Efficacy and safety of manual acupuncture for the treatment of upper limb motor dysfunction after stroke: Protocol for a systematic review and meta-analysis.

INTRODUCTION: The incidence of stroke sequelae among patients is as high as 70%-80%. Flexor spasm is the most common stroke sequela, presenting a heavy burden to the patients and their families. This study will evaluate the results of randomized controlled trials to determine the efficacy and safety of hand manipulation acupuncture for the treatment of upper limb motor dysfunction after stroke.
METHODS: Eight databases, including China National Knowledge Infrastructure, Chinese Scientific Journal Database, Cochrane Central Register of Controlled Trials, Embase, MEDLINE, PubMed, Wanfang Database, and Web of Science, will be searched using English and Chinese search strategies. In addition, manual retrieval of research papers, conference papers, ongoing experiments, and internal reports, among others, will supplement electronic retrieval. All eligible studies published on or before January 15, 2021 will be selected. To enhance the effectiveness of the study, only clinical randomized controlled trials related to the use of manual acupuncture for the treatment of upper limb motor dysfunction after stroke will be included. ANALYSIS: The Fugl-Meyer upper extremity assessment will be the primary outcome measure, whereas the Wolf Motor Function Test, Modified Ashworth Scale, arm movement survey test table, and upper extremity freehand muscle strength assessment scores will be the secondary outcomes. Side effects and adverse events will be included as safety evaluations. To ensure the quality of the systematic evaluation, study selection, data extraction, and quality assessment will be independently performed by two authors, and a third author will resolve any disagreement. ETHICS AND DISSEMINATION: This systematic review will evaluate the efficacy and safety of manual acupuncture for the treatment of upper limb motor dysfunction after stroke. Since all included data will be obtained from published articles, it does not require ethical approval and will be published in a peer-reviewed journal. INPLASY registration number: INPLASY202110071.

Introduction

Stroke, also known as cerebrovascular accident, is a common cardiovascular and cerebrovascular disease. It is classified into different forms, including ischemic and hemorrhagic stroke. According to the data released by the World Health Organization, one person has a stroke every 5 s, and about 15 million people experience a brain injury after stroke every year [1]. About 85% of stroke survivors have upper limb dysfunction, and more than 60% of them have persistent hand dysfunction and cannot live independently after treatment [2]. Studies have shown that the common clinical manifestations of upper limb motor dysfunction after stroke include muscle weakness, muscle spasm, and muscle tension changes. These symptoms can lead to difficulty in carrying out daily activities, such as reaching out, picking up, moving, and dressing, etc., thereby affecting a patient’s quality of life [3, 4]. Fine motor dysfunction of the upper limbs after stroke, though a vital challenge, is a necessity of post-stroke treatment in order to reduce the stroke disability rate. Currently, the most commonly used rehabilitation therapies include physical factor therapy, exercise and occupational therapy, compensatory training, biofeedback, motor imagery therapy, contralateral C7 nerve root transfer, acupuncture, and massage [5, 6].

Studies have shown that manual acupuncture can stimulate the nerves of the human body, improve the motor status of patients, and have a positive effect on the recovery of patients and their independent actions [7-10]. According to the Chinese guidelines for the diagnosis and treatment of acute ischemic stroke published in 2018, acupuncture (level II recommendation, level B evidence) can be selected according to specific situations and the wishes of patients [11]. It is obvious that the curative effect of acupuncture in the treatment of upper limb motor dysfunction after stroke has been recognized by clinical experts.

Currently, the evidence levels of the available evidence-based research on manual acupuncture for the treatment of upper limb motor dysfunction after stroke are not high. This is because the existing studies have limitations such as small sample size, loosely implemented randomization, different degrees of blinding, use of nonstandard intervention measures in the control groups, and lack of evidence from high-quality randomized controlled trials (RCTs). Therefore, the aim of this study is to analyze the results of RCTs to ascertain the efficacy and safety of manual acupuncture for the treatment of upper limb motor dysfunction after stroke. This will allow for the provision of reliable evidence-based clarification of the efficacy of manual acupuncture for the treatment of upper limb motor dysfunction after stroke.

The proposed date for the completion of this study is October 15, 2021.

