Quality of healthcare can be improved when the best external evidence available is integrated in clinical decision-making in a systematic explicit manner. With the rapid expansion of clinical evidence, the opportunities for evidence-based high-quality healthcare increase. Paradoxically, the likelihood of any one person to get a complete and balanced picture of the evidence available decreases. This is especially true for rehabilitation interventions that are complex in nature and where clinical research is rather diverse. Given the complex nature of the evidence, there is a substantial risk of misinterpreting the complex information both at the level of individual sources  and for aggregated data syntheses . These risks are inherent in these sources themselves and are in addition related to the methodological expertise necessary to make valid use of the evidence for clinical decision-making. Taken together, there is a great demand for systematic structured guidance from evidence to clinical decision. This methodology paper describes a structured process for the development and report of evidence-based clinical practice recommendations that uses systematic reviews and meta-analyses as evidence source. It provides a comprehensive framework with specific requirements for the development group, the formulation of the healthcare question addressed, the systematic search for the evidence, its critical appraisal, the extraction and the outcome-centered presentation of the evidence, the rating of its quality, strengths and weaknesses, any further considerations relevant for decision-making, and an explicit recommendation statement along with its justification, implementation, and resource aspects. The suggested methodology uses international standards in evidence synthesis, critical appraisal of systematic reviews, rating the quality of evidence, characteristics of recommendations, and guideline development as developed by Cochrane, GRADE , AMSTAR (A MeaSurement Tool to Assess systematic Reviews), and AGREE . An added distinctive feature of the methodology is to focus on the most up-to-date, most valid evidence and hence to support the development of valid practice recommendations in an efficient way. Practice recommendations generated by such a valid methodology would be generally applicable and promote evidence-based clinical practice globally. Globally, disabilities affecting everyday life, occupational and other social activities, and hence participation restrictions have dramatically been increasing for the last decades , a tendePersons with health conditions that cause limitations in functioning can benefit from rehabilitation. The need for rehabilitation continues to grow worldwide, especially in low- and middle-income countries. The demand for rehabilitation services does, however, already exceed their availability, leaving needs unmet .Given the restricted resources and facing an increasing demand requires the use of the available resources efficiently and further development of healthcare services in a way that promotes the greatest clinical benefit combined with the lowest risk of harm and a high degree of acceptability to those in need for healthcare.Indeed, rehabilitation services promote autonomy and participation as, e.g., has been shown for multidisciplinary stroke units . Such seIndeed, quality of healthcare can be improved when the best external evidence available is integrated in clinical decision-making in a systematic explicit manner. With the rapid expansion of clinical evidence, the opportunities for evidence-based high-quality healthcare increases. Paradoxically, the likelihood of any one person to get a complete and balanced picture of the evidence available decreases.https://pubmed.ncbi.nlm.nih.gov/?term=stroke+rehabilitation&filter=pubt.meta-analysis&filter=years.2014-2021; accessed April 24, 2021). Hence, for many healthcare questions, such evidence can be used as a “primary source” for clinical decision-making.Systematic reviews and meta-analysis that provide a synthesis of the available evidence, e.g., for a specific intervention, can provide more precise estimates of therapeutic effects and provide more refined information for clinical decision-making, e.g., by sub-group analyses . Aside fCochrane's systematic reviews provide high-quality information to support informed decision-making, i.e., they provide the current status of evidence in a valid, critically appraised and comprehensive way. They do, however, not provide practice recommendations based on this evidence.The same holds true for the many other sources of systematic reviews and meta-analyses available in the literature. In addition, there is a risk that informed decision-making could even be misled by such information. When systematic reviews and meta-analyses are based on poor methodology, they are at risk to provide aggregated data that are invalid, and thus, any recommendations based on such information would be at risk to be invalid.Yet, it would be important or even mandatory to integrate valid up-to-date therapeutic information in clinical decision-making and thereby improve global health.Several barriers exist that might reduce the chance for an adequate integration of Cochrane and other systematic review evidence into clinical practice:1. Clinicians, their patients, and other stakeholders might, in many instances, have difficulties to apprehend a systematic review and its direct implications for clinical practice. They might be uncertain when it comes to implications for clinical decision-making based on Cochrane and other evidence. This can be caused by many reasons, one being that Cochrane reviews and other systematic reviews are complex reports and that their structure is not easy to follow for somebody not trained to do so.2. Not all systematic reviews that are relevant for a healthcare question fulfill the high-quality standards of Cochrane reviews. While systematic reviews can provide a valid summarizing picture of the currently available best evidence, they are at risk for flaws, invalid meta-analyses, and thereby conclusions. Therefore, it is necessary to critically appraise systematic reviews and their meta-analyses before practice recommendations can be deduced.3. While evidence is a fundamental aspect for decision-making in evidence-based practice, it is in itself not a recommendation. Several steps have to be taken from a body of evidence to recommendations. Recommendations need to be based on different available alternative options for treatment that usually would not be addressed in a single systematic review. Systematic reviews frequently focus on a specific intervention. Furthermore, stakeholders' views and preferences need to be considered. Weighing of benefits, side effects, risks and their overall balance, together with potential resource implications and implementation issues across healthcare settings all need to be taken into account.Even when looking at existing healthcare guidelines many show restrictions. Many guidelines are not systematically evidence-based, or if they are, they cover only a restricted scope of healthcare questions, and apply to specific healthcare situation only, mostly as prevalent in high-income countries .As a consequence, the World Federation of Neurorehabilitation (WFNR) and its Special Interest Groups (SIG) developed evidence-based practice recommendations for stroke rehabilitation . Here, pThis methodology paper extends this practice recommendation development methodology and describes a structured process for the development and report of evidence-based clinical practice recommendations that specifically use systematic reviews and meta-analyses as evidence source. It provides a comprehensive multi-step outcome-centered framework for the development and reporting of such practice recommendations based on a combination of internationally agreed methods. An added distinctive feature of the methodology is to focus on the most up-to-date most valid evidence and hence to support the development of valid practice recommendations without investing too much time for the critical appraisal of less informative and/or less valid evidence.The general methodology is used as described by Appraisal of Guidelines for REsearch & Evaluation (AGREE) II , 8. The The recommendations provide both a structured abstract  and a plain language summary .The description of scope and purpose of the recommendations includesthe overall objective,the health question addressed, anda specification of the target population, condition(s), intervention(s) or exposures, comparison(s), outcome(s), and healthcare setting(s) of interest.A clear description of the population  covered should be provided. The age range, sex, clinical description, and comorbidity may be provided.The practice recommendation development group should include individuals from all relevant professional groups. This may include members of the steering group, the research team involved in selecting and reviewing/rating the evidence, and individuals involved in formulating the final recommendations.For each member of the guideline development group, the following information is included:name,discipline/content expertise ,institution ,geographical location , anddescription of the member's role in the guideline development group.A statement of type of strategy, the data acquisition or search strategy used to capture patients'/public's views and preferences , and the outcomes/information gathered on patient/public information should be given.A clear description of intended practice recommendation audience  and a description of how the recommendation may be used by its target audience  should be documented.https://amstar.ca/index.php; accessed April 24, 2021).Since, for any health question, both high-quality Cochrane reviews and/or other systematic reviews might contribute to the evidence synthesis, it is important to critically appraise systematic reviews before their results can be used for practice recommendations. AMSTAR (A MeaSurement Tool to Assess systematic Reviews) is a valid, reliable, and useable instrument that helps users differentiate between systematic reviews, focusing on their methodological quality and expert consensus  .The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group developed a common, sensible, and transparent approach to grading both the quality (or certainty) of evidence and the strength of recommendations   explicitly needs to be taken into consideration. The general approach used should be reported . The strength of recommendation for or against a specific management option should be expressed using two categories (weak or strong recommendation) and the definitions/interpretation for each category should be consistent with those used by the GRADE Working Group.Since the GRADE approach is used to judge the quality of evidence in Cochrane systematic reviews , the sysThis methodology paper makes use of the Cochrane methodology to assess, synthesize, and report evidence , the GRAAll these methodological approaches that are compatible with each other are explicitly used. They are not modified for the purpose presented in this methodology paper.Based on the strength of all three approaches, a methodology is described on how to develop evidence-based practice recommendations using Cochrane reviews and other systematic reviews.This approach does not neglect the need to systematically base practice recommendations on reports of experimental and/or observational clinical studies . It is aIt does, however, suggest a systematic approach from evidence to clinical decision in case information from systematic reviews and meta-analyses can be used. The methodology suggested is primarily described for a comprehensive use of meta-analytic data for a given healthcare question (where this is available).Any results of this type of work can be used by