwong PWH, Ng SSM, Chung RCK, et al. . A structural equation model of the relationship between muscle strength, balance performance, walking endurance and community integration in stroke survivors. PLoS One 2017;12:e0185807. 10.1371/journal.pone.0185807
    1. Forster A, Young J. Incidence and consequences of falls due to stroke: a systematic inquiry. BMJ 1995;311:83–6. 10.1136/bmj.311.6997.83
    1. Xu T, Clemson L, O'Loughlin K, et al. . Risk factors for falls in community stroke survivors: a systematic review and meta-analysis. Arch Phys Med Rehabil 2018;99:563–73. 10.1016/j.apmr.2017.06.032
    1. Maeda N, Urabe Y, Murakami M, et al. . Discriminant analysis for predictor of falls in stroke patients by using the Berg balance scale. Singapore Med J 2015;56:280–3. 10.11622/smedj.2015033
    1. Fulk GD, Reynolds C, Mondal S, et al. . Predicting home and community walking activity in people with stroke. Arch Phys Med Rehabil 2010;91:1582–6. 10.1016/j.apmr.2010.07.005
    1. van de Port IG, Kwakkel G, Lindeman E. Community ambulation in patients with chronic stroke: how is it related to gait speed? J Rehabil Med 2008;40:23–7. 10.2340/16501977-0114
    1. Durcan S, Flavin E, Horgan F. Factors associated with community ambulation in chronic stroke. Disabil Rehabil 2016;38:245–9. 10.3109/09638288.2015.1035460
    1. Schmid AA, Van Puymbroeck M, Altenburger PA, et al. . Balance is associated with quality of life in chronic stroke. Top Stroke Rehabil 2013;20:340–6. 10.1310/tsr2004-340
    1. Bonan IV, Guettard E, Leman MC, et al. . Subjective visual vertical perception relates to balance in acute stroke. Arch Phys Med Rehabil 2006;87:642–6. 10.1016/j.apmr.2006.01.019
    1. Bonan IV, Hubeaux K, Gellez-Leman MC, et al. . Influence of subjective visual vertical misperception on balance recovery after stroke. J Neurol Neurosurg Psychiatry 2007;78:49–55. 10.1136/jnnp.2006.087791
    1. Yelnik AP, Lebreton FO, Bonan IV, et al. . Perception of verticality after recent cerebral hemispheric stroke. Stroke 2002;33:2247–53. 10.1161/01.STR.0000027212.26686.48
    1. Molina F, Lomas-Vega R, Obrero-Gaitán E, et al. . Misperception of the subjective visual vertical in neurological patients with or without stroke: a meta-analysis. NeuroRehabilitation 2019;44:379–88. 10.3233/NRE-182642
    1. Barra J, Chauvineau V, Ohlmann T, et al. . Perception of longitudinal body axis in patients with stroke: a pilot study. J Neurol Neurosurg Psychiatry 2007;78:43–8. 10.1136/jnnp.2006.089961
    1. Rossetti Y, Rode G, Pisella L, et al. . Prism adaptation to a rightward optical deviation rehabilitates left hemispatial neglect. Nature 1998;395:166–9. 10.1038/25988
    1. Rousseaux M, Honoré J, Vuilleumier P, et al. . Neuroanatomy of space, body, and posture perception in patients with right hemisphere stroke. Neurology 2013;81:1291–7. 10.1212/WNL.0b013e3182a823a7
    1. Richard C, Honoré J, Bernati T, et al. . Straight-ahead pointing correlates with long-line bisection in neglect patients. Cortex 2004;40:75–83. 10.1016/S0010-9452(08)70921-3
    1. Chokron S, Bartolomeo P. Correlation between the position of the egocentric reference and right neglect signs in left-brain-damaged patients. Brain Cogn 2000;43:99–104.
