Canadian 24-Hour Movement Guidelines for the Early Years (0–4 years): An Integration of Physical Activity, Sedentary Behaviour, and Sleep. These novel guidelines for children of the early years embrace the natural and intuitive integration of movement behaviours across the whole day (24-h period).The Canadian Society for Exercise Physiology convened representatives of national organizations, research experts, methodologists, stakeholders, and end-users who followed rigorous and transparent guideline development procedures to create the n = 546), 10 key informant interviews, and 14 focus groups (n = 92 participants) were completed to gather feedback on draft guidelines and their dissemination.The development process was guided by the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Four systematic reviews  examining the relationships within and among movement behaviours and several health indicators were completed and interpreted by a Guideline Development Panel. The systematic reviews that were conducted to inform the development of the guidelines, and the framework that was applied to develop the recommendations, followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Complementary compositional analyses were performed using data from the Canadian Health Measures Survey to examine the relationships between movement behaviours and indicators of adiposity. A review of the evidence on the cost effectiveness and resource use associated with the implementation of the proposed guidelines was also undertaken. A stakeholder survey , toddlers (1–2 years) and preschoolers (3–4 years) should achieve for a healthy day (24 h). Proactive dissemination, promotion, implementation, and evaluation plans were prepared to optimize uptake and activation of the new guidelines.These guidelines represent a sensible evolution of public health guidelines whereby optimal health is framed within the balance of movement behaviours across the whole day, while respecting preferences of end-users. Future research should consider the integrated relationships among movement behaviours, and similar integrated guidelines for other age groups should be developed.The online version of this article (10.1186/s12889-017-4859-6) contains supplementary material, which is available to authorized users. Canadian 24-Hour Movement Guidelines for Children and Youth: An Integration of Physical Activity, Sedentary Behaviour, and Sleep [Movement behaviours across the whole day 24-h period) have recently garnered increased interest in public health research and practice. For example, Canada released evidence-informed nd Sleep  in respo-h periodnd Sleep . Systemand Sleep –10. Subsnd Sleep –14, suppnd Sleep , 16.Recent systematic reviews that focused on children of the early years (0–4 years) and examined the relationships between health indicators and physical activity –19, sedeCanadian 24-Hour Movement Guidelines for Children and Youth [Canadian 24-Hour Movement Guidelines for the Early Years (0–4 years): An Integration of Physical Activity, Sedentary Behaviour, and Sleep released by the Canadian Society for Exercise Physiology and partners on November 20, 2017. There are no previously developed Canadian evidence-based guidelines integrating recommendations for all movement behaviours for the early years. These new, integrated recommendations are intended to provide parents, caregivers, health professionals, and policy-makers with guidance on the quality and quantity of physical activity, sedentary behaviour, and sleep in a 24-h period to achieve the greatest health benefits in children 0 – 4 years of age. Throughout this paper the term “movement behaviours” is used to encompass physical activities of all intensities, sedentary behaviours , and sl posture .Canadian 24-Hour Movement Guidelines for the Early Years (0–4 years) followed the 15-stage framework described in detail by Tremblay and Haskell [The process used to develop the  Haskell . The pro Haskell –40 from In November 2015, a Leadership Committee was formed that included the project principal investigators, representatives from each of the funding partners , methodologists, and support staff. In August 2016, the Public Health Agency of Canada (PHAC) provided support for the guideline development and also joined the Leadership Committee. The Leadership Committee met monthly to provide oversight, strategic direction, fiscal accountability, and attentiveness to AGREE II criteria. Subsets of the Leadership Committee met as required to ensure the project advanced efficiently. In January 2016, a Guideline Development Panel (GDP) was formed with members including research experts, stakeholder groups, knowledge users, international collaborators, methodology consultants, parents, and project managers  grant to update the previous early years sedentary behaviour guidelines , the Leand Youth , and addnd Youth , 21–23. nd Youth , 43.Canadian Physical Activity Guidelines for the Early Years [GRADE evidence to decision framework: summary below). “Important” health indicators were also identified by the GDP but given lower weighting through the evidence to decision process.The first systematic review examined the relationships between objectively and subjectively measured physical activity and health indicators in the early years , updatinly Years , 44. As ly Years  includedly Years . Note thCanadian Sedentary Behaviour Guidelines for the Early Years [Updating and extending the earlier systematic review that LeBlanc et al.  conductely Years , the secly Years . PICO paly Years .The objective of the third systematic review was to examine the associations between sleep duration and health indicators in children of the early years (PROSPERO Registration no. CRD42016040096) . The revThe fourth systematic review examined combinations of two or more movement behaviours and the associations with health indicators in children of the early years (PROSPERO Registration no. CRD42015015493) . The PICResearch on movement-related behaviours and the resultant public health guidelines have typically taken a segregated rather than integrated approach. Not surprisingly, the evidence base is similarly constructed. While three of the systematic reviews outlined above provide a comprehensive assessment of the relationships between individual movement behaviours  and indicators of health, only the review by Kuzik et al.  examinedn = 552) of Canadian preschool-aged children from the CHMS [The specific objectives of the compositional analyses were twofold: (1) to explore the combined associations of the composition of sleep duration, sedentary time, light-intensity physical activity (LPA), and moderate- to vigorous-intensity physical activity (MVPA) with adiposity indicators, and (2) to explore the association of the time spent in sleep, sedentary behaviour, LPA, and MVPA with adiposity indicators relative to the time spent in the other behaviours in a representative sample , balance of benefits and harms, end-user preferences and values, resource implications, feasibility, acceptability, and equity issues. This collection of information is used to inform the direction  and the strength  of the recommendation.Guidelines recommendations and stakeholder consultations section). To further explore resource requirements (costs), a review of the evidence on cost and resource use related to 24-h movement behaviours was conducted. However, no evidence was found that met the inclusion criteria.The quality of the evidence was assessed and reported in the systematic reviews , 21–23. The second meeting of the GDP was held in January 2017. The objectives of this three-day meeting were to review, discuss, debate, and interpret findings from systematic reviews and compositional analyses; review results of cost-effectiveness/resource use analysis; craft individual components of the movement behaviour guidelines; create 24-h integrated movement behaviour guidelines; identify research gaps; and plan the launch, dissemination, promotion, and evaluation activities. Draft guideline recommendations were created by the GDP based on the overall balance between the possible benefits and harms of various levels of physical activity, sedentary behavior, and sleep; stakeholder and end-user preferences and values related to these movement behaviours; and considerations related to feasibility, accessibility, resource use, and equity. The draft guidelines were translated into French and back-translated for verification. All GDP members approved the draft guidelines for the stakeholder consultations.A cross-sectional survey  engaged in telephone interviews and end-users (n = 92) participated in focus groups (n = 14) to discuss perceived clarity and need for the guidelines, potential barriers to implementation, identification of credible messengers, and methods for dissemination of the guidelines. Audio-recordings from the focus groups and interviews were transcribed verbatim and thematic analysis was conducted consistent with that reported by Faulkner et al. [In addition to the online stakeholder survey, a series of focus groups and key informant interviews were completed to examine stakeholders’  and end-users’ (parents and early childhood educators) perceptions of the draft guidelines . Ethics r et al. . Full der et al. .A sub-committee of the GDP reviewed summaries of the stakeholder survey, focus group and interview results, and revised the guidelines based on the feedback, ensuring changes remained true to the available evidence base. The revised guidelines were circulated to the entire GDP for comment and final revisions. Consensus was achieved on the final guidelines. Revisions were translated to finalize the French version.Canadian 24-Hour Movement Guidelines for Children and Youth [www.buildyourbestday.com). Members of the GDP, with additional members from CSEP and ParticipACTION , formed a sub-committee (Guideline Implementation and Activation Committee) to facilitate strategic and proactive dissemination, promotion, and implementation of the new early years guidelines, building off the work completed for the children and youth guidelines, and maintaining the same “look and feel”. The harmonized visual identity was used in the preparation of materials, tools and resources, both digital and print, for the release of the Canadian 24-Hour Movement Guidelines for the Early Years. The Guideline Implementation and Activation Committee also developed an integrated marketing and communications plan for sustained dissemination and implementation following the guideline launch. Finally, the work of the sub-committee responsible for evaluation of the child and youth