Materials and methods

This protocol is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines [12] and the corresponding checklist. The systematic review protocol is registered in the INPLASY International Registry of Systematic Reviews (ID:INPLASY202110071; https://inplasy.com/?s=INPLASY202110071; DOI: 10.37766/inplasy2021.1.0071).

Inclusion and exclusion criteria

Types of participants

Patients’ age will be between 18 and 75 years old. In line with China’s 2015 diagnostic criteria for classifying cerebrovascular diseases, patients who had a first stroke confirmed using computed tomography or magnetic resonance imaging, a disease course longer than 1 month, but less than or equal to 6 months, and moderate to severe upper extremity and hand dysfunction that meet the standard criteria (Brunnstrom grade 2–4, Fugl Meyer Assessment [FMA] score < 20, improved Ashworth Spasm Scale score less than level 3 [13]) will be included, regardless of their sex and nationality. Exclusion criteria will include: 1) presence of other diseases resulting in serious cognitive or speech disorders 2) inability to understand and complete the therapist’s instructions (Mini-Mental State Examination score < 21 points [14]) 3) history of drug or alcohol dependence 4) serious liver or kidney disease 5) other diseases that may affect brain structure and function; and 6) other mental disorders.

Types of interventions

We will include studies in which the intervention group received manual acupuncture alone or in combination with routine rehabilitation treatment (manual therapy, exercise therapy, and electronic biofeedback, etc.), and in which the control group received only conventional rehabilitation treatment.

Types of outcome measures

The primary outcome measure will be the FMA score. Secondary outcomes will include the Wolf Motor Function Test (WMFT), Modified Ashworth Scale(MAS), arm movement survey test table(ARAT), and upper extremity freehand muscle strength assessment scores(MMT) [15].

Relaxation periods and spasmodic periods will be analyzed in subgroup analyses.

Types of studies

Randomized controlled clinical trials and quasi-RCTs will be included.

Data sources

A structured and systematic literature search for eligible and relevant articles published on or before January 15, 2021 will be conducted. The following databases will be searched:China National Knowledge Infrastructure, Chinese Scientific Journal Database, Cochrane Central Register of Controlled Trials, Embase, MEDLINE, PubMed, Wanfang Database, and Web of Science. Selected studies will be published in either Chinese or English. The search terms include “cerebral apoplexy”, “sequelae of stroke”, “upper extremity motor dysfunction”, “upper limb hemiplegia”, “hemiplegia”, “acupuncture”, “clinical RCT”.

Searching other resources

TA manual search will mainly be used in searching for relevant studies. Details of the selection process are shown in a flow chart and the screening process is summarized in a flow diagram (Fig 1).

Fig 1

PRISMA flow diagram of study and exclusion.

Search strategy

The search strategy will be based on the Cochrane handbook guidelines (5.1.0) and will include keywords, such as “post-stroke”, “after stroke”, “acupuncture” or “manual acupuncture”, “upper extremity motor dysfunction”, and “clinical RCT”. Subsequent searches will involve the use of Medical Subject Headings terms headings, in addition to keywords from the initial retrieval. Additional article searches will involve a review of the reference lists of relevant research articles. As an example, the search strategy for PubMed is summarized in Table 1.

Table 1

Search strategy for PubMed.

Number	Search terms
1	acupuncture.ti,mesh.
2	manual acupuncture.ti,ab.
3	or 1–2
4	post-stroke. ti,ab.
5	after stroke. ti,ab.
6	or 4–5
7	Upper extremity motor dysfunction. ti,mesh.
8	Upper limb hemiplegia. ti,ab.
9	or 7–8
10	randomised controlled trial.pt.
11	Controlled clinical trial.pt.
12	randomised.ab.
13	Randomly.ab.
14	trial.ab.
15	or 10–15
16	3 and 6 and 9 and 15

Selection of studies

Two researchers (GTJ and CL) will independently select the eligible literature according to the inclusion and exclusion criteria after reading their titles and abstracts. Subsequently, the full texts of the papers will be read and uncontrolled research, nonrandomized studies, and studies with inconsistent evaluation criteria or similar data will be excluded. If any differences occur during the screening, the third author (CST) would intervene.

Data extraction and management

Two researchers (GTJ and CL) will use a predesigned data extraction table to extract the data of the included studies. The extracted data will include author, year, sample size, course of treatment, intervention measures, outcome indicators, adverse reactions, etc. The study selection procedure will be performed according to the PRISMA guidelines, which are presented in the flow diagram (Fig 1).

