Clinical practice guidelines are developed to improve the quality of healthcare. However, clinical guidelines may contribute to health inequities experienced by disadvantaged groups. This study uses an equity lens developed by the International Clinical Epidemiology Network (INCLEN) to examine how well clinical guidelines address inequities experienced by individuals with intellectual disabilities.Nine health problems relevant to the health inequities experienced by persons with intellectual disabilities were selected. Clinical guidelines on these disorders were identified from across the world. The INCLEN equity lens was used as the basis for a purpose-designed, semistructured data collection tool. Two raters independently examined each guideline and completed the data collection tool. The data extracted by each rater were discussed at a research group consensus conference and agreement was reached on a final equity lens rating for each guideline.Thirty-six guidelines were identified, one of which (2.8%) explicitly excluded persons with intellectual disabilities. Of the remaining 35, six (17.1%) met the first criterion of the equity lens, identifying persons with intellectual disabilities at high risk for the specific health problem. Eight guidelines (22.9%) contained any content on intellectual disabilities. Six guidelines addressed the fourth equity lens criterion, by giving specific consideration to the barriers to implementation of the guideline in disadvantaged populations. There were no guidelines that addressed the second, third, and fifth equity lens criteria.The equity lens is a useful tool to systematically examine whether clinical guidelines address the health needs and inequities experienced by disadvantaged groups. Clinical guidelines are likely to further widen the health inequities experienced by persons with intellectual disabilities, and other disadvantaged groups, by being preferentially advantageous to the general population. There is a need to systematically incorporate methods to consider disadvantaged population groups into the processes used to develop clinical guidelines. International health policy is focused on tackling health inequalities . Howeverinequalitiesdisparities, and inequities have been used differently across geographical settings and specialities. Since the terms inequalities and disparities are used interchangeably, we will use inequalities in this paper. In this paper, we use the definitions of health inequalities and inequities provided by Whitehead [The terms hitehead . Health hitehead . Health Individuals with intellectual disabilities have consistently been reported to experience significant health inequalities -10. IndiClinical guidelines aim to improve the quality of healthcare and patient outcomes by systematically evaluating the evidence base and contributing to cost-effective healthcare . ClinicaThe aim of this study was to examine whether clinical guidelines address the health inequalities experienced by people with intellectual disabilities. Three research questions were examined:1. Do clinical guidelines identify individuals with intellectual disabilities as a group who are at increased risk of the disorder?i.e., statements and recommendations)?2. Do clinical guidelines include content relevant to the specific health needs of persons with intellectual disabilities  supports the role that clinical guidelines can have in influencing practice and potentially reducing health inequities. To support groups developing clinical guidelines that address health inequities, INCLEN developed an “equity lens” to evaluate how well a clinical guideline addresses issues of equity . This waThis study used the INCLEN equity lens to examine whether existing clinical guidelines address the health inequities experienced by people with intellectual disabilities. We also looked in more detail at the information provided on the guideline development process to identify potential means to address the health inequities experienced by individuals with intellectual disabilities and other disadvantaged groups.To answer the research questions, the INCLEN equity lens was used to inform the design of a semistructured data collection tool, to extract information from the guidelines. Additional questions to look in more detail at the guideline development process and the content of guidelines were inserted. The data collection tool was divided into three sections:1. Population relevance:· Are any population groups, and specifically persons with intellectual disabilities, excluded from the guideline remit?· Are groups at high risk of a disorder and, specifically, are persons with intellectual disabilities identified (equity lens criterion one)?2. Guideline content:· Are statements relevant to the specific health needs of individuals with intellectual disabilities made? Statements were divided into four categories: diagnosis and intervention (equity lens criteria two and three), guideline implementation (equity lens criteria four and five), and a category for other statements.· Are recommendations specific to the health needs of individuals with intellectual disabilities made?3. Guideline development process:· Is an expert in intellectual disabilities included in the guideline development group?· Is there evidence that the design of the literature search strategy could identify studies relevant to intellectual disabilities, for example, the use of relevant search terms or the citation of specific references relevant to intellectual disabilities?· Is there evidence of consultation with people with intellectual disabilities and /or their carers in the development and implementation of the guideline (equity criterion three)?To meet the aim of the study, it was necessary that clinical guidelines on these disorders could meet at least one, or more, of the equity lens criteria. In the description of this first equity criterion , it is sOn this basis, we selected nine health problems with research evidence from population-based, epidemiological studies demonstrating higher rates of these disorders in individuals with intellectual disabilities ,13,21. Ihttp://www.guideline.gov).Since clinical guideline development is of relevance to health inequities globally, the inclusion of guidelines published in different countries was felt to be important. The National Guideline Clearing House lists guidelines produced worldwide so was used to identify a representative sample of relevant clinical guidelines  to identify any content of specific relevance to intellectual disabilities. Since there are several different terms for intellectual disabilities used internationally, individual search terms used to identify relevant content included In extracting data relevant to the first equity lens criterion, we wanted to examine whether guidelines did not see the identification of high-risk groups as part of the guideline remit or whether they were including information on some high-risk groups and omitting intellectual disabilities. To achieve this, the raters scored guidelines on whether the guideline identified any population group at high risk of the health problem, and then separately scored whether the guideline identified individuals with intellectual disabilities at high risk.The 36 guidelines in Table One of the guidelines (2.8%) explicitly excluded persons with intellectual disabilities. Of the remaining 35, six (17.1%) met the first criterion of the equity lens, identifying persons with intellectual disabilities at high risk for the specific health problem.As described above, the study design meant that all 36 guidelines could potentially meet the first equity lens criteria for intellectual disabilities. Although 29 guidelines (82.9%) met the first equity lens criteria by identifying population subgroups at increased risk for this specific disorder, only six of these (71.1%) identified people with intellectual disabilities at increased risk of the disorder , five (14.3%) included content relevant to interventions , and seven (20%) included other relevant content . The Scottish Intercollegiate Guideline Network (SIGN) obesity guideline included an appendix listing useful resources for professionals working with individuals with intellectual disabilities or communication difficulties.In order to look beyond the equity lens criteria, we examined the 35 guidelines for all content relevant to specific needs of people with intellectual disabilities. Eight guidelines (22.9%) contained any content making specific reference to intellectual disabilities. Of these eight, seven (20%) contained statements on diagnosis . As shown in Table Four (11.4%) of the 35 guideline development groups included members with intellectual disabilities expertise. An intellectual disabilities dietician was on the specialist review panel for the SIGN obesity guideline but was not part of the development group.This lack of expertise in the development guideline groups may, in part, explain the small number of guidelines identifying individuals with intellectual disabilities at high risk (equity criterion one) or making specific reference to intellectual disabilities anywhere in the guideline. This effect could have been compounded by the fact that only two (5.7%) of the guidelines contained evidence that the literature search strategy had included search terms that would have identified evidence relevant to the health needs of individuals with intellectual disabilities (NICE obesity and NICE epilepsy). Although several guidelines that did not use specific intellectual disabilities search terms included references relevant to intellectual disabilities in the bibliography , it could be that the methodology used to identify relevant evidence does not readily identify intellectual disabilities research. One final point of note from the examination of the guideline development process is that only one guideline (SIGN epilepsy) carried out consultations with service users and service users with intellectual disabilities and carers.This is the first study to examine whether clinical guidelines address the health inequities experienced by individuals with intellectual disabilities. We found that the majority of clinical guidelines did not contain content relevant to intellectual disabilities or meet any of the equity lens criteria for intellectual disabilities. Since there is available evidence to allow all the guidelines to meet equity lens criterion one, the findings of this study suggest that current guideline development processes may be missing an important opportunity to address the inequities experienced by individuals with intellectual disabilities. For example, none of the guidelines on osteoporosis, obstructive sleep apnea, upper gastrointestinal problems, and accidents/injuries or falls identified individuals with intellectual disabilities as being at increased risk. If this had been included in the guidelines, it could have led to better assessment and diagnosis of those health problems that individuals with intellectual disabilities are at high risk of experiencing. Appropriate diagnosis and management would subsequently be expected to reduce the inequities experienced by persons with intellectual disabilities by allowing fairer access to relevant management and services.This study benefited from the use of the INCLEN equity lens, developed by a group of international experts, independent of the research group involved in this study. We found that the five equity lens criteria provided a useful framework to consider whether clinical guidelines address the inequities experienced by individuals with intellectual disabilities. The use of the equity lens as the basis of the study ensures that the process can be repeated in future intellectual disabilities studies and studies examining the relevance of clinical guidelines to other disadvantaged groups.The process used to rate the clinical guidelines was a strength of this study. Three separate aspects of the process reduced the risk of rater error: independent rating of the guidelines by two researchers, use of a standardized data extraction tool, and a consensus group process to agree on final ratings for each guideline. To further improve the rigor of the rating process, any future studies could consider blinding the researchers and consensus process to which guideline was being rated.Since clinical guidelines are of international significance to the inequities experienced by individuals with intellectual disabilities, the inclusion of guidelines from different countries adds to the relevance of the findings. The development of guidelines is highly complex and influenced by multiple factors at any one time. A potential weakness of the study is that the research group