guidelines was expanded to include assessment of the impact of the dissemination and implementation efforts of the guidelines for the early years.The release of the nd Youth  marked tnd Youth . In addiAustralian 24-Hour Movement Guidelines for the Early Years were prepared [The guideline development process in Canada instigated a similar process in Australia. Leveraging the background work done in Canada, and guided by the GRADE “adolopment” procedures , the Ausprepared  and concResearch gaps were identified and recorded throughout the guideline development process . The new paradigm of the 24-h movement guidelines requires earlier surveillance measures to be reconsidered, with a shift from an individual behaviour focus to the combination or composition of the behaviours.To make recommendations in this regard a Surveillance Sub-committee of the GDP, with additional members with extensive movement behaviour surveillance experience, convened via teleconferences to discuss and develop preliminary recommendations for the monitoring and surveillance of the new 24-h guidelines, following an approach similar to what was done for the child and youth guidelines .BMC Public Health were provided to the independent assessors.Four independent reviewers were contracted to conduct an AGREE II assessment on the entire guideline development process using the guideline materials and systematic reviews –40. All The guideline development process successfully adhered to the framework outlined by Tremblay and Haskell . ThroughBMC Public Health [A brief summary of the findings of each systematic review is provided below, with detailed results available elsewhere in this special issue of c Health , 21–23. n = 8), clustered randomized controlled trials (n = 4), non-randomized interventions (n = 9), cross-over trials (n = 3), longitudinal (n = 7), longitudinal with additional cross-sectional analyses (n = 5), case-control (n = 4), case cross-over (n = 1), and cross-sectional (n = 55). One small meta-analysis  was conducted examining adiposity as a health indicator; otherwise narrative syntheses were employed. Physical activity was consistently associated with improved motor and cognitive development as well as psychosocial and cardiometabolic health in randomized and non-randomized intervention studies, and with favourable motor development, fitness, and bone and skeletal health in observational studies. Light- and moderate-intensity physical activity were not consistently associated with any health indicators, whereas moderate- to vigorous-intensity, vigorous-intensity, and total physical activity were consistently favourably associated with multiple health indicators. Across study designs, consistent favourable associations with health indicators were observed for different types of physical activity, including active play, aerobic activity, dance, prone position , and structured/organized activities. For toddlers and preschoolers, the most favourable frequency and duration of physical activity were unclear, however, more physical activity appeared better for health. For infants, ≥30 min/day of the prone position, or “tummy time”, was most favourably associated with health indicators. The quality of the evidence ranged from “very low” to “high” and the majority of evidence was in preschool-aged children (3–4 years).Ninety-six studies  were included in the review on physical activity and health indicators in the early years . Study dn = 1), case-control (n = 3), longitudinal (n = 25), longitudinal with additional cross-sectional analyses (n = 5), and cross-sectional (n = 62). Associations between objectively measured total sedentary time and indicators of adiposity and motor development were predominantly null; associations between screen time and indicators of adiposity, motor or cognitive development, and psychosocial health were primarily unfavourable or null. Associations between reading/storytelling and indicators of cognitive development were favourable or null. Associations between time spent seated  or in the supine position, and indicators of adiposity and motor development, were primarily unfavourable or null. The quality of evidence ranged from “very low” to “moderate” across study designs and health indicators.A total of 96 studies  were included in the sedentary behaviour systematic review . Study dn = 3), non-randomized interventions (n = 1), longitudinal studies (n = 16), cross-sectional studies (n = 42), and longitudinal studies that also reported cross-sectional analyses (n = 7). Sleep duration was assessed by parental report in 70% of studies (n = 48) and was measured objectively (or both objectively and subjectively) in 30% of studies (n = 21). In general, shorter sleep duration was associated with higher adiposity, poorer emotional regulation, impaired growth, more screen time, and higher risk of injuries. The evidence related to indicators of cognitive development, motor development, physical activity, and quality of life/well-being was less clear, with no consistent associations. The quality of evidence ranged from “very low” to “high” across study designs and health indicators.The systematic review on sleep duration and health indicators in the early years  includedn = 3), non-randomized intervention (n = 1), cross-sectional (n = 4), and longitudinal (n = 2). Across study designs the most ideal combinations of sedentary behaviour and physical activity  were favourably associated with motor development and fitness among preschool-aged children; both favourably and not associated with adiposity among toddlers and preschool-aged children; and not associated with growth among toddlers and preschool-aged children. The most ideal combinations of sleep and sedentary behaviour were favourably associated with adiposity among infants and toddlers. The quality of evidence ranged from “very low” to “moderate”. These data indicate that ideal combinations of physical activity, sedentary behaviour and sleep may be important for health in the early years.The systematic review that examined associations among combinations of movement behaviours and health indicators in children of the early years  includedOverall, the reviews showed that a need exists for better quality studies with stronger research designs, especially those that can provide information on dose-response relationships, if they exist. Furthermore, they identified a need for future research to determine the ideal distribution and pattern of daily movement behaviours  for optimal health throughout the early years.Complete data for cross-sectional compositional analyses were available on 552 participants aged 3–4 years from cycles 2 and 3 (2009–2013) of the CHMS . The aveThe draft guidelines are available in Additional file Demographics: Data from 695 stakeholders and end-users were collected by the online survey; missing data ranged from 130 to 287 per closed-ended item. There were participants from all provinces and territories except the Northwest Territories and Nunavut; the greatest proportion were employed in Ontario (51.7%), followed by Western Canada (36.7%), the Maritimes (3.0%), Quebec (2.7%), and Yukon Territory (0.2%). In addition, 1.2% indicated their work was national in scope and 4.5% worked outside of Canada. By sector, participants were primarily associated with physical activity/fitness (22.9%), public health (16.2%), healthcare (14.2%), education (12.4%), and research (10.2%).Content and format of the Guidelines: A complete summary of the stakeholder survey results is provided in Table GRADE Evidence to Decision Framework: There was high agreement (>60% was considered high agreement) among participants that the 24-h guidelines are a priority for them (95.8%). There was also high agreement that implementing the guidelines would be feasible (85.0%), acceptable (79.1%), useful (78.3%), cost-effective (64.8%), and equitable across population groups (85.8%). An additional item prompted participants to judge the incremental cost relative to the net benefit of implementing the guidelines; most (81.1%) indicated that the benefits of using the guidelines would likely outweigh the costs.Open-ended response options were available for participants who wished to explain or elaborate on their responses to closed-ended items for items assessing acceptability, resource use, perceived incremental cost-benefit ratio, and equity. Fifty-seven of the 112 participants who provided feedback to the acceptability item, “Would you use the 24-Hour Guidelines?” responded favourably. Thirty participants provided favourable or neutral feedback and also suggested an addition or change to some element of the guidelines, most commonly requesting examples or added descriptions. Fourteen respondents provided negative feedback and 11 indicated the guidelines were not relevant in their work or their personal life. Fifty-five participants elaborated on their responses to the resource use item. Of those, 10 indicated the cost of using the guidelines would be small to negligible, 4 indicated the cost would be difficult to manage, and 13 described the costs but did not indicate if it would be easy or difficult to absorb into their operating budget. Other responses suggested respondents did not understand the question. Forty participants provided written feedback on the perceived incremental cost-benefit ratio item. Among them, 19 provided favourable responses, one responded that there would be no benefit and only cost, and 19 participants did not provide clear feedback. Fifty-seven participants expanded on their responses to the equity item. Eleven indicated that following the guidelines would benefit all groups equally while two disagreed, expressing a belief that socioeconomic status would moderate the relationship between guideline adherence and any expected health indicators. Thirty-three participants described barriers or facilitators to implementation and 11 did not answer the question.Implementation and activation of the guidelines: Stakeholders  indicated childcare providers (176), parents (173), and health care providers (107) were the most important intermediaries to target for implementation and activation of the guidelines. The most endorsed modalities for supporting intermediaries to implement and activate the guidelines  included training opportunities such as prenatal workshops as well as pre-service and in-service training (n = 55), and products such as “toolboxes” or posters, with explanations and examples of how to adopt ad activate the guidelines (n = 43).The focus groups and key informant interviews reinforced the findings from the stakeholder survey, that the proposed guidelines