different stakeholders such as healthcare professionals, patients, healthcare organizations, or guideline developers.The presented methodology can also be used to provide guidance based on a single systematic review, i.e., to make clinical decision implications transparent for a given piece of information. Implications in terms of lack of comprehensiveness  should explicitly be stated in a report.The proposed methodological approach is thus based on the original work published by these groups (as stated above) and used for a given purpose, i.e., to develop evidence-based recommendations for certain health questions by generating a systematic link from evidence to practice recommendations.For each systematic search, its strategy based on search terms used, sources consulted, and dates of the literature covered should be documented. Electronic databases , databases of systematic reviews , handsearching journals, and reviewing conference proceedings can be sources.The information provided should include the following:named electronic database(s) or evidence source(s) where the search was performed ;time periods searched ;search terms used ; andfull search strategy included .Other guidelines  can serve as a valuable reference for comparison, but rarely as a primary source.Criteria for including/excluding evidence, e.g., systematic reviews identified by the search, should be provided. These criteria should be explicitly described, and reasons for including and excluding evidence should be clearly stated. For example, guideline authors may decide to only include evidence from randomized clinical trials and to exclude articles not written in English.A description of the eligibility criteria includes the target population characteristics, study design, comparisons, outcomes, language, and context.In addition, the evidence to decision process needs to be based on the most up-to-date valid evidence. Therefore, a decision is taken to select among systematic reviews and meta-analyses that cover the same comparison for a given outcome the one high-quality review with the broadest coverage, i.e., the most recent review including the largest population of participants for the EtD process. In that case, the other reviews can be excluded from the data extraction process (“secondary exclusion” as compared to “primary exclusion” by exclusion criteria). In case the two dimensions  are not congruent, case-by-case judgment is recommended to select the most informative valid information (review). It needs to be taken into account that this evidence selection procedure has a rather specific focus. A review that does not have the broadest coverage for one outcome  of interest might well do so for another outcome of interest  and would then be used as evidence source for that aspect. Overall, the evidence selection process is outcome-centered.There should be at least two independent assessors for study selection. A consensus process should be used when disagreement arises in study selection.A list of included studies and a list of excluded potentially relevant studies and justification of their exclusion should be given. Non-inclusion of evidence may be necessary for a range of reasons such as inappropriate/irrelevant populations, study design, interventions, comparisons, outcomes, or healthcare settings. “Primary” exclusion should, however, not be based on risk of bias, which is dealt with separately and later in the review process.There should be at least two independent assessors for data extraction. A consensus process should have been used when disagreements arose in data extraction.The methods to assess the quality of included (systematic) reviews and the quality of evidence of clinical trials included in these reviews as well as the methods used for best evidence synthesis should be described. Recommendations for such methods are given below (section Synthesizing Evidence and Developing Recommendations).An explicit link between the recommendations and the evidence on which they are based should be included in the practice recommendation. The detailed methods recommended for this process are given below.In addition, a description of the methods used to formulate the recommendations and how final decisions were arrived at should be provided. For example, methods may include a voting system, informal consensus, and formal consensus techniques . Areas Practice recommendations should be reviewed externally before they are published. Reviewers should not have been involved in the guideline development group. It is preferable that both experts in the clinical area and some methodological experts are involved. Target population (patients and the public) representatives may also be included.The description of the external review process includes:purpose and intent of the external review ;methods taken to undertake the external review ;description of the external reviewers ;outcomes/information gathered from the external review ; anddescription of how the information gathered was used to inform the guideline development process and/or formation of the recommendations .A recommendation should provide a concrete and precise description of which healthcare option is appropriate in which situation and population group based on the body of evidence. In case of uncertainty, this should also be stated.Practice recommendations that target the management of a disease should consider the different possible options for screening, prevention, diagnosis, or treatment of the condition they cover. These possible options should be clearly presented with a description of options and of population or clinical situation most appropriate to each option.Users should be able to find the most relevant recommendations easily.Existing facilitators and barriers that will impact the application of recommendations along with advice and/or tools on how the recommendations can be put into practice should be provided.The potential resource implications of applying the recommendations need to be considered, and suggestions for monitoring and/or auditing criteria  should be provided.The formulation of recommendations should not unduly be biased with competing interests.Therefore,the name of the funding body or source of funding (or explicit statement of no funding) and a statement that the funding body did not influence the content of the report should be given; andcompeting interests of development group members need to be recorded and addressed including- a description of the types of competing interests considered,- methods by which potential competing interests were sought,- a description of the competing interests, and- a description of how potentially competing interests were managed.Practice recommendations need to reflect the current research. A clear statement about the procedure for updating the recommendations should be provided.This part of the methods section has primarily been based on the methodology as described in the GRADE Handbook  and the Recommendations should answer focused healthcare questions. A sensible way to frame a healthcare question is the PICO framework . Any evidence needs to be reflected against the PICO framework set forth for the practice recommendations to be developed  and the respective PICO framework of a systematic review.Two different formats for questions about management can be used:Should [intervention] vs. [comparison] be used for [health problem]?Should [intervention] vs. [comparison] be used in [population]?As well as one format for questions about diagnosis:Should [intervention] vs. [comparison] be used to diagnose [target condition] in [health problem and/or population]?With regard to patient populations, it has to be taken into account whether populations are sufficiently homogeneous that interventions apply to them in a comparable way. Otherwise, sub-populations should be specified.For practice recommendations, it is important to consider all outcomes that are important or critical for decision-making, especially including all patient-important outcomes; outcomes of limited importance do not have to be included (mostly are not). The determination of relevant outcomes should be related to patients' values and preferences regarding the intervention(s) in question.In many instances, a healthcare intervention is designed to improve a health condition. Any recommendation should be based on the fact that there is evidence to suggest that the intervention does change the health condition of interest, to what degree it does so (magnitude of effect), and with which certainty. For such an instance, a precondition for a recommendation would be that there is  evidence that therapy A improves health condition B . Patient-important outcomes can, at times, measure different constructs, e.g., whether disability, health-related quality of life, and participation in social activities are improved by a healthcare intervention for the condition they suffer from. The recommendation should put considerable weight on these findings. Both the causal relationship between an intervention and the improvement of a health condition, and the therapeutic impact on patient-important outcomes are relevant for clinical decision-making.Furthermore, both benefit and harm need to be assessed. A harmful incident (adverse event) is an incident that results in harm to a patient . Harm is constituted by disease, injury, and suffering that may be physical, social, or psychological disability, or death . DiseaseThe degree of harm is as follows:None—patient outcome is not symptomatic or no symptoms detected and no treatment is required.Mild—patient outcome is symptomatic, symptoms are mild, loss of function or harm is minimal or intermediate but short term, and no or minimal intervention  is required.Moderate—patient outcome is symptomatic, requiring intervention , an increased length of stay, or causing permanent or long-term harm or loss of function.Severe—patient outcome is symptomatic, requiring life-saving intervention or major surgical/medical intervention, shortening life expectancy, or causing major permanent or long-term harm or loss of functionDeath—on balance of probabilities, death was caused or brought forward in the short term by the incident.It is suggested that all these aspects are specifically addressed and the overall practice recommendation is based on the combined evaluation of the evidence.Furthermore, third-party relevant outcomes might be important as well.Similarly, all relevant therapeutic alternatives need to be entertained .Systematic reviews are subject to a range of biases and increasingly include non-randomized studies of intervention (NRSI). It is important to critically appraise the quality of systematic reviews when their evidence is supposed to be used in the development of practice recommendations. AMSTAR 2 is a critical appraisal tool for systematic reviews that include randomized or non-randomized studies of healthcare interventions, or both . It is uAMSTAR 2 rates 16 different quality aspects :Item 1: Did the research questions and inclusion criteria for the review include the components of PICO? To score “Yes,” appraisers should be confident that the four elements of PICO are described somewhere in the report.Item 2: Did the report of the review contain an explicit statement that the review methods were established prior to conduct of the review and did the report justify any significant deviations from the protocol?To score “Yes,” authors should demonstrate that they worked with a written protocol with independent verification  before the review was undertaken.Item 3: Did the review authors explain their selection of the study designs for inclusion in the review?The selection of study types for inclusion in systematic reviews should not be arbitrary. To justify restriction of the review to randomized controlled trials (RCTs), the authors should argue that