Statistical analysis

We will use SAS (SAS Institute, Cary, NC) and Stata (StataCorp, College Station, TX) to analyze the standard deviation, standard error and mean of each group. When we encounter literature with missing data, we will try to contact the author. If we are unable to get full data, then that study will not be included. We will use the Review Manager 5.3 software provided by the Cochrane Collaborative Network for statistical analysis [16]. For continuous variables, the means and standard deviations of each study will be obtained and pooled as a mean difference or a standardized mean difference with a 95% confidence interval. The statistical heterogeneity of the included clinical RCTs will be analyzed. The I2 test will be used to test for heterogeneity. When I2 is <50% or P>0.05, it indicates that there is no statistical heterogeneity between studies [17]. A fixed-effects model will be selected to combine the effect amount; otherwise, a random effects model will be adopted.

Methodological assessment of quality

The qualities of the included studies will be evaluated using the risk of bias table proposed by the Cochrane Collaborative Network [17]. The risk table includes six items: random sequence generation mode, whether to use allocation concealment, whether to blind the subjects and intervention providers, whether to blind the result evaluators, whether the result data are complete, whether to select the result report, and other bias sources. The criteria used to assess the risk of bias are “low risk”, “high risk”, and “unclear” [17]. Two evaluators will independently evaluate the methodological qualities of the studies. In cases of disagreement, the third author would intervene.

Assessment of heterogeneity

If there is no significant heterogeneity (I2<50%)between studies, the fixed-effects model will be used for evaluation. If there is significant heterogeneity (I2>50%), the random-effects model will be used for evaluation [17]. Sensitivity analysis or subgroup analysis will then be conducted as required to explain the heterogeneity.

Subgroup analysis

If possible, subgroups will be analyzed according to relaxation and spasm or different acupuncture manipulation.

Sensitivity analysis

When possible, we will perform sensitivity analysis to explore the effects of a trial’s risk of bias on primary outcomes. Lower quality trials will be excluded from these analyses and the meta-analyses will be repeated according to sample size and insufficient data to assess quality and robustness when significant statistical heterogeneity arises.

Assessment of publication bias

If more than 10 trials meet the study criteria, we will use Review Manager 5.3 software to draw and analyze a funnel chart and use the funnel chart to evaluate the potential publication bias.

Grading the quality of evidence

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [18] is recommended for the analysis of the level of evidence.

Discussion

Stroke is a major disease that threatens human health. It has high rates of incidence, mortality, disability, recurrence, and economic burden. Data reported in the 2015 China Stroke Prevention report indicates that stroke has become China’s foremost cause of death, resulting in an economic burden of up to 40 billion Yuan [19]. About 65%–80% of new stroke patients have upper limb dysfunction every year [20]. The recovery of upper limb motor function is slow and difficult, and it seriously affects the life and work of patients. It is a challenging and controversial point of rehabilitation treatment. Currently, the methods for treatment of upper limb motor dysfunction after stroke include the use of a robotic upper limb, contralateral controlled functional electrical stimulation, brain computer interface, and mirror therapy, among others [21-24]. However, these methods have some limitations in terms of clinical efficacy, popularity, and safety.

Acupuncture has become an important method for rehabilitation of upper limb motor dysfunction after stroke

Acupuncture for the treatment of stroke has unique advantages [25]. With the increasingly widespread use of acupuncture globally, the mechanism of acupuncture in functional recovery after stroke has become a research hotspot. Studies [Evid Based Complement Alternat Med. 2017 ">25-27] have demonstrated that acupuncture can promote the proliferation of central nervous system cells in cerebral ischemia-reperfusion injury; promote angiogenesis in infarcted areas; regulate local blood flow by vasoactive mediators, inhibit cell apoptosis; facilitate the regulation of neurochemicals, such as neurotransmitters, antioxidants, inflammatory related factors, and neurotrophic factors, and activate specific motor functional areas like the cortex. Acupuncture treatment has been widely accepted because of its simplicity, convenience, fewer side effects, and exact curative effect. It is a popular trend to combine acupuncture with modern rehabilitation technology [28].