were very well received by both stakeholders and end-users . A clearFollowing the Guideline Revision Meeting, three changes were made that altered the content of the preamble: 1) in the description of the groups for whom the guidelines are relevant, the GDP decided that replacing “race and ethnicity” with “cultural background”  would better indicate the diversity of populations to whom the guidelines apply; 2) in the description of the context of children’s activities it was decided that all adults have a role in helping children of the early years to meet the guidelines and therefore, “parents and caregivers” was replaced with “adults”; and 3) in describing the expected balance of benefits and unfavourable outcomes associated with following the guidelines, the term “risk” was replaced with “harm” for accuracy.GRADE Evidence to decision framework: summary section, including a summary of the rationale for these decisions, with more extensive explanations provided in Additional file Three changes that altered the content of the guidelines were made: 1) “while awake” was added to the infant tummy time recommendation to avoid potential harm in having the recommendation misinterpreted as contradicting safe sleep recommendations; 2) based on feedback from the focus groups and from discussions at the Australian guideline development meetings, “energetic play”  was added to the toddler physical activity recommendation; and 3) the term “sedentary” was added to the screen time recommendation based on the Australian Guideline development process and to better reflect the evidence, which did not include data on non-sedentary screen-based activities. Other changes were minor results of the copy-editing process. The final guidelines, with preamble, in English and French are provided in Figs. Canadian 24-Hour Movement Guidelines for the Early Years are provided below with corresponding statements indicating the quality of the evidence informing the recommendation and the strength of the recommendations.The specific guideline recommendations in the Moderate quality evidence, strong recommendation.Being physically active several times in a variety of ways, particularly through interactive floor-based play; more is better. For those not yet mobile, this includes at least 30 min of tummy time spread throughout the day while awake. Moderate quality evidence, strong recommendation.Not being restrained for more than 1 h at a time . Screen time is not recommended. When sedentary, engaging in pursuits such as reading and storytelling with a caregiver is encouraged. High quality evidence, strong recommendation.14–17 h (for those aged 0–3 months) or 12–16 h (for those aged 4–11 months) of good-quality sleep, including naps. For infants (less than 1 year), a healthy 24 h includes:Moderate quality evidence, strong recommendation.At least 180 min spent in a variety of physical activities at any intensity, including energetic play, spread throughout the day—more is better. Moderate quality evidence, strong recommendation.Not being restrained for more than 1 h at a time  or sitting for extended periods. For those younger than 2 years, sedentary screen time is not recommended. For those aged 2 years, sedentary screen time should be no more than 1 h; less is better. When sedentary, engaging in pursuits such as reading and storytelling with a caregiver is encouraged. High quality evidence, strong recommendation.11–14 h of good-quality sleep, including naps, with consistent bedtimes and wake-up times. For toddlers (1–2 years), a healthy 24 h includes:Moderate quality evidence, strong recommendation.At least 180 min spent in a variety of physical activities spread throughout the day, of which at least 60 min is energetic play—more is better. Moderate quality evidence, strong recommendation.Not being restrained for more than 1 h at a time  or sitting for extended periods. Sedentary screen time should be no more than 1 h; less is better. When sedentary, engaging in pursuits such as reading and storytelling with a caregiver is encouraged. High quality evidence, strong recommendation.10–13 h of good-quality sleep, which may include a nap, with consistent bedtimes and wake-up times. For preschoolers (3–4 years), a healthy 24 h includes:Very low quality evidence, strong recommendation.Replacing time restrained or sedentary screen time with additional energetic play, and trading indoor for outdoor time, while preserving sufficient sleep, can provide greater health benefits. For all age groups:Overall quality of the evidence supporting the recommendations.The quality of the evidence from the four systematic reviews informing the recommendations was considered in the process of assessing the overall quality of the evidence supporting each recommendation , 43. AftAfter considering the quality of the evidence associated with the four “critical” health indicators in the sedentary behaviour review, the GDP did not change the sedentary behaviour recommendation . DespiteAfter considering the quality of the evidence associated with the five “critical” health indicators associated with the sleep review, the GDP concluded that despite the “low” quality evidence that sleep duration is not related to adiposity, and the “very low” quality evidence that sleep duration is not related to motor development or growth, “high” quality evidence indicating that longer sleep durations are associated with improved cognitive development and emotional regulation  was suffAfter considering the quality of the evidence associated with the six critical health indicators considered in the integrated movement behaviours systematic review , the GDPValues and preferences of stakeholders and end-users.While selecting “important” and “critical” health indicators, the GDP considered the importance  of each indicator to parents, stakeholders and end-users in terms of the development and health of children of the early years. A study was not conducted to have these groups identify important health indicators, per se. However, almost all GDP members were parents, including parents of children of the early years, and several stakeholder and end-user representatives were on the GDP. In addition, many external reviewers of the guidelines were also parents, stakeholders or end-users and provided input during the stakeholder survey; almost all (95.8%) external reviewers indicated the recommendations were important to them. Considering the indirect assessments of target group values and preferences together with the broad range of indicators included in the systematic reviews that informed these recommendations, the GDP concluded that there would likely be no important variability in values and preferences of health indicators if target groups had rated the indicators directly.Resource requirements (costs).A literature search was conducted using systematic review searching techniques to inform the GDP’s understanding of the expected short-term costs (resource use) required to implement the guidelines as a population-health strategy and to gain insight into the cost-effectiveness of applying these recommendations to children of the in early years. No evidence was found that related to these guidelines. Given the lack of evidence, the GDP sought input from external reviewers (via the stakeholder survey) on their opinions about cost and resource use. Most stakeholders (64.8%) agreed that the costs associated with applying the recommendations would be small or negligible. In terms of the perceived incremental cost relative to the perceived net benefit, most (81.1%) agreed that over the course of a lifetime, the health benefits of applying the recommendations would likely outweigh the costs, which in the judgment of the GDP is likely to generate large savings from a health care systems perspective. In the judgment of the GDP considering the available information, the cost-effectiveness of the recommendations is supported.Equity, acceptability, and feasibility.A systematic review of the evidence examining equity, acceptability, and feasibility amongst stakeholders was not conducted. Thus, these elements of the recommendations were informed by external reviewer input and by judgments made by the GDP. Most external reviewers (85.5%) agreed that following these recommendations would benefit all groups of the population equally. In the judgment of the GDP, implementing these recommendations would probably increase health equity . Similarly, most external reviewers (78%) indicated that they would “always” or “frequently” use the recommendations. Thus, in the judgment of the GDP, these recommendations are acceptable. Finally, most external reviewers (85%) indicated that in their view the recommendations were “somewhat” to “very easy” to use. Based on this information, in the judgment of the GDP, the recommendations are feasible to implement.Benefits vs harms (justification)Physical Activity: Based on the systematic review by Carson et al. [n et al. , higher In balancing the benefits against the harms, in the judgment of the GDP, the desirable indicators (moderate benefits) are likely to outweigh the undesirable indicators (very minor harms); therefore, a recommendation in favour of increasing physical activity is warranted. The GDP placed more value on “moderate” quality evidence showing improvements on adiposity and psychosocial health and on “high” quality evidence showing a benefit in motor development, and less value on “very low” quality evidence showing contradicting findings related to the effect of physical activity on cardio-metabolic health, and on “very low” quality evidence showing that physical activity resulted in an increase in the number of injuries. The GDP also placed more value on evidence showing that total physical activity (TPA), moderate-intensity (MPA), and MVPA resulted in improved fitness.A strong recommendation in favour of increasing physical activity is supported by the assessment of overall “moderate” quality evidence supporting the recommendation, the moderate magnitude of the effect, the low variability in how parents and stakeholders value the recommendation, the anticipated small or negligible costs associated with implementing the recommendation, the large savings to the healthcare system expected over the course of a lifetime, and the stakeholder input suggesting that these recommendations would be feasible and acceptable to stakeholders.Sedentary behaviour: According to Poitras et al. [s et al. , limitinIn considering the balance of the benefits versus the harms, it is the judgment of the GDP that the moderate benefits of limiting/avoiding restrained time, sedentary time, and