has little experience of the complexities surrounding the guideline development process used across the organizations that produced the guidelines included in this study. The study is exploratory in nature and will hopefully allow equity to be considered further as part of guideline development. However, future studies of this nature would benefit from involvement of international experts in clinical guideline development.Several of the guidelines reviewed illustrate that it is possible to improve the equity of clinical guidelines in relation to intellectual disabilities. For example, five guidelines made statements on the barriers to implementation Table . This suINCLEN used the PROGRESS framework shown in Table Previous studies that examined the equity of guidelines regarding gender  and ethnhttp://www.g-i-n.net ) or the Appraisal of Guidelines Research and Evaluation Enterprise . Perhaps the first stage would be to ensure that information about the work on guideline equity by INCLEN is disseminated. A revised AGREE II instrument has been published [The potential solutions shown in Table ublished  and doesublished . One sughttp://www.guideline.gov) does not make reference to any guidelines specifically dedicated to the health needs and priorities of individuals with intellectual disabilities. Hence, it is important that more generic guidelines do address the health needs of people with intellectual disabilities where possible. Findings from this study suggest that, at present, clinical guidelines may be missing the opportunity to have a positive impact on the health inequities experienced by person with intellectual disabilities, and may even be making these worse. Content of clinical guidelines should endeavor to meet the five INCLEN equity lens criteria for individuals with intellectual disabilities and other groups. To achieve this, guidelines should recognize different disease patterns, including different prevalence, incidence, and etiologies; the interventions and supports needed by disadvantaged groups; and any necessary reasonable adjustments to healthcare delivery, organization, and policy in order to equally meet the needs of individuals with intellectual disabilities. For example, recommendations of clinical guidelines for the investigation of upper gastrointestinal cancers—which are more common in individuals with intellectual disabilities [The National Guideline Clearing house website .Bibliography for guidelines used in the study and URLs for online access to guidelines.Click here for file


H. heidelbergensis evolved from H. erectus” (p. 12). These claims are marred by their selective review of the literature; the use of equivocal evidence as definitive support for their interpretation; and the lack of any evolutionary evidence regarding the computations and representations that mediate modern linguistic competence.Dediu and Levinson  link twointernal phonological, syntactic and semantic representations, and nothing in the fossil record is ever likely to tell us: (a) what those representations were like; or (b) whether the human brain had yet formed the necessary connections between, e.g., phonological representations and vocal output. This does not bode well for the type of argument Dediu and Levinson advance, but let us examine the evidence they present.Our language phenotype is a competence consisting of three systems—syntax, semantics, and phonology—that are internal to the mind/brain, along with two mediating interfaces, the first linking the representational/computational systems to external speech or sign, the second linking language to internal thought. The internal combinatorial computations are generative and rule-governed, engaging representations that are both language-specific and domain-general. Generalized claims such as Dediu and Levinson's require evidence for all of these processes. But most of them do not leave fossil evidence; and genetic clarification is unlikely given how poorly we understand simpler phentoypes. For example, though language is expressed through articulate speech today, the anatomical capacity for speech cannot by itself be taken as a proxy for language. The peripheral organs have to connect with the Homo neanderthalensis and Homo sapiens as evidence of conspecificity, minor gene flow is to be expected between closely related sympatric species . Because the phenotype is not specified at the required level of detail for evolutionary analysis, it is difficult to test their evolutionary claims. But this lack of detail does permit them to assert that language competence was likely among Neanderthals, due to nothing more than their large brains, cognitive complexity, and proclaimed conspecificity with modern humans. Still, hominids can be smart without implying modern cognition , among others, so the evidence is actually equivocal. The survey they themselves cite  genomic similarity among Neanderthals, Denisovans and modern humans, Dediu and Levinson present several gene-level commonalities as evidence for Neanderthal genomic compatibility with language, e.g., Dediu and Levinson conclude that (1) “saltationist” stories for language origin must be rejected; (2) language evolved incrementally; (3) gene-culture interaction greatly affected language's “design”; (4) a “deeper” historical linguistics is called for; and (5) modern human languages might not reflect the full space of language possibilities. All this is speculative to the point of irrelevance. (1) is contradicted both by the modern understanding of evolutionary patterns (Thompson, could be any evidence to support such claims. At the archaeological level, our core linguistic competence does not fossilize. As for molecular evidence, we are nowhere near identifying the relevant “language genotype” and they provide no “language phenotype” to guide us. For the present, abstinence from speculation may be the best remedy.In short, Dediu and Levinson's extraordinary claims are not supported by the evidence they present. More significantly, we doubt that there Robert C. Berwick, Marc D. Hauser, and Ian Tattersall contributed equally to the writing of this commentary.


N = 689) dataset including more than 200 left-handers. There were degree of handedness effects on BIS and BAS-Fun Seeking, but effects are largely driven by differences between consistent left-handers and other groups. Choice of cut-off point substantively influenced results, and suggests that unless a suitable sample of left-handers is included, researchers clarify that their degree of handedness effects are applicable only to right-handers. We concur that strength of hand preference is an important variable but caution that differences related to consistency may not be identical in right and left-handers.Hand preference is often viewed as a troublesome variable in psychological research, with left-handers routinely excluded from studies. Contrary to this, a body of evidence has shown hand preference to be a useful variable when examining human behavior. A recent review argues that the most effective way of using handedness as a variable, is a comparison between individuals who use their dominant hand for virtually all manual activities (consistent handers) versus those who use their other hand for at least one activity (inconsistent handers). The authors contend that researchers should only focus on degree of handedness rather than direction of preference (left versus right). However, we argue that the field suffers from a number of methodological and empirical issues. These include a lack of consensus in choice of cut-off point to divide consistent and inconsistent categories and importantly a paucity of data from left-handers. Consequentially, researchers predominantly compare inconsistent versus consistent right-handers, largely linked to memory, cognition and language. Other research on response style and personality measures shows robust direction of handedness effects. The present study examines both strength and direction of handedness on self-reported behavioral inhibition system (BIS) and behavioral activation system (BAS) scores, using evidence from a large ( MacCallchoice of cut-off may influence results.Assuming that handedness should be examined using a non-continuous categorization, the third issue relates to the choice of the cut-off point to divide populations into consistent versus inconsistent handers (IH). The majority of studies use a notional median value of 80 on the EHI to split their groups into consistent and inconsistent e.g., , but it The final, and arguably the most important issue relates to how left-handers fit into this area of research. As a group, left-handers present a challenge to researchers, as they are generally less strongly lateralized than right-handers  and are The current study seeks to examine the issues of cut-off point choice and a lack of empirical data from left-handers, in light of N = 202) number of left-handers, seeking to understand the potential relationship both strength and direction may have on findings. As noted previously, recent work on degree of handedness has been extensively linked to areas of cognition such as memory. The present study extends this into an area of personality, focusing on the relationship between handedness and motivation measured by the behavioral inhibition system (BIS) and behavioral activation system (BAS) scales of In order to do this, the present research examines the influence that strength of handedness has on a dataset which has a relatively large  Systematically examining the influence of cut-off points on strength of handedness findings. This will be done by comparing the dataset using a range of cut-off points derived from both the literature and the data itself.(2) Examining how strength of handedness relates to other variables? This will use regression to examine whether the relationship between variables is the same for both handedness groups.N = 502) were in the 18–29 year category, comprising 76% of males and 71% of females. Two hundred and two were left-handed, 481 were right-handed, and the remaining six had no overall preference.Six hundred and eighty-nine participants took part in this study, 272 were male and 417 were female. The majority  were collected. The EHI  was usedParticipants were recruited from both university and the general public through a sustained campaign of emails, website notices, recruitment at public science centers, and at science fairs over the course of around 12 months. We paid particular attention to the recruitment of left-handers, asking for people who considered themselves to be “left-handed” but we also recruited people more generally and tested all individuals who agreed to participate regardless of hand preference. Testing was carried out via a web-based presentation of the questionnaires, in a randomized order, after participants agreed to participate. The research was approved by the school research ethics committee and abided by the British Psychological Society Code of Human Research Ethics.