    1. Bonan IV, Leman MC, Legargasson JF, et al. . Evolution of subjective visual vertical perturbation after stroke. Neurorehabil Neural Repair 2006;20:484–91. 10.1177/1545968306289295
    1. Stone SP, Halligan PW, Greenwood RJ. The incidence of neglect phenomena and related disorders in patients with an acute right or left hemisphere stroke. Age Ageing 1993;22:46–52. 10.1093/ageing/22.1.46
    1. Pérennou DA, Leblond C, Amblard B, et al. . The polymodal sensory cortex is crucial for controlling lateral postural stability: evidence from stroke patients. Brain Res Bull 2000;53:359–65. 10.1016/s0361-9230(00)00360-9
    1. Barra J, Oujamaa L, Chauvineau V, et al. . Asymmetric standing posture after stroke is related to a biased egocentric coordinate system. Neurology 2009;72:1582–7. 10.1212/WNL.0b013e3181a4123a
    1. Roelofs JMB, van Heugten K, de Kam D, et al. . Relationships between Affected-Leg motor impairment, postural asymmetry, and impaired body sway control after unilateral supratentorial stroke. Neurorehabil Neural Repair 2018;32:953–60. 10.1177/1545968318804405
    1. Roerdink M, Geurts ACH, de Haart M, et al. . On the relative contribution of the paretic leg to the control of posture after stroke. Neurorehabil Neural Repair 2009;23:267–74. 10.1177/1545968308323928
    1. van Asseldonk EHF, Buurke JH, Bloem BR, et al. . Disentangling the contribution of the paretic and non-paretic ankle to balance control in stroke patients. Exp Neurol 2006;201:441–51. 10.1016/j.expneurol.2006.04.036
    1. Hugues A, Di Marco J, Ribault S, et al. . Limited evidence of physical therapy on balance after stroke: a systematic review and meta-analysis. PLoS One 2019;14:e0221700. 10.1371/journal.pone.0221700
    1. Kitago T, Krakauer JW. Motor learning principles for neurorehabilitation. Handb Clin Neurol 2013;110:93–103. 10.1016/B978-0-444-52901-5.00008-3
    1. Maier M, Ballester BR, Verschure PFMJ. Principles of neurorehabilitation after stroke based on motor learning and brain plasticity mechanisms. Front Syst Neurosci 2019;13:74. 10.3389/fnsys.2019.00074
    1. Jacquin-Courtois S, O'Shea J, Luauté J, et al. . Rehabilitation of spatial neglect by prism adaptation: a peculiar expansion of sensorimotor after-effects to spatial cognition. Neurosci Biobehav Rev 2013;37:594–609. 10.1016/j.neubiorev.2013.02.007
    1. Rode G, Lacour S, Jacquin-Courtois S, et al. . Long-term sensorimotor and therapeutical effects of a mild regime of prism adaptation in spatial neglect. A double-blind RCT essay. Ann Phys Rehabil Med 2015;58:40–53. 10.1016/j.rehab.2014.10.004
    1. Luauté J, Villeneuve L, Roux A, et al. . Adding methylphenidate to prism-adaptation improves outcome in neglect patients. A randomized clinical trial. Cortex 2018;106:288–98. 10.1016/j.cortex.2018.03.028
    1. Redding GM, Rossetti Y, Wallace B. Applications of prism adaptation: a tutorial in theory and method. Neurosci Biobehav Rev 2005;29:431–44. 10.1016/j.neubiorev.2004.12.004
    1. Prablanc C, Panico F, Fleury L, et al. . Adapting terminology: clarifying prism adaptation vocabulary, concepts, and methods. Neurosci Res 2020;153:8–21. 10.1016/j.neures.2019.03.003
    1. O'Shea J, Gaveau V, Kandel M, et al. . Kinematic markers dissociate error correction from sensorimotor realignment during prism adaptation. Neuropsychologia 2014;55:15–24. 10.1016/j.neuropsychologia.2013.09.021
    1. Jeannerod M, Rossetti Y. Visuomotor coordination as a dissociable visual function: experimental and clinical evidence. Baillieres Clin Neurol 1993;2:439–60.
    1. Panico F, Rossetti Y, Trojano L. On the mechanisms underlying prism adaptation: a review of neuro-imaging and neuro-stimulation studies. Cortex 2020;123:57–71. 10.1016/j.cortex.2019.10.003
    1. Rossetti Y, Jacquin-Courtois S, Calabria M. Testing cognition and rehabilitation in unilateral neglect with wedge prism adaptation: multiple interplays between sensorimotor adaptation and spatial cognition. In: Kansaku K, Cohen LG, Birbaumer N, eds. Clinical systems neuroscience. Tokyo: Springer Japan, 2015: 359–81.