they can provide a complete picture of the effects they are interested in. Restriction of a review to only NRSI is justified when RCTs cannot provide the necessary outcome data, or in the case where reviews of RCTs have been completed and the review of NRSI will complement what is already known. Inclusion of both RCTs and NRSI may be justified to get a complete picture of the effectiveness and harms associated with an intervention.Item 4: Did the review authors use a comprehensive literature search strategy?At least two bibliographic databases should be searched. The report should include years and databases examined . Keywords and/or MESH terms should be reported and the full search strategy should be available on request. Publications in all relevant languages should be sought and a justification should be provided when there are language restrictions. Where the gray literature is considered important, authors should have searched appropriate sources, such as trial registries, conference abstracts, dissertations, and unpublished reports on personal websites . In addition, trials of medical interventions may not have been published in peer-reviewed journals but can be obtained directly from company sponsors or directly from investigators. To score “Yes,” appraisers should be satisfied that all relevant aspects of the search have been addressed by review authors.Item 5: Did the review authors perform study selection in duplicate?Best practice requires two review authors to determine eligibility of studies for inclusion in systematic reviews. A consensus process should have been used when disagreements arose in study selection. If one individual carried out selection of all studies, with a second reviewer checking agreement on a sample of studies, it is recommend that a kappa score indicating “strong” agreement (0.80 or greater) should have been achieved.Item 6: Did the review authors perform data extraction in duplicate?As in Item 5, there should have been at least two independent assessors performing data extraction. A consensus process should have been used when disagreements arose. In the event that one individual carried out data extraction, a second reviewer should have checked agreement on a sample of studies, and they should have achieved a kappa score of 0.80 or greater.Item 7: Did the review authors provide a list of excluded studies and justify the exclusions?This item requires review authors to provide a complete list of potentially relevant studies with justification for the exclusion of each one.Item 8: Did the review authors describe the included studies in adequate detail?The description of subjects, interventions, controls, outcomes, design, analysis, and settings of the studies should be provided. The detail should be sufficient for an appraiser, or user, to make judgments about the extent to which the studies were appropriately chosen (in relation to the PICO structure) and whether the study populations and interventions were relevant to their own practice or policy.Item 9: Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?This is a crucial part of the appraisal of any systematic review, particularly those that include NRSI. The key appraisal question is whether review authors have taken account of the risk of bias when summarizing and interpreting the results.Whatever instrument was used by the review authors, appraisers should be satisfied that it addresses the items listed in item 9 of the instrument.Item 10: Did the review authors report on the sources of funding for the studies included in the review?Several investigations have shown that commercially sponsored studies are more likely to have findings that favor a sponsor's product than independently funded studies. It is valuable for review authors to document the funding sources for each study included in the review or to record that the information was not provided in the study reports.Item 11: If meta-analysis was justified, did the review authors use appropriate methods for statistical combination of results? Review authors should have stated explicitly in the review protocol the principles on which they based their decision to perform meta-analysis of data from the included studies. These include the desire to obtain a single pooled effect  and the extent to which the studies are compatible (in terms of populations controls and interventions) and therefore capable of being combined.Where meta-analysis was considered appropriate, authors should have explained their decisions to use fixed or random effects models in the case of RCTs, and set out the methods they intended to use to investigate heterogeneity.If results from large NRSIs are combined with those from smaller RCTs, the pooled estimates of effect will be dominated by the data from the nonrandomized studies. In addition, the results from NRSI may be affected by a range of biases (see above), meaning that the overall pooled estimates may be precise but biased. It is rare for a NRSI to have as low risk of bias as a high-quality RCT of the same research question and confidence intervals for NRSI (and pooled estimates based on NRSI) should be viewed with caution. Review authors should therefore report pooled estimates separately for the different study types.Furthermore, when combining the results of NRSI, review authors should pool the fully adjusted estimates of effect, not the raw data. If they do the latter, there should be a clear justification.Item 12: If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?In cases where review authors have chosen to include only high-quality RCTs there may be little discussion of the potential impact of bias on the results, but where they have included RCTs of variable quality, they should assess the impact of this by regression analysis, or by estimating pooled effect sizes with only studies at low ROB. In the case of NRSI, they should estimate pooled effect sizes while including only studies at low or moderate risk of bias, and/or only those at low ROB (if there are any). If meta-analyses  were not performed, the authors should still provide some commentary on the likely impact of ROB on individual study results.Item 13: Did the review authors account for RoB in individual studies when interpreting/discussing the results of the review?Even if meta-analyses were not conducted, review authors should include discussion of the impact of ROB in the interpretation of the results of the review. This is always important, but especially when reviews include RCTs with variable ROB, and with any review that includes NRSI. This discussion should not be limited to the impact of ROB on the pooled estimates (see above), but should also consider whether it may account for differences between the results of individual studies.Item 14: Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?There are many more potential causes of heterogeneity in the results of NRSI than in RCTs. Many factors were considered in this instrument, including different study designs, different methods of analysis, different populations, and differing intensities of the intervention(s)—dosages in the case of drugs. Both the PICO elements and the domains of bias listed in Item 9 should also be considered as important potential sources of heterogeneity in the results. Review authors should explore these possibilities and discuss the impact of heterogeneity on the results conclusions and any recommendations.Item 15: If they performed quantitative synthesis, did the review authors carry out an adequate investigation of publication bias (PB)  and discuss its likely impact on the results of the review?This is a very important issue, but can be difficult for review authors and appraisers to resolve completely. Typically, statistical tests or graphical displays are used, and if they are positive, then it indicates the presence of PB. However, negative tests are not a guarantee of the absence of PB as the tests are insensitive. To some extent, the importance of PB depends on context and setting.Item 16: Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?As noted above (under ROB), individual studies funded by vested interests may generate results that are more likely to favor the intervention than do independent studies. The same assumption applies to systematic reviews, and authors should report their direct funding sources. Journals generally will require this. However, assessment of the reviewers' conflicts of interest does not stop there. They should report their other ties. The review may be independently funded, but the authors have ties to companies that manufacture products included in the systematic review. Professional conflicts of interest are powerful, but harder to discern as they are seldom reported. When investigators have a career-long investment in a field of research, a review that conflicts with their long-held beliefs can be confronting. Potential conflicts of interest of this type will be hard to assess but may be inferred from the fact that the reviewers have published extensively in the field being reviewed and their studies are included in the systematic review. While it can be argued that the effects of competing interests might manifest as flaws in the other domains, this item should nevertheless always be rated separately.I2 statistics are used, a rough guide for the interpretation and verbal description of the level of heterogeneity can be  magnitude and direction of effects, and (2) strength of evidence for heterogeneity .The quality of evidence reflects the extent to which our confidence in an estimate of the effect is adequate to support a particular recommendation. The quality of evidence is rated for each outcome across studies . This does not mean rating each study as a single unit. Rather, GRADE is “outcome centric”; rating is done for each outcome, and quality may differ—indeed, is likely to differ—from one outcome to another within a single study and across a body of evidence.In case a review included in the “evidence to decision” process presents a GRADE quality of evidence rating this will be considered, yet critically appraised, and in case the information available indicates a more valid rating in the specific context modified accordingly. Such deviations should be noted.High—We are very confident that the true effect lies close to that of the estimate of the effect.Moderate—We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low—Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.Very low—We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.Quality of evidence is a continuum; any discrete categorization involves some degree of arbitrariness. Nevertheless, advantages of simplicity, transparency, and vividness outweigh these limitations.In the GRADE approach to quality of evidence:randomized trials without important limitations provide high-quality evidence, andobservational studies without special strengths or important limitations provide low-quality evidence.Limitations or special strengths can, however, modify the quality of the evidence of both randomized trials and observational studies.Limitations in study design or execution (risk of bias) in RCTs may include inadequate randomization, lack of allocation concealment, lack of blinding leading to performance and/or detection bias, attrition bias, selective reporting bias, and other types of bias.For a more refined explanation of risk of bias and other factors modifying the quality of the evidence, see the GRADE Handbook  and the All abovementioned factors need judgment; they can be combined, yet they are not strictly additive. Up- or downgrading rests on the assessment that limitations are serious and there is a substantial risk of bias for the results. Reasons for (and at times for not) down- or upgrading should be provided .Recommendations are based on evidence for interventions and certain outcomes across