α was set at 0.05. The strength of hand preference scores were initially examined in terms of median scores, compared by direction of hand preference and gender. This was followed by an investigation of the influence of categorization system on measures of BIS/BAS, with all participants being assigned into Consistent/Inconsistent categories based on six separate classification systems with different cut-off points on the EHI. As gender has been shown to influence BIS/BAS scores, it was also included as a factor in all analyses. For each classification scheme the following three analyses were carried out:Statistical analyses were carried out using SPSS v21. Consistent handedness versus inconsistent handedness regardless of direction [ANOVA 2 (Gender) × 2 (Consistency)].Consistent left , and inconsistent (IH) handers [ANOVA 2 (Gender) × 3 (Consistency)].Consistent left (CL), inconsistent left (IL), consistent right (CR), and inconsistent right (IR) handers [ANOVA: 2 (Gender) × 4 (Consistency)].post hoc tests with Bonferroni corrections were calculated where a main effect of consistency was found. Only significant results will be reported.This was undertaken on BIS, FFFS, BAS-Reward Responsiveness (BAS-RR), BAS-Fun Seeking (BAS-FS), BAS-Drive (BAS-D), as well as a combined BAS score. For the second and third analyses, Handedness was also examined in terms of a regression model, undertaking the following regression analyses:EHI scores to include directionality and absolute scores to assess general relationship to strength.Left versus right  to 57.8% (loosest).F > 4.7, with p values = 0.035 or lower. There were no interactions between gender and handedness categories. The remaining analyses, therefore, focus on the influence of categorization. There were no main effects using either the EHI60 or EHI40 classifications.For all variables  gender was a significant factor. Females were significantly higher on BIS, FFFS and BAS-RR, while males were significantly higher on BAS-D and BAS-FS. All are Table 3 shows that CH had a significantly higher FFFS score only when using the EHI85 cut-off point . Looking at BIS scores, CH had significantly higher values in the EHI85 , EHI80 , and EHI75  classifications. IH had a significantly higher value of BAS-FS, and like the BIS scores, these were only significant in EHI85 , EHI80 , and EHI75  classifications. There were no other significant effects.F = 6.23, p = 0.002. Post hoc analyses revealed that only CR was significantly higher than IH (p = 0.002). For BIS, there was an influence of category on differences from EHI85 through to EHI70, all F > 3.34, p values = 0.036 or lower. Further analyses showed that CL was significantly different from CR in only the EHI85 system, but differed from IH in all classifications. For BAS-FS, there were main category effects in EHI85, EHI80 and EHI75 – F > 4.55, with p values = 0.011 or lower. In all cases, only CL was significantly lower than IH. There was an additional main effect of categorization on BAS-RR, for both EHI75  and EHI70 . In both cases CL were significantly higher than IH, and in EHI70 CL were also significantly higher than CR.There was a significant main effect of category on FFFS scores (EHI85), Table 3). Again the FFFS main effect is linked to the EHI85 classification only, F = 4.27, p = 0.005 and post hoc analyses revealed CR were significantly higher scoring than both IL and IR. The consistent groups did not significantly differ. For BIS, there were significant main effects of classification system from EHI85 through to EHI70, all with F > 2.66, p values = 0.047 or lower. In all cases CL were significantly greater than IR, except for EHI80 (p = 0.052). For EHI85, CL were also significantly higher in BIS than CR and IL. There were also main effects of classification system on BAS-FS scores for EHI85, EHI80 and EHI75 categories . In all three cases, CL were significantly lower than both IL and IR. Finally, for EHI70 there was also a difference in BAS-RR scores, F = 3.07, p = 0.027, where only the CL group had significantly higher scores than CR (p = 0.019).Comparing fully across hand direction and consistency categories helps to clarify where differences are arising  = 50.22, p < 0.0001, R2 = 0.07] and BAS-FS  and was also the case in step 2 (Gender and Handedness), for both BIS  and BAS-FS . In the case of BIS, the introduction of handedness in Step 2 significantly improved the model, F = 4.41, p = 0.012, ΔR2 = 0.012. Both EHI  and absolute strength  were significant but weak predictors of BIS. In the case of BAS-FS, handedness failed to significantly improve the model, and absolute strength was not a significant predictor. In general, handedness only explained a very small amount of overall variance.In step 1 (Gender) the model successfully predicted BIS  and Step 2  but the introduction of strength of handedness in Step 2 did not significantly improve the model. The model failed to successfully predict BAS-FS.Neither BIS nor BAS-FS were significantly correlated with absolute strength. The model successfully predicted BIS in both Step 1  and Step 2  and the introduction of strength of handedness in Step 2 significantly improved the model F = 4.78, p = 0.030, ΔR2 = 0.023, with strength of handedness a significant predictor of BIS . BAS-FS was also successfully predicted in both Step 1  and Step 2  but introduction of handedness in Step 2 did not significantly improve the model.BIS significantly correlated with absolute hand strength The current study did not find a median hand preference score of 80, a value which has been used in most previous studies e.g., . The preExamining the influence of strength and direction of handedness on measures of As expected, it was clear that the choice of cut-off point influenced the extent to which consistency effects on BIS/BAS were shown. This is an important finding, as comparing across other handedness consistency research there is a range of cut-off values for defining the “consistent hander” group, mainly equivalent to EHI85, EHI80, and EHI75 classifications used here. The present work is the first demonstration of the direct effect of choice of how to operationalize the median split point within the same dataset, highlighting the influence and also the need for consensus. A wider examination of the use of median splits across psychology yields a similarly mixed picture. A large proportion of them are largely silent in terms of how a median split is operationalized, for example, indicating that the variable in question was split into two groups based on the median, but not stating what was done with those at the median e.g., . It is c, allowing them to better coordinate across both hemispheres, that is, having better interhemispheric interaction . When taincreased right-hemisphere access arguments for mixed-handers untenable for left-handers. Also contrary to the “IH having an increased right-hemisphere access” model is work by Indeed, for left-handers the right-hemisphere access argument can also be questioned due to anatomical evidence. This suggests that there are structural asymmetries in the central sulcus, where the dorsolateral motor cortex of right-handers is larger in the left-hemisphere, while the opposite is found for left-handers e.g., . AdditioHowever, taking a wider examination of evidence, then it becomes apparent that compared to right-handers, left-handers appear to be more heterogeneous in terms of hemispheric organization and specialization see . Right-ha priori reason to expect that the rate of error would differ according to handedness category, so the main findings should be robust. In addition, although web-based data was collected, the initial recruitment of participants was made before passing on the survey link, meaning that there was some degree of control of the process. It is therefore acknowledged that there will be an element of self-selection in terms of willingness to participate, but again there is no strong reason to believe that this would introduce a bias that would artificially create handedness based results. In order to improve accuracy from self-report questionnaires, future work should include either a pre-existing lie scale or add validity questions, to allow for removal of any clearly invalid responses (The current study has some limitations, including the presentation of questionnaires using a web-based approach. By using this medium, there is the potential problem of participants not responding accurately or honestly. However, while this could occur within the dataset, there is no esponses . FinallyThe present study reinforces the view that consistent left- and right-handers do not always behave in the same way. The clear implication is that researchers need to gather sufficient data on consistent left-handers in order to delineate where behavior either converges with, or diverges from, right-handers. It also highlights the need for the handedness research community to be able to robustly defend the dichotomization of hand consistency on the basis of a strong theoretical and empirical evidence base, including an agreed split-point.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.


Numerous tools and items have been developed in all health areas to assess the risk of bias of randomized controlled trials (RCTs). The Cochrane Collaboration (CC) released a new tool to assess bias in RCTs, based on empirical evidence quantifying the association between some design features and estimates of treatment effects (TEs). However, this evidence is limited to medicine and investigating a selected set of components. No such studies have been conducted in other health areas such as Physical Therapy (PT) and allied health professions. Evidence specific to the PT area is needed to understand and quantify the association between design features and TE estimates to inform practice and decision-making in this field. The overall goal of this project is to provide direction for the design, conduct, reporting and bias assessment of PT RCTs. We will achieve this through the following specific objectives and methods.Cochrane Database of Systematic Reviews. Trials will be evaluated independently by two reviewers using the most commonly used tools in the PT field. A two-level analysis will be conducted using a meta-meta-analytic approach; 2) to identify relevant items to evaluate risk of bias of PT trials, an exploratory factor analysis (EFA) will be used to identify the latent structure of the items; 3) to develop guidelines for the design, conduct, reporting, and risk of bias assessment of PT RCTs, items obtained from the factor analysis and the meta-epidemiological approach will be further evaluated by experts in PT through a web-based survey following a Delphi procedure.1) to measure the association between methodological components and other factors  and TE estimates in RCTs in PT, 40 randomly selected meta-analyses of RCTs involving PT interventions will be identified from the The results of this project will have a direct impact on research and practice in PT and are valuable to a number of stakeholders: researchers when designing, conducting, and reporting trials; systematic reviewers and meta-analysts when synthesizing trial results; physiotherapists when making day-to-day treatment decision; and, other healthcare decision-makers, such as those developing policy or practice guidelines. Randomized controlled trials (RCTs), as well as systematic reviews (SRs) and meta-analyses (MAs) of these trials, are considered the gold standard to evaluate the efficacy and effectiveness of health care interventions . The resIt has been demonstrated that different design features of a trial can have a substantial impact on estimates of treatment effects -7. For eWhile the impact of primary trial bias on evidence synthesis has been recognized for years, the approach to quality assessment has been inconsistent and controversial . Many toAs a result of these shortcomings with existing tools and methods for quality assessment, there has been a shift in the traditional scoring approach to the assessment of trial quality. Instead of examining trial quality with tools that have not been validated and often use composite scores, the assessment of 'risk of bias’ was proposed in 2008 by the Cochrane Collaboration, one of the most important and influential groups working on evidence based practice worldwide ,19 recomMost of the empirical evidence regarding the relationship between trial components and treatment effect estimates comes from RCTs in the area of medicine and is based only on dichotomous outcomes ,6,7. No Therefore, the overall goals of this project are to provide direction for the design, conduct, and reporting of allied health RCTs, especially Physical Therapy (PT) and provide clear benchmarks for evaluating the RoB of RCTs in this area.We will achieve this through the following specific objectives:1) To measure the association between methodological components and treatment effects (TE) estimates in RCTs in PT;2) To determine the influence of other factors  on TE estimates;3) To identify the underlying component structure of items to evaluate risk of bias of PT trials;4) To identify relevant items to evaluate risk of bias of PT trials through experts’ opinion;5) To develop guidelines for the design, conduct, reporting, and implementation of PT RCTs and provide clear benchmarks for evaluating the RoB of PT RCTs.This Research protocol has been approved by the Ethics Board of the University of Alberta (Pro00038172).Cochrane Database of Systematic Reviews  using the words physical therapy or physiotherapy, rehabilitation, exercise, electrophysical agents, acupuncture, massage, Transcutaneous Electrical Nerve Stimulation (TENS), interferential current, ultrasound, stretching, chest therapy, pulmonary rehabilitation, manipulative therapy, mobilization. Meta-analyses and their trials will be included if: 1) they included at least five RCTs comparing at least two interventions, at least one of which is currently or potentially part of PT practice according to the World Confederation for PT (WCPT) [Meta-analyses and their RCTs will be obtained by searching the T (WCPT) ; 2) the Two reviewers  will independently screen the abstracts of the meta-analyses found in the Cochrane database and will analyze all papers initially selected by the abstract or title using the pre-defined inclusion/exclusion criteria (described above). Each criterion will be graded on a