Our findings support the existence of thresholds for literacy attainment. We argue that language external factors may override positive effects of bilingualism. In addition, these factors may compensate negative effects attributable to low literacy attainment in German and the heritage languages. We also show that low attainment levels in migrant children's heritage languages preempt high literacy attainment in additional languages.Bi- and multilingualism has been shown to have positive effects on the attainment of third and additional languages. These effects, however, depend on the type of bi- and multilingualism and the status of the languages involved Cenoz, . In this In Germany and elsewhere, it remains highly debated if bilingualism has a positive impact on cognitive development or academic attainment  in the interpretation of the Threshold Hypothesis. Cummins seems to use the term “language proficiency” to refer to both competence and performance, including school literacy. MacSwan , p. 34, We do not regard the Threshold Hypothesis as a competence-related construct, but rather as a performance-based concept relating to educational attainment. Performance data are used to measure attainment, which only reflect the underlying linguistic competence. In this descriptive trend study, we investigate the effects of high and low attainment levels in informants' heritage language and their language of environment, i.e., German, on their attainment of English as a foreign language. We aim to do so by investigating the attainment of academic literacy in English by Turkish-German, Vietnamese-German, and Russian-German simultaneous and successive bilinguals in subtractive bilingual contexts who acquire English as their third or additional language.The present study aims to investigate whether 16-years-olds with high literacy assessment scores in English also achieve high literacy assessment scores in German and their heritage languages, and whether a high assessment score in the heritage language in addition to the L2 German has a perceivable positive influence on literacy in the target language English.It is important to emphasize that we are here measuring aspects of language performance, especially literacy achievement, and not proficiency understood as competence. To avoid confusion, we here opt to avoid the term “proficiency” altogether and use the terms “attainment” and “literacy achievement” instead. Furthermore, we here define the attainment of English as an academic achievement, i.e., educational attainment. We argue that the effects we can observe depend on a double threshold, meaning that thresholds for positive influence of literacy skills in informants' background languages are lower if socioeconomic factors are favorable.Linguistic Diversity Management in Urban Areas  in the second wave of this pilot study (henceforth main panel). In this study, we will only be focusing on the 16-years-old informants. The informants represent each of the language groups. The initial target number of participants we aimed to extract from the main panel was n = 160 , but we encountered difficulties extracting data from the Turkish-German group in particular. In cases where the target number could not be achieved, additional interviews were conducted. Furthermore, we conducted interviews with monolingual student control groups equally distributed across the same ages with English as their L2 in Russia, Turkey, and Vietnam.We extracted We differentiate between bilingual and monolingual informants, although it is possible to construe our German control group as bilinguals and our bilingual informants as multilinguals, as both groups have acquired English in addition to their native languages. We here opt to use the terms “bilingual” and “monolingual” because these appear in the main panel. Furthermore, we use the term “heritage language” instead of “home language” or “community language,” because it is the term utilized in the main panel.Background variables and informants' attainment levels for different text types, both in German and their heritage language, were tested in the context of the main panel study. When additional interviews were conducted, we relied on questionnaires with smaller sets of background variables. In addition to this, we conducted an additional socioeconomic background interview and a parental questionnaire with all of our informants.The English language tasks consisted of an oral description based on a picture sequence, a written narrative based on a picture sequence, and an academic language task, likewise based on a sequence of pictures. The latter was only conducted with the 16-years-old and aimed for instructive texts. All of the instruments were piloted in advance with children of the same ages and with the same language backgrounds as well as with adults. We piloted specifically for manageability of the task to avoid any cultural or sex-based bias. Interviews were conducted by bilingual interviewers in the children's homes. Most of the bilingual children we interviewed spoke primarily their heritage language at home, while the German monolinguals spoke only German at home. The informants were chosen based on a mixed method of random sampling relying on data obtained from Hamburg's registration office and snowballing. The aim was to collect representative data rather than data from homogeneous groups, as we have informants with a wide range of socioeconomic and educational backgrounds in our sample.Fast Catch Bumerang,The instructive task was an English translation of the first part of Six-digit numbers were assigned to each of the informants as IDs. The first digit encodes for city , the second digit encodes for language group , and the third digit encodes for the age of the informants . The last three digits are randomized sequences that allow us to identify each informant and to assign background variables from different testing sequences to each of them.n = 52 informants, distributed as follows: N = 20 Russian-German bilinguals, n = 11 Vietnamese-German bilinguals, n = 5 Turkish-German bilinguals, and n = 16 German monolinguals.In this trend study, we focus exclusively on 16-years-old informants who were also part of the main panel and handed in completed versions of the Boomerang task in English,n = 10 informants with the highest and lowest proficiency scores in English, and examine whether there are any correlations between language assessment scores in German and/or the heritage languages.In a first step, we will look at all of the informants and take into account not only the language assessment scores for German, their heritage languages, and English, but also socioeconomic background variables that have been shown to have effects on language development and, subsequently, on language production. We try to assess whether bilinguals with similar socioeconomic backgrounds show differences in comparison to their monolingual peers regarding their production of instructive texts in English. In a second step, we will look at the To this end, we will compare their scores in English to their scores in German and their heritage languages, as supplied by the main panel. It needs to be pointed out that different scoring schemes were used in the main panel and our study. These differences in measurement are due to the fact that students encounter English almost exclusively as a school subject, while they encounter both German and their heritage languages in informal environments. While the target varieties for German and children's heritage languages are diverse, there is a clear target variety for English, i.e., standardized British or American English, as it is taught in the German school context. Moreover, informants often have experienced no formal language education in their heritage languages. Consequently, while an overall correctness score is part of the English scoring paradigm, it is not part of the scoring paradigms for either German or the heritage languages.The typologies of the background languages of our informants are highly diverse. Russian is an inflectional-fusional language that has free word order (but a preference for SVO). It has no articles and fairly complex conjugation and declension paradigms Wade, . VietnamGerman, the language of environment for all of the informants in our sample, has V2 word order in main clauses and SOV patterns in subordinate clauses. It has indefinite and definite articles and is classified as a moderately inflecting language. English, finally, is a weakly inflecting language. It has a basic SVO word order and definite as well as indefinite articles.Based on the typologies of the languages involved, positive as well as negative transfer to the target language English is hypothetically possible from all of the source languages, i.e., informants' heritage languages and the language of environment, German. We here define transfer in the sense of Odlin's  “cross-lScores for each of the tasks in English were measured as a combined score of lexical richness , structural complexity , overall correctness score (target-like occurrences/tokens), and the length of the text. The score for the length of the text was measured against the highest token output, i.e., the text with the highest number of produced words, in the sub-sample. This method led to scores that range from 8 to 70, with the majority ranging from 40 to 70. In principle, it would have been possible to achieve higher scores, but none of the informants in our subsample achieved a score higher than 70. In a next step, scores were transferred to a categorical scoring system that ranges from zero to seven (zero being the lowest and seven being the highest), which in turn corresponds to a category in the Common European Framework of References for Language  in Table n = 52 informants investigated for the purposes of this study are listed from highest to lowest in Supplementary Table 1 . They were generated for the Boomerang task. We generated independent scores for the other tasks. These may differ from results in the Boomerang task, as they measure other aspects of language production. In Supplementary Table 1, informants are listed according to their ID and language group. In addition to the scores, the following information is given: language background, informants' sex, age of onset for German, the HISCEDThe scores of all All of the bilingual informants in our subsample save one (133044) used their heritage language as their primary language of communication with their parents and spoke primarily their heritage language at home. Some of the Russian-German bilinguals (those who had started acquiring German after the age of six) underwent