    1. Rode G, Rossetti Y, Boisson D. Prism adaptation improves representational neglect. Neuropsychologia 2001;39:1250–4. 10.1016/S0028-3932(01)00064-1
    1. Girardi M, McIntosh RD, Michel C, et al. . Sensorimotor effects on central space representation: prism adaptation influences haptic and visual representations in normal subjects. Neuropsychologia 2004;42:1477–87. 10.1016/j.neuropsychologia.2004.03.008
    1. Rode G, Pisella L, Rossetti Y. Bottom-up transfer of sensory-motor plasticity to recovery of spatial cognition: visuomotor adaptation and spatial neglect. In: Progress in brain research. Elsevier, 2003: 273–87.
    1. Luauté J, Michel C, Rode G, et al. . Functional anatomy of the therapeutic effects of prism adaptation on left neglect. Neurology 2006;66:1859–67. 10.1212/01.wnl.0000219614.33171.01
    1. Luauté J, Schwartz S, Rossetti Y, et al. . Dynamic changes in brain activity during prism adaptation. J Neurosci 2009;29:169–78. 10.1523/JNEUROSCI.3054-08.2009
    1. Saj A, Cojan Y, Vocat R, et al. . Prism adaptation enhances activity of intact fronto-parietal areas in both hemispheres in neglect patients. Cortex 2013;49:107–19. 10.1016/j.cortex.2011.10.009
    1. Lunven M, Rode G, Bourlon C, et al. . Anatomical predictors of successful prism adaptation in chronic visual neglect. Cortex 2019;120:629–41. 10.1016/j.cortex.2018.12.004
    1. Tilikete C, Rode G, Rossetti Y, et al. . Prism adaptation to rightward optical deviation improves postural imbalance in left-hemiparetic patients. Curr Biol 2001;11:524–8. 10.1016/S0960-9822(01)00151-8
    1. Hugues A, Di Marco J, Lunven M, et al. . Long-lasting reduction in postural asymmetry by prism adaptation after right brain lesion without neglect. Cogn Process 2015;16 Suppl 1:371–5. 10.1007/s10339-015-0704-y
    1. Nijboer TCW, Olthoff L, Van der Stigchel S, et al. . Prism adaptation improves postural imbalance in neglect patients. Neuroreport 2014;25:307–11. 10.1097/WNR.0000000000000088
    1. Shiraishi H, Yamakawa Y, Itou A, et al. . Long-term effects of prism adaptation on chronic neglect after stroke. NeuroRehabilitation 2008;23:137–51.
    1. Padula WV, Nelson CA, Padula WV, et al. . Modifying postural adaptation following a CVA through prismatic shift of visuo-spatial egocenter. Brain Inj 2009;23:566–76. 10.1080/02699050902926283
    1. Chan A-W, Tetzlaff JM, Altman DG, et al. . Spirit 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200. 10.7326/0003-4819-158-3-201302050-00583
    1. Guillebastre B, Rougier PR, Sibille B, et al. . When might a cane be necessary for walking following a stroke? Neurorehabil Neural Repair 2012;26:173–7. 10.1177/1545968311412786
    1. Azouvi P, Samuel C, Louis-Dreyfus A, et al. . Sensitivity of clinical and behavioural tests of spatial neglect after right hemisphere stroke. J Neurol Neurosurg Psychiatry 2002;73:160–6. 10.1136/jnnp.73.2.160
    1. Blum L, Korner-Bitensky N. Usefulness of the berg balance scale in stroke rehabilitation: a systematic review. Phys Ther 2008;88:559–66. 10.2522/ptj.20070205
    1. Ruhe A, Fejer R, Walker B. The test-retest reliability of centre of pressure measures in bipedal static task conditions--a systematic review of the literature. Gait Posture 2010;32:436–45. 10.1016/j.gaitpost.2010.09.012
    1. Sawacha Z, Carraro E, Contessa P, et al. . Relationship between clinical and instrumental balance assessments in chronic post-stroke hemiparesis subjects. J Neuroeng Rehabil 2013;10:95. 10.1186/1743-0003-10-95