screen based behaviours outweigh the potential for very minor harms, warranting a recommendation in favour of the sedentary behaviour recommendations. The GDP placed relatively more value on “moderate” quality evidence showing that reducing sedentary time improved adiposity  and psychosocial health , and relatively less value on limited “very low” quality evidence on the impact of sedentary behaviour on motor development  and the lack of evidence about injuries (important).The overall quality of evidence supporting the recommendation was deemed to be of “moderate” quality, and the magnitude of the effect is expected to be moderate. Taken together with conclusions drawn from the parent and stakeholder survey, focus groups and interviews  and the large savings to the healthcare system expected over the course of a lifetime, a strong recommendation is warranted.Canadian Sedentary Behaviour Guidelines for the Early Years (aged 0 to 4 years) [Although the body of evidence indicated that limiting sedentary behaviour is likely to improve health indicators in children in this age group, there was a lack of evidence in relation to the optimal sedentary time in a 24-h day. To address this uncertainty, experts recommended supporting the current 4 years)  from 2014 years)  and, theSleep: The systematic review conducted by Chaput et al. [t et al.  showed tIn considering the balance of the benefits versus the harms, it is the judgment of the GDP that the moderate benefits of longer sleep durations are likely to outweigh any potential minor harms, warranting a recommendation in favour of longer sleep durations including napping. The GDP placed more value on “high” quality evidence showing that longer sleep durations improved emotional regulation  and cognitive function , and less value on limited “low” quality and “very low” quality evidence showing that increasing the duration of sleep may impact adiposity or physical activity, and on the lack of evidence examining metabolic health.The overall quality of evidence supporting the recommendation was deemed to be of “high” quality and the magnitude of the effect is expected to be moderate; the GDP is very confident that the true effect lies close to the estimate of the effect. Taken together with the conclusions drawn from the parent and stakeholder survey, focus groups and interviews , and the large savings to the healthcare system expected over the course of a lifetime, a strong recommendation in favour of longer sleep durations, including napping is warranted.Although the body of evidence indicated that longer sleep durations, when compared to shorter sleep durations, were generally favourably associated with health indicators regardless of age, no conclusions could be drawn in terms of optimal durations for infants, toddlers, or preschoolers. Content experts from the GDP pointed to the USA National Sleep Foundation  and AmerCombined movement behaviours: The systematic review conducted by Kuzik et al. indicated that the most ideal combinations of sedentary behaviour and physical activity were favorably associated with motor development and fitness; both favorably and not associated with adiposity; and not associated with growth [h growth . ReplaciIn considering the balance of the benefits versus the harms shown in the four systematic reviews, it is the judgement of the GDP that the potential benefits associated with the most ideal combinations of movement behaviours are likely to outweigh any potential minor harms, warranting a strong recommendation in favour of engaging in higher physical activity, less time restrained and less sedentary screen time, and longer sleep durations , 21–23. The overall quality of evidence supporting the recommendation was deemed to be of “very low” quality and the magnitude of the effect is expected to be very low. Taken together with the conclusions drawn from the parent and stakeholder survey, focus groups and interviews , and the large savings to the healthcare system expected over the course of a lifetime, a strong recommendation is warranted.The body of evidence showed that replacing sedentary time or light physical activity with energetic play (MVPA) is likely to improve health indicators in children of the early years. However, there was no information available about combinations of all three movement behaviours included in the systematic review that would inform a specific recommendation for the amounts of sedentary time to be traded for light, moderate, and vigorous physical activity, and sleep.The GDP followed the GRADE system to make determinations about the strength of each recommendation by considering; 1) the quality of the supporting evidence, 2) the values and preferences of stakeholders and end-users, 3) whether the recommendations would be considered a wise use of resources, 4) equity, acceptability, and feasibility, and 5) whether the potential benefits outweigh the potential harms .OverallMost stakeholders agreed that if implemented in all Canadian children of early years age, the recommendations would benefit all groups of the Canadian population equally. A few raised concerns about the difficulty that families from low socio-economic status may have in meeting these guidelines. In the judgment of the GDP, these are implementation issues, many of which could be addressed by developing knowledge translation tools targeting families with low socio-economic status. Therefore, the GDP decided not to issue a separate recommendation for this subgroup of the population.A more detailed version of the “evidence to decision framework” is provided in Additional file Canadian 24-Hour Movement Guidelines for the Early Years (0–4 years): An Integration of Physical Activity, Sedentary Behaviour, and Sleep were officially released on November 20, 2017 through a comprehensive media relations strategy to optimize exposure and coverage. Dissemination, implementation, communication, and evaluation plans for the new guidelines intend to build on work that is ongoing with the Canadian 24-Hour Movement Guidelines for Children and Youth [www.buildyourbestday.com) that will enable clear, consistent and targeted communication with early childhood educators, primary care practitioners, and public health promoters, and indirectly with parents/caregivers. Proactive national media relations outreach, hard copy and e-distribution of guideline-related materials have been orchestrated through Leadership Committee distribution networks. A cross-Canada lecture tour in both French and English is also planned to raise knowledge and awareness of the guidelines among important stakeholders and end-users, including researchers. Webinars targeted to different end-user groups were developed, delivered, and preserved on-line (www.csep.ca/guidelines). All promotional materials, campaigns, and initiatives are available in both English and French.The Canadian 24-Hour Movement Guidelines for Children and Youth was adapted for use with the Canadian 24-Hour Movement Guidelines for the Early Years (0–4 years) , poster(s), printable messaging materials , and promotional content pieces such as Twitter cards, Facebook images, Instagram images, sample ads, and sample social media content.A digital platform was created as a knowledge portal that provides the three key audiences identified through stakeholder consultation  with the information and resources they need to understand and implement the new guidelines. This resource will be available at Metrics on the success of the guidelines launch will be gathered including traditional media impressions, social media activity, hard-copy and electronic distribution in the first two weeks post-launch as well as the general tone (positive/negative) of any media coverage. Canadian parents’ baseline awareness of the guidelines immediately post launch will be collected via a ParticipACTION survey consistent with evaluation procedures being employed with the guidelines for children and youth. Beliefs among identified key stakeholders  about the relative benefits of the 24-h movement guidelines  versus separate guidelines for each behaviour are being assessed via an online, survey.Global 24-Hour Movement Guidelines for the Early Years (see www.who.int/end-childhood-obesity/news/public-consultation-2017/en for further details). This global momentum should facilitate awareness and uptake of the various jurisdictional guidelines.An unplanned outcome of the development of these new Canadian guidelines was that they initiated the development of similar guidelines in Australia . Indeed,The systematic reviews, GDP meetings, and stakeholder and end-user consultations highlighted several research needs that are listed in Table Canadian 24-Hour Movement Guidelines for the Early Years, with due consideration to the existing surveillance structures in Canada : An Integration of Physical Activity, Sedentary Behaviour, and Sleep following the rubric of the AGREE II [www.csep.ca/guidelines.The four independent assessors scored the procedures used to develop the AGREE II . A summaCanadian 24-Hour Movement Guidelines for the Early Years (0–4 years): An Integration of Physical Activity, Sedentary Behaviour, and Sleep. The development of these guidelines that integrate all movement behaviours follows the shift toward a whole-day approach to conceptualizing movement behaviours that was initiated by the Canadian 24-Hour Movement Guidelines for Children and Youth: An Integration of Physical Activity, Sedentary Behaviour, and Sleep [This paper outlines the process and outcomes for the development of the nd Sleep . This rend Sleep , 21–23, nd Sleep , evidencnd Sleep , and logThe guideline development procedures used here followed comprehensive, rigorous, and transparent processes , 37, 43,Canadian Physical Activity Guidelines for the Early Years [Canadian Sedentary Behaviour Guidelines for the Early Years [The individual behaviour components of the guidelines have not changed significantly from the earlier ly Years  and Canaly Years . The majIt is possible that busy parents may initially view the 24-h guidelines as just another challenge and potential source of stress. Nevertheless, the overall conceptualization of the integrated approach to all behaviours on the movement continuum holds wide appeal with stakeholders and end-users , 33, 67 Agreement existed amongst the GDP that proceeding with the 24-h guidelines for the Early Years using the best available evidence, expert consensus, and stakeholder and end-user input, while being transparent about the quantity and quality of the evidence base and the strength of the guideline recommendations, was the most responsible