yes/no basis. Discrepancies between reviewers regarding inclusion will be resolved through consensus or in consultation with a third reviewer.Most meta-epidemiological work carried out until now has not formally performed sample size calculations since they have been exploratory in nature. However, according to a recent report,  most of A unique code generated by the Reference Manager bibliographic program will be assigned to each meta-analysis and trial that meets the inclusion criteria. This code will be used to randomly select the studies to be analyzed for this project and also to randomize the order of evaluation. The first author will randomly select each of the meta-analyses (MA) to be included, and accompanying trials, by drawing the code of the selected MA from an opaque envelope.All of the trials will be evaluated independently by two reviewers using seven tools with their items  that are most commonly used or most validated in the PT field . AltogetIn addition, the Cochrane Collaboration Risk of Bias (RoB) tool introduced in 2008 [A data extraction template hosted in an access program database will be used to store data extraction results.A review panel comprised of five reviewers with experience in different areas of health sciences research will participate in this study.Reviewer training will be carried out with ten papers not included in the set of papers to be reviewed. Each of the ten training papers will be independently reviewed by all member of the review panel and then discussed by the panel. The first author will perform the training for all raters and will make sure that all reviewers have clarity regarding data extraction.The two reviewers that assessed the same study will compare their assessments. Any discrepancies will be resolved by discussion between the two reviewers. If a consensus rating would not be achieved, then the two reviewers will consult with a third reviewer (first author) to achieve consensus. Consensus answers will be used for all analyses.In order to determine the methodological trial components that affect treatment effect estimates, a two-level analysis will be conducted using a meta-meta-analytic approach with a random-effects model to allow for within and between meta-analyses heterogeneity . The firExploratory factor analysis (EFA) will be used to identify the latent structure of the items from the seven PT existing tools. First, the 45 items will be examined to be sure that there was variability across the three response options. Items with no variability will be deleted at this point. The next step will be to estimate the number of common factors. The Kaiser-Guttman rule  to make recommendations regarding items to use when assessing risk of bias of PT trials. Results of these analyses will be compiled by the research team. If these two approaches  have contradictory results regarding items/factors to be included when evaluating the risk of bias of PT trials, items will be further evaluated by methodological and research experts in PT field. They will provide input for item reduction and selection providing face and content validity evidence to these items.The input of experts will be obtained through a web-based survey following a Delphi procedure. The Delphi technique has been recognized as an appropriate method when the aim of the study is to reach group consensus from individual expert opinion . The DelItems obtained from the analyses  and the evidence obtained from the previous studies carried out by our team will be presented to each of the PT experts. Each expert has to choose the most relevant items s/he considers to evaluate the quality/risk of bias for PT RCTs. Each expert will be asked to formulate the following question for each item: 'is this item relevant to evaluate the quality/risk of bias for PT RCTs?’ The answer options will use a nine-point Likert scale , with a score of 5 indicating no opinion or not enough information or experience to judge. Recommendations will be drafted by the research team and will be presented to the expert’s panel in two or three rounds of internet-based surveys using a password-protected Delphi survey instrument.In addition, personal data such as age, country, place of work and details of research and clinical experience will be collected. It should not take more than 15 minutes to complete all of this activity each time.Experts in PT research from different geographical areas , will be indentified and contacted by Email and they will be invited to participate. To be considered an expert in the field of PT, the participant has to have the following:1) Be a physical therapist or has worked in PT research area for at least five years.2) To have participated in at least one RCT or at least three systematic reviews of interventions in the area of PT.3) To have knowledge/expertise regarding methodological quality/risk of bias of primary research, specifically RCTs in the area of PT.In order to have accurate information regarding items/factors that are necessary to evaluate the risk of bias of PT trials, a selected group of experts (with these characteristics) are needed to be able to discern and determine which of the items/factors are relevant to the study question.Recommendation-specific medians will be estimated for each of the rounds. The inter-rater agreement between participants in each round will be evaluated using the intraclass correlation coefficient (ICC) with 95% confidence intervals (CI).Recommendations rated by < 10% of the experts will be discarded. Recommendations rated by 10% to 90% of the experts will be deferred until the second round. Recommendations rated by > 90% of the experts will be discarded if the overall median score fall within the bottom tertile (1 to 3) and deferred until the second round if the overall median score is 4 to 6. Recommendations with overall median scores within the top tertile (7 to 9) will be classified as follows: those rated by < 90% of the experts will be deferred until the second round, and those rated by > 90% of the experts will be classified as 'high agreement’ if they had an overall median score of 9 or as 'agreement’ if they had an overall median score of 7 or 8.Data from factor analysis, meta-epidemiological approach and Delphi procedure will be integrated by the research team to develop guidelines for the design, conduct, implementation, and reporting of PT RCTs. In addition, guidelines to assess the RoB in PT RCTs will be developed.The results of this project will make an important contribution to research and practice in the field of PT and the allied health professions. This work will be valuable to a number of stakeholders including researchers, systematic reviewers and meta-analysts, methodologists, clinicians, and policy-makers. The results of the proposed project will be the development and refinement of methods of evidence synthesis for PT, so that the final products are valid and meaningful to the end users. First, this knowledge will provide guidance to researchers for the design, conduct, implementation, and reporting of RCTs in the PT field as well as other similar health areas. Second, the findings of this project will provide clearer benchmarks for evaluating the quality of intervention trials for systematic reviewers and meta-analysts in the area of PT. Third, the information will allow practitioners to better determine the most effective interventions in order to provide their patients with treatment options that are likely to yield greater treatment benefits. Fourth, this information will help policy-makers to make informed decisions regarding implementation and support of PT interventions. The results of this research have important implications for knowledge translation by providing empirical evidence that allows more accurate interpretation of study findings. This is critical for informed decision-making in order to understand the likely effect that therapeutic interventions will have when applied in practice. More informed decision making regarding clinical care based on empirical evidence will ultimately improve patient outcomes and will increase efficiency in the health care system because interventions that are most likely to improve patient outcomes will be taken up and implemented.We will develop guidelines for the design, conduct, implementation, and reporting of PT trials and guidelines to assess risk of bias in PT RCTs. These products will be disseminated in different ways to a variety of target audiences. Key groups with an interest in evidence based practice in PT such as the Center of Evidence Based Physiotherapy in the Netherlands, the Australian Center for Evidence Based Physiotherapy, the World Confederation for PT Evidence Based Practice team, the Canadian Physiotherapy Association, the Cochrane Bias Methods Group, and the Cochrane Rehabilitation and Related Therapies Field will be engaged. We will disseminate our results to these groups through standard means  and will also work with these groups to identify tools  and methods  to distribute the results to a wider audience. Results will also be disseminated to the editors of PT journals. We will also develop innovative methods of training and dissemination such as on-line modules and web-based resources. An advisory working committee will be created to guide implementation of the project findings. Researchers and clinicians in the field will also be targeted using traditional dissemination methods such as presentation at international conferences , seminars, workshops as well as publications in relevant peer reviewed journals. The findings of this project will be freely available to other researchers and graduate students on request in the form of a final report.EFA: Exploratory factor analysis; MAs: Meta-analyses; PT: Physical therapy; RCTs: Randomized controlled trial(s); RoB: Risk of bias; SRs: Systematic reviews; TENS: Transcutaneous electrical nerve stimulation; TEs: Treatment effects; WCPT: World confederation for physical therapy.The authors declare that they have no competing interests.Dr. Armijo-Olivo provided concept/idea/research design and writing. Dr. Greta Cummings, Dr. Jorge Fuentes, Dr. Todd Rogers, Dr. Lisa Hartling and Dr. Humam Saltaji provided feedback for concept/idea/research design. All authors critically revised the study protocol and provided final approval of the version to be published.Susan Armijo-Olivo has a BSc in Physical Therapy (PT) from the Pontifical University Catholic of Chile, a MSc PT and a PhD in Rehabilitation Sciences from the University of Alberta. Her major field of research is diagnosis, evaluation, and treatment of patients with musculoskeletal pain especially temporomandibular and cervical spine disorders along with physical therapy evidence based practice, knowledge synthesis and knowledge translation in health research areas. Susan is interested in optimizing and validating methods used to synthesize research and to conduct high quality research particularly in the area of allied health professions. Her post-doctoral project focuses on the methodological predictors of effect size estimates in PT trials. This research is critical to accurately provide conclusions for health care and decision making. This will help disseminate evidence in a useful and understandable way for end-users such as patients, health care clinicians, and policy/decision-makers. This project will be an important contribution to the area of knowledge synthesis and translation in the physical therapy field and allied health professions.


Perceptual discrimination may be interpreted as a decision between alternatives based on available sensory evidence. In many experiments, the different alternatives are encoded by quite distinct neuronal groups. In this case, proposed neural models consider that the decision results from the competition between decision-specific neuronal groups, each of these integrating distinct sensory evidence . Alterna1 and f2) by keeping the memory of the first one during a delay period, have been reproduced in a spiking neuron network model with short-term facilitating synapses [1 > f2 or f1 < f2. Based on the experimental evidence, we model a heterogeneous PD neuronal population, encoding both frequencies in multiple ways. Downstream to the first network, we add a competition-based decision making spiking neuron network [To address these questions, we use a modeling approach. We concentrate on the particular case of the vibrotactile discrimination task on which experimental insight has been accumulated over the last years . The parsynapses . We want network . LearninIn conclusion, the present biologically plausible two-networks model is able to solve a perceptual discrimination task under sequential sensory evidence.