Clinical effect of manual acupuncture in the treatment of upper limb motor dysfunction after stroke is better than that of electroacupuncture

There are many reports on the treatment of upper limb motor dysfunction after stroke by manual acupuncture and electroacupuncture. While the electroacupuncture procedure is simple than manual acupuncture, we found that the effect of manual acupuncture is better through clinical research. Because the upper limb motor dysfunction in ischemic stroke occurs in the six stages of Brunnstrom motor function recovery [29], electroacupuncture treatment can decrease the patient’s muscle strength lower in the flaccid period and increase it abnormally in the spasmodic period. Manual acupuncture is better during the six Brunnstrom stages because it can be changed according to what is needed.

FMA-UE and other outcome indicators are closely related to upper limb motor dysfunction after stroke

The FMA-UE is a motor function assessment method designed by Fugl Meyer AR and colleagues for hemiplegic stroke patients with upper limb motor dysfunction according to Brunnstrom’s theoretical framework [30]. It covers five areas of motion, sensation, balance, joint range of motion and pain, with a total of 113 assessment items and a full score of 226. It is the most commonly used scale to evaluate the therapeutic effect of upper limb motor function after stroke, and it is often used as the “gold standard” to test the validity of other scales [31, 32]. It can effectively evaluate the motor function and coordination of the shoulder, elbow, forearm, hand, and wrist. The evaluation content is more detailed, but the evaluation of fine finger fine activity is lacking [33]. On the other hand, ARAT can better evaluate the motor function of the distal end of the upper limb, including the evaluation of fine finger activity of stroke patients at various stages, and it is easy to operate, time-consuming, and easy to apply in clinical and scientific research [34, 35]. The WMFT can quantitatively evaluate the upper limb movement ability of patients through the timing of single joint movement, multi joint movement, functional activity, and the evaluation of movement quality. It has good validity and reliability. It is the most commonly used scale around the world to evaluate the improvement of upper limb function by compulsory exercise therapy [36]. The advantage of this method is that it does not only evaluate the quality of the work activity, but also measures the time of the operation activity, and has a good standard validity with the upper limb of FMAS [37]. Different from FMA-UE, WMFT can reflect many functions. The effect of task training on upper limb motor function. It can not only evaluate the degree of upper limb motor function injury, but can also evaluate the therapeutic effect of different interventions on upper limb injury. The operation method of elbow flexion spasm is more detailed, which is easy to achieve the evaluation standard. The reliability of the study is partly reliant on the evaluator’s operation experience, repeated tests and discussions. It is mainly used in the auxiliary evaluation of elbow flexion spasm in the rehabilitation process of patients with upper limb motor dysfunction after stroke [38]. Combined with these evaluation methods, they can be evaluated from multiple angles and play a complementary role, making the evaluation results more reliable. The mental state of stroke patients is also very important for the recovery of dysfunction. There is currently no commonly used scale to evaluate the mental state of stroke patients in the literature.

There are currently no data on the systematic reviews or meta-analyses of the therapeutic effect of manual acupuncture on upper limb motor dysfunction after stroke. Therefore, we plan to conduct a systematic review and meta-analysis to provide high-quality evidence of the efficacy of manual acupuncture for upper limb motor dysfunction after stroke.

Limitations

As manual acupuncture is a holistic method and follows the concept of “treatment based on syndrome differentiation,” different patients and different acupuncturists will produce different therapeutic effects, leading to a certain level of heterogeneity. In addition, different types of manual acupuncture, including reinforcing and reducing, flat reinforcing and reducing, and other manipulations, also produce different therapeutic effects.

Second, the following drawbacks cannot be avoided during literature collection: the quality of literature not being high enough, the exclusion of studies not published in Chinese or English, and the sample size of the included literature not being large enough.

PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: Recommended items to address in a systematic review protocol*.

(DOC)

Click here for additional data file.

10 May 2021

PONE-D-21-03553

Efficacy and safety of manual acupuncture in the treatment of Upper Limb Motor dysfunction after stroke: A protocol for systematic review and meta-analysis

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Reviewer #2: Yes

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Reviewer #1: There are a number of English errors in this document. Examples are:

INTRO:

…these damages can lead to daily activities (such as reaching out, picking up, moving, dressing, etc.) obstacles…

Therefore, as an important part of reducing stroke disability rate, upper limb rehabilitation after stroke is the difficulty of post-stroke treatment.

Part 2 Starting with 2.2. Data source

Past, present, and future tenses are comingled within sentences and paragraphs.