approach in providing public health recommendations regarding movement behaviours for a healthy day for children of the early years. The GDP believes that the evidence is supportive of all the recommendations, and the potential for benefits still exists even where the evidence is weakest, while the likelihood of harm is very small. Challenges to these recommendations are encouraged and will result in more refined and informed guideline recommendations in the future.Despite being presented as “24-h movement guidelines”, it is not possible to give precise recommendations that add exactly to 24 h, because there are ranges provided for all behaviour components . Obviously if one child sleeps 11 h and another 14 h, the former has three additional hours of time to be distributed among the wake-time behaviours. Moreover, some degree of day-to-day variability is normal, and provision of ranges allows for this flexibility, accommodating to different schedules and changes in schedules. Collectively, guidance for a healthy 24-h period is provided.A study examining the proportions of preschool-aged Canadian children 3–4 years) meeting the new guidelines and different recommendations within the guidelines was completed using CHMS data . Associa years mewww.csep.ca/guidelines. These materials present a relative advantage over previous guidelines, in that they show how the guidelines can be easily assimilated into current practice by organizations (compatibility), and how they can most clearly and succinctly be conveyed (simplicity). These clear, supporting messages are essential to informing stakeholders, parents, early childhood educators, public health/health care professionals, and governments, of the value and use of the 24-h movement guidelines. The guidelines themselves provide evidence-informed targets associated with health benefits for children of the early years to follow (under the direction of caregivers).A suite of materials to complement and message the guideline recommendations to various subgroups was developed and is publicly available at The Leadership Committee partners  will take the lead to disseminate the new guidelines to Canadians both directly and through the partners’ networks. Each partner has a national mandate related to the promotion of healthy active living to Canadians. In addition, the knowledge user representatives on the GDP come from diverse fields concerned with the movement behaviours of children of the early years, and are committed to mobilizing this work to various settings and populations. CSEP will embed these new guidelines into their training materials in order to ensure CSEP members as well as public health professionals, health care practitioners, teachers, and parents understand the importance of all movement behaviours across the 24-h period. As with previous guidelines, ParticipACTION will actively participate in the dissemination, promotion, implementation, and activation of these new guidelines.In order to motivate adoption, the new guidelines should be followed up with messages that explain the “why” and “how” to the various stakeholder groups, as well as sustained implementation and activation strategies , 57, 67.The impact and success of the launch of the new guidelines will be assessed through media hits and impressions. Dissemination reach will be assessed with metrics from online and hard-copy distribution. Funding is in place to collect baseline data on parents’ and other stakeholders’ awareness of the new guidelines, allowing for future follow-up research.Through these various implementation, activation, and evaluation efforts, the long-term goal is that that these guidelines will enhance the promotion of healthy active lifestyles and improved sleep quality and hygiene among infants, toddlers, and preschool children across Canada, and inform healthy active living policy at the local, provincial, and national levels. It is further anticipated that in the long-term this project will provide international leadership and will advance a global healthy active living agenda. Early evidence of success in the form of international leadership can be found with these new Canadian guidelines being the impetus for the development of similar guidelines in Australia , New ZeaThe final stage in the guideline development cycle is the planning of updates and revisions . It was Canadian 24-Hour Movement Guidelines for the Early Years (0–4 years): An Integration of Physical Activity, Sedentary Behaviour, and Sleep including adhering to a rigorous, robust and transparent guideline development process [There were several strengths of the process used to develop the  process , 37, 43;Despite these strengths, the guideline development process also had limitations. First, the evidence base for the guidelines was generally incomplete and of low quality, though it does represent the best available evidence collected through systematic reviews and original research. Second, there was very little research available to inform specific aspects of the guidelines . Third, very little research exists on integrated movement behaviours and health indicators in this age group. Because of this limitation, evidence is presently insufficient to provide specific advice on behaviour substitution options for a particular early years child, in a particular situation. Nevertheless, behaviour changes that ensure adequate sleep, reduced screen time, and increased energetic or outdoor play are likely to provide health benefits to most children of the early years. Fourth, it is possible that the various consultation processes used resulted in biased feedback and that voices of important subsets of the population were missed. Fifth, evidence of the cost effectiveness of the guideline recommendations was not available.Specific research needs identified in the development of these guidelines are listed in Table Canadian 24-Hour Movement Guidelines for the Early Years (0–4 years): An Integration of Physical Activity, Sedentary Behaviour, and Sleep are part of a paradigm shift in thinking about daily movement behaviours. This shift from focusing on movement behaviours in isolation to a whole-day approach is supported by the available evidence and stakeholder opinion. These guidelines represent a sensible evolution of public health guidelines whereby optimal health is framed within the balance of movement behaviours across the whole day, while respecting preferences of end-users. The GDP rated these as strong recommendations with the potential benefits of following these guidelines far exceeding the potential risks. It is hoped that these guidelines open new avenues for population health promotion and instigate new research on the health effects of integrated movement behaviours.The new Additional file 1:Stakeholder Survey (English followed by French version). (DOC 202 kb)Additional file 2:Detailed evidence to decision framework explanation for the Canadian 24-Hour Movement Guidelines for the Early Years (0–4 years): An Integration of Physical Activity, Sedentary Behaviour, and Sleep. (DOC 90 kb)


Countries with major public health challenges do not always base their health-care decisions on the best available scientific evidence. Charles Shey Wiysonge tells Fiona Fleck how he and his colleagues are trying to change that. Q: How did you become interested in medicine and public health?A: Growing up in Cameroon I wanted to study mathematics and was drawn to complex equations and aeronautics, but people said I should study medicine, so I did. At medical school most students wanted to become clinical specialists, public health was not popular at all. After graduating, several things drew me to public health. I worked as a hospital physician and saw several outbreaks of measles. People used to say “don’t count your children until measles have come and gone.” Children were dying of measles every day. This experience eventually led me to work on immunization. Also, while working in internal medicine, there were several treatment options for hypertension and heart disease. I was not always sure which was the best. That’s when I discovered evidence-based medicine. At that time – around the year 2000 – the Cochrane Collaboration started a new fellowship to train leaders in evidence-based medicine from low- and middle-income countries. I applied, became the first holder of the award and trained at the Cochrane Centre in Oxford.Q: What is evidence-based medicine?A: Research and other evidence are constantly changing and health-care professionals need to keep up with the latest developments so they can offer the interventions that are known to work and not those that are harmful or ineffective. There are many examples of unspeakable and unnecessary suffering resulting from the failure to take an evidence-based approach to clinical care. For example, in 1999 Cochrane researchers did a systematic review to find out whether drugs that inhibited massive calcium influx into cells reduce the risk of death or dependency after stroke. At the time, stroke patients were widely treated with calcium channel blockers. They found no evidence of a beneficial effect. Evidence-based medicine has been defined as the “conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients”, although today, health-care professionals prefer the term “evidence-based health care” for a more holistic approach.