schooling and literacy development in Russian.Gymnasium is the highest form of secondary schooling. The biggest gaps in attainment levels can normally be observed between students who attend the Gymnasium and those attending other school forms. Differences in attainment between other school types are not as high. The Stadtteilschule—like the Gesamtschule—is a hybrid combining middle and secondary school tracks. The Realschule offers middle school education only. There are special school forms, such as the Förder- and Sonderschule, which tend to children with learning disabilities and are attended by students with significantly lower attainment levels. Differences in attainment within classes of the same school type are typically not as high in countries with tracked school systems as they are in countries with comprehensive school systems , both German monolinguals, who attend schools for children with learning disabilities. They completed the task primarily in German with interspersed English function words. The informants at the lower end of the scoring spectrum attend diverse school forms. Most of the informants who do not attend the Gymnasium achieve comparatively lower scores. In cases in which informants attend the Gymnasium and still have lower scores for English, we typically find comparatively lower HISEI and HISCED scores. The educational background of informants' families seems to play a more pronounced role than household income. Age of onset seems to be irrelevant, as we find simultaneous and successive bilinguals both at the higher and lower end of the scoring spectrum. Similarly, sex does not seem to be an influencing factor.The majority of informants achieving high scores in the English Boomerang task attends the Although influences from the heritage languages are observable, especially with informants who acquired German after the age of three, the majority of non-target-like effects occur regardless of differences in language background. They may be explainable in terms of (partly fossilized) language acquisition stages.Non-target-like occurrences in informants' texts include code mixing, as in Example 1. It occurs exclusively from German, especially at the lower end of the scoring spectrum. Moreover, we find non-target-like subject-verb-agreement and tense- and aspect marking, again primarily at the lower end of the scoring spectrum. This is illustrated in Example 2. Non-target-like word order, particularly in the placement of adverbs and prepositional phrases, is portrayed in Example 3. The latter phenomenon occurred regardless of the scores that informants' achieved. As most informants were not accustomed to the specialized English vocabulary the task required, all of them used coping strategies such as direct lexical transfer (Example 4) and paraphrasing (Example 5). We use angled brackets to indicate the non-target like specimens under discussion.123241 Turkish-German bilingual         I have a Boomerang <Schablone ‘template’>, we <schneiden es ‘cut it’>133150 Vietnamese-German bilingual         […] that you <has> the same form [… ] and your boomerang <are> finish113161 Russian-German bilingual         You have to fix the wood with the table and cut it <carefully> out143577 German monolingualdrill; German: Bohrmaschine)         <boring machine>  speaks primarily German at home. Her scores in German are higher than in Vietnamese. Her assessment scores for German, however, are lower than those of the monolingual German informants (except informant 143411). Further background variables reveal that informant 133044 is a special case, as she attended an international school in Vietnam where English was the first language that she formally acquired. This is one of the primary reasons for her high literacy score in English.Gymnasium, shows low assessment scores in German and her heritage language, even though she achieved comparatively high literacy levels in the English Boomerang task. HISCED and HISEI levels are both high in her case.Three of the Russian-German bilinguals achieved high scores in their heritage language Russian. Informant 113090, a Russian-German bilingual attending the n = 5 informants in our sub-sample being of Turkish descent.At the lower end of the scoring spectrum for English (see Table We may suspect a correlation between literacy attainment in German and English. A Pearson correlation for our bilingual informants reveals that the raw scores for the English Boomerang task correlate at the 0.01 level with the scores in the German Boomerang task. There is no significant correlation between the scores for the heritage languages and English. These results are summarized in Table If we look only at our bilingual informants and rearrange our results according to the 10 informants with the highest literacy scores in their heritage languages, we find mixed results for their scores in English. If, however, we look at the 10 informants with the lowest assessment scores in their heritage language, this results in the picture shown in Table Informants with comparatively lower language assessment scores in the heritage language versions of the Boomerang task reach comparatively low literacy scores in the English Boomerang task. The exception to this is informant 133044, who, as has already been established, acquired English as her first formal language and achieves a relatively high score in the German version of the Boomerang task. Informant 113209 is an interesting case, because she reaches an above average literacy score in English, but comparatively lower levels of literacy in German and her heritage language. In this case, however, the family has a comparatively high educational background. Moreover, in the first wave of testing, she obtained a relatively high literacy score in Russian.To sum up, it does seem to be the case that higher academic literacy scores in both German and the heritage language coincide with higher academic literacy scores in English. Whether or not literacy resources are accessible, however, seems to be dependent on language external factors. Moreover, comparatively higher academic literacy assessment scores in German seem to coincide more frequently with high academic literacy scores in English. Higher literacy scores in the informant's heritage language coinciding with comparatively lower attainment scores in German result in a lower academic literacy score in English. In general the lowest assessment scores in bilingual informants' heritage languages coincide with low academic literacy outcomes for English.In this exploratory, qualitative analysis of our data set, we found no evidence for advantages of bilinguals regarding the production of written instructive texts in English, in comparison to their monolingual peers. Our results, however, show that bilingual informants with high assessment levels for academic literacy in both German and their heritage language are more likely to achieve better results in the production of academic English. In our view, this finding supports Cummins' Threshold Hypothesis as long as we view English literacy as a form of academic attainment. Moreover, informants with low literacy attainment levels in their heritage languages achieved comparatively lower scores for the task at hand.Our results also show that there are individual thresholds, as some informants seem to be able to access their literacy resources on lower levels than others. The accessibility of these lower level resources seems to be dependent on socioeconomic background variables, as informants with low literacy scores in their background languages—though attaining high literacy scores in the English task—have a high socioeconomic and educational background.Although we did not find evidence for advantages of bilingual informants regarding their literacy levels in English, it must be noted that there may be factors overriding our results. For example, 16-years-old students in Germany are likely to have encountered instructive text types in school and in their environment in German, but are much less likely to have encountered them in their heritage language, especially since the majority of our informants received no formal training in their home languages. Other overriding factors include the quality of English language education and students' motivation to learn English.Typological Primacy Model (Even though our study is primarily concerned with literacy attainment, it would appear justified to take a brief look at the influencing factors identified in L3 acquisition studies. In this context, for example, typological proximity has been identified as an important factor (De Angelis, cy Model , Rothmancy Model  and rececy Model  and Falkcy Model 5. Accordand their heritage language are more likely to show higher literacy scores in English, though high assessment scores in German seems to be a precondition in this particular case. Moreover, informants with low literacy levels in their heritage languages have lower literacy scores in English. Informants' literacy levels in their heritage languages, therefore, contribute directly to their attainment of English literacy.It is important to note that we do not find any negative effects of high literacy scores in bilingual informants' heritage languages regarding their production of English academic texts. To the contrary, informants with high literacy assessment scores in both German As already alluded to, it is difficult to compare informants' literacy skills in their heritage language to their literacy skills in German. Still, we would like to emphasize that due to the nature of bilingualism, comparing bilingual children's results in German or their heritage languages to monolingual children's results in German is also quite problematic. This follows from the fact that bilinguals cannot be viewed as a combination of two monolinguals, as established by Grosjean .Pursuing this line of thought further, we would also like to note that the comparison of bilingual and monolingual learners in the acquisition of English as an additional language poses similar difficulties. That is to say, advantages for bilinguals are more likely in domains where the same attainment levels have been reached for both their native languages. As children and adolescents who grow up in a monolingual environment are likely to have a more diverse knowledge of different registers than their bilingual peers, this may account for the high literacy scores that some of our monolingual informants achieve in English and disadvantage multilingual children in language assessment tasks for additional languages.Another important factor to keep in mind with regard to our data is that there were 16 