Antidepressants (ADs) are commonly prescribed in primary care and are mostly indicated for depression. According to the literature, they are now more frequently prescribed for health conditions other than psychiatric ones. Due to their many indications in a wide range of medical fields, assessing the appropriateness of AD prescription seems to be a challenge for GPs. The aim of this study was to review evidence from guidelines for antidepressant prescription for non-psychiatric conditions in Primary Care (PC) settings.Data were retrieved from French, English and US guideline databases. Guidelines or reviews were eligible if keywords regarding 44 non-psychiatric conditions related to GPs’ prescription of ADs were encountered. After excluding psychiatric and non-primary care conditions, the guidelines were checked for keywords related to AD use. The latest updated version of the guidelines was kept. Recent data was searched in the Cochrane Database of Systematic Reviews and in PubMed for updated reviews and randomized control trials (RCTs).Seventy-eight documents were retrieved and were used to assess the level of evidence of a potential benefit to prescribing an AD. For 15 conditions, there was a consensus that prescribing an AD was beneficial. For 5 others, ADs were seen as potentially beneficial. No proof of benefit was found for 15 conditions and proof of no benefit was found for the last 9. There were higher levels of evidence for pain conditions,  incontinence and irritable bowel syndrome. There were difficulties in summarizing the data, due to a lack of information on the level of evidence, and due to variations in efficacy between and among the various classes of ADs.Prescription of ADs was found to be beneficial for many non-psychiatric health conditions regularly encountered in PC settings. On the whole, the guidelines were heterogeneous, seemingly due to a lack of trials assessing the role of ADs in treatment strategies. Antidepressants (ADs) are commonly prescribed in primary care (PC). Among the general population, the 12 month prevalence of ADs consumption ranges from 6% to nearly 10% . SelectiThe overall review process is summarised in Figure To retrieve the level of evidence for the prescription of ADs in non-psychiatric PC settings, an initial search was performed using the MeSH terms for the 24 medical conditions collected in our previous qualitative study and the terms “antidepressants” and “therapeutic use” in PubMed . During The terms matching with the 44 conditions and medical circumstances for possible AD prescription were listed in French and English. The MeSH validated translation and synonyms were searched for in the terminology section of the catalogue and index of the French-language Health Resources Website (CISMeF). When there was no MeSH term available for the medical condition or circumstance, the researchers used a broader MeSH term, on a higher level of hierarchy, including the description . Using this list, searches were performed to find the available guidelines (GL) in the databases of the following government agencies: the French “Haute Autorité de Santé” (HAS), the English National Institute for Clinical Excellence (NICE) and the National Guideline Clearinghouse (NGC), the last one including most international guidelines. The searches were performed from March 2011 to August 2011. The search covered all of the documents made available by the three agencies.During the same period, we performed simultaneously, a search in the Cochrane database of systematic reviews (CDSR) and in Medline on the same basis, using the same criteria and process. For the Medline search, the following limits were used: “clinical trial, meta-analysis, clinical guidelines, randomized controlled trial, and adults, published after 2004”. The aim was to find scientific data published after the launch of the guidelines. Those studies might change the evidence and possibly lead to a change in prescription attitudes. All detailed searches are available in the full version of all guidelines. Individual studies (RCTs in Pubmed) included in this review did not constitute the bulk of the results.All guidelines before 1997 were excluded, as were those regarding paediatrics, nursing practices, patient information or education, medical records, continuing medical education for care providers, medical imaging, biology and surgical techniques. Full text of guidelines have been downloaded from the agencies databases. All non-psychiatric conditions were included and all standalone psychiatric conditions were excluded. Remaining documents on anxiety, depression and side effects of ADs were also excluded after reading. The documents were independently read and assessed by two researchers (AM & IAA) and disagreements were resolved by discussion. Duplicates were removed. The documents in the databases were crosschecked using a search with the generic term “antidepressants” in order to retrieve any documents that may have been missed by previous searches. In the full text documents, the terms “antidepressant”, “Tricyclic agents”, “TCA”, “SNRI”, “serotonin”, “SSRI”, “tricyclic”, “imipramine”, “monoamine”, “duloxetine”, “venlafaxine” and their French translations were searched for. All guidelines containing the keywords were selected. In order to find the latest evidence, the most recent documents available on each topic in each guideline database were retained when available, and the most up-to-date version of the selected guidelines was kept. The overall process ended with a list of 78 documents.The final stage of the study aimed to retrieve guidelines on recommended therapeutic use of ADs from these documents. Sections of specific interest were extracted and analysed. Information on pharmaceutical classes, drugs, recommended therapeutic use and level of evidence was collected when available. Agreements and discordances were noted, and inconsistencies between the various guidelines were highlighted. Recommendations from the guidelines were graded according to the EFNS scheme  Additio.We collected 1,325 documents on 44 conditions. After exclusion, 141 remained. After applying our criteria for data extraction, 78 documents were retrieved, including 36 GLs, 38 reviews or systematic reviews  and 4 RCTs. The guidelines enabled us to describe the evidence for AD prescription for 27 conditions. For 14 conditions, searches in CDSR and PubMed retrieved updated information. For 3 conditions , no data were found. Among the 44 conditions, ADs were found to be potentially beneficial with a high level of evidence in treating 15 conditions and potentially beneficial with a lower level of evidence in treating 5 others. No proof of benefit was found for 15 conditions and proof of no benefit for 9. All results are detailed in Table All results for pain conditions are described in Table The guidelines, reviews and RCTs found prescription of sertraline, citalopram and trazodone to be potentially beneficial in treating behavioural perturbations, mood disorders and agitation in patients with dementia, though no level of evidence was available ,41. PoteConcerning stroke, three kinds of problems were assessed: treatment of emotionalism, prevention of depression and the benefit of prescribing an AD in the acute stage to facilitate recovery of motor skills. ADs were recommended for emotional instability (Level B) ,45. TheyAntidepressants were found to provide no benefit in treating isolated sleeping disorders and primary insomnia even though they were found to be potentially beneficial in the event of psychiatric comorbidity .Antidepressants were not recommended for use in cases of restless legs syndrome, which was in fact presented as a side effect of ADs .As well, there was no evidence of a benefit in prescribing ADs for cases of sialorrhea related to neurological conditions , Parkinson’s disease), although prescription was sometimes recommended . AntidepDuloxetine was found to have potential benefits as a second-line (Level C) treatment for patients with stress urinary incontinence. Duloxetine significantly improved quality of life but TCAs did not. Anticholinergic agents, such as TCAs, were found to have potential benefits for patients with overactive bladder syndrome -54. ProoOne Cochrane review attested that all SSRIs were highly effective in reducing symptoms related to severe premenstrual syndrome,   with no level of evidence available . AnotherSSRIs were not recommended for erectile dysfunction. They were, however, recommended as a first-line (Level A) treatment for premature ejaculation ,59.Nortriptyline was shown to be effective for tobacco withdrawal (OR 2.79 (95% CI: 1.70-4.59) whereas moclobemide, venlafaxine and SSRIs did not show any effectiveness (no level of evidence available) . All guiThe term “fatigue” pooled together a wide variety of health problems. No data was retrieved for isolated fatigue. In the NICE guideline, ADs were not found to be beneficial in treating chronic fatigue syndrome. ADs were considered as useless for cancer-related fatigue but beneficial in treating depression related to purely physical conditions, with no effect on the physical conditions themselves .Prescribing an AD provided no benefit for musculoskeletal symptoms, except for fibromyalgia, which is assessed in the “pain conditions” section of the results  (no level of evidence available) ,65.Antidepressants were found to be potentially useful with a high level of evidence for 15 conditions and potentially useful with a lower level of evidence for 5 others. Prescribing an AD was found to be potentially beneficial for patients with many pain conditions as well as urological, gastroenterological and gynaecological conditions. Nevertheless, while prescribing, the GP has to refer to on-label use for his own country, because unfortunately, proof of benefit is not related to “on label use”. The evidence reviewed provided insufficient support for prescribing ADs for 24 other conditions. Restless legs syndrome, non-specific urinary incontinence and erectile dysfunction exposed in the “proof of no benefit” section were side effects of ADs. For rheumatologic conditions,  the “proof of no benefit” should be interpreted with caution, due to the difficulty in assessing these patients in a primary care setting. Pain symptoms or somatoform complaints may be similar to those encountered in fibromyalgia, a clinical syndrome that lacks a clear definition and is still a subject of debate . For theThe first strength of the study was the meticulous methodology and careful step-by-step process used to extract the data. The analysis was not started from a theoretical framework, but from real daily practice in primary care, based on the qualitative material of our previous research . No prevPerforming a strict assessment and comparison of several conditions appeared arduous: although the subjects of the recommendations were similar, the guidelines did not refer to strictly comparable conditions. For example difficulties were encountered with fibromyalgia, chronic fatigue syndrome and rheumatologic pain, which were difficult to distinguish from one another. This lack of precision can lead to difficulties in assessing and summarizing information, and consequently in correctly understanding the potential benefit of ADs for patients. As well, the randomised trials were designed for well-defined conditions and homogeneous populations, which is rarely the case for PC