“There are many examples of unspeakable and unnecessary suffering resulting from the failure to take an evidence-based approach.”Q: You did not learn about evidence-based health care at medical school, is it included in medical curricula today?A: Some medical and dental schools in South Africa offer separate courses on evidence-based health care, others have embedded the approach in all courses, and some do both. Our Cochrane collaborators at the universities of Calabar in Nigeria and Yaoundé I in Cameroon also offer programmes in the evidence-based approach for physicians. Evidence-based health care is included in the curricula for health-care professionals in these and some other African countries, but more needs to be done at the undergraduate and the postgraduate levels across the continent.Q: The Cochrane Collaboration prepares and disseminates information on what works and what doesn’t in health care globally. How is the South African Cochrane Centre doing this in Africa?A: Our centre was set up in 1997 as a unit of the South African Medical Research Council. It is the only Cochrane centre in Africa and has a branch in Nigeria. There is increasing recognition in sub-Saharan African countries, that policy-making should be based on the best available scientific evidence. To this end, we have been training researchers in these countries to do systematic reviews and recently expanded these activities via the recently established Cochrane African Network. The Cochrane Collaboration charges a fee to access its global library of systematic reviews and other evidence. Low-income countries can access this evidence via a special online platform, thanks to the Evidence Aid initiative. In South Africa, free access to the Cochrane Library is now provided by the South African Medical Research Council and we hope other middle-income countries in Africa will follow this model.Q: Are the Cochrane reviews useful in Africa too, or do countries in Africa need evidence that is tailored to their specific situation?A: Not all Cochrane reviews are applicable to Africa. Since 2007, the South African Cochrane Centre has collaborated with the Centre for Informed Health Choices in Norway and others to improve the use of reliable research evidence in policy and management decisions in Africa. We found, overall, that most primary studies on health system issues are from high-income countries and that only some of these reviews are applicable in low-income settings, including parts of sub-Saharan Africa. For this reason, reviews that synthesize such studies have limited relevance to Africa, especially those written by researchers with no experience in Africa.Q: So more research is needed that is specific to sub-Saharan Africa?(AIDS) denialism in South Africa from 1998 to 2003, characterized by the refusal to use antiretrovirals for human immunodeficiency virus (HIV) prevention and treatment. This resulted in a reversal of gains in child survival and life expectancy and the loss of a generation of economically active adults in their prime.A: Our analyses suggest that external partners, rather than national priorities, have driven health research in most African countries over the last two decades. However, we don’t need to re-invent the wheel, as much of the global research evidence is applicable to Africa. A major priority for new research in African countries should therefore be implementation research. This type of research helps us understand which health-care interventions work in specific contexts and which do not, and to test different ways to make health-care more effective. African countries often fail to make optimal use of evidence in decision-making, resulting in unnecessary loss of life, reduced quality of life and lost productivity. An example, is acquired immune deficiency syndromeQ: How are you working to make policy-makers in Africa more aware of the need to base their health-care decisions on the best available scientific evidence?A: The use of health research in decision-making in African countries is generally weak. That’s why we advocate for the dissemination and use of evidence, and building partnerships to promote evidence-informed health care in collaboration with decision makers. African countries sometimes develop new guidelines, but often adopt or adapt existing WHO guidelines to suit national contexts. Our analyses of the development or contextualization of guidelines used in African countries reveals deficiencies in the rigour of development and adherence to international reporting standards. We advise countries on how to develop guidelines for their specific national contexts. We try to work with the health ministries through expert groups to encourage governments to base their policies on the best available evidence and we are involved in initiatives, such as the Effective Health Care Research Consortium, an international group with partners in Cameroon, Kenya, Nigeria and South Africa. However, we are limited by financial constraints, as our work does not attract much funding.Q: What are the barriers stopping African countries from basing their public health policies and practice on the best scientific evidence?A: There are several barriers. The health research field in Africa is characterized by numerous players, diverse interests, dispersed efforts and uncertain outcomes in relation to its impact on the major health challenges of the continent. For a better understanding and uptake of scientific evidence in health policy-making, we need a stronger research community – research is not well funded or supported in many African countries – and this community needs to forge closer links with policy-makers, programme managers and implementers. Sometimes the evidence is difficult for policy-makers to understand. That’s why we provide easy-to-read summaries for them. Sometimes, policy-makers ignore the evidence because it’s not what they want to hear. For example, the South African Department of Health once asked the South African Cochrane Centre to prepare a review of the evidence on how best to prevent mother-to-child transmission of HIV infection. But when we gave them the review, they ignored it.“We have seen a positive change in attitudes towards the use of evidence in health-care planning.”Q: Have you noticed any improvement in the uptake of evidence in health policy-making?A: We have seen a positive change in attitudes towards the use of evidence in health-care planning. For example, the Paediatric Association of Kenya has been using explicit, transparent guideline development procedures when developing recommendations for the prevention and treatment of childhood conditions for the last decade. Another example is the increasing number of African countries with functioning national immunization technical advisory groups, which provide evidence-based advice to national health authorities on how to implement WHO vaccine policies and recommendations.Q: How will the conference you are hosting in Cape Town from 13 to 16 September contribute to improving the uptake of scientific evidence in policy-making in Africa?A: The Cochrane Collaboration holds a colloquium every year. This year will be the first time that Cochrane will be joined by the four other biggest players in evidence-based policy: the Campbell Collaboration, the Johanna Briggs Institute, the Guidelines International Network and the International Society for Evidence based Health Care, to organise the first ever Global Evidence Summit. We are expecting thousands of participants, including those from every health-care discipline and from virtually every country on the continent of Africa. There is strong evidence that such interactive, educational meetings, can help health-care workers improve their performance. Participants will have the chance to learn more about guideline development, using evidence for emerging global health and social crises and how the evidence community can overcome denial of clear scientific findings. We are really excited about this opportunity to highlight the evidence-based approach to policy and practice in health for countries in Africa.


Modified vaccinia virus Ankara (MVA) is the vector of choice for human and veterinary applications due to its strong safety profile and immunogenicity in vivo. The use of MVA and MVA-vectored vaccines against human and animal diseases must comply with regulatory requirements as they pertain to environmental risk assessment, particularly the characterization of potential adverse effects to humans, animals and the environment. MVA and recombinant MVA are widely believed to pose low or negligible risk to ecosystem health. However, key aspects of MVA biology require further research in order to provide data needed to evaluate the potential risks that may occur due to the use of MVA and MVA-vectored vaccines. The purpose of this paper is to identify knowledge gaps in the biology of MVA and recombinant MVA that are of relevance to its hazard characterization and discuss ongoing and future experiments aimed at providing data necessary to fill in the knowledge gaps. In addition, we presented arguments for the inclusion of uncertainty analysis and experimental investigation of verifiable worst-case scenarios in the environmental risk assessment of MVA and recombinant MVA. These will contribute to improved risk assessment of MVA and recombinant MVA vaccines. Poxviridae , Retroviridae (including lentivirus), Adenoviridae , Parvoviridae , Herpesviridae  and Paramyxoviridae  [Vaccines and vaccine vectors are termed genetically modified (GM) if recombinant gene technology is used to create the vaccine or vector. Genetically modified viruses (GMVs) or virus vectors of homologous or heterologous disease antigens are considered highly desirable for vaccinations against diseases that are difficult to treat or for which there exists no effective conventional vaccine, e.g., acquired immune deficiency syndrome (AIDS), malaria, tuberculosis and neoplastic disorders. Some of the advantages of GMVs in vaccination are the enhancement of immunogenicity without an adjuvant and induction of robust cytotoxic T lymphocyte response to eliminate virus-infected cells. Many viruses have been used as GMVs for vaccination purposes, the major ones being us; SeV) ,2. Each 8 pfu) of MVA [VACV-based vectors have good historical precedence on safety in that VACV and modified vaccinia virus Ankara (MVA) were used in smallpox vaccination. VACV-based vectors were also well tolerated in clinical trials, although adverse effects were recorded in some studies at high dose over 10) of MVA . Disadva) of MVA . Recombi) of MVA . The AdV) of MVA ,7,8. Sim) of MVA . Retrovi of MVA .) of MVA ,12. Vect) of MVA . SeV inf) of MVA . These aEnvironmental risk assessment (ERA) is governed by regulatory instruments of different countries and regions. In the European Union (EU), the ERA is governed by Directive 2001/18/EC  and contOrthopoxvirus and family Poxviridae [Poxviruses have a linear double stranded DNA genome of approximately 130 kbp –360 kbp (canarypox virus) and their entire morphogenesis is within the cytoplasm of infected cells. A milestone in vaccinology was achieved when smallpox, a highly lethal disease caused by variola virus (VARV), a member of the genus xviridae  was offixviridae . Smallpoxviridae . Some prxviridae . In 1796xviridae . Initialxviridae ,25 and lxviridae . Smallpoxviridae  and the xviridae . The sucThe discovery that VACV can be used as a vector to express heterologous transgenes in mammalian cells ,29, the MVA is arguably the most promising virus vector due to its capacity to express a wide array of transgenes with correct post-translational modification and its immunogenicity in vivo along with its safety profile including host restriction in mammalian cells and attenuation in vivo. Both domestic and international legislations require that the ERA of virus-vectored vaccines