monolingual and 36 bilingual informants in total, and that the bilingual group was heterogeneous in terms of language background. Out of the bilingual informants, 11 were Vietnamese-German bilinguals and only 5 were Turkish-German bilinguals, while the others belonged to the Russian-German group. It is therefore difficult to draw conclusions concerning specific migration or language backgrounds.The exploratory study presented here is primarily intended as a trend study for further research. While we do find tendencies supporting Cummins' Threshold Hypothesis, the highly heterogeneous nature of the investigated data has to be kept in mind. Moreover, literacy and socioeconomic conditions do not cumulatively impact on the attainment of English as an additional language, at least not necessarily. Bilingual individuals achieving high literacy in German and their heritage languages also show high literacy achievement in English. While socioeconomic and educational background intensify these effects, informants with favorable socioeconomic preconditions are more likely to achieve high literacy levels. This means that they are able to access linguistic, or more specifically literacy, resources at a lower threshold.and their heritage languages. In other words, they are able to access literacy resources at a higher threshold, but once they do, they perform at a high level. In our task, high literacy achievement in German coincided more often with high literacy achievement in English than high literacy achievement in informants' heritage languages. We argue that this is due to both the typologies of the languages involved and the task at hand, which tested for academic language and the production of instructive text types. More importantly, low literacy achievement in informants' heritage languages resulted in lower literacy achievement in English. A low level of literacy achievement in these languages can therefore be viewed as detrimental to literacy attainment in the acquisition processes of additional languages. Our results are therefore in line with findings by Swain et al. (At the same time, bilinguals of lower socioeconomic backgrounds can realize high literacy scores in English, if they achieve higher assessment scores in German n et al.  who suggThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


More specifically, we have reviewed the literature concerning the clinical application of PRP in peripheral neuropathies and investigated if there is strong evidence to establish the use of PRP in clinical practice as a therapeutic option. In contrast with animal studies, we have been able to identify only few clinical data concerning the use of PRP in peripheral neuropathies. We found five trials matched to our research that yields positive and promising results for the future for the application of PRP for the therapy of disorders of the peripheral nervous system. It is obvious that this interesting field of research gives to the scientists the ability to expand it extensively, in terms of both quality and quantity.Platelet-rich plasma (PRP) is defined as an autologous concentrated preparation of platelets and their associated growth factors in a small volume of plasma. The presence of these growth factors has stimulated the scientific community to search about possible benefits of the use of PRP in tissue regeneration. Provided that previously  Platelet-rich plasma (PRP) is an innovative and promising approach in tissue regeneration. PRP is defined as an autologous concentrated preparation of platelets and their associated growth factors in a small volume of plasma . PlateleThe application of PRP has been documented in many fields. Musculoskeletal practitioners began using PRP for chronic tendinopathy in the early 1990s. The growth of PRP therapy has relied primarily on anecdotal or case studies. Historically, there have been few controlled trials to prove the efficacy of PRP. Recently, however, there has been an emerging literature on the beneficial effects of PRP for tendon, ligament or muscle injuries, maxillofacial therapies, dentistry, cosmetics, wound healing, cardiothoracic surgery, ear–nose–throat surgery, neurosurgery, urology, and ophthalmology.Among all these data, a relatively new question upon basic science’s researchers is the effect of PRP on neural tissue. There is an important number of animal studies that argue in favor of the use of PRP in neuropathies. Most recently, Giannessi et al.  experimePlatelets include alpha granules, which contain mitogenic and chemotactic growth factors such as IGF-1, bFGF, and TGF-beta . AlthougAbout nerve entrapment syndromes, Mulvaney  introducGiannessi  believesin vitro and animal research demonstrated that PRP could probably play an important role in the treatment of neural tissue disorders, we aimed to review the current literature, regarding the clinical studies that have been conducted to confirm this hypothesis. More specifically, we have reviewed the literature concerning the clinical application of PRP in peripheral neuropathies and investigated if there is strong evidence to establish the use of PRP in clinical practice as a therapeutic option.Provided that the previously mentioned We searched on Medline, Cochrane Database, and EMBASE using the key words “PRP,” “clinical study,” “peripheral neuropathy,” and “trial.” Initially, one reviewer conducted the literature search and retrieved the references to be evaluated. A second reviewer independently selected the trials to be included in the review and also screened the reference list from the selected articles in order to identify studies that have been missed at the initial search.In contrast to animal studies, we have been able to identify only few clinical data concerning the use of PRP in peripheral neuropathies. We found five trials matched to our research.Mycobacterium leprae, is characterized by granulomatous inflammation of the epineuron of peripheral nerves. The sensory loss appears to be earlier and more frequent among patients. In this research, patients were divided randomly in two comparable groups and treated either with a PRP perineural injection or a PPP injection as control. Perineural injection of PRP proved to be significantly more effective in visual analog scale (VAS) and two-point discrimination test. This result is in favor of the positive effect of PRP in nerve regeneration. However, the conclusions of this high-quality study need to be confirmed with further research in the future, with longer observation times, while, on the other hand, the optimal frequency of PRP injections should be determined  , entrapmWe have been able to identify two randomized trials regarding the clinical application of PRP in peripheral neuropathies. Two other studies had a level of evidence 5, and one had a level of evidence 4. Besides, there are several techniques of preparation of PRP  and diffin vivo or in vitro) animal studies  about the use of PRP in peripheral neuropathies, literature cannot yet give a convincing answer about the value of this therapeutic strategy. Nevertheless, results of the so-far published clinical studies are encouraging. Consequently, it is obvious that this interesting field of research gives to the scientists the ability to expand it extensively, in terms of both quality and quantity. It is obvious that more clinical trials are needed to yield more secure evidence regarding the beneficial effect of PRP usage in peripheral neuropathies.Although there are many published (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Systematic reviews are important for decision-makers. They offer many potential benefits but are often written in technical language, are too long, and do not contain contextual details which makes them hard to use for decision-making. There are many organizations that develop and disseminate derivative products, such as evidence summaries, from systematic reviews for different populations or subsets of decision-makers. This systematic review will assess the effectiveness of systematic review summaries on increasing policymakers’ use of systematic review evidence and to identify the components or features of these summaries that are most effective.We will include studies of policy-makers at all levels as well as health-system managers. We will include studies examining any type of “evidence summary,” “policy brief,” or other products derived from systematic reviews that present evidence in a summarized form. The primary outcomes are the following: (1) use of systematic review summaries decision-making  and (2) policy-maker understanding, knowledge, and/or beliefs . We will conduct a systematic review of randomized controlled trials (RCTs), non-randomized controlled trials (NRCTs), controlled before-after studies (CBA), and interrupted time series (ITS) studies.The results of this review will inform the development of future systematic review summaries to ensure that systematic review evidence is accessible to and used by policy-makers making health-related decisions.The online version of this article (doi:10.1186/s13643-015-0116-1) contains supplementary material, which is available to authorized users. Systematic reviews are becoming increasingly important for policy-makers making decisions –3. SystePolicy-makers include health ministers and their political staff, civil servants, and health-system stakeholders . Health Systems Evidence provides policy briefs for policy-makers making health-systems decisions . Communicate to vaccinate (COMMVAC) is creating user-friendly summaries to translate evidence on vaccination communication for policymakers and the community in LMICs (http://www.commvac.com). Rx for change is a searchable database for evidence about intervention strategies to alter behaviors of health technology prescribing, practice, and use (www.cadth.ca/resources/rx-for-change). In fact, Lavis et al. identified 16 organizations involved in the production of summaries for policymakers in low- and middle-income countries [In addition to Evidence Aid, there are many organizations that develop and disseminate evidence summaries for different populations or subsets of decision-makers. For example, SUPPORT Summaries were developed for policy-makers in low- and middle-income countries making decisions about maternal and child health programs and interventions  assess the effectiveness of evidence summaries on policy-makers’ use of the evidence and (2) identify the most effective components of the summaries for increasing policy-makers’ use of the evidence.We will include randomized controlled trials (RCTs), non-randomized controlled trials (NRCTs), controlled before-after studies (CBA), and interrupted