studies and potentially across systematic reviews. Thus, there is a need to critically appraise the quality of evidence across clinical trials and at times across systematic reviews. In deciding the overall quality of evidence (across studies and reviews), the contribution of individual studies, e.g., based on sample size and number of outcome events needs to be taken into consideration.Two independent assessors should extract the information and perform all related judgments. A consensus process should be used when disagreements arise in information extraction and judgments are declared in advance.A GRADE evidence profile is particularly useful for the presentation of evidence supporting a clinical practice recommendation.It is augmented by a commentary of the validity assessment of the systematic review used for the outcome-related evidence (based on AMSTAR 2).The evidence profile is the first part of the EtD table that in addition to the evidence part includes further aspects that are taken into consideration before an overall recommendation for a type of therapy is given. The latter reasoning will be presented below (paragraph “GRADE recommendations”).The standard format for the evidence profile includes:A list of primary and secondary outcomes, and for each outcome and analysis:the reference ;the study design (including PICO information);number of studies and participants;relevant limitations of the review as indicated by the critical appraisal tool for systematic reviews (AMSTAR 2);rating (GRADE) of the quality of evidence for each outcome (which may vary by outcome) and reasons why the rating was up- or downgraded, i.e., risk of bias , imprecision, heterogeneity, indirectness, imprecision, publication bias, magnitude of effect, dose–response relationship, and other considerations;the assumed risk; a measure of the typical burden of the outcomes, i.e., illustrative risk or also called baseline risk, baseline score, or control group risk;the corresponding risk; a measure of the burden of the outcomes after the intervention is applied, i.e., the risk of an outcome in treated/exposed people based on the relative magnitude of an effect and assumed (baseline) risk;the relative effect; for dichotomous outcomes, the table will usually provide risk ratio, odds ratio, or hazard ratio;the absolute effect; for dichotomous outcomes, the number of fewer or more events in treated/exposed group as compared to the control group; for ratio scaled outcomes, standardized mean differences or mean differences;a verbal description of the therapeutic effect and uncertainties regarding its estimate;indication whether the evidence for an outcome favors or discourages the decision for a therapy; andfootnotes, if needed, to provide explanations about information in the table such as elaboration on judgments about the quality of evidence.Symbols used to indicate whether the evidence for a given outcome favors or discourages the decision for a therapy are:++ clearly favors therapy+ favors therapy somewhat0 does not favor or discourage use of therapy- discourages use of therapy– clearly discourages use of therapyA recommendation reflects the extent to which the group developing the recommendation is confident that desirable effects of an intervention outweigh undesirable effects in case of a positive recommendation, or that undesirable effects of an intervention outweigh desirable effects in case of a negative recommendation.The recommendation implies that it is valid across the range of patients for whom the recommendation is intended.Even though the balance between desirable and undesirable effects of an intervention reflects a continuum, GRADE specifies two categories of strength of recommendation, i.e., a weak or a strong recommendation in favor or against an intervention.For a strong recommendation, it is necessary to be certain about the various factors that influence the strength of recommendation and to have the information at hand that support a clear balance toward either the desirable or the undesirable effects of an intervention. When the information is such that the desirable effects of an intervention probably outweigh the undesirable effects (or vice versa), but appreciable uncertainty exists, a weak recommendation for (or against) an intervention is warranted.Various domains contribute to the strength of a recommendation:Balance between desirable and undesirable outcomes: The larger the difference between the desirable and undesirable outcomes and the more important an outcome is based on estimated typical values and preferences, the more likely a strong recommendation is warranted. For the judgment of magnitude of effect, both measures of effect size (comparable across outcome measures) and judgments of the absolute effects, e.g., compared to the minimally important difference (MID) for an outcome measure, are suggested.Quality of evidence: The higher the quality of evidence and hence the confidence in the magnitude of effect, the more likely a strong recommendation is warranted.Values and preferences of those affected: The greater the confidence that the observed effects (invariably) apply to the values and preferences of patients, the more likely a strong recommendation is warranted.Resource use: The less resources are used for the implementation of an intervention, the more likely a strong recommendation is warranted.With regard to resource use, a decision whether or not to consider resource use, and if so, its integration in the recommendation, the perspective taken , any differences in resource use between intervention and control, and the evidence for incremental cost should be taken into consideration and made transparent.While this guidance frequently applies, there are instances where recommendations are and need to be taken on different grounds. GRADE has identified several situations when a strong recommendation is warranted in spite of low or very low quality of evidence:When low-quality evidence suggests benefit in a life-threatening situation (evidence regarding harms can be low or high).When low-quality evidence suggests benefit and high-quality evidence suggests harm or a very high cost.When low-quality evidence suggests equivalence of two alternatives, but high-quality evidence of less harm for one of the competing alternatives.When high-quality evidence suggests equivalence of two alternatives and low-quality evidence suggests harm in one alternative.When high-quality evidence suggests modest benefits and low/very-low-quality evidence suggests possibility of catastrophic harm.It is an option to recommend using interventions only in research, ifthe evidence thus far is insufficient to support a decision for or against an intervention,further research has a high potential to reduce this uncertainty, andand if it is thought to be of good value for the anticipated costs.The final recommendation made by the development group is a consensus based on the judgments of the group members, informed by the evidence presented and the group members' expertise and experience.Recommendations ideally are accompanied byplain language phrasing of the recommendation,the justification for the recommendation (report on the decisions taken about the strength of recommendation),specific implementation aspects related to subgroups,implementation issues related to acceptability and feasibility,suggestions for monitoring and evaluation of its implementation, andany uncertainties that warrant further research.Along these lines, generic EtD tables can be used and facilitate decision-making, record judgments, and document the process of going from evidence to the decision.They typically describewhether there is a priority problem,the benefits and harms of the options,the certainty how much people value the main outcome,the size of desirable and undesirable effects and their balance,associated resource use,the incremental resource use relative to the net benefit,the impact on health inequities,the acceptability of options,the feasibility,the recommendation,its justification,subgroup considerations,implementation considerations,monitoring and evaluation considerations, andimplications for research priorities.Symbols used to indicate the strength of recommendation:↑↑: strong recommendation for an intervention↑: weak recommendation for an intervention↓: weak recommendation against an intervention↓↓: strong recommendation against an interventionThe strength of recommendations has different implications for patients, healthcare professionals, and other stakeholders as illustrated next.It is important to note, however, that recommendations never serve as dictates. Even strong recommendations based on high-quality evidence will not apply to all circumstances and all patients.Results of the EtD process for practice recommendation projects are:A protocol before the work commences, andA report on evidence-based practice recommendations once the work is done.Prior to the development of evidence-based practice recommendations, a protocol should be developed, agreed on by the working group (and significant others as indicated), and made publicly available before the work commences. The suggested framework is given below.Scope and purposea. Objectiveb. Health questionc. Population, condition(s), intervention(s), outcome(s), and healthcare setting(s) of interestStakeholder Involvementa. Practice recommendation developer groupb. Integration of views and preferences of the target populationc. Practice recommendation target user descriptionMethods for evidence synthesis and recommendation developmenta. Systematic searchb. Criteria and methods for evidence selectionc. Data extraction and managementd. Methods used to assess the strengths and limitations of the body of evidencei. quality of included reviewsii. quality of evidence in included reviewse. Methods applied for best evidence synthesisf. Methods used for formulating the recommendationsg. External review of the recommendationsh. Procedure for updating the practice recommendationsEditorial independencea. Fundingb. Competing interests of the practice recommendation developer groupThe practice recommendation report gives all the information necessary to make the development process, the evidence, its critical appraisal, the main results, further considerations taken into account, the recommendations, and their implications transparent. The suggested framework is given below.Abstract Plain language summary Scope and purposea. Objectiveb. Health questionc. Population, condition(s), intervention(s), outcome(s), and healthcare setting(s) of interestStakeholder Involvementa. Practice recommendation developer groupb. Integration of views and preferences of the target populationc. Practice recommendation target user descriptionMethods for evidence synthesis and recommendation developmenta. Systematic searchb. Criteria and methods for evidence selectionc. Data extraction and managementd. Methods used to assess the strengths and limitations of the body of evidencequality of included reviewsquality of evidence in included reviewse. Methods applied for best evidence synthesisf. Methods used for formulating the recommendationsg. External review of the recommendationsh. Procedure for updating the practice recommendationsa. Results of the searchb. Description of included reviewsc. Methodological quality of included reviewsd. Quality of evidence in included reviewse. Best evidence synthesis—stratified by condition(s), intervention(s), outcome(s), and healthcare setting(s) of interestEvidence synthesisa. for clinical practice, stratified by condition(s), intervention(s), outcome(s), and healthcare setting(s) of interestb. for researchRecommendationsResults of external reviewReferencesa. References to included reviewsb. References to excluded reviews (primary and secondary)c. Additional referencesEditorial independencea. Fundingb. Competing