be submitted and evaluated as part of MAA and clinical trial application. Of particular interest to the ERA is the characteristics of the MVA vector, its interaction with the host and the environment that may result in immediate or delayed risk to human and animal health as well as to the environment. The strong safety profile of MVA-vectored vaccines as well as its history of safe use as smallpox vaccine have stagnated research into aspects of the biology of the vector that are still poorly understood but also relevant for further optimization of the safety of MVA. Thus, there is an underlying assumption that MVA is so safe that studies aimed at risk characterization of the vector is either regarded as irrelevant or has been unequivocally addressed in scientific literature .Hazard characterization (ERA step 2) of MVA and MVA-vectored vaccines would require knowledge of: (i) nature and distribution of naturally circulating OPVs that may rescue the MVA during co-infection and superinfection; (ii) recombination between MVA-vectored vaccines and naturally occurring OPVs during co-infection/superinfection of cell cultures, immune-competent and immune-compromised animals; (iii) MVA host restriction in human cells and the molecular basis for the restriction; (iv) clonal purity of MVA stocks; (v) genome and transgene stability of MVA and MVA-vectored vaccines following multiple serial passages; (vi) virus and host factors that modulate transgene stability; (vii) effect of the expressed transgene(s) on the virus-host transcriptome, proteome, metabolome and epigenome and (viii) biodistribution and shedding in immune-competent and immune-compromised individuals.The aim of this review is to identify gaps in knowledge with respect to hazard characterization of MVA vector/MVA-vectored vaccines and highlight ongoing and future experiments aimed to address these knowledge gaps. This will contribute to a more robust ERA of MVA vector/MVA-vectored vaccines and further optimization of MVA as a safe vaccine vector.Different variants of VACV were used for vaccination against smallpox. MVA was originally generated by serial passages of chorioallantois Vaccinia virus Ankara (CVA) in chicken embryo fibroblast cells (CEF). It was produced in the Bavarian State Vaccine Institute (Germany) during 1968–1985 and used as a human smallpox vaccine . The serThe MVA vaccine against smallpox was administered mostly intradermally or subcutaneously. It was often used in Germany from 1968 to 1988 as a first vaccination, usually to vaccinia-naive children and adults that could be at risk for adverse effects if vaccinated with other and less attenuated smallpox vaccines . The MVA® (MVA-BN), as a smallpox vaccine. MVA-BN is a single clone derived from MVA-584 following six rounds of plaque purification [The development and optimization of MVA as a smallpox vaccine continued post smallpox eradication. This in part is driven by the concern that the smallpox virus may re-emerge, either due to accidental escape from containment or due to bioterrorism. Hence, there is a public health need to optimize MVA as an effective but safer alternative to multiplication competent smallpox vaccines. The European Medicines Agency (EMA) has registered Imvanexfication . Currentfication .MVA was developed from CVA by over 570 passages in CEF. This resulted in the loss of about 15% (approximately 30 kbp) of the parental CVA genome ,46 and sThe attenuation of MVA in vivo depends on the strain or variant. Most MVA strains produce abortive infection in intact animal hosts and have been shown to be non-pathogenic even in immune-deficient animals and humans ,60,61,62Following the discovery in 1982 that VACV can express heterologous genes efficiently in mammalian cells ,29, MVA The MVA vector is generally believed to pose a very low or negligible risk to humans, animals and the environment ,19,42. I® as a smallpox vaccine within EU, the EMA Committee for Medicinal Products for Human Use (CHMP) stated, “With regard to safety, the vaccinia virus in Imvanex cannot replicate in human cells and hence is less likely to cause side effects than previous smallpox vaccines. Imvanex would therefore be beneficial for people who cannot be given vaccines containing replicating viruses such as patients with weakened immune system” [KIL and C7L) with functional copies did not restore the host cell tropism of wild-type CVA [The inability of MVA to undergo productive infection in human and most cells of mammalian origin is the main reason why MVA is regarded as a safe virus vector. In approving the licensing of Imvanex system” . The mol system” ,98; (ii)type CVA ,98; (iiitype CVA  and (iv)type CVA . Thus, tResearch on identifying the molecular determinants of the MVA host cell defect in human and other mammalian cells have stagnated presumably because of the belief/assumptions that MVA cannot undergo productive infection in human cells. At present, the role of insertions/deletions (indels) and single nucleotide polymorphism (SNP) in MVA non-productive infection of human cells either singly or in combination with the six major deletions remain uninvestigated. There is also no attempt to re-adapt MVA to multiply in human cells as a way of understanding the virus and host cell determinants of host cell tropism. Since MVA host cell restriction in human and other mammalian cells was achieved by multiple serial passage in CEF, we hypothesized that MVA can be re-adapted to multiply in human cells by multiple serial passaging in human cell lines. We infected non-permissive human Caco-2 (ATCC HTB-37) cells  with MVA® vaccine has been shown to be polyclonal using genome wide sequencing designed to examine if variants are present [A robust hazard characterization of a virus vector will demonstrate that the vector is clonally pure and genetically stable at a passage level and titer that is equivalent to what is present in the production batch. The MVA vector is assumed to be homogenous following over 570 passages in CEF and subsequent three rounds of plaque purification . The ide present , isolati present . HoweverSince MVA is subjected to selection pressure (multiple multiplication cycles) during production of a high titer virus stock intended for vaccination, it is essential to examine the genome stability of the virus across MSV + 1 to MSV + 5 in human cell lines and in immune-competent and immune-compromised animal models. At present, this information is not provided in ERA dossiers submitted for clinical trials or MAA because relevant EU directive (Directive 2001/18/EC) has not made the provision of such data obligatory. Data on evolution of MVA in permissive cells during Good Manufacturing Practice (GMP) manufacturing will enable risk assessors to evaluate the genome stability of MVA and the presence of variants in the production batch intended for vaccination. The emergence of quasi-species and their role in the modulation of the MVA phenotype including host range, infectivity, attenuation, virulence and biodistribution is an omitted research field that needs to be addressed.In order to reach the scale required for current GMP of MVA-vectored vaccines intended for clinical application, the vaccine needs to be amplified multiple times. Such high titer amplification creates a selective pressure that may result in instability of the recombinant MVA. Instability may occur within the transgene expression cassette (transgene instability) or outside the expression cassette (genome instability). Provision of genome sequences of MSV for up to five passages is necessary in order to evaluate the genome stability of recombinant vaccines based on MVA. However, provision of whole genome sequences is not mandatory under Directive 2001/18/EC. Thus, the genome stability of all MVA-vectored vaccines intended for clinical application remains unknown and potential mutations outside the expression cassette and the phenotypic implications of such mutations go unreported. Transgene stability of recombinant MVA-vectored vaccine is routinely examined during hazard characterization. In 2004, our group reported that the influenza virus hemagglutinin (HA) transgene in some CPXV-MVA recombinants is unstable resulting in the loss of the transgene following serial passages  and soutStudies on viral and host factors that modulate transgene stability are miniscule. With few exceptions, the effect of transgene insertion site ,107,108,The interaction between virus-vectored vaccines and naturally circulating wild-type viruses is essential to ERA since baseline data on the occurrence, nature and geographic distribution of the later is required in order to evaluate the potential for recombination, complementation, reactivation or reversion to wild-type virus. In case of MVA, this will require knowledge of the occurrence, distribution and characteristics of naturally circulating OPVs in locations and ecosystems in which recombinant MVA vaccines are to be deployed, especially for the vaccination of domesticated animals and wildlife. With the exception of Germany ,115,116,Even when recombinant poxvirus vaccines are released in areas where some knowledge exists on the characteristics and occurrence of naturally circulating relatives, no systematic study has been undertaken post release to monitor the occurrence of potential adverse effect due to the interactions between genetically modified poxvirus vaccines and naturally circulating OPVs. Raboral-VRG, a VACV-vectored rabies vaccine  was, aloRecombination between poxvirus-vectored vaccines and naturally circulating OPVs during co-infection and superinfection of cells/hosts is significant in terms of ERA. This is because recombination has the potential of restoring productive infection of a multiplication-incompetent vaccine-vector as well as generating hybrid viruses with altered host range, cell tropism, transmissibility and virulence. Although recombination is known to occur among replicating poxviruses ,143,144 To examine the potential for recombination in cells in which MVA multiplies poorly, Vero cells were co-infected with MVA-vectored influenza vaccine (MVA-HANP)  and a feThese results demonstrated that: (i) recombinant MVA vaccine can recombine with naturally circulating OPVs during co-infection and superinfection of mammalian cells that are semi-permissive to MVA and (ii) repulsion of superinfecting virions does not prevent recombination between recombinant MVA and wild-type OPVs. At present, we are extending these experiments to non-permissive cells and to immune-competent and immune-deficient animal models, as well as mapping genome-wide patterns of recombination in the already isolated