time series (ITS) studies.We will include studies which include health policy-makers at all levels  and health system managers making decisions on behalf of a large jurisdiction or organization (6). We will not include studies related to decision-making for an individual person or patient.We will include studies examining any type of “friendly front end,” “evidence summary,” or “policy brief” or other product derived from systematic reviews or guidelines based on systematic reviews that presents evidence in a summarized form to policy-makers and health system managers. Interventions must include a summary of a systematic review and be actively “pushed” to target users. For example, a potentially included study used an intervention that evaluated the effectiveness of friendly front ends by assessing changes in policy-maker beliefs . An examWe will exclude studies in which evidence summaries are one component of a multi-component intervention.We will include any comparisons including active comparators  or no intervention.Use of systematic review derivative product in decision-making .The primary outcomes are the following:Perceived relevance of systematic review summariesPerceived credibility of the summariesPerceptions and attitudes regarding the specific components of the summaries and their usefulnessPerceived usefulness and usability of systematic review summariesUnderstandability of summariesDesirability of summaries  We will also include studies that report on any of the following outcomes:We recognize that some studies may use different terms to describe these outcomes. For example, the term “satisfaction” maybe used as an umbrella term to capture relevance, usability, and desirability. These outcomes will be assessed by the team and categorized according to the above list.This systematic review has not been registered with PROSPERO since there we are not assessing health outcomes.An information specialist will help develop the search strategy using the PRESS Guideline . We willThe search conducted by Perrier et al. identified 11,297 records (after removing duplicates) and included four papers reporting two studies. We will expand this search by including additional databases, as suggested by John Eyres, of the International Initiative for Impact Evaluation (3ie) and the Campbell International Development Review Group. These include databases such as Global Health (CABI), Global Health Library (from WHO), Popline, Africa-wide, Public Affairs Information Service, Worldwide Political Science Abstracts, Web of Science, and DfiD (Research for Development Database) .We will check reference lists of relevant studies to identify additional studies. We will contact researchers to identify ongoing and completed/published work. We will report the results of the search using the PRISMA flow diagram.https://www.covidence.org/) for screening of studies. All completed studies will be included if they meet the inclusion criteria listed above.Two reviewers will independently screen titles and abstracts to identify relevant studies meeting the pre-specified inclusion criteria. The full text of potentially included studies will be screened independently by two authors. Data extraction and quality assessment will be conducted independently and in duplicate. We will use software Covidence  Mode of deliveryTopic of evidence summaryRecommendation of evidence summaryInterventionPolicy/decision-makers’ self-reported use of summaries in decision-makingPolicy/decision-makers’ knowledge of the summary content and the measurement usedPolicy/decision-makers’ understanding and measurement usedPerceived relevance of the summaries and measurement usedPerceived credibility of the summaries and measurement usedPerceived usefulness and usability of the summaries and measurement usedPerceived understandability of the summaries and measurement usedPerceived desirability of the summaries and measurement usedOutcomesHow the systematic review was selected for summary How the evidence summary was developed Involvement of stakeholders in evidence summary development—which stakeholders, description of involvementProcess indicatorsData will be extracted for the following:The methodological quality will be specifically examined using the risk of bias tools from the Cochrane Handbook for randomized trials and the Effective Practice and Organization of Care (EPOC) Review Group criteria for interrupted time series and controlled before-after studies , 20 and Effect estimates and confidence intervals for individual studies will be calculated (where possible) irrespective of whether a pooled effect estimate is calculated. When it is possible to combine studies, dichotomous outcomes will be reported as relative risks. Continuous outcomes will be reported as weighted mean differences. If an outcome has been reported in different scales , and we consider the scales to measure a similar construct, standardized mean differences will be used to summarize the data. When it is not possible to combine the data, we will present the results for each study separately.http://www.abdn.ac.uk/hsru/research/delivery/behaviour/methodological-research/ or the Campbell Collaboration website of ICCs for education). Sensitivity analyses will be used to assess the effects of incorporating these corrected analyses in our analysis.When possible, any studies with cluster allocation  analyses with errors in the unit of analysis will be adjusted using the variance inflation factor, as described in the Cochrane Handbook, if the necessary data can be obtained from the study authors. We will obtain ICC from other similar studies with similar outcomes if the ICC is not published  approach to assess the quality of evidence for the outcomes reported in this review .Target audience of summary Type of decision maker Components of friendly front end Heterogeneity will be explored, if possible, by conducting meta-regression to assess the role of mediating factors, including the following:The impact of including studies assessed as high risk of bias or studies in which there were unit of analysis errors that could not be reanalyzed will be considered in sensitivity analysis.We will assess applicability of the findings of the review to specific settings of relevance to end-users. We will use the most up to date methods from the Cochrane Applicability and Recommendations Methods Group which include assessing the directness of the evidence to specified settings of interest using GRADE .This review will summarize the evidence on the use of systematic review summaries in policy-making and policy-makers’ understanding of systematic review evidence, and assess evidence about different components and design features. To the best of our knowledge, this is the first systematic review to assess the use of systematic review summaries in policy-making. The results of this review will inform researchers and systematic review summary developers of the best way to present the evidence to ensure that evidence summaries fulfill their goal of informing policy-makers with the best possible evidence needed to make health-related decisions.


In our last issue, I talked about care in the context of end of life, in particular the expense and futility of care given in the last months of life or when patients are facing an incurable condition. I believe that it is entirely appropriate to refuse care or decline aggressive therapies at the end of life.Recently, the news has been full of reports detailing the story of Cassandra Fortin, a 17-year-old girl from Connecticut diagnosed with Hodgkin lymphoma this past September. Cassandra (with her mother’s support) refused therapy for her potentially curable cancer. The Connecticut Supreme Court recently ruled unanimously to uphold the state’s decision to place the teenager in the custody of child welfare authorities . She wasTeenagers are known for many things, but maturity is not generally one’s first thought when referring to this age group. Teenagers often exhibit risk-taking behavior, although we’ve yet to discover a concrete biological explanation for these actions. Historical precedence shows differences in societal measurement of maturity . For exaThere are many aspects unique to the adolescent brain. Studies have demonstrated that the adolescent brain continues to evolve and change past the teens . Scans oIn my youth, my parents saw me make a number of poorly thought-out decisions, but most of those mistakes could be easily rectified . However, the decision Cassandra faces is exponentially more serious. If she doesn’t receive the appropriate therapy, Cassandra will most likely die of a potentially curable disease.if no harm would occur as a result of the change. But replacing the evidence-based standard of care with alternative therapy alone without evidence? That is not a decision that I could personally choose or support.Alternative therapies can seem very attractive to patients. One of the most intriguing aspects of these therapies is the idea that alternative treatments are "less toxic" than traditional therapies. I certainly agree that traditional chemotherapy can be toxic and often causes significant side effects for patients. But I’m a believer in evidence-based medicine. I think tumor treatment should be based on the evidence gained from multiple clinical trials designed to demonstrate effectiveness of therapies for different cancers. If an alternative therapy has substantial evidence in treatment of a specific tumor type, then I would be in favor of adding it to the standard of care. If there is no substantial evidence but anecdotal evidence of helpfulness, I would consider adding it to the standard of care If an adult patient chose to make the above decision rather than undergoing traditional, evidence-based care, I would educate, counsel, and cajole, but I would ultimately respect the adult patient’s choice. However, when an adolescent makes that choice, I have to side with the Connecticut Supreme Court: Cassandra lacks the maturity to make such a decision.Steve Jobs, the co-founder of Apple, died of a rare pancreatic cancer in 2011. His biographer told the media that Jobs regretted his decision to refuse surgery and undergo alternative herbal treatments for his disease, especially when his health declined . Jobs haI’ve always been proud of the level of education found in articles we’ve published in JADPRO. But now I’m excited to announce that going forward, at least one article in each issue of JADPRO will be associated with free CE/CME/pharmacy credits! Read the Grand Rounds article by Malangone et al., then follow the instructions on how to earn your free credit and receive your certificate.