interests of the practice recommendation developer groupAppendixa. Search algorithm(s)b. Further tablesCharacteristics of included reviewsCharacteristics of excluded reviews.As the number of people living with disabilities are on the rise globally , there iEvidence-based clinical practice is defined as the conscientious, explicit, and judicious use of the best evidence in making decisions about the care of individual patients , combineAs not only the available evidence of clinical trials for rehabilitation interventions is rapidly increasing, but also the number of systematic reviews and meta-analyses, the potential to support healthcare decisions by evidence is greatly increased nowadays.Yet, individual healthcare workers are facing a situation where they can no longer manage to use the best external evidence if they were not systematically supported by the development and provision of evidence-based clinical practice recommendations. Necessary steps for such developments are a systematic search for and critical appraisal of the available evidence, followed by a systematic process to deduce practice recommendations using that body of evidence .A methodology for such evidence-based clinical practice recommendations development had been provided  and was The methods described in this paper add to this methodology for situations where systematic reviews and meta-analyses are sufficiently available to be considered a valid up-to-date representation of the best external evidence for a healthcare question.Given the increasing number of available systematic reviews for many healthcare questions, this is and will more and more frequently be the case. In addition, different systematic reviews might contribute to our knowledge for different outcomes of interest  that are all relevant for the generation of well-balanced practice recommendations.For such situations, an explicit multi-step approach is suggested that includes the formulation of the healthcare question addressed, the systematic search for the evidence, its critical appraisal, the extraction and the outcome-centered presentation of the evidence, the rating of its quality, strengths and weaknesses, any further considerations relevant for decision-making, and an explicit recommendation statement along with its justification, implementation, and resource aspects, i.e., a comprehensive EtD methodology.The methodology suggested is a combination of valid and internationally accepted methods  as develIf practice recommendations for major topics in clinical rehabilitation could be developed in such a systematic methodologically valid way and without restricting their applicability to specific  healthcare situations, a relevant impact could be achieved for many societies.The healthcare implications of the best available external evidence could be made transparent in a systematic, valid, and well-balanced way and become accessible for many. Healthcare workers around the globe could greatly benefit for their evidence-based clinical practice by such guidance and hence those in need for effective rehabilitation interventions. Disease-related disability could more effectively be reduced and participation could be promoted.In addition, those in charge to set up, manage, and develop healthcare structures for rehabilitation could be guided as to which interventions should be made available in their services to support certain clinically relevant outcomes.Hence, the resources invested to develop such guidelines could promote societal benefits both at an individual and at a structural level.While the practice recommendations themselves would have an “international” validity, their appropriate contextualization to healthcare system realities could be done regionally. In that way, the suggested methodology is also efficient; practice recommendations would not have to be developed for each region separately.TP designed and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Scholars agree that Torbjörn Caspersson’s lab at the Institute of Medical Cell Research and Genetics at the Karolinska Institute, Sweden, played a key role in the first description of the so-called Q-banding technique. It laid the foundation for a new era of cytogenetic diagnostics and had a lasting impact in several areas of biology and medicine.Based on a mixed-method approach, essential aspects of the history of human cytogenetics are considered via primary and secondary analysis of biographical interviews as well as the qualitative evaluation of bibliometrics. Drawing on interviews with colleagues of lab member Lore Zech (1923–2013) and contemporary publications, this paper illuminates the role of and contribution by Zech: To what extent is the discovery attached to her and what does her legacy look like today?The analysis of the contemporary witness interviews with colleagues, students and junior researchers shows that Lore Zech was a committed member of Caspersson's research group. In addition, memoirs by contemporary colleagues describe her outstanding skills in microscopy. The different sources paint a multifaceted picture. In addition to the historians' patterns of interpretation, different legacies can also be found within the peer group.We argue that Zech represent the type of scientist who, although her research was acknowledged with several prizes, so far has not been part of the canon of pioneers of international cytogenetics. Everyone knows iconographic representations of the chromosome set, but very few in the international research community can trace the origins around the discovery of specific banding patterns on human chromosomes. In the case of the geneticist Lore Zech 1923–2013), the question arises as to whether discrepancies exist in the perception and transmission of scientific quality and professional reputation.923–2013,Cell growth and cell function: a cytochemical study (1950). Zech was engaged in several areas of research in the Caspersson lab in the 1950’s and in the 1960’s,6Born in 1923 in Gütersloh, Lore (birthname Vogt-Köhne) grew up at the German countryside with her grandparents, after both her parents had passed away due to tuberculosis. Zech first studied medicine in Marburg but changed field and completed a degree biology, chemistry and physics in Bonn. After receiving her doctor diploma at the Max Planck Institute in Tübingen, Zech followed her husband Hendrik Zech to the Karolinska Institute in Solna, Sweden. There, she started her postdoc studies at the Institute of Cell Research and Genetics, headed by geneticist and cytologist Torbjörn Caspersson, in 1953.Standardization in Human Cytogenetics” in Paris.13In 1969, Zech developed the first technique for the differential representation of human chromosomes, based on chromosome bands in plant genetics.Zech’s breakthrough was recognized with several prizes and honorary memberships, including the German Federal Cross of Merit 1st class. She was the first scientist to receive the Mauro Baschirotto Award by the European Society of Human Genetics; in addition, she was also one of the first scientists to receive the Medal of Honour of the German Society for Human Genetics (GfH). It exists a Lore Zech-Prize, awarded by the German Society for Human Genetics. Still, Zech is not a household name to many researchers in the international scientific community. In addition, she received the honorary doctorate of the Medical Faculty of the Christian-Albrechts-University, Kiel, the Björkén prize of the Medical Faculty of the Uppsala University and the Gunnar Dahlberg-Medal of the Northern Society of Pathology.During the last decade, historians have dealt with her professional activity and influence. Focusing on research done by women, the Spanish historian María Jesús Santesmases recently stated that the Q-banding technique was established by Lore Zech.16Against this historiographical background, this article brings together several perspectives to further trace the legacy of Lore Zech. How was she portrayed in interviews, in contemporary publications, and what does her status in the scientific community look like today?Starting from the previously formulated perspectives of the historiographers and historians of science, this article draws on primary and secondary literature in English, Swedish and German, but also on oral history. The latter method collects biographical accounts and examines them for narrative strands and themes, which are then compared with other source material.19In addition to written memory, the oral history approach offers complementary access to different perspectives. The empirical basis is formed on the one hand by expert interviews conducted by Felicitas Söhner between 2016 and 2018 with human and medical geneticists active between 1970 and 2000.Further, recorded expert interviews from an interview series with founders of human and medical genetics conducted by Peter Harper between 2003 and 2014 were included. In Harper's series of 100 recorded interviews with experts, some conversations delve into the beginnings of cytogenetics in the late 1950s and research into its medical genetic application in the 1960s and 1970s .These interviews were analysed using qualitative, historical-hermeneutic and social science methods. The approaches of qualitative content analysis according to MayringThe performances of researchers are attributed by the scientific community in various ways. In the academic world, social networks play a significant role; good networking guidesWritten sources show that Zech was in close contact with German-speaking researchers, including Thomas Cremer, Christa Fonatsch, Simone Heidemann, Anna Jauch, Peter Lichter, Brigitte Schlegelberger and Evelin Schröck.“and of course the professors (Lore) Zech and Janet Rowley and Margareta Mikkelsen from Denmark… those are the most important ones…”.31The retrospective perception paints a picture of a mentor to numerous young researchers who sought contact through regular letters, invitations and open discussion at conferences. In the recollection of her colleague and mentee Schlegelberger, Zech enjoyed the trust of many and was always surrounded by scholars at conferences. This had contributed to her being valued as an inspiring mentor.The professional networking went beyond collegial exchange and professional support. It can be seen that Lore Zech's visibility is also evident in the perception of her participation at international conferences and congresses, important arenas for building and participating in networks.In a biographical review, Schlegelberger pointed out that, in 1971, Zech's achievement was recognised by an invitation to the International Congress of Human Genetics in Paris to present the structure of human chromosomes that she had elucidated with the help of the Q-banding technique. The first version of the international cytogenetic nomenclature ISCN was also established at this conference.32But I had talked about the Y chromosome at the conference in Reykjavik … I had to show Caspersson my manuscript and … he wrote on the big space on the side ‘This is ridiculous. You shouldn’t talk about it. People will laugh at you’. But anyhow, Albert de La Chapelle was there and he became very interested and the next opportunity he came to Stockholm. But when he came to see my chromosomes, Caspersson thought there might be something with them.”34These perspectives are reflected in the oral memories of Lore Zech. The impact of her participation in this congress is also recalled by Zech in the interview with mixed feelingsThe memories of witnesses paint a picture of good institutional integration of Lore Zech in Caspersson’s lab and intensive networking with external colleagues and scholars from other disciplines. The biographical documents refer to diverse professional collaborations with Lore Zech, which presumably strengthened the perception of her research.Philadelphia translocation”.35Schlegelberger underlined the collegial exchange with Janet Rowley, which led to the description of the origin of the so-called “Now even that became a problem after some time, because Caspersson was so fascinated by machines and measurements and he made very good machines. He was very good at that. … He was interested in measuring in itself, which is legitimate I must say, but that was not my interest. So Lore and I had so many problems we wanted to do, but Caspersson more or less prevented us from pursuing all these ideas we had.”