patients. The inclusion criteria for the studies often involved secondary care and did not reflect primary care situations.The limitations of available data and the wide variety of conditions made it difficult to formulate clear recommendations. In any case, the results of the study provide new insight to enable clinicians to prescribe ADs with more accuracy, and could potentially serve as a point of reference for health policy organizations in specifying prescription rules.Comparing the 24 non-psychiatric health conditions for which the GPs claimed to prescribe ADs  with theOn the whole, the guideline agencies often stressed a lack of head-to-head comparative trials assessing the clinical effectiveness of the drugs, which would allow physicians to prioritise the choice of therapy for a given condition. This is impossible without any involvement from healthcare institutions. Another challenge is to better understand the way physicians prescribe ADs in actual PC settings. We currently know that GPs’ decisions are shaped by a combination of diseases and psychosocial influences. The potential benefit of a prescription for a patient cannot be assessed without incorporating all of the dimensions of actual prescription. This requires a strict comparison that directly assesses the prescriptions, indications and patients’ environment, based on observational cohort studies to collect data on medical conditions, psychosocial environment and prescriptions in PC settings.Prescription of ADs was found to be useful for many non-psychiatric health conditions commonly encountered in primary care. Evidence against prescribing ADs was also found. The overall inconsistency of available information hindered precise assessment of the evidence. There remains much uncertainty as regards the role of prescribing ADs in therapeutic strategies, as well as the appropriateness and accuracy AD prescriptions. It is important to emphasise the difference between assessing the scientifically proven effect of an AD for a certain condition and the potential benefit of an AD at the right dose for a specific patient despite a lower level of evidence. Further studies are required to provide physicians more comprehensive knowledge and to improve patient care.AD(s): Antidepressant(s); ALS: Amyotrophic lateral sclerosis; CDSR: Cochrane database of systematic reviews; Cismef: Catalogue and index of the French-language health resources; HAS: French “haute autorite de sante”; IBS: Irritable bowel syndrome; NICE: English National Institute for clinical excellence; NGC: National guideline clearinghouse; PC: Primary care; SMD: Standardized mean difference; TCA: Tricyclic agent; SSRI: Selective serotonin reuptake inhibitors; SNRIs: Selective norepinephrine reuptake inhibitors.The authors declare that they have no competing interests.Conception of the idea for the study: AM. Development of the protocol: AM, IAA, JPL, MS, and PB. Data collection and extraction: AM, IAA, JPL. Critical assessment: AM, IAA, JPL, MS, and PB. PVR and LP participated in the design and coordination and helped to draft the manuscript. Writing of the manuscript: AM. All of the authors have read the draft critically, to make contributions, and have approved the final text.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/14/55/prepubRating of recommendations.Click here for file


Significant advances in our understanding of the genetic defects and the pathogenesis of juvenile myelomonocytic leukemia (JMML) have been achieved in the last several years. The information gathered tremendously helps us in designing molecular targeted therapies for this otherwise fatal disease. Various approaches are being investigated to target defective pathways/molecules in this disease. However, effective therapy is still lacking. Development of specific target-based drugs for JMML remains a big challenge and represents a promising direction in this field. Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy of early childhood with high mortality. It represents 2% to 3% of all pediatric leukemias , 2, and μL); less than 20% blasts in the bone marrow; absence of Philadelphia (Ph) chromosome or BCR-ABL fusion gene AND at least two of the following criteria: increased HbF levels; presence of immature myeloid precursors in the peripheral blood; white blood cell count >10,000/μL; GM-CSF hypersensitivity of myeloid progenitors in vitro [Prior to the revision in 2008, JMML was diagnosed based on the following criteria: presence of peripheral blood monocytosis  [NF1, neurofibromin (NF1), contains a GTPase-activating protein- (GAP-) related domain. It inhibits RAS signaling by increasing the intrinsic GTPase activity of RAS-GTP and, thus, the generation of inactive RAS-GDP [NF1, providing confirmatory evidence that the NF1 gene is crucial for the increased incidence of JMML in NF1 patients [de novo malignant myeloid disorders, particularly JMML [In 1994, Shannon et al. demonstrated loss of the wild-type  1 (NF1) . The pro RAS-GDP . Eleven  RAS-GDP  and 15%  RAS-GDP , 45. A mpatients . In addirly JMML .c-CBL mutations were detected in 27 of 159 JMML samples, and 13 of these mutations alter codon Y371 [c-CBL mutation was also found in another study with a smaller cohort of JMML patients [CBL mutations in 65 patients with JMML [CBL was found in leukemic cells of 4/65 (6%) patients. A heterozygous germ line CBL Y371H substitution was found in each of them and was inherited from the father in one patient. The germ line mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells [CBL mutations are at increased risk of developing JMML, which might follow an aggressive clinical course or resolve without treatment [The Casitas B-cell lymphoma  protein is a member of the CBL family of E3 ubiquitin ligases. Loh et al. first reported that don Y371 . The sampatients . A recenith JMML . A homozML cells . Individreatment . PTPN11, RAS, and NF1 mutations, other mutations have been reported to occur rarely in JMML, such as additional sex combs like 1 (AXSL1) [RAS genes in JMML. It is possible that other microRNAs known to bind to NRAS- or KRAS-UTR, or other let-7 family mi-RNAs may play a role in the development of JMML [TET2), runt-related transcription factor 1 isoform (RUNX1), janus kinase 2 (JAK2) V617F [ SHOC2 [In addition to  (AXSL1)  and fms- (AXSL1) . Mutatio of JMML . However2) V617F , and Soc [ SHOC2  are not Some chromosome abnormalities were found in JMML. The most common chromosome abnormalities in JMML patients are monosomy 7 or deletion 7q (-7/del(7q)) . In addiThe recent focus in JMML has concentrated on using the information gained from knowledge of these molecular defects in order to design targeted drug therapy. Animal models, especially mouse models of the disease, are commonly used to test molecularly targeted agents. Since RAS hyperactivation is very important in the pathophysiology of JMML, agents designed to decrease RAS activity are being evaluated. There are numerous approaches that have been tested to target this pathway .in vitro and in a xenograft model of JMML. When immunodeficient mice engrafted with JMML cells were treated continuously with this enzyme for 4 weeks, JMML cell numbers in the recipient murine bone marrows were profoundly reduced. No effect of the enzyme on the proliferation of normal bone marrow cells was found in vitro, indicating its specificity and potential safety [RAF1 is a MAP kinase (MAP3K) that functions downstream of the RAS subfamily of membrane-associated GTPases to which it binds directly and plays an important role in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade. A DNA enzyme designed to specifically cleave mRNA for RAF1, named RAF1 enzyme, was tested on JMML cells cultured both l safety .in vivo activity in three human tumor xenograft models with mutant KRAS genes  and one human tumor xenograft with a wild-type KRAS but exhibiting overexpression of growth factor receptors for epidermal growth factor (EGF) and HER 2 (SKOV-3) [BAY 43-9006 is a low-molecular-weight agent that inhibits both the wild-type BRAF and the activated V599E mutant BRAF by binding at the active site of the kinase . BAY 43-(SKOV-3) . Based oin vitro growth of myeloid progenitor colonies in response to GM-CSF, and increase the amount of unprocessed HRAS in bone marrow cells. However, FTIs had no detectable effect on NRAS, and the mouse model with JMML features created by transplantation of Nf1−/− fetal liver cells did not respond to L-744,832 treatment [in vitro, indicating a potential treatment for JMML [RAS is first activated at the cell membrane via the addition of a farnesyl group to the newly translated protein. Farnesyltransferase inhibitors (FTIs) can prevent RAS translocation to the plasma membrane, thus, leading to downregulation of RAS-activated cellular pathways, so its competitive inhibitors have been developed as a novel class of anticancer therapeutics. L-744,832 is one such farnesyltransferase inhibitor. It can inhibit HRAS prenylation in cell lines and in primary hematopoietic cells, abolish the reatment . L-739,7for JMML . Unfortufor JMML , 66.PTPN11 and JMML indicates that SHP-2 may be a useful target for mechanism-based therapeutics for this disease. It is very important to develop selective SHP-2 inhibitors. The availability of SHP-2-specific inhibitors could lead to the development of new drugs that would ultimately serve as treatments for JMML. However, development of selective SHP-2 inhibitors has been challenging as the catalytic site of SHP-2 shares a high homology with those of other tyrosine phosphatases, especially SHP-1 that plays a negative role in cytokine signaling in contrast to SHP-2 phosphatase [The direct connection between activating mutations in sphatase –28. Sevesphatase –70. Howeα may increase the production of GM-CSF [α monoclonal antibody (MoAb) cA2 in suppressing JMML cell growth. Remarkably, E21R preferentially eliminated leukemic cells [GM-CSF markedly promotes proliferation and survival of JMML cells and, thus, contributes to the aggressive nature of this malignancy . Iversenf GM-CSF , E21R alic cells . These dAngiogenesis is essential for growth and metastasis of solid tumors and probably also for hematological malignancies. Endostatin and PI-88, two kinds of angiogenic inhibitors, were used to treat JMML xenograft mice and resulted in a reduction of about 95% of the malignant cell load. Furthermore, it was evident that neither endostatin nor PI-88 interfered with the engraftment of normal cells .In addition to activation of the RAS pathway in JMML, there are several studies that have also shown enhanced signal transducer and activator of transcription 5 (STAT5) activation downstream of activated RAS. In a KRAS G12D mouse model, STAT5 activation was also associated with ERK and S6K phosphorylation . KRAS alThe clinical therapy of JMML has significantly improved over the last 20 years. However, the low incidence of the disease has limited the capacity to perform large-scale pathophysiological studies and testing newer therapeutic strategies. JMML is a disease that only occurs in children, and drug dosage modifications are needed in children as compared to adults. All these factors limit the development of JMML treatment to some extent. Specific inhibitors for the molecular targets identified in this disease are still lacking. Molecular mechanisms of JMML have been elucidated in almost 85% of patients, but it is also true that a few JMML patients with Noonan syndrome can spontaneously recover without intervention , 80. Thi