Cerebral palsy is a permanent disorder of posture and movement caused by disturbances in the developing brain. It affects approximately 1 in every 500 children in developed countries and is the most common form of childhood physical disability. People with cerebral palsy may also have problems with speech, vision and hearing, intellectual difficulties and epilepsy. Health and therapy services are frequently required throughout life, and this care should be effective and evidence informed; however, accessing and adopting new research findings into day-to-day clinical practice is often delayed.This 3-year study employs a before and after design to evaluate if a multi-strategy intervention can improve research implementation among allied health professionals (AHPs) who work with children and young people with cerebral palsy and to establish if children’s health outcomes can be improved by routine clinical assessment. The intervention comprises (1) knowledge brokering with AHPs, (2) access to an online research evidence library, (3) provision of negotiated evidence-based training and education, and (4) routine use of evidence-based measures with children and young people aged 3–18 years with cerebral palsy. The study is being implemented in four organisations, with a fifth organisation acting as a comparison site, across four Australian states. Effectiveness will be assessed using questionnaires completed by AHPs at baseline, 6, 12 and 24 months, and by monitoring the extent of use of evidence-based measures. Children’s health outcomes will be evaluated by longitudinal analyses.Government, policy makers and service providers all seek evidence-based information to support decision-making about how to distribute scarce resources, and families are seeking information to support intervention choices. This study will provide knowledge about what constitutes an efficient, evidence-informed service and which allied health interventions are implemented for children with cerebral palsy.Trial is not a controlled healthcare intervention and is not registered. Children with cerebral palsy have a ‘permanent disorder of the development of movement and posture, causing activity limitations that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication and behaviour, by epilepsy and by secondary musculoskeletal problems’ . CerebraOne pertinent example of the consequences of a research-practice gap in the management of children and young people with cerebral palsy is the development of secondary musculoskeletal deformities that are a common feature of the condition. These deformities can include hip dislocation, which may result in pain, contractures and problems with functional activities such as walking, fractures, skin ulceration and difficulty with perineal care, pelvic obliquity and scoliosis . In AustKnowledge translation is required to close the ‘research-practice gap’  for chilIndividual practitioner barriers included obsolete knowledge, influence of opinion leaders who may go against research evidence and personal beliefs and attitudes, including a perception among many health professionals that they lack the authority to change clinical practice .Workplace barriers included a lack of financial and human resources, policies that did not promote cost-effective interventions or advocated unproven interventions, lack of access to evidence-based data, time limitations and a lack of disease registers.Educational system barriers included a failure of curricula to reflect current research evidence, inappropriate continuing professional development or education and a lack of incentives to participate in effective educational activities.Patient barriers included demands for care that is ineffective and perceptions or cultural beliefs about appropriate care.A number of barriers to implementing research evidence in clinical practice have been identified ,20 whichEducational strategies have been traditionally used with the aim of bridging the research-practice gap. Such strategies include provision of educational materials, promoting attendance at conferences and professional development courses, establishing interactive small-group meetings within departments, use of opinion leaders and feedback on performance ,19,20. IA single-blind clustered randomised controlled trial (RCT) has investigated the effect of a tailored complex intervention on the research implementation of AHPs that work with children with cerebral palsy in a single organisation . The taiCerebral palsy check up: providing the best service at the best time. This paper describes the rationale and methodology for a ‘real-world’ implementation study that aims to improve evidence-based practice behaviours of AHPs that work with children with cerebral palsy via the application of a tailored multi-strategy knowledge translation intervention. The intervention will be applied pragmatically in ‘real-world’ settings in different disability service organisations in Australia.This paper describes the study protocol for a partnership project funded by the National Health and Medical Research Council of Australia. The ethically approved project title is This project is guided by the diffusion, dissemination and implementation of innovation conceptual framework described by Greenhalgh et al. . This moimprove allied health professional research implementation behaviours using a tailored multi-strategy intervention package [This study aims to  package  and to rHow does AHP knowledge of evidence-based interventions and outcome measures for children with cerebral palsy in the four organisations in which the intervention is introduced compare to the organisation in which the practices are mandated?Does the tailored multi-strategy intervention change AHP behaviours via greater use of evidence-based outcome measures and/or interventions, and improved AHP knowledge of evidence-based interventions and outcome measures for children with cerebral palsy?How do barriers in the four organisations in which the intervention is introduced compare to the organisation in which the practices are mandated?What is the relationship between the numbers and/or type of barriers to knowledge translation and the level of uptake of routine use of outcome measures in different healthcare organisations?How does the size and scope of the organisation impact the implementation of the multi-strategy approach?Do time trends show a reduction in rates of adverse outcomes, including severe scoliosis, hip dislocation (MP >100%) and progressive limb contractures over the study period, for children with cerebral palsy whose parents consent to be a part of this project? If so, are these trends comparable to Swedish cerebral palsy follow-up outcomes?Our specific research questions includeThis study will employ a before and after design  in four AHPs: All physiotherapists, occupational therapists and speech pathologists working, or having the potential to work with children with cerebral palsy in participating service providers, will be eligible to participate. Organisation-specific recruitment strategies will be implemented including advertising posters, newsletter commentaries, email contact and face to face sessions for staff and families. Written informed consent will be sought from AHPs; consent to participate is voluntary, and there will be no adverse consequences for any eligible participant who chooses not to take part.Children and families: Children aged 3–18 years with a diagnosis of cerebral palsy will also be recruited to the study. All families whose children with cerebral palsy receive services at participating organisations will be provided with detailed information about the study. Consent to collect longitudinal child-specific data to monitor health service inputs and outcomes related to the project will be sought. Again, consent to participate will be voluntary, and there will be no adverse consequences for any eligible participant who chooses not to take part.Ethical approval for this study has been granted from the Australian Catholic University Research Ethics Committee (Reference: 2013-309 V), the Department of Education and Early Childhood Development (Reference: 2013_001962) and the Cerebral Palsy Alliance Research Ethics Committee (Reference: 2013-04-02). Approval documents from the Australian Catholic University Research Ethics Committee were lodged and accepted by each partner organisation’s ethics committee or chief executive officer.Knowledge Brokers’ (expert research translators) based at each organisation who will aim to redress workplace barriers unique to each site. Each organisation will nominate one or more knowledge brokers for their site who has demonstrated leadership skills, excellent communication skills, peer respect and a specific interest in evidence-based practice. The knowledge brokers will work with the project team, the organisation’s management and the AHPs to act as agents in the process of translating and contextualising evidence for users within the organisation. This will involve taking part in training and cross-organisational knowledge broker support groups to develop the knowledge brokering role, identifying facilitators and ameliorating context-specific barriers, contributing to the delivery of education packages and providing day-to-day support to AHPs as they engage in project activities and outcomes.Identification of ‘customised e-evidence library—‘CP Decision’ [CP Decision is to decrease the amount of time it takes AHPs to retrieve the highest levels of published evidence.Provision of a ecision’ —to enablecision’  and willNegotiated education and professional development days for AHPs at partner organisations (implemented by the project investigators and the organisation-based knowledge brokers) about ‘how to’ implement or administer the current and most effective treatment and measurement options for cerebral palsy, using concrete and precise descriptions of the clinical processes involved.electronic cerebral palsy clinical outcomes database . This electronic tool will be used by AHPs to record routine valid and reliable clinical measurements of participating children and to summarise the therapeutic interventions provided to these children. Through instant generation of an electronic report, the tool will provide real-time feedback about changes in outcomes of individual children over time, guiding evidence-based clinical decision-making to support direct therapeutic intervention and timely referral to ancillary services.Provision of an The tailored multi-strategy intervention aims to address known barriers to evidence use and will consist of:Change in AHP behaviour  will be determined in two ways:(i).The Best Service Best Time Evaluation questionnaire of evidence-based practice behaviours reported by participating AHPs .Data extracted from the electronic cerebral palsy clinical outcomes database. This tool and associated database has been developed for the Australian context by Cerebral Palsy Alliance, the study comparison site, and is based on the Swedish cerebral palsy follow-up surveillance programme -16. It iChildren aged less than 6 years will be assessed at 6 monthly intervals; children aged 6–18 years will be assessed at baseline, 6, 12 and 24 months. Data extracted from the clinical outcomes database to determine change in AHP behaviour will include proportion of eligible professionals routinely contributing data, proportion of clinical outcome measures completed per child, proportion of cerebral palsy caseload with data reported and comparisons between expected proportions in the population who