… but as Lore and I wanted to continue we had so many ideas of what to do, but he stopped it more or less. Of course I could continue with the banding techniques myself, but he stopped the collaboration between me and Lore because it became tangled. It grew too fast and too much and he hadn’t any control over it.”38The interviewees also mentioned Zech's involvement in the research contexts at the Karolinska Institute. Karolinska geneticist Jan Lindsten, for example, described the joint scientific work and professional interests,We saw the Y chromosome and then we had real luck, because one of our students at the Institute, who is now a professor in Lund [Sweden], he travelled to Germany and told everywhere, in our Institute they have very interesting methods to get bands on chromosomes and they can see the human Y chromosome, and so on and so on. But nobody used this.”39In addition to good interdisciplinary networking, international, intradisciplinary networking was also essential for the visibility of the research results. Thus, in Zech's recollection, in addition to the presentation of current results at conferences, the personal report of directly involved people to colleagues in other institutes also contributed to the popularity of their results: “Caspersson and Zech have repeatedly been described as key figures in the discovery of banding in human chromosomes, a view shared by Caspersson himself and Zech's long-time Karolinska Institute colleague Gösta Gahrton. But how is Zech's scientific achievement classified in the respective historical retrospectives?my long-time collaboratress Dr. Lore Zech.”Who first discovered the bands is unclear, maybe Evy Simonsson, maybe Lore Zech, but probably it was Lore who saw that two plant chromosomes had band patterns that seemed identical while other chromosomes had other band patterns.”Zech's pioneering discovery as employee of Caspersson's laboratory”.42The director of the institute Caspersson himself introduced her in 1989 “At that time Torbjorn Caspersson had just begun to start getting somewhere with fluorescence microscopy and using quinacrine, and Lore Zech worked with him. Lore, she did all the work actually, but for Tjorbjörn [Caspersson] everything had to be done with a spectrometer.”very outstanding”.44Furthermore, in the interview her colleague Henry John Evans (Edinburgh) described an unequal distribution of work that he perceived. In his memory, Zech did not work under him, but together with him – and she had the main workload: “Zech and Caspersson”banding technique of Lore Zech”.46In the interview, Jan Murken assessed the discovery of “Looking back on Caspersson's role, she referred several times to the fact that Caspersson did not believe in the existence of the banding at first, but understood the weight of the discovery.48under” Caspersson, who nevertheless worked “independently” on this development and thus achieved a scientific breakthrough.mother of modern cytogenetics “.50In the obituary by Schlegelberger it is described that Zech was a collaborator “In conclusion, the perceptions and interpretations of geneticists appear heterogeneous. Here we find both statements that downplay Zech's achievements and passages that praise her.According to Siebert, researchers who are rarely cited have only a very small chance of coming to the attention of other scientists.The quantitative comparison in “Experimental Cell Research” that has published articles from the field of cell biology since 1950 shows that she published in that forum on a regular basis , but also several years later.A look at Zech's bibliography shows that she only appeared as first author every sixth time and more frequently as co-author. At the same time, she published repeatedly in journals of higher impact with different subject foci and together with renowned co-authors. It is noticeable that all of Lore Zech's papers from Casperson's laboratory were written by Caspersson as first author.It also gives the impression that the question of arrangement was consistently justified by alphabetical order.Several sources and reports of contemporary witnesses substantiate the conclusion that that all papers from Caspersons labs are first authored by him because he published usually with alphabetical list of all authors and never had an employee starting with last name A, B or C. The question of the effect of alphabetical order on the careers of scholars was discussed in the late 1970s.52It is important to look into how excellence has been attributed to individual scientists to deepen our understanding of reward mechanisms in medicine. By reconstructing views on Zech’s scientific achievements and reputation, this article aims at stimulating a discussion about the recognition of female scholars in genetics and beyond.Scholars agree that the team of Caspersson in general and Zech in particular played key roles in the discovery of the Q-banding technique, which became an important diagnostic tool and also provided a means to unravel pathogenetic mechanisms by pinpointing the location of cancer-initiating genes. It laid the foundation for a new era of cytogenetic diagnostics and had a lasting impact in several areas of biology and medicine. Even though Q-banding was superseded within a few years by G-banding, which was developed in 1971, the priority for human chromosome banding lies with Lore Zech.It should be noted that Zech developed the Q-banding method as an employee of Caspersson's laboratory. At that time, it was common for the head of an institute to claim the research results for himself; even today, in some disciplines, group or institute leaders are listed as first or last authors by default. These observations are also set against the backdrop of a time when it was considered common that researchers in the second row of a research team did not get the attention they deserved. Lore Zech was one of them.Against this background, we considered the question of how to assess Zech's visibility in the national and international research community and how to evaluate the memory of her role in the biographical documents and scientific publications. The analysis of the contemporary witness interviews with colleagues, students and junior researchers shows that Lore Zech was a committed member of Caspersson's research group. In addition, memoirs by contemporary colleagues describe her outstanding skills in microscopy.That said, in these accounts there exist differences in the culture of remembrance.mother of modern cytogenetics “.The different sources paint a multifaceted picture. In addition to the historians' patterns of interpretation, different legacies can also be found within the peer group. They range from relativising her findings to describing her as „On a more general level, we argue that such a mixed-method presented here via primary and secondary analysis of biographical interviews such as the qualitative evaluation of bibliometrics offers a rewarding concept for historical analysis not only of the history of human cytogenetics, but also for other areas in the history of medicine and science.


Evidence-based practice (EBP) is an ambition for health service administrators. We aimed to systematically review the major relevant articles in case of barriers and facilitators to implementing evidence-based practice in health services.  The type of study was a systematic review. We searched the libraries and online sources such as PubMed, MEDLINE, Wiley, EMBASE, ISI Web of Knowledge, Scopus, Science Direct, Cochrane Library, and Google scholar. We used keywords included "Evidence-Based Practice", "Evidence-Based Management", "Healthcare", "Care Management, Evidence-Based Healthcare Management", "Health Care", Health", "Barrier", "Facilitator", policy and "Evidence-Based Healthcare". In total, 12 studies were included. Several barriers and facilitators were recognized through the included papers, the factors such as organization support and a helpful education system improved skills, knowledge, and confidence to EBP. The outcomes of studies were identified as the employ of the internet as a highest-rated skill for increasing EBP quality.  Generally, the results showed health service administrators should first identify barriers of EBP then transferred them to facilitators to the implementation of proper and efficient EBP. Evidence-based practice (EBP) is an ambition for health service administrators. EBP has been the combination of best study evidence with clinical expertise and patient uses in the decision-making method for patient administration -4. EBP iMany eastern Mediterranean countries are lagging behind in biomedical study publications and interpretation of study evidence into health policy and programs, the applications have been restricted in developing such capability -8. One o We searched the libraries and online sources such as PubMed, MEDLINE, Wiley, EMBASE, ISI Web of Knowledge, Scopus, Science Direct, Cochrane Library, and Google scholar. We used keywords included “Evidence-Based Practice”, “Evidence-Based Management”, “Healthcare”, “Care Management”, “Evidence-Based Healthcare Management”, “Health Care”, “Health”, “Barrier”, “Facilitator”, “Policy and Evidence-Based Healthcare.” Two reviewers AA and AAN were independently evaluated the titles and abstracts of all studies. The conflicts were solved by the third reviewer (LN). The two reviewers AA and AAN who conducted the literature search also individually made decisions and selected studies. The differences were solved by either discussing a third reviewer (LN) or argument. For methodological quality before inclusion papers in the review, the CASP checklist for qualitative research was used. The CASP checklist was used from 10 questions with 3 potential responses: “yes”, “no” and “can’t tell” to evaluate qualitative research. If greater than eight of the questions on the questionnaire were fitted, the research was assessed as good quality; if five to seven were fitted, it was assessed as fair quality; and if less than five were fitted, it was marked as poor quality.  Our search initially retrieved 168 studies published up to January 2019. However, 150 articles were removed for the reason duplication between databases. Then, 18 papers were involved for initial selection. Upon screening abstracts and titles, 12 papers were recognized for full-text review . Table-1In the nurses, barriers constituted a shortage of accessible data in Chinese, nurses’ absence of knowledge of what EBP indicates, and worry that patients will be offended of obtaining overhaul that is regarded as modern. Facilitators involved administration support and the fast grown of social network services . The moset al.reported that negative attitudes and lack of training were as the most important barriers [et al showed that time shortage was the main barrier to EBP [et al. and Mitton et al. evaluated the obstructions to EBDM in health management and policymaking. They divided the obstructions of EBDM as follows: organizational level , personal level , time-related factors (limited time for decision making and diverse time-frame), communication factors , low-quality research, and disputes over power and financial resources. Another study recognized like factors as obstructions, plus the organizational system of government and its rigidity toward alteration, and the lake of a ‘functioning policy network’ including the policy-maker, researcher, and official [In general, different groups of health care providers have less knowledge about proprietary evidence-based terminology, and reference books are the most important source of information for EBP. The key concepts in EBP include scientific and professional care, patient-centeredness, and attention to the quality of service. The factors such as organization support and a helpful education system improved skills, knowledge, and confidence to EBP -17. The barriers  also, Bar to EBP . The levr to EBP ,13,22-24official -28.et al. [et al. [Certainly, the most frequently presented associated with the absence of particular techniques or skills, knowledge, and education or training. This is confirmed by several studies, interestingly, these barriers were parallel to the facilitators. The health professionals showed that certified education is as the facilitator for barriers including the absence of particular techniques or skills, knowledge, and education or training. Most of research reported that knowledge achieves during education and autonomous learning. This is coordinated with previous studies that representative formal education is deficient in health professional training programs -29. For et al.  in Denma [et al.  in Germa [et al. , the use [et al. -45, whil [et al. -48; incr [et al. -51. The  [et al. -56; ther Generally, the results showed health service administrators should first identify barriers of EBP then transferred them to facilitators to the implementation of proper and efficient EBP. The authors would like to express their appreciation to the reviewers to evaluated articles. The authors declare that they have no conflicts of interest.