Dirofilariaimmitis but distinct from reference sequences, including those ofD. immitis infesting dogs in the samearea. A zoonotic Dirofilaria species infesting wild mammals inBrazil and its implications are discussed.A case of human intraocular dirofilariasis is reported from northern Brazil. Thenematode was morphologically and phylogenetically related to  Dirofilaria are among the most common agents infecting humans and has external longitudinal ridges inD. repens and other species of the subgenusNochtiella. However, in many reported cases of zoonoticdirofilariasis, specific identification was not adequately addressed , an intraocularpressure of 44 mm Hg, and pain in the left eye. Ophthalmologic examination showed anematode  in the aThe parasite  was a malefilarial nematode . It had large caudal alae,several pairs of pedunculated papillae , panel BDirofilaria spp (D.repens or a Nochtiella species because of thesmooth body cuticle. The left spicule (length 378 µm), with a handle andlamina of equal length, was similar to that of D.immitis   and 12S rDNA gene fragments as described(http://blast.ncbi.nlm.nih.gov) analysis of both genes showed overallhighest nucleotide similarity with those of D.immitis available in GenBank .To confirm morphologic identification, a DNA barcoding approach was used (cox1 sequences by MEGA 4.0 (www.megasoftware.net), a neighbor-joining algorithm, and Kimura2-parameter correction confirmed that 143 YU clustered with D.immitis from different countries, including Australia (GenBankaccession no. DQ358815) and Italy .Phylogenetic analysis using D. immitis reference specimens but was notpresent in the specimen from Brazil. In addition, the deirids were more anterior inthe worm from Brazil than in reference specimens. This finding might be caused byless growth of the nematode found in the patient from Brazil.Morphologic comparison with male worms isolated from dogs  showed that the area rugosa  was similar among all specimens examined andwas composed of ≈8 longitudinal crests, each containing aligned segments(length 15–30 µm) extending 1–8 mm from the tail tip , panel DD. immitis male worm from a dog in Cayenne,French Guiana  have been reported ina D.immitis has been reported sporadically  were 5%and 6% for 12S rDNA and cox1 genes, respectively, which are higherthan the range of intraspecific variation (<0.8%) reported forD. immitis originating from the United States,Italy, and Japan (Dirofilaria species and its primary hosts and vectors.In Brazil, human pulmonary dirofilariasis caused by


Current guidelines recommend screening cirrhotic patients with an endoscopy to detect esophageal varices and to institute prophylactic measures in patients with large esophageal varices. In this study, we aimed at identifying non-endoscopic parameters that could predict the presence and grades of esophageal varices.In a prospective study, 229 newly diagnosed patients with liver cirrhosis, without a history of variceal bleeding, were included. Demographic, clinical, biochemical and ultrasonographic parameters were recorded. Esophageal varices were classified as small and large, at endoscopy. Univariate analysis and multivariate logistic regression analysis were done to identify independent predictors for the presence and grades of varices.Of the 229 patients  with liver cirrhosis, 97 (42.3%) had small and 81 (35.4%) had large varices. On multivariate analysis, low platelet count , Child Pugh class B/C , spleen diameter  and portal vein diameter  were independent predictors for the presence of varices. Likewise, for the presence of large esophageal varices, low platelet count , Child Pugh class B/C  and spleen diameter  were the independent risk factors.The presence and higher grades of varices can be predicted by a low platelet count, Child-Pugh class B/C and spleen diameter. These may be considered as non-endoscopic predictors for the diagnosis and management of large grade varices. Esophageal varices develop as a consequence of portal hypertension in patients with chronic liver disease and are present in approximately 50% of patients with cirrhosis of the liver. The grade of esophageal varices often correlates with the severity of liver disease. While approximately 85% of individuals with Child-Pugh C cirrhosis have varices, they are present in only 45% those with Child-Pugh A cirrhosis. The rate2Large size varices, the presence of red color signs, severe liver disease and portal pressure greater than 12 mm Hg5 predict6Predicting the grade of varices by non-invasive methods at the time of registration is likely to predict the need for prophylactic β blockers or endoscopic variceal ligation in patients with cirrhosis and portal hypertension. Therefore, the present study has been undertaken to determine the appropriateness of the various clinical, biochemical and imaging parameters in predicting the existence and also the grade of esophageal varices in cirrhosis of the liver.Consecutive newly diagnosed patients with cirrhosis of the liver, presenting to the liver clinic of our centre, between July 2004 and December 2007, were included in this prospective study. Individuals presenting with variceal bleed, those with a past history of bleed and who had undergone sclerosis or band ligation of esophageal varices, portal vein thrombosis, hepatoma, or on current or past treatment with beta-adrenergic receptor blockers were excluded from the study. All the patients underwent detailed clinical evaluation, appropriate investigations, imaging studies (ultrasound with Doppler) and endoscopy at our centre. Diagnosis of cirrhosis was based on clinical, biochemical and ultrasonographic findings.History included details and duration of alcoholism, jaundice, ascites, oliguria, pedal edema and gastrointestinal bleed. Presence or absence of jaundice, ascites, splenomegaly and hepatic encephalopathy was noted. Hemoglobin, platelet count, prothrombin time, blood urea, serum creatinine, blood glucose, liver function tests including serum bilirubin, albumin/globulin ratio and transaminases were estimated. Modified Child-Turcotte-Pugh (CTP) class was calculated for each patient. Special investigations included HBsAg, anti HCV antibody assay, slit lamp examination, serum Ceruloplasmin, 24 h urine copper, iron studies, antinuclear antibody, anti smooth muscle antibody and antimitichondrial antibody assays. Patients with an alcohol etiology were included in the study after at least six months of abstinence.At ultrasonogram and Doppler study (VJ), the portal vein and spleen diameter along with echo texture of the liver and direction of blood flow were noted. The portal vein diameter and platelet count / spleen diameter ratio were determined. Coefficient of variation for repeated measurements of these parameters was less than 2%. All endoscopies were performed in a single endoscopy unit using a video-endoscope. At endoscopy, the esophageal varices were graded as large (Grade III-IV) or small (Grade I-II), based on Paquet’s grading system. The endo2 test for categorical variables. A P value of less than 0.05 was considered as significant. All variables that were found to be of significance on univariate analysis were included as candidate variables in a forward-conditional step-wise logistic regression analysis to identify independent predictors for the presence of esophageal varices and their size.Univariate analyses were done using the Mann-Whitney U-test for continuous variables and the χReceiver operating characteristic curves (ROC curves) were applied to find the best sensitivity and specificity cut off values of the continuous variables for the presence or absence of esophageal varices and for the presence of large esophageal varices Figures  and 2.Two hundred and twenty nine eligible patients  with cirrhosis of the liver were included in the study. The etiology included alcohol  followed by hepatitis B virus  and hepatitis C virus  infection. Other/mixed causes were non alcoholic fatty liver disease: 10, alcohol and HCV: 4, alcohol and HBV: 3, Budd-Chiari syndrome: 4, Wilson’s disease: 3, autoimmune hepatitis: 3, HBV and HCV: 1, secondary biliary cirrhosis: 1 and the cause remained unknown in 45 patients (19.7%).There were 42 patients in CTP class A and 187 in class B or C . Overall, 51 patients had no esophageal varices (22.3%), 97 (42.3%) had small varices (Gr I-II) and 81 (35.4%) had large varices (Gr III-IV).On univariate analysis, CTP class (B/C), platelet count, prothrombin time, spleen diameter, portal vein diameter and platelet count /spleen diameter ratio were significantly associated with the presence of esophageal varices . On multOn multivariate analysis, the platelet count-spleen diameter ratio was not predictive for the presence of varices; however, a cut-off value of ≤ 666 had a sensitivity of 66.3%, specificity of 80.4%, positive predictive value of 92.2% and a negative predictive value of 40.6% for the presence of esophageal varices.μl  and spleen diameter > 160 mm .The predictors of large varices on univariate analysis were CTP class B/C, platelet count, spleen bipolar diameter, portal vein diameter and platelet count /spleen diameter ratio . On multUsing the significant factors on multivariate analysis, which predicted large varices, CTP class was the most sensitive in picking up large grade varices at endoscopy . When all the three parameters i.e CTP score, platelet count and spleen diameter were considered together, the sensitivity was low but specificity was high (sensitivity: 33% and specificity: 92%). CTP class B/C had the lowest miss rate for large varices (9.5%), and the gastroscopies saved was 16.6%. Other parameters had an unacceptable level of miss rates for large esophageal varices (>20%) .Several studies in the past have shown independent parameters like splenomegaly,11171822 1117181218201319et al,[et al,[et al,[The present study further corroborates the results of earlier studies. Giannini et al, proposedet al, The studl,[et al, from Pakl,[et al, found thet al,[In the present study, on univariate analysis, a platelet count-spleen diameter ratio of ≤ 666 was significantly associated with the presence of esophageal varices in a predominant alcohol related cirrhosis subset. This ratio was insignificant on multivariate analysis. Sen et al, made simet al,[et al,[Non endoscopic assessment for presence and grades of varices from India are few. Amarapurkar et al, report tl,[et al, in a proFrom the present study, Child Pugh class B/C, low platelet count and spleen diameter emerged as significant predictors for the presence of large esophageal varices. Of these variables, CTP class B/C missed less than 10% of patients with large varices and saved one endoscopy procedure for every six procedures performed. Four out of forty-two patients in CTP class A had large varices. All the four patients had either a platelet count of < 90,000/μl or spleen bipolar diameter > 160 mm. The following algorithm  could beWe believe that these predictors may be of help to the physicians practicing in rural areas where endoscopy facilities are not readily available, in helping them to initiate appropriate primary pharmacological prophylaxis in these patients. In an urban setting where the endoscopy workload is high, a non invasive predictor, as in this study, can help one to initiate drug therapy while waiting for the endoscopy procedure.