might be eligible for specific management, such as hip surveillance, and the observed proportions receiving them.Change in AHP evidence-based practice knowledge (research question 1) will be measured using the Evidence Based Practice and Outcome Measurement Competency quiz [ncy quiz  that hasImpact of organisational factors on implementing the strategies (research questions 2 and 3) will be assessed using mixed methods, including a questionnaire that evaluates AHP perception of the extent to which organisational factors act as supports or barriers to implementation of evidence-based practices  and quaLongitudinal outcomes of children with cerebral palsy (research question 4) will be assessed using clinical data extracted from the clinical outcomes database. Specific musculoskeletal measurements will be modelled from data collected at 6, 12 and 24 months.Additional data relating to potential confounders for uptake of evidence-based practices will be collected including organisational characteristics such as profile of children attending the service , size and number of sites that an organisation operates from and professional characteristics of AHPs including discipline, years of experience and proportion with higher degrees. In addition, a record of implementation at each site, including number and timing of recruitment of knowledge brokers and staff, days and topics of professional development provided and frequency of hits (number of times accessed) on the e-library, will be kept to provide process measures for the study.Statistical plans addressing each specific research question will be pre-specified, to prevent bias due to post hoc analyses. Cross-sectional data will be examined and reported; however, primary analyses will focus on the longitudinal design of this study, assessing change over time in AHP evidence-based practice behaviours and in clinical outcomes for participating children.Quantitative analyses will be carried out with multivariate statistical models such as population-averaged generalised estimating equations and subject-specific generalised linear and latent mixed models. These models allow for correlated longitudinal data structures and intraclass correlation coefficients (required due to children being clustered within AHPs and AHPs within organisations). In addition, these models can include outcomes of mixed types including counts, ordered and unordered responses, and dichotomous and metric outcomes. Potential confounders will be examined, and study sites will be treated as covariates to account for differing adoption of new practice rates. The significance of the covariates will be ascertained with 95% confidence intervals.Qualitative focus group and interview data will be digitally recorded and transcribed, coded and analysed using a grounded theory approach to thematic analysis . Themes Based on organisational commitment to the project, and expected workforce changes during the course of the study, it is anticipated that 80% of the eligible AHPs will take part in the study . Calculations indicate that this sample will be sufficient to detect a difference of 6 points on the Best Service Best Time Evaluation with >90% power.Pre-study estimation of the number of participating children suggests a sample size of 614 may be achieved .A 10% arithmetic difference between baseline and subsequent child-based quality measures (e.g. range of movement) will be able to be detected with >90% power .The project steering committee will comprise an external chair, the chief investigators, one associate investigator from each partner organisation, the project manager and a consumer representative. The steering committee will hold four face-face meetings in the course of the project and meet monthly by teleconference. Local advisory committees will be established in each partner organisation. At a minimum, these committees will include an associate or chief investigator, who also sits on the steering committee, one knowledge broker, one AHP leader/manager from within the organisation and a consumer representative. These groups will oversee the site-specific implementation of the project, identify and ameliorate risks to implementation, ensure record keeping associated with project implementation is maintained and report monthly to the steering committee on project progress. A data monitoring committee will also be established, consisting of the chief investigator, project manager and two other members of the research team to monitor the implementation of the project and audit data collection processes. Day-to-day management of the project will be undertaken by a full-time project manager supported by one part-time research assistant per state.Governance for the project will include a project steering committee, partner organisation local advisory groups and a data monitoring committee. To ensure integrity in the management of the project across multiple organisations and to safeguard participating AHPs and patients’ rights and the security and quality of data, project-specific standard operating procedures will be developed and provided to each organisation for implementation. Standards will be developed in the following areas: procedure for consenting AHPs, procedure for consenting children and families, clinical data collection and electronic data entry.Data will be managed and analysed centrally. Site-specific consent forms and AHP questionnaire data will be scanned locally and hard copies forwarded to the coordinating centre. AHP questionnaire data entry will be completed by state-based research assistants using standardised spreadsheets; a minimum of 20% of questionnaire data will be double entered to determine data quality. Child data collected during the clinical assessment will be entered by the assessing AHP or state-based research assistant into the electronic cerebral palsy clinical outcomes database. This database will provide ‘real-time’ feedback to professionals about changes in children’s status on reassessment, flagging whether the child has lost function and requires immediate review or is progressing as expected. This process confers validity to both the measurement and data entry processes, as deviation from normal parameters is flagged in real time.The evidence library (CP Decision) and electronic database are pre-existing intellectual property of the Cerebral Palsy Alliance and have been provided as an ‘in-kind’ contribution for use within this research project. Knowledge generated within this project will be the collective property of the research team. A publication plan will be developed by the steering committee, including identification of named authors based on contribution to each manuscript and acknowledgment of all team members and organisations.Study findings will be disseminated through publication in peer-reviewed journals and presentation at relevant academic and clinical conferences and forums. Key findings will also be available on the study web pages  and willThe study is ongoing. We have collected questionnaire data from AHPs and conducted focus groups but have not commenced data cleaning or analyses. We have not yet extracted data from the cerebral palsy clinical outcomes database. Data collection will continue until the end of 2015.This project aims to reduce the research-practice gap in provision of AHP services to children with cerebral palsy via a multi-strategy intervention. The project has the potential to influence future practice with children with cerebral palsy. The demonstration of effective uptake of routine clinical assessment in multiple organisations will positively impact the implementation of outcome measurement in routine practice across Australia and internationally. The use of the electronic clinical outcomes database will support endeavours to link child outcomes data with diagnostic data held on the Australian Cerebral Palsy Register (ACPR). Together, these databases can enhance new knowledge about cerebral palsy.With the implementation of the National Disability Insurance Scheme (NDIS) in Australia , serviceIn the long term, this partnership project aims to embed systems, processes and professional behaviours within organisations in the health industry that will increase the responsiveness of health services to new evidence to inform clinical practice with children with cerebral palsy. The research utilisation model that includes identifying and supporting knowledge brokers, providing up-to-date summarised evidence via electronic platforms and routine data collection with real-time feedback will drive long-term, population-based research and practice. It will provide the structures and processes to successfully link research, AHP actions and child and family outcomes where the child has cerebral palsy.


Studies in U. maydis and Aspergillus nidulans reveal a complex interplay of the motor proteins kinesin-3 and dynein, which co-operate to support bi-directional motion of early endosomes. Genetic screening has shed light on the molecular mechanisms underpinning motor regulation, revealing Hook protein as general motor adapters on early endosomes. Recently, fascinating insight into unexpected roles for endosome motility has emerged. This includes septin filament formation and cellular distribution of the machinery for protein translation.Hyphal growth of filamentous fungi requires microtubule-based long-distance motility of early endosomes. Since the discovery of this process in  Current Opinion in Microbiology 2014, 20:10–18Host–microbe interactions: fungiThis review comes from a themed issue on Jay C Dunlap and Jean Paul LatgéEdited by Issue and the EditorialFor a complete overview see the Available online 15th May 2014http://dx.doi.org/10.1016/j.mib.2014.04.001http://creativecommons.org/licenses/by/3.0/)1369-5274/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license , named Yup1. Temperature-sensitive Yup1ts mutants showed defects in vacuolar sorting of FM4-64, a marker dye for tracking endocytic uptake in fungi [A. nidulans [Neurospora crassa [Box 1Uromyces fabae with the lipophilic marker FM4-64. At this time, the dye was already well-established as a tracer for the endocytic pathway in the yeasts Saccharomyces cerevisiae [Ustilago maydis [Magnaporthe grisea [Aspergillus nidulans [Neurospora crassa and 6 additional other fungi [U. maydis, A. nidulans, A. oryzae, Candida albicans, Ashbya gossypii and N. crassa [Filamentous fungal growth is characterized by apical extension of the hyphal cell. This process requires the constant supply of membranes and proteins, such as cell wall-forming enzymes, to the growing hyphal tip. The Spitzenkörper, an apical vesicle accumulation found in many fungal species , 80, 81,revisiae . Therefoo maydis , 20, Mage grisea , Asperginidulans , Neurosper fungi  confirmeer fungi , 85. In er fungi . To-dateer fungi . In addier fungi , 88, liver fungi , 62, com. crassa , 95, 96,. crassa , 15).The endocytic system comprises several compartments that receive cargo from the plasma membrane for processing and recycling back to the cell surface or its degradation in the lysosomes . Early en yeasts , 9, 10, n yeasts , 12, 13.n yeasts , 15), bu. maydis   interase RabB . WhetherU. maydis also controls kinesin-3 binding to EEs. A short and highly conserved part of the N-terminal coiled-coil region of Hok1 is crucial for this, but also for dynein binding to EEs. This suggests that an unidentified Hok1-binding protein bridges between Hok1 and both motors. In U. maydis, homologues of the human proteins FTS and FHIP bind to Hok1 and localize to EEs [S. cerevisiae