2.8.Subgroup analysis If possible,Subgroups will analyzed according to relaxation and spasm or different acupuncture manipulation

Discussion:

Chinese medicine acupuncture treatment of stroke has its unique advantages，In recent years, with the application of acupuncture in the world more and more widely, the mechanism of acupuncture in functional recovery after stroke has become a research hotspot. [sentence structure, run-on sentence]

Editing is needed before this manuscript can be published

Reviewer #2: General comment:

The manuscript needs extensive linguistic correction. There are so many typos and punctuation errors. Some words and sentences are hardly understandable (e.g. “The fine dysfunction of the upper limbs, …”, “bind method”, “.. and Spasmodic periowill be…, MEDLIN, …high Gao Zhican rate… etc.). The tenses used are inconsistent throughout the methods section and should be carefully reviewed. Some sections are simply copied and repeated in different sections of the manuscript.

INTRODUCTION:

-Please ascertain that this description of the purpose statement is concise and accurate: “Therefore, in order to better study the efficacy and safety of manual acupuncture in the treatment of upper limb motor dysfunction after stroke, this study will be combined with the published clinical randomized controlled trials for analysis in order to provide reliable evidence-based basis for the efficacy of manual acupuncture in the treatment of upper limb motor dysfunction after stroke.”

- The described problem of the lack of high-quality RCTs (please provide some references) is not necessarily solved by conducting a systematic review and meta-analysis. This point should rather be addressed in the discussion section.

METHODS:

-Some parts (e.g. 2.1.1. Types of participants, 2.8. Sensitivity analysis, etc.) of this manuscript are almost identical with a recent publication of the same study group (Zhang X, Cao D, Liu J, et al. Effectiveness and safety of brain-computer interface technology in the treatment of poststroke motor disorders: a protocol for systematic review and meta-analysis. BMJ Open 2021;11:e042383. doi:10.1136/bmjopen-2020-042383). As it is mainly “copy paste” it should be reviewed and rewritten carefully or at least referenced throughout.

- Please list the databases used alphabetically

- Search terms are repeated in chapter 2.2 und search strategy.

- Reference on chapter 2.6 is missing.

- Chapter 2.11 “It is recommended to use…”. Are the authors going to use GRADE or not?

STATISTICAL ANALYSIS

-How will the authors deal with missing data? Please add the details.

-To the best of my knowledge RevMan does not offer any statistical tools (e.g., Egger’s test, I2-Test etc.). Which data analysis tools will the authors use to perform statistical tests? Please add details.

DISCUSSION:

- Please discuss and put in relation pro and cons between already established therapeutic options and acupuncture treatment.

- The authors mentioned that “at present, acupuncture treatment has been widely accepted because of its simple operation, convenience, less side effects and exact curative effect…” Please provide a rationale and add references.

- In my personal experience of treating stroke sequelae with acupuncture in China, I have seen electroacupuncture used almost exclusively. Why is this treatment option not included in the review but only manual acupuncture? Please provide a rationale or address this topic in the discussion section.

TABLES/SUPPL. TABLES:

- Search strategy for PubMed – Number 15 (or 10-15) should be corrected.

- Please provide an explanation for the used abbreviations e.g. ti,ab

ABSTRACT:

Please apply the revisions to the abstract as well.

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Reviewer #1: Yes: Jennifer Brett, ND, L.Ac.

Reviewer #2: Yes: Jan Valentini

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2 Jun 2021

Dear Editors and Reviewers:

Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled “Efficacy and safety of manual acupuncture in the treatment of Upper Limb Motor dysfunction after stroke: A protocol for systematic review and meta-analysis” (ID: PONE-D-21-03553). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our research. We have studied comments carefully and have made the correction which we hope meet with approval. The revised portion is marked in red in the paper. The main corrections in the paper and the responses to the reviewer’s comments are as flowing:

Responds to the reviewer’s comments:

Reviewer #1:

1. Response to comment: (……There are some mistakes in English in this document……)

Response: Because English, as a second language, does suggest to you that there are some mistakes in the article. This time, we have carefully revised and checked sentence by sentence, and even applied for professional translation assistance from the translation and editing agency.

Reviewer #2:

1. Response to comment: (Please ascertain that this description of the purpose statement is concise and accurate: “Therefore,...... stroke.”)