Different studies have shown that the presence of electrolytes modifies the nanofiltration performances and that the variation of the neutral solute transfer is mainly governed by the modification of the solute properties. The objective of this work is to strengthen the understanding of the impact of the ion composition and to progress in the long-term objective for the prediction of the nanofiltration performances. The methodology is based on the comparison of the hydration properties obtained by experimental and theoretical approaches with the mass transfer of saccharides. The key role of the saccharide hydration number to understand the impact of the ionic composition on the saccharide transfer is clearly demonstrated. Moreover, it is established that the number of saccharide/cation interactions, which increases with the cation coordination number, is a key parameter to understand the mechanisms governing the impact of the nature of the cation on the saccharide mass transfer modification. Finally, correlations are obtained between the saccharide hydration number decrease and the variation of the saccharide radius calculated using a hydrodynamic model for different ionic compositions and operating modes (diffusion and filtration). From these results, it could be possible to evaluate the saccharide transfer for a given saccharide/electrolyte system transfer. Membrane separation techniques, such as nanofiltration (NF), constitute an interesting alternative for developing high-performance processes capable of treating fluids containing variable proportions of organic and mineral solutes ,2. HowevIn recent years, various studies have shown that the presence of electrolytes significantly modifies the performances of NF due to the variation of the neutral solutes transfer ,11,12,13The relation between the solute hydration properties and the dehydration phenomenon has also been proposed to explain the impact of the nature of the ions  on their transfer through membranes . For insConcerning the impact of the presence of ions on the neutral solute transfer, the solute dehydration has been confirmed within the works of Bouranene and et al. ,19 and BThen, in order to further understand the impact of the ionic composition on the transfer of a neutral solute, recent investigations using complementary approaches at different scales were carried out to investigate the mechanisms governing the saccharide/electrolyte interactions.2SO4, K2SO4, CaCl2, MgCl2 and MgSO4) confirmed that most of the contributions to saccharide dehydration in the presence of electrolytes is due to the ion valence . Additionally, it was also observed that the saccharide dehydration increases according to the following sequences: Na+ < K+ < Mg2+ < Ca2+ and Cl−< SO42−, and that the anions (Cl− or SO42−) have no influence on the cation sequence [First, at the macroscopic scale, a thermodynamic method, based on the determination of the apparent molar volume of saccharides in the presence of electrolytes, was used to characterize the saccharide hydration. The determination of the volumetric properties of saccharides  in different electrolytes  does not lead to a change in the first cation hydration layer  [+ < K+ and Mg2+ < Ca2+. Simulation results showed that the number of saccharide/cation interactions increases with the cation coordination number in water , and that this increase is directly linked to an increase in the saccharide dehydration. More recently, the interactions in saccharide/electrolyte systems were also determined at the microscopic scale using a theoretical method . First, the computation of the ion hydration properties in water confirmed that the presence of an anion (Clnd Ca2+) . Considend Ca2+) . In agreFinally, ion and saccharide properties, obtained from thermodynamic data as well as simulation works, were compared in order to rationalize the relation between the saccharide hydration number and the hydration properties of ions . It was As previously mentioned, mass transfer models, such as the hydrodynamic model, can be considered to investigate the impact of the dehydration phenomenon on the mass transport of neutral solutes in confined space through the determination of the solute radius . HoweverThen, based on these recent results, the aim of this paper is to advance the knowledge of the mechanisms and the estimation of the mass transfer of neutral solutes through nanofiltration membranes as a function of the ionic composition. More precisely, the objective of this work is to strengthen the understanding of the impact of the ion nature, especially for a given valence, since it has not been completely explained to date. The envisaged methodology is based on the comparison of the hydration properties obtained by experimental and theoretical approaches (volumetric properties from a thermodynamic method and quantum mechanics data) with the mass transfer of saccharides through an NF membrane. Thus, correlations between the solute hydration properties obtained at different scales ,24,25,26In order to understand and highlight the impact of the nature of the ion on the modification of saccharide transfer in nanofiltration, additional transfer measurements were performed in this work. The experiments were performed in the diffusion operating mode (concentration gradient driving force) to avoid the impact of ion retention on saccharide mass transfer . −1) in electrolytes containing Cl−  with a purity > 99%, for given glucose and cation concentrations (1 mol·kg−1). The schematic device of the experimental setup is shown in The mass transfer study was carried out for glucose  and a Jasco RI 2031 refractometer. The mobile phase was a 0.02 mol·LThe experiments were carried out at least twice. For all experiments, the evolution of the number of moles of glucose as a function of time was linear, confirming that the glucose concentration gradient was constant throughout the experiment. The same membrane sample was used for all the experiments.S,WJ. The impact of electrolytes on the saccharide properties was estimated from the additional saccharide flux, ∆J, expressed as the difference between the saccharide flux measured in saccharide/electrolyte systems, S,ElJ, and the one determined in saccharide/water systems:The specific protocol developed by Boy et al.  was usedϕ is the partitioning coefficient; dK is the hindrance factor for diffusion; D∞ (m2·s−1) is the diffusion coefficient of the solute at infinite dilution; kA is the membrane porosity; L (m) is the pore length; and ΔC (mol·m−3) is the concentration difference between the feed and eluate compartments, i.e., across the membrane. The partition coefficient, ϕ, and the hindrance factor for diffusion, dK, are related to the pore radius, Pr, and the solute radius, Sr. The equations are given in ref. [In diffusion mode, the solute transfer was modelled using a hydrodynamic model  in which in ref. .S,Elr, can be obtained by assuming that the variation of the saccharide transfer in the presence of electrolytes compared to that in water is due to a decrease in the solute radius (Pr is assumed constant and independent of the electrolyte composition). More precisely, the solute radius in the electrolyte was determined from the comparison between the ratio of the experimental and calculated values of the diffusion flux in the electrolyte, S,ElJ, and in water, S,WJ, using a mean square method.Then, the solute radius in the electrolyte, Sr, was calculated according to the following expression:S,Wr is the saccharide radius in water.Then, the modification of the solute radius in the presence of electrolytes, ΔThe values of the membrane pore radius considered in this work for xylose, glucose and sucrose are 0.45, 0.50 and 0.54 nm, respectively. They were obtained for the same membrane with saccharide water systems in filtration operating mode (pressure driven driving force) ,29. IndeThe objective is to improve the understanding and evaluation of mass transfer in nanofiltration in the presence of electrolytes. In order to progress in this objective, the methodology developed in the present work is based on the comparison between quantities characterizing the impact of the ionic composition on the saccharide transfer and the hydration properties of solutes. These properties are obtained by different methods characterizing the hydration at macroscopic and microscopic scales.− with different cations, are given in The results obtained in this work with glucose/water and glucose/electrolyte systems in diffusion mode and in the presence of various electrolytes containing ClValues obtained in the present study are of the same order of magnitude than those obtained in a previous work . The difS,WJ, measured for the membrane conditioned with NaCl, MgCl2 and CaCl2 were identical. For the membrane soaked with KCl, the values of S,WJ were lower than those measured in the other electrolytes.The saccharide fluxes in water, S,ElJ > S,WJ (factor of 1.5 to 6). The glucose flux in water ranged between 2.7 and 4.7 × 10−7 mol·m−2·s−1, while it ranged between 8.6 and 25.2 × 10−7 mol·m−2·s−1 in glucose/electrolyte systems.Results showed that the saccharide flux increased in the presence of electrolytes, J, into the electrolytes followed the given sequence: NaCl < KCl < MgCl2 < CaCl2. Although for the membrane soaked in KCl, S,WJ was smaller than S,WJ for the membrane soaked in NaCl, S,ElJ in the presence of KCl still remained larger than the glucose flux in NaCl. In spite of the singularity of the glucose flux in water for a membrane soaked with KCl, which is not investigated in this work, one can notice that there was no singularity of K+ on the glucose flux in the presence of electrolyte. Therefore, the additional glucose flux, ∆J, depends on the nature of the electrolyte, and the increase in saccharide flux is greater in electrolytes containing divalent cations than in electrolytes containing monovalent ones.Results reported in Hn, is more relevant than the variation of the partial molar volume to reveal the solute hydration degree. The Hn glucose values, calculated from thermodynamic data, are reported in H values in different electrolyte showed that glucose dehydration increased according to the following sequence: Na+ < K+ < Mg2+ < Ca2+. Thus, with regard to the influence of the nature of the cation, a good agreement was obtained between the two sequences characterizing the increase in saccharide transfer and its dehydration in the presence of electrolyte.As specified in the introduction, the saccharide hydration number at an infinite dilution, −  were compared and represented in Then, in order to further understand the impact of the cation on the additional saccharide flux, the glucose hydration numbers and the glucose additional flux values measured in the presence of electrolytes containing ClIt can be observed that a good relationship was obtained between the decrease in the glucose hydration number and the increase in glucose flux, under diffusion conditions, in the presence of electrolytes containing different cations. It is interesting to note that it was not possible to establish this kind of correlation from the variation of the apparent molar, which also revealed the solute hydration state .In order to confirm the key role of the saccharide hydration number, the additional saccharide fluxes obtained for various ionic compositions and operating modes (diffusion and filtration) obtained in a previous study were also considered .