    1. Karnath HO, Ferber S, Dichgans J. The origin of contraversive pushing: evidence for a second graviceptive system in humans. Neurology 2000;55:1298–304. 10.1212/WNL.55.9.1298
    1. Quinn TJ, Langhorne P, Stott DJ. Barthel index for stroke trials: development, properties, and application. Stroke 2011;42:1146–51. 10.1161/STROKEAHA.110.598540
    1. Klein A, Andersson J, Ardekani BA, et al. . Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration. Neuroimage 2009;46:786–802. 10.1016/j.neuroimage.2008.12.037
    1. Avants BB, Tustison NJ, Song G, et al. . A reproducible evaluation of ants similarity metric performance in brain image registration. Neuroimage 2011;54:2033–44. 10.1016/j.neuroimage.2010.09.025
    1. Foulon C, Cerliani L, Kinkingnéhun S, et al. . Advanced lesion symptom mapping analyses and implementation as BCBtoolkit. Gigascience 2018;7:1–17. 10.1093/gigascience/giy004
    1. Rorden C, Karnath H-O, Bonilha L. Improving lesion-symptom mapping. J Cogn Neurosci 2007;19:1081–8. 10.1162/jocn.2007.19.7.1081
    1. Rojkova K, Volle E, Urbanski M, et al. . Atlasing the frontal lobe connections and their variability due to age and education: a spherical deconvolution tractography study. Brain Struct Funct 2016;221:1751–66. 10.1007/s00429-015-1001-3
    1. Thiebaut de Schotten M, Tomaiuolo F, Aiello M, et al. . Damage to white matter pathways in subacute and chronic spatial neglect: a group study and 2 single-case studies with complete virtual "in vivo" tractography dissection. Cereb Cortex 2014;24:691–706. 10.1093/cercor/bhs351
    1. Zhang S, Paul J, Nantha-Aree M, et al. . Empirical comparison of four baseline covariate adjustment methods in analysis of continuous outcomes in randomized controlled trials. Clin Epidemiol 2014;6:227–35. 10.2147/CLEP.S56554
    1. Pocock SJ, Assmann SE, Enos LE, et al. . Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems. Stat Med 2002;21:2917–30. 10.1002/sim.1296
    1. Twisk J, Bosman L, Hoekstra T, et al. . Different ways to estimate treatment effects in randomised controlled trials. Contemp Clin Trials Commun 2018;10:10.1016/j.conctc.2018.03.008:80–5. 10.1016/j.conctc.2018.03.008
    1. Liston RAL, Brouwer BJ. Reliability and validity of measures obtained from stroke patients using the balance master. Arch Phys Med Rehabil 1996;77:6–430. 10.1016/S0003-9993(96)90028-3
    1. Hiengkaew V, Jitaree K, Chaiyawat P. Minimal detectable changes of the berg balance scale, fugl-meyer assessment scale, timed "up & go" test, gait speeds, and 2-minute walk test in individuals with chronic stroke with different degrees of ankle plantarflexor tone. Arch Phys Med Rehabil 2012;93:1201–8. 10.1016/j.apmr.2012.01.014
    1. Flansbjer U-B, Blom J, Brogårdh C. The reproducibility of Berg balance scale and the Single-leg stance in chronic stroke and the relationship between the two tests. Pm R 2012;4:10.1016/j.pmrj.2011.11.004:165–70. 10.1016/j.pmrj.2011.11.004
    1. Alghadir AH, Al-Eisa ES, Anwer S, et al. . Reliability, validity, and responsiveness of three scales for measuring balance in patients with chronic stroke. BMC Neurol 2018;18:10.1186/s12883-018-1146-9. 10.1186/s12883-018-1146-9
    1. Higgins J, Thomas J, Chandler J, eds. Cochrane handbook for systematic reviews of interventions version 6.1 (updated September 2020). Cochrane, 2020.

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