Rare diseases are defined as life-threatening or chronically debilitating diseases with a prevalence of 50 out of 100,000 individuals or less. Orphan medicinal products (OMPs) are intended for the treatment of rare diseases. The assessment of quality of evidence in small populations is often complex. Many generic tools are unfit. Therefore, the aim of this study was to develop and validate a new tool to assess the quality of OMPs' clinical evidence (COMPASS).Firstly, a draft version of the COMPASS tool, developed by the authors and consisting of three parts, was amended based on suggestions obtained in four rounds of expert consultation. Secondly, the tool was put through three rounds of validation. The data source was information provided on the Orphanet website and in European Public Assessment Report (EPAR) document of the European Medicines Agency.The first pilot round revealed a high (92.2%) inter-rater agreement for part one of the tool. After further improvements, the final inter-rater agreement was 86.4% for part two  and three  of the tool. The COMPASS tool does not attempt to score or rank the quality of clinical evidence, but rather to give an outline of various, key elements with respect to quality of clinical evidence of OMP studies.The COMPASS tool can be applied to assess the quality of evidence of an OMP based on information in the registration dossier, for example by local reimbursement agencies, pharmacists or clinicians. In that way, the tool can contribute to making reimbursement and/or treatment decisions increasingly more founded on the principles of evidence-based decision making. Even so, achieving the highest quality of evidence should still be aimed for [Rare diseases are defined as life-threatening or chronically debilitating diseases with a prevalence of 50 out of 100,000 individuals or less . Orphan imed for .But how do we define quality of clinical evidence? According to GRADE , quality of evidence reflects the extent of our confidence that the estimates of an effect are correct . TraditiThe assessment of quality of evidence in small populations at the time of registration and/or reimbursement is often complex. However, the rising number of authorized OMPs and their increased use in clinical practice emphasizes the need for an objective assessment. Quality assessment involves evaluation of a study’s validity, i.e. the degree to which its design, conduct and analysis have minimised biases or errors . In geneTherefore, the aim of this study was to develop and validate a new tool, COMPASS , to assess the quality of OMPs clinical evidence that is presented for OMPs at the time of marketing authorization in the EU.The design of the tool was conceptualised after consulting the Centre for Evidence-Based Medicine (CEBAM), Leuven, Belgium. A draft version of the tool was drawn up based on elements derived from existing checklists supplemented with items specifically related to rare diseases and OMPs -15.verbatim. The transcripts were analyzed in three steps. The first step was aimed at familiarizing with the data by reading and re-reading the transcripts. Secondly, a framework of key issues was identified. Finally, all issues were grouped according to the framework and interpreted. The draft version of the tool was adapted in accordance with all relevant issues, as deemed upon consensus by the researchers, raised at all consultations.The draft version of the tool was proofread by two laymen to increase readability. Subsequently, four expert consultations were organised with six experts (in a two-two-one-one fashion) with a view to increasing content validity Table . All conThe data source of the tool consisted only of information provided on the Orphanet website and in European Public Assessment Report (EPAR) and/or the Scientific Discussion (SD) document prepared by the Committee for Human Medicinal Products (CHMP) of the European Medicines Agency (EMA). These documents provide information about chemical, pharmaceutical, biological, toxico-pharmacological and clinical aspects of a drug . For praA first pilot round was undertaken, in which five randomly selected OMPs , histamine dihydrochloride , idursulfase , pirfenidone  and sorafenib ) were analysed by two raters (E.P. and S.S.). The two raters completed all three parts of the COMPASS tool. A second pilot round was undertaken, in which four alphabetically successive OMPs  were analysed by two raters (E.P. and D.C.). One rater completed all three parts of the tool, whereas the other completed the second and third part. The final version  of the study. The last part assesses the quality of reporting. The Orphanet website was consulted to provide information on the prevalence of the rare disease in which the indication is authorized and its therapeutic need . The regIn a third and final round, two raters (E.P. and S.S.) completed the tool for a sample of OMPs (n = 29). One rater (E.P.) completed all three parts of the tool, whereas the other (S.S.) completed the second and third part. Additionally, expertise in the medical field was believed necessary to answer the question “Is the duration of the study relevant to the natural history of the disease?”. Therefore, a third rater (D.C.) (ie a trained physician) also answered this question for all 29 OMPs. Upon disagreement between the raters, the assessment of D.C. was considered decisive.In all three rounds, raters completed the tool independently and once-only. Additionally, raters were blinded with respect to results of others. The same information was available to all raters. After data collection, E.P. was responsible for comparison of the results.All analyses  were performed using MS Office Excel 2010.valid method of randomization). The total number of issues discussed per consultation is shown in Table During the expert consultations, a number of issues were discussed related to both the design  and to the content of the tool  than raters without a medical background (E.P. 27.8% and S.S. 22.2%). Additionally, the raters without a medical background experienced more difficulties in evaluating study duration, as shown by their choice of “Don’t know” respectively nine and two times.The goal of this research was to develop and validate a new tool COMPASS to assess the quality of OMPs clinical evidence presented at the time of marketing authorization in the EU. The COMPASS tool  treatment. Registration and reimbursement bodies currently acknowledge the data limitations for OMPs by providing them special considerations . HoweverTo improve the reliability of results, data extraction should be performed independently by at least two raters. The reliability of results has shown to be independent of blinding, for that reason data extraction should not necessarily be blinded . An exceStudy quality is dependent, not only on methodological quality, but also on the quality of reporting . Indeed,The COMPASS tool has several strengths and weaknesses. The tool was developed after iterative rounds of expert consultation and underwent several pilot rounds to increase its validity. The tool assesses the level of clinical evidence that is presented in the pivotal studies at the time of marketing authorization. As such, it does not take into consideration the evidence in any of the supporting studies or evidence generated as part of post-marketing commitments. Adding data from publications would allow for quality control of the EPAR data, but was considered outside the scope of this study. Also, the tool is dependent on the quality of reporting in the EPAR and/or SD documents. Finally, a general medical knowledge of the rater is advisable to complete the tool. Additional check boxes ('Don’t know’ and 'Not reported’) were provided, to account for possible problems related to these last issues.In conclusion, we developed and validated a new tool for the assessment of clinical evidence of OMPs. The COMPASS tool can for example be used by local reimbursement agencies for the review of clinical evidence from OMP registration dossiers or by clinicians and pharmacists upon considering a (new) treatment. Furthermore, we hope that the COMPASS tool can initiate and add to the open debate on study standards for orphan medicinal products. In that way, the COMPASS tool can contribute to making reimbursement decisions increasingly more founded on the principles of evidence-based decision making.COMPASS: Clinical evidence of orphan medicinal products – an assessment tool; OMP: Orphan medicinal product; EPAR: European public assessment report; FDA: Food and drug administration; SD: Scientific discussion; CHMP: Committee for human medicinal products; EMA: European medicines agency.The authors declare that they have no competing interests. No sources of funding were used to assist in the preparation of this manuscript.The work presented was carried out in collaboration between all authors. EP, SS, DC and BA were involved in the initiation of the project and the design of the methods. EP, SS and DC actively participated in the expert consultations and in the data collection. EP analysed the data and interpreted the results. EP, SS, DC and BA discussed the results. EP and SS wrote the draft paper. SS, DC and BA revised the draft paper. All authors have read and approved the final manuscript.COMPASS tool.Click here for file


We have previously reported induction of robust immune responses in rhesus macaques following a prime boost immunization with candidate HIV-1 vaccines, SAAVI DNA-C (DNA) and SAAVI MVA-C (MVA). These vaccines are already in clinical evaluation. In the current study, we investigated whether re-boosting these animals with a single MVA inoculation after more than 3 years was sufficient to restore previous magnitudes of HIV-specific immune responses.9 pfu MVA/dose) in a past study, >3 years previously, were re-boosted with a single dose of MVA. HIV-1-specific responses were quantified in the peripheral blood using an IFN-gamma ELISPOT assay.Seven rhesus macaques which had been vaccinated with three doses of DNA vaccine (4mg DNA/dose) and two doses of MVA (106 PBMC) was reached 1 week after vaccination with the first dose of MVA. The second MVA inoculation did not increase these responses which declined to undetectable levels by 1 year post vaccination. After re-boosting with MVA after 3.5 years post the second MVA, all animals responded, with a peak response (1824±672 sfu/106 PBMC) being reached 1 week after vaccination. Although the mean magnitude of the second peak was not significantly higher than the one seen in the first peak, boosting of responses in 3 of 7 animals with an apparent broadening of the breadth of responses was observed.A peak magnitude of response (1146±240 sfu/10These preliminary data suggest a long-term preservation of vaccine memory following a prime-boost vaccination regimen with SAAVI DNA-C and SAAVI MVA-C vaccines.