recombinants. If our results from cell cultures are replicated in intact animal models, the potential for recombination should be examined for each MVA-vectored vaccine for which MAA and clinical trial application is being sought. In addition, the present emphasis on the likelihood or frequency of occurrence but not on the consequences needs a re-examination. Consideration should also be given to the impact or consequences of a presumably rare event like recombination. A rare recombination event may generate progeny hybrid viruses that are more virulent than any of the parental strains. Naturally occurring OPVs like CPXV, MPXV or VACV may become more virulent if they acquire the transgene encoding co-stimulatory molecules from an MVA-vectored vaccine following an unlikely recombination event. Among alphaherpesviruses, recombination between attenuated infectious laryngotracheitis virus vaccine strains resulted in the emergence of virulent field isolates .A vaccine virus/vector will be dispersed to cells, tissues and organs of the patient (biodistribution) from the initial administration site . The virus can be introduced into the environment via body fluids . Following shedding, survival of the shed virus/vector outside the host (persistence) will depend on the virus/vector biological properties and the nature of the environment. Thus, assessment of pathways through which genetically modified and/or transgenes may interact with the ecosystem (other than the vaccine recipient) is critical in ERA. In this Section, the relevance of biodistribution, shedding and persistence of GMVs to ERA is briefly discussed.The virus/vector/transgene can potentially be dispersed throughout the body when administered via a route other than the alimentary canal and this has potential of transmission to sex cells (with the attendant risk of transmission to offspring). MVA can reach target tissues other than the site of administration ,154. HowThe environment is exposed to the virus vector/virus-vectored vaccine if it is shed by the vaccine recipient. In this case, hospital personnel, caregivers, non-vacinees and others may be exposed especially if the virus vector is shed via body fluids. When evaluating shedding, the biological properties of the virus vector/virus-vectored vaccine such as biodistribution, the status of the host including immunocompetence, dose and route of administration, sampling frequency and duration of sampling, methods for sample analysis and data interpretation are important considerations. In addition, information on the biological properties of the wild-type strain can provide guidance in shedding evaluations.Similar to biodistribution, multiplication competence of the virus vector is an important consideration in evaluating shedding given that multiplication competent virus vector may persist in the vaccinee for extended periods of time and can increase in amount leading to higher shedding of infectious particles with an associated likelihood of virus transmission. For such multiplication competent virus vectors, it is important to analyze their molecular variants, which can also influence virus shedding. In general, the basic assumptions in the ERA of multiplication competent virus vectors are that there is a likelihood of spread of the viral vector from the vaccinee into the environment . Immune The ability of the virus vector to survive after being shed by the vaccinee, as well as the stability of the inserted genetic material in the environment will influence the chance of non-vaccinated organisms being exposed. Persistence of the most commonly used viral vectors in genetically modified (GM) vaccines and gene therapy has been discussed in Baldo et al. . AlthougPersistence of viral particles and DNA in the environment can be affected by several factors (reviewed in ), includin vitro in relevant cell cultures, as well as in both immune-competent and immune-deficient animals for each MVA-vectored vaccine. This will confirm that multiplication competence has not been restored in the recombinant MVA vaccine.In transmission to non-target hosts, persons considered at risk of exposure to virus vector/virus-vectored vaccine are those that come in close contact with the vaccinee. These often are family members, health care workers as well as pets and other animals in close contact with the vaccinee. Knowledge about biodistribution, shedding and the immunological status of the vaccinee close contacts will help in identifying the route of transmission. If the virus-vector is inadvertently transmitted to these individuals, clearance should be effective given that a good proportion of the population already have pre-existing immunity to VACV/MVA. However, should the close contacts have compromised immunity due to old age, very young, sick or are on immunosuppressive drugs, clearance may be inefficient and the consequences of infection might be more significant. In these individuals, interactions  between GM virus vector and resident natural viruses could generate quasi virus species that are unstable and constantly mutate. This could lead to species with altered epitopes and thus less infectivity . AlteredA41L and B15R genes. Single removal of these genes resulted in increased viral-specific CD8+ T cell response and enhanced protection against challenging with virulent VACV WR in mice [A35R or C12L [MVA is considered a safe vaccine against smallpox. However, animal studies showed that higher or multiple doses (boosts) are required to obtain the same anti-VACV antibody response as obtained with a single dose of wild-type VACV . Thus, M in mice ,171. Inc or C12L ,88. ThesThe effect of deleting MVA genes in MVA-based vectors expressing foreign antigens on the immune response against these antigens has also been examined. Deletion of single or multiple MVA immunomodulatory genes stimulated the immune response against the foreign proteins expressed by the recombinant MVA mutant ,172,173.C7L gene (MVA-ΔCL7) could not prevent phosphorylation of eIF2α, an event important in the antiviral response mediated by interferons. Reinsertion of the K1L gene, which is involved in NF-κB inhibition and which is absent in MVA, restored eIF2α phosphorylation, indicating the complementary function of the K1L and C7L proteins.Reintroducing VACV genes in MVA to modify the immune response to MVA warrant caution as illustrated by the study of Backes and co-workers . They foThe immunogenicity of MVA cannot only be altered by deletion of immunomodulatory genes, but also by posttranslational modifications of viral structural proteins. Rojas and colleagues found that the glycosylation state of VACV particles had an impact on the immune response . VACV naB15R compared to MVA [F1L gene [The Th1 cytokine profile is characterized by IFNγ, Interleukin (IL)-2 and IL-12 production, while IL-4, IL-5, IL-6, IL-10 and IL-13 are typical for a Th2 response ,179. Infd to MVA . MVA-C, F1L gene . When geF1L gene  due to tF1L gene . At presO1L gene; a gene fragmented in MVA [MVA not only depends on host pathways to successfully generate its progeny, it must also counteract inflammatory, innate and acquired immune response pathways that prevent viral replication . VACV ind in MVA . The used in MVA ,191. Infd in MVA . Infectid in MVA . Whetherd in MVA .Knowledge is always accompanied by uncertainty. Uncertainty with respect to risk characterization refers to (i) lack or incomplete knowledge on the likelihood of an adverse effect occurring and (ii) the lack or insufficient knowledge on the magnitude of the consequences if such an adverse effect occurred. As we have shown in Although Directive 2001/18/EC and its supplementary Commission Decision 2002/623/EC recommend identifying uncertainties and analyzing them during ERA of GMOs and medicinal products containing GMOs, the ERA of MVA-vectored vaccines (in peer-reviewed literature and publicly available dossiers submitted to EMA) does not incorporate methodological identification of uncertainty and uncertainty analysis . On the Worst-case assumptions that can be tested and eventually rejected or proven are an essential sub-step in the risk characterization of GMOs including genetically modified viruses  and planIn this paper, we have highlighted the knowledge gaps and paucity of scientific data on key aspects of MVA biology required for its hazard characterization and presented data obtained in vitro on some worst-case scenarios demonstrating that: (i) MVA productively infects human Caco-2 cells after multiple serial passages in Caco-2 cells and (ii) recombination in vitro between MVA vectored vaccine and a wild type CPXV in a cell line that is semi-permissive to MVA. Provision of empirical data to fill in the gaps in knowledge will improve the hazard characterization of MVA-vectored vaccines resulting in a more robust ERA.


Reduce Avoidable Imaging Initiative, designed to “reduce testing and imaging with low risk patients through the implementation of Choosing Wisely recommendations.” However, it is unknown whether New England emergency departments (ED) have already implemented evidence-based interventions to improve adherence to ACEP Choosing Wisely recommendations related to imaging after their initial release in 2013. Our objective was to determine this, as well as whether provider-specific audit and feedback for imaging had been implemented in these EDs.In June 2016, the American College of Emergency Physicians (ACEP) Emergency Quality Network began its Choosing Wisely-focused interventions in 2014. Initial mailings included cover letters denoting the endorsement of each state’s ACEP chapter, and we followed up twice with repeat mailings to non-responders. Data analysis included descriptive statistics and a comparison of state differences using Fisher’s exact test.This survey study was exempt from institutional review board review. In 2015, we mailed surveys to 195 hospital-affiliated EDs in all six New England states to determine whether they had implemented Choosing Wisely imaging scenario; 57% reported implementing a specific guideline/policy/clinical pathway and 28% reported implementing a computerized decision support system. The most common interventions were for chest computed tomography (CT) in patients at low risk of pulmonary embolism (47% of EDs) and head CT in patients with minor trauma (45% of EDs). In addition, 40% of EDs had implemented provider-specific audit and feedback, without significant interstate variation (range: 29–55%).A total of 169/195 (87%) of New England EDs responded, with all individual state response rates >80%. Overall, 101 (60%) of responding EDs had implemented an intervention for