Response: ××××××

2. Response to comment: (……The described problem of the lack of high-quality RCTs (please provide some references) is not necessarily solved by conducting a systematic review and meta-analysis. This point should rather be addressed in the discussion section.……)

Response: ××××××

3.Response to comment: (……Some parts (e.g. 2.1.1. Types of participants, 2.8. Sensitivity analysis, etc.)……)

Response: We have completed the modification according to the suggestions. We mistakenly thought that the repetitive part is that we can quote the previous articles published in BMJopen.

4.Response to comment: (……- Please list the databases used alphabetically……)

Response:According to the suggestion, we have listed the databases used in this paper in alphabetical order.

5.Response to comment: (……STATISTICAL ANALYSIS

-How will ……perform statistical tests? Please add detail……)

Response:We will use Statistics Analysis System and Stata to analyze the Standard Deviation, Standard Error and Mean of each group.

When we encounter the literature with missing data, we will try to contact the author. If we can't get the full data through contact, we will exclude the author's full data.

6.Response to comment: (…… In my personal ……Please provide a rationale or address this topic in the discussion section……)

Response:Because the upper limb motor dysfunction of ischemic stroke occurs in the six stages of Brunnstrom motor function recovery, sometimes electroacupuncture treatment is easy to make the patient's muscle strength lower in the flaccid period and increase abnormally in the spasmodic period. And manual acupuncture can avoid this problem very well. At the same time, it can achieve better curative effect by changing the manual in six different periods.

Submitted filename: Response to Reviewers.doc

Click here for additional data file.

1 Jul 2021

PONE-D-21-03553R1

Efficacy and safety of manual acupuncture for the treatment of upper limb motor dysfunction after stroke: Protocol for a systematic review and meta-analysis

PLOS ONE

Dear Dr. Chen,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The prerequisites for a successful re-submission are:

1) major improvements in language and style (please consult a native speaker)

2) a thorough revision of the discussion section

Please submit your revised manuscript by Aug 15 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Johannes Fleckenstein

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Revised document corrected the English language errors of the original submission.

Reviewer #2: The authors did a good job in revising the manuscript. Although many typos and language punctuation errors were corrected, there are still some remaining in the manuscripts (e.g. high Gao Zhican rate .. the collation of literature, etc.). Please check once again for spelling and language errors.

Some references are still missing in the manuscript. Please check whether you have provided sufficient references for your statements. E.g.:

- Methods: -pg. 36: The qualities of the included studies will be evaluated using the risk of bias table proposed by Cochrane collaborative network.

- Discussion pg. 28: Acupuncture for the treatment of stroke has unique advantages. With the increasingly widespread use of acupuncture globally, the mechanism of acupuncture in functional recovery after stroke has become a research hotspot.

Or

It is a popular trend to combine acupuncture with modern rehabilitation technology.

While some of the reviewers' comments from the first submission were addressed in the revision, others were neither addressed nor mentioned in the response to the reviewers. A point-by-point response would be welcome and could solve this problem.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Jennifer Brett

Reviewer #2: Yes: Jan Valentini, MD

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

10 Jul 2021

Dear Prof. Fleckenstein and Reviewers:

Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled “Efficacy and safety of manual acupuncture in the treatment of Upper Limb Motor dysfunction after stroke: A protocol for systematic review and meta-analysis” (PONE-D-21-03553R1). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our research. We focused on the two main problems that the editor helped us to summarize. First of all, we added a large number of relevant information according to the full text, consulted relevant experts, and completed the discussion part again. Then, we have made great improvements in the language and style of the full text, and invited "editing" organizations to help with native language services.

The revised portion is marked in red in the paper. The main corrections in the paper and the responses to the reviewer’s comments are as flowing:

Responds to the reviewer’s comments:

Reviewer #2:

1. Response to comment: (there are still some remaining in the manuscripts (e.g. high Gao Zhican rate .. the collation of literature, etc.). Please check once again for spelling and language errors.)

Response: First of all, we are sorry that we have not completely checked out spelling and language errors. This time, we have carefully checked spelling and language errors for many times to minimize errors.

2. Response to comment: (Some references are still missing in the manuscript)

Response:Thank you very much for helping us find some references missing. After careful proofreading, we added 9 references in the right place.

We tried our best to improve the manuscript and made some changes in the manuscript. These changes will not influence the content and framework of the paper. And here we did not list the changes but marked in red in revised paper.

We appreciate for Editors and Reviewers’ warm work earnestly and hope that the correction will meet with approval.

Once again, thank you very much for your comments and suggestions.

Authors:Di Cao, Xiaolin Zhang, Mingjun Liu, Qiguang Yang, Shuhong Gu, Tianjiao Gao, Lin Cong, Dehui Ma, Hongju Lin, Shaotao Chen.

E-mail:Shaochenchen3600@163.com.

Institutional: Changchun University of Chinese medicine

Submitted filename: Response to Reviewers.doc

Click here for additional data file.

7 Aug 2021

PONE-D-21-03553R2

Efficacy and safety of manual acupuncture for  the treatment of u pper l imb m otor dysfunction after stroke: P rotocol fo r a  systematic review and meta-analysis

PLOS ONE

Dear Dr. Chen,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We acknowledge that the authors sought help with linguistic proofreading. Whereas grammar and style improved, in agreement with reviewer #2,  the manuscript still needs revisions in accuracy and punctuation.

Please submit your revised manuscript by Sep 21 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Johannes Fleckenstein

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have again done a good job in revising the manuscript. However, there are still some punctuation and grammatical errors (e.g. Modified Ashworth Scale(MAS),, arm movement survey test table(ARAT),and upper extremity freehand muscle strength assessment scores(MMT).[15] OR While the electroacupuncture procedure is more simple than manual acupuncture, but we found that the effect of manual acupuncture is better through clinical research). Please also provide a reference for this statement.

I would suggest seeking the help of a language editor again after the revision.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Jan Valentini, MD

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

6 Oct 2021

Dear Prof. Fleckenstein and Reviewers:

Thank you for your letter and for the reviewers’ comments concerning our manuscript entitled “Efficacy and safety of manual acupuncture in the treatment of Upper Limb Motor dysfunction after stroke: A protocol for systematic review and meta-analysis” (PONE-D-21-03553R1). Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our research.

English is not our mother tongue and may still be not particularly accurate in some expressions, so there are still problems in language expression after the previous three modifications. This time, we specially invited a professional language polishing organization "Yideji" to help with native language services.

The revised portion is marked in red in the paper.

In addition, This is our first time to contribute to our "PLoS One". We found that"Funding Statemen" is different from other magazines. Our actual funding information is as follows:This work was supported by the School construction project of National Administration of traditional Chinese medicine (Grant Number LPGZS22014-11，http://www.satcm.gov.cn/renjiaosi/zhengcewenjian/2018-03-24/1840.html) , The Jilin Local Standard Construction Project (Grant Number: DBXM097-2020，http://scjg.jl.gov.cn/zw/gsgg/202105/t20210526_8082979.html) and the State Administration of Traditional Chinese Medicine of Jilin Province(Grant Number: zybz-zc-2020-004，http://jltcm.jl.gov.cn/tzgg/xgdt/202107/t20210706_8130847.html). Please help to modify it.

We tried our best to improve the manuscript and made some changes in the manuscript. These changes will not influence the content and framework of the paper. And here we did not list the changes but marked in red in revised paper.

We appreciate for Editors and Reviewers’ warm work earnestly and hope that the correction will meet with approval.

Once again, thank you very much for your comments and suggestions.

Authors:Di Cao, Xiaolin Zhang, Mingjun Liu, Qiguang Yang, Shuhong Gu, Tianjiao Gao, Lin Cong, Dehui Ma, Hongju Lin, Shaotao Chen.

E-mail:Shaochenchen3600@163.com.

Institutional: Changchun University of Chinese medicine

Submitted filename: Response to Reviewers.doc

Click here for additional data file.

11 Oct 2021

Efficacy and safety of manual acupuncture for the treatment of upper limb motor dysfunction after stroke: Protocol for a systematic review and meta-analysis

PONE-D-21-03553R3

Dear Dr. Chen,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Johannes Fleckenstein

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

25 Oct 2021

PONE-D-21-03553R3

Efficacy and safety of manual acupuncture for the treatment of upper limb motor dysfunction after stroke: Protocol for a systematic review and meta-analysis

Dear Dr. Chen:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Priv.-Doz. Dr. Johannes Fleckenstein

Academic Editor

PLOS ONE