+ with different anions (Cl− and SO42−) for a given cation molality (1 mol·kg−1), as well as the corresponding saccharide hydration number, are given in The saccharide additional flux values  obtained in diffusion mode and in the presence of electrolytes containing Na2SO4 than with NaCl is related to higher saccharide dehydration in the presence of Na2SO4. This confirms thermodynamic results [− < SO42−. Moreover, as observed with the cations, a good relationship was obtained between the saccharide hydration number and the increase in saccharide flux, under diffusion conditions, in the presence of electrolytes containing different anions. results , showing2SO4) and filtration mode (NaCl) with the corresponding saccharide hydration number are given in The additional saccharide flux values obtained for various electrolyte concentrations in both diffusion mode (NaIn both operating modes (diffusion or filtration), To summarize, it was demonstrated that the saccharide hydration number is a key parameter to describe the impact of the presence of electrolytes on the saccharide mass transfer since good correlations were obtained for different ionic compositions (ion nature and concentration) and operating modes (diffusion and filtration).Hn, decreases linearly with the increase in the cation coordination number, CN, which reflects the ion’s ability to form direct interactions with the saccharide hydroxyl groups.In our previous work, an original approach combining a quantum mechanics technique (DFT) and experimental measurements (thermodynamic properties) was developed to explain the relationship between the saccharide hydration and the hydration properties of cations . More prCN, which is defined as the number of water molecules directly bonded to the central ion in its solvation first layer, was determined [inter S/C+n, defined as the number of oxygen belonging to the saccharide in direct interaction with the ion, was calculated [inter S/C+n [CN.In our previous works, the solute hydration properties (ions and saccharides) in pure water and in mixture were studied via a full geometry optimization using the DFT method ,25,26. F+ < K+ < Mg2+ < Ca2+).For a given cation valence, the saccharide dehydration sequence, as a function of the cation, was found to be identical to that obtained with the thermodynamic method (NaCN cations) were compared  on the additional glucose flux. Contrarily, as observed in + and Mg2+.It was observed that the additional glucose flux increased linearly with the cation coordination number of the electrolyte. However, it was not possible to distinguish the impact of the cations of different valences with the same coordination number . The variation of the number of saccharide/cation interactions is very sensitive to small variations in saccharide/cation interactions. Thus, one can expect that the number of glucose/cation interactions should be higher in the presence of Ca2+ than in the presence of Mg2+, as previously observed with sucrose [2+ is able to create more interactions with glucose than Mg2+, due to its higher coordination number. Thus, as observed in 2+ interactions by one unit (intern Glucose/Ca2+ = 4). This point merits further investigation. sucrose . Indeed,CN, and the number of saccharide/cation interactions, inter S/C+n, are necessary to understand the mechanisms governing the impact of the nature of the cation on the saccharide mass transfer modification in the presence of electrolytes.Consequently, it was demonstrated that both the cation coordination number, As mentioned in the introduction, the performances of the nanofiltration process depend on the combination of quite complex and imbricated mechanisms, such as the impact of the ion composition on the transfer of neutral species investigated in this work. As a result, it was barely possible to predict them, and this is a bottleneck for the development of this operation. This problem will be solved once the parameters required for the mass transfer modelling, such as membrane and solutions properties, are accessible. It is a long-term objective that requires the elucidation of the phenomena.Then, based on the better understanding of the mechanisms governing the mass transfer of saccharide in the presence of electrolyte, i.e., the phenomena of saccharide dehydration, one can expect to progress in this long-term objective.S,Elr, and to deduce the variation of the saccharide radius, ΔSr (see Equation (3)), in both diffusion and filtration operating modes [Typically, the mass transfer of a neutral solute can be described and predicted using a hydrodynamic model ,28. Moreng modes .In the present work, the correlation between the saccharide flux variation and the saccharide hydration number for various ionic compositions was clearly demonstrated. Then, in order to progress in the mass transfer prediction, the relation between the saccharide hydration number in the presence of the electrolyte and the variation of the saccharide radius calculated from the modelling of the saccharide flux using the hydrodynamic model, was investigated.pr, was assumed to be constant since it was shown that the saccharide fluxes measured in water, S,WJ, are weakly influenced by the nature of the electrolyte used for the membrane soaking. Usually, the membrane pore radius is obtained in filtration operating mode from the modelling of a neutral solute transfer using the hydrodynamic model.The membrane properties and, more precisely, the membrane pore radius, S,Elr, and the variation of the saccharide radius, ΔSr, were determined according to the procedure developed by Boy et al. [S,Elr, and the variation of the saccharide radius, ΔSr, in filtration mode were obtained from [In diffusion mode, the saccharide radius in the presence of electrolyte, y et al.  and descned from  and giveThe variations of saccharide hydration numbers as a function of the saccharide radius variation, calculated in diffusion mode, as a function of the cation and anion nature, are reported in As expected, it was observed that the variation of the saccharide radius in the presence of electrolytes increased, i.e., lower saccharide radius, with the decrease in the saccharide hydration number. More precisely, it is worth noting that in the condition investigated in this work, a linear relation was observed in the presence of electrolytes containing a given anion , it was shown again that the variation of the saccharide radius in the presence of electrolytes of various concentrations increased linearly with the decrease in the saccharide hydration number.Consequently, the key role of the saccharide hydration number was strengthened, since clear correlations with the saccharide radius in the presence of electrolytes were obtained for different ionic compositions (ion natures and concentrations) and operating modes (diffusion and filtration). Moreover, linear correlations were obtained for the conditions considered in this work.As previously discussed, the saccharide hydration number in the presence of electrolytes can be determined from the experimental determination of thermodynamic properties (volumetric properties)  or evaluVarious studies focusing on the study of the influence of ionic composition on the transfer of neutral solutes across nanofiltration membranes have shown that the increase in the transfer of the neutral solute in the presence of electrolytes is mainly governed by the modification of the neutral solute hydration properties due to solute/electrolyte interactions. Recently, investigations on the mechanisms governing the saccharide/electrolyte interactions using complementary approaches at different scales have shown that the saccharide hydration numbers in the presence of electrolytes are closely linked to the hydration properties of the ions. Thus, the objectives of the present work were to strengthen the understanding of the impact of the ion nature, especially for a given valence, since it has not been completely explained to date, and to progress towards the long-term objective in the prediction of nanofiltration performances.− , were compared. A good agreement was obtained between the increase in the glucose transfer and its hydration number in the presence of electrolytes according to the following sequence: Na+ < K+ < Mg2+ < Ca2+. This result was confirmed from the additional saccharide flux values obtained for various ionic compositions and operating modes (diffusion and filtration). Consequently, the key role of the saccharide hydration number to understand the impact of the ionic composition on the saccharide transfer through an NF membrane was clearly demonstrated.The influence of the nature of the cation on the transfer of glucose in diffusion mode was first investigated. The glucose hydration numbers, calculated from thermodynamic data, and the glucose additional flux values measured through an NF membrane in the presence of electrolytes containing Clinter S/C+, which increases with the cation coordination number, is a key parameter to understand the mechanisms governing the impact of the nature of the cation on the saccharide mass transfer modification in the presence of electrolyte.Second, in order to strengthen the understanding of the mechanisms governing the impact of the presence of electrolytes on the saccharide transfer, the additional saccharide flux and hydration properties of cations were compared. Indeed, on one hand, the relation between the saccharide hydration number and the cation coordination number has been established in previous works, and on the other hand, the correlation between the saccharide hydration number and the saccharide mass transfer was demonstrated in the present work. Thus, it was demonstrated that the number of saccharide/cation interactions, nFinally, in order to progress in the long-term objective toward the prediction of NF performances, the relation between the saccharide hydration number in the presence of the electrolyte and the variation of the saccharide radius calculated using the hydrodynamic model was investigated. The key role of the saccharide hydration number was strengthened since clear correlations with the saccharide radius in the presence of electrolyte were obtained for different ionic compositions and operating modes. Thus, based on the knowledge of the saccharide hydration number and the linear correlations established in this work, it could be possible to evaluate the saccharide transfer for a given saccharide/electrolyte system transfer using the hydrodynamic model. This last point merits further investigation.