and S. pombe. As both are found in filamentous fungi and in animals [Surprisingly, Hok1 in e to EEs ••. The pe to EEs ••). Inte animals ••, they A. nidulans, A. oryzae, N. crassa and Ashbya gossypii [U. maydis [A. oryzae uptake of uric acid-xanthine permease, from the plasma membrane and delivery to vacuoles, occurs in the absence of EE motility [A. nidulans, EEs convert into late endosomes and, finally, subapical vacuoles [A. nidulans) is replaced by Rab7 (RabS in A. nidulans). In temperature-sensitive dynein mutants, retrograde EE motility is blocked and Rab7-positive late endosomes/vacuoles, stained with the blue dye CMAC (7-Amino-4-Chloromethylcoumarin), cluster near the hyphal tip. These results suggest that endosomes mature and fuse to form vacuoles as they move away from the tip [U. maydis [hook deletion mutants (see above), or when the dynein heavy chain was inactivated in temperature-sensitive mutants, EEs formed clusters at the hyphal tip and delivery of FM4-64 to the vacuoles was blocked [Endocytic recycling near the hyphal apex supports fungal tip growth in gossypii , 62, 63 . maydis . Recycli. maydis , 24, whimotility . While tmotility • demonstvacuoles . During  the tip •. A role. maydis ••. When  blocked ••. Surpr blocked ••, whileU. maydis, the putative RNA-binding protein Rrm4 moves along microtubules [in vivo observation of fluorescent Rrm4 particles demonstrated that Rrm4 motility is bi-directional and that extended runs of these particles are rare [cdc3 and cdc12 is actively-translated on moving EEs and both proteins bind to EEs. Interestingly, the presence of Cdc3 on EEs requires Cdc12, suggesting that assembly of septin complexes occurs on EEs. This is important for proper septin filament formation and, in turn, hyphal growth.An unexpected insight into a cellular role for EE motility in fungi was provided by work on RNA-binding proteins. In otubules . This mootubules •, motorsotubules , 37. Indotubules •. Rrm4 botubules . It was otubules . Howeverare rare . These rare rare •• providU. maydis confirms translation of mRNA on moving EEs, but it came to the conclusion that ribosome binding to mRNA serves to distribute polysomes throughout the cell [U. maydis revealed that passive diffusion is too slow to ensure even cellular distribution of the ribosomal subunits [rrm4 and the kinesin-3 gene kin3 exhibit a very similar phenotype [U. maydis.A second study in the cell ••. Ribosthe cell . Indeed,subunits ••. Mathesubunits ••. Whilehenotype ••, suggeU. maydis and A. nidulans has elucidated the molecular machinery underlying EE motility and has provided insight into fundamental principles of motor co-operation in membrane trafficking [Aspergillus parasiticus involves EEs [U. maydis and A. nidulans has turned this pioneering field into a fast-moving research area in fungal cell biology (The existence of endocytosis and EEs in fungi was a matter of debate until relatively recently. Today, it is well-established that endocytic recycling supports fungal morphology and that EEs rapidly move within the fungal cell. Intensive research in fficking . Most relves EEs  (J.E. Lilves EEs . Highly  biology . Future • of special interest•• of outstanding interestPapers of particular interest, published within the period of review, have been highlighted as:


In 2012, the World Health Organization (WHO) published recommendations on the use of optimization or “task-shifting” strategies for key, effective maternal and newborn interventions (the OptimizeMNH guidance). When making recommendations about complex health system interventions such as task-shifting, information about the feasibility and acceptability of interventions can be as important as information about their effectiveness. However, these issues are usually not addressed with the same rigour. This paper describes our use of several innovative strategies to broaden the range of evidence used to develop the OptimizeMNH guidance. In this guidance, we systematically included evidence regarding the acceptability and feasibility of relevant task-shifting interventions, primarily using qualitative evidence syntheses and multi-country case study syntheses; we used an approach to assess confidence in findings from qualitative evidence syntheses  approach); we used a structured evidence-to-decision framework for health systems (the DECIDE framework) to help the guidance panel members move from the different types of evidence to recommendations.The systematic inclusion of a broader range of evidence, and the use of new guideline development tools, had a number of impacts. Firstly, this broader range of evidence provided relevant information about the feasibility and acceptability of interventions considered in the guidance as well as information about key implementation considerations. However, inclusion of this evidence required more time, resources and skills. Secondly, the GRADE-CERQual approach provided a method for indicating to panel members how much confidence they should place in the findings from the qualitative evidence syntheses and so helped panel members to use this qualitative evidence appropriately. Thirdly, the DECIDE framework gave us a structured format in which we could present a large and complex body of evidence to panel members and end users. The framework also prompted the panel to justify their recommendations, giving end users a record of how these decisions were made.By expanding the range of evidence assessed in a guideline process, we increase the amount of time and resources required. Nevertheless, the WHO has assessed the outputs of this process to be valuable and is currently repeating the approach used in OptimizeMNH in other guidance processes. In 2012, the World Health Organization (WHO) published evidence-based recommendations regarding the use of optimization or “task-shifting” strategies for key, effective maternal and newborn interventions (OptimizeMNH) [While task-shifting strategies have the potential to increase access to care in settings with critical shortages of specialised health workers, there is also concern that the delivery of health care by health workers with less training could cause harm to people already in vulnerable situations. The effectiveness and safety of such interventions therefore needs to be rigorously evaluated. However, task-shifting strategies that have been assessed as effective and safe in the context of experimental studies may be challenging to implement at scale within a health system. The shifting of tasks from one group of health workers to another can involve social, behavioural and organisational change and, like other complex interventions, its success may depend not only on characteristics of the intervention itself but also on characteristics of the systems in which the intervention is implemented or on interactions between properties of the intervention and systems –4. The sAs these issues can represent important challenges to successful implementation, information about an intervention’s feasibility and acceptability can therefore be as important as information regarding intervention effectiveness and safety when recommendations are made. Initiatives that aim to improve the quality of guidelines, such as the AGREE II instrument, also emphasise the importance of seeking stakeholders’ views and preferences, and of discussing potential organisational barriers to the application of recommendations . But desAs the technical team responsible for developing the OptimizeMNH guidance Table , we saw Broadening the range of evidence used in the guidance by including systematic reviews of qualitative research, multi-country case study syntheses and results from a primary qualitative studyUsing the Grading of Recommendations, Assessment, Development and Evaluation-Confidence in Evidence from Reviews of Qualitative Research  approach to assess our confidence in the evidence from systematic reviews of qualitative researchUsing a structured health systems framework (the DECIDE framework) to help the guidance panel move from this wider range of evidence to recommendationsIn developing the OptimizeMNH guidance, we followed the standard procedures set out in the WHO’s Handbook for Guideline Development . These pThe WHO’s Handbook for Guideline Development describes not only several types of questions that can legitimately be addressed in a WHO guideline, including the effectiveness or efficacy of an intervention, but also the negative consequences of the intervention, its social acceptability and its cost-effectiveness. The Handbook describes how qualitative evidence synthesis can be used to explore contextual barriers as well as values and preferences . The maiFor OptimizeMNH, we systematically assessed the effectiveness and safety of the relevant task-shifting interventions through systematic reviews and the use of GRADE. In addition, we used an innovative approach in this stage of guidance development by systematically including other types of evidence. Specifically, we compiled evidence on the acceptability of the interventions among health workers, recipients of care, policy makers and other stakeholders and on the feasibility of these interventions, taking into account the organisational changes to health systems that each task-shifting intervention would entail.While systematic reviews of randomised trials are seen as the most robust source of evidence when assessing intervention effectiveness, this approach is not well-suited for exploring issues surrounding intervention acceptability and feasibility, particularly for more complex health and social interventions , 16. To The qualitative evidence syntheses provided us with information that was clearly relevant to the questions we had asked. However, most of the studies were of relatively small-scale or pilot programmes, often implemented in the context of research, and focused on factors unfolding at the level of programme delivery in communities and primary care facilities. We decided therefore to complement this evidence with two multi-country case study syntheses focusing on factors affecting the implementation of large-scale programmes. When selecting these programmes, we aimed for broad geographical representation and looked for countries in Africa, Asia and South America that had implemented large-scale programmes. To make the synthesis manageable, we limited ourselves to seven programmes and only selected programmes where a reasonable amount of English-language documentation was available. The multi-country case study syntheses aimed to identify “upstream”, system-level factors associated with programme policies, governance, financing, planning, management and organisation , 22. TheAnother limitation of the evidence we identified through the qualitative evidence syntheses was that it focused primarily on the views and experiences of service users and healthcare providers but paid less attention to the viewpoints of programme managers, policy makers and other stakeholders. We attempted to address this imbalance by carrying out our own primary study. We undertook qualitative analyses of the views and experiences of those contributing to the “Health Information For All By 2015” electronic discussion list, which covers a diverse membership of programme managers, healthcare providers, policy makers, academics and others from 170 countries . These aWhen presenting the evidence from the qualitative evidence syntheses, the country case studies and the primary qualitative studies, we attempted to extract findings that were relevant to specific recommendations being considered by the guidance panel and that concerned specific tasks and groups of health workers. These findings were used to (a) support the guidance panel when reaching recommendations and (b) develop information for end users of the guidance regarding implementation considerations for each recommendation. Tables We also wanted to offer those using the OptimizeMNH guidance more general information about the acceptability and feasibility of task-shifting strategies. We therefore carried out a “cross-cutting” analysis of findings from all of the sources described above. This cross-cutting analysis provided evidence regarding task-shifting in general where no direct evidence was available for specific task-shifting interventions. The cross-cutting analysis also contributed to a chapter in the WHO OptimizeMNH guidance on overarching implementation considerations.The WHO Guideline Handbook notes that guideline technical teams need to provide an assessment of the quality of the evidence included in a WHO guideline . For eviWork to develop this approach was carried out in collaboration with other qualitative researchers , informeWhen assessing the different factors that influence recommendations, including effectiveness, acceptability, feasibility, and cost, the Guideline Handbook  suggestsThe DECIDE framework aims to help guidance panel members move from evidence to health system recommendations by informing judgements about the balance of consequences of each option. The framework is based on a review of relevant literature, brainstorming, feedback from stakeholders , and theThe benefits and harms of the intervention/s (sometimes referred to as “effectiveness and safety”)Anticipated resource useAcceptability of the intervention/sFeasibility of the intervention/sFor each guidance question, the framework presented, in a structured format, a summary of the evidence regarding the following considerations:A judgement regarding the balance of desirable and undesirable consequences for the intervention/sA recommendation and a justification for thisImplementation considerations for the intervention/sRelevant monitoring and evaluation/research priorities in relation to the intervention/sFor each of these elements, the framework also included an assessment of the certainty of the evidence, using GRADE (for evidence of effectiveness) and CERQual . The following were also included for each guidance question:In addition to the evidence collated in the DECIDE frameworks, full evidence profiles for the reviews of the effectiveness of interventions, as well as summaries of findings for the qualitative evidence syntheses on the acceptability, feasibility and implementation of these interventions, were made available to the guidance panel. These summaries were, in turn, linked to full systematic reviews. The DECIDE Team also prepared a video to help guidance panel members understand the purpose of the framework and how to use it. This was made available prior to the guidance panel meeting and also shown at the start of the meeting.The first innovative approach that we used in the development of the OptimizeMNH guidance was the systematic inclusion of additional types of evidence to complement the evidence of effectiveness Table . This apWe had originally planned to gather evidence about stakeholder acceptability and feasibility through qualitative evidence syntheses only. As described above, these syntheses, which only included published qualitative studies, primarily offered evidence surrounding factors and stakeholders at the community or primary healthcare facility level. This led us to carry out the multi-country case studies, where we included a broader set of information sources, and also led us to carry out our own primary study among stakeholders poorly represented in the qualitative evidence syntheses. In retrospect, we think that the findings of this primary study should have been included in the qualitative evidence syntheses rather than being treated as a stand-alone product.Although this innovation expanded the preparatory work needed for the guidance, we would argue that the inclusion of evidence from qualitative evidence syntheses and country case study syntheses offered relevant information for the guidance panel on the feasibility and acceptability of the interventions. When such evidence is not systematically assessed and included, acceptability and feasibility issues may either be overlooked altogether or incorporated into guideline decisions based only on anecdotal evidence. Our experience from the development of the OptimizeMNH guidance suggests that the inclusion of evidence from qualitative evidence syntheses and country case study syntheses reduced the use of anecdotal evidence by guidance panel members when assessing the balance of consequences for each guidance question. In addition, our use of such evidence appeared to address guideline panel members’ perceptions that the WHO often over-emphasises evidence from randomised trials at the expense of evidence from programme experience. One additional benefit of synthesising relevant qualitative evidence was that we were able to use this to develop implementation considerations for task-shifting in maternal and newborn health .Our second innovation was the use of the GRADE-CERQual approach in order to systematically and transparently assess our confidence in findings from the qualitative evidence syntheses conducted to inform the guidance.Our use of CERQual was received well by the guidance panel, in part because it addressed the need to systematically incorporate a wider range of evidence into the guidance process. The approach also had a number of advantages. When making recommendations, all guidance panels need to take into account how confident they can be in the underlying evidence. Had we not provided the OptimizeMNH panels with the CERQual assessments of our confidence in the findings from the qualitative evidence syntheses, they would have had to make their own judgments and may not have done this in a systematic way. The use of CERQual also allowed us to identify and highlight gaps in the evidence. For instance, where we assessed the confidence in the evidence for a qualitative finding to be low or very low, this was an indication that further research was needed in this area. These research gaps were also reflected in the information presented to the guidance panel and carried through to the recommendations.We were initially concerned that using the CERQual approach would confuse guidance panel members as they would not have encountered this approach before. In practice, this did not appear to be a problem, probably because members were already familiar with GRADE for assessing findings regarding the effectiveness of interventions, which uses the same principles, and because the panel was briefed on the approach at the start of the meetings.Some of the findings contributing to OptimizeMNH were based on a very wide range of evidence types. In particular, the country case studies included both qualitative and quantitative studies as well as programme reports, which often did not provide detailed descriptions of methods used. Using CERQual to assess our confidence in the findings from the country case study syntheses was not feasible as the CERQual approach is not designed, at present, to accommodate this range of evidence .Our final innovation was the use of DECIDE evidence-to-decision frameworks  to preseThe use of the evidence-to-decision frameworks also led to a number of challenges. First of all, preparation of the frameworks took considerable time in advance of the panel meeting, although this may have saved time later on when preparing the final guidance document. Secondly, because the DECIDE framework is a new tool, it required some explanation in advance of the panel meetings. However, panel members appeared to grasp the function and content quickly, and the informal feedback on the framework was positive.Because the OptimizeMNH guidance included a very large number of recommendations , the amount of time available in the panel meetings to discuss each evidence-to-decision framework was limited. The inclusion of additional types of evidence also added to the amount of information that panel members were expected to read. Nonetheless, our experience suggests that the structured format of the DECIDE framework allowed the technical team to present a large and complex body of evidence to panel members in a fairly straightforward and easy-to-assimilate way. Further work is now needed to explore guidance panels’ views of such evidence-to-decision frameworks and to examine how the presentation of evidence in these formats impacts on the deliberations and decisions of guidance panels and on the transparency to users of these decisions.In this paper, we have described our use of a number of innovative strategies to expand the range of evidence used to develop WHO global recommendations and discussed our experiences with these strategies. Expanding the range of evidence contributing to a guidance process increases the amount of time and resources needed and the range of skills required within the technical team developing the guidance. However, our experience with the OptimizeMNH guidance suggests that such efforts may be valuable, particularly for recommendations on more complex health and social interventions. This view is supported by efforts within WHO to replicate the OptimizeMNH approach in other guidance processes . When coAs more qualitative evidence syntheses are produced, methods for synthesising this type of evidence are becoming more sophisticated and the number of people able to produce these types of syntheses is growing. These developments will make the process of including qualitative evidence in evidence-to-decision processes easier in the future. However, a number of challenges remain, as discussed above. Elsewhere, we have described how evidence from qualitative research can be used in developing guidelines , includiOur experience from OptimizeMNH suggests that relevant programmatic experience regarding “upstream” systems-level factors is often unexplored or undocumented using traditional research approaches. Researchers should explore these issues to a greater extent . AlongsiThe OptimizeMNH experience suggests that the DECIDE evidence-to-decision frameworks are a useful way of guiding panels through a wide range of evidence and towards the development of transparent recommendations. We have learnt a great deal about how to populate these frameworks with evidence of the effectiveness, feasibility and acceptability of health interventions. However, more research is needed, in particular on how these kinds of evidence are used by guidance panels in their decision-making and how different kinds of evidence influence the final recommendations made. In addition, we need further worked examples of approaches for including evidence regarding resource use and cost-effectiveness. This is one area that those involved in the DECIDE work are exploring .Finally, we need to explore how this type of health system guidance can best be disseminated to and utilised by end users, including national and regional policy makers and programme planners. For most health systems questions, evidence regarding effectiveness, acceptability, feasibility, and resource use is all likely to be context-specific to some degree. End users therefore need help in adapting the recommendations to their own contexts. The OptimizeMNH guidance includes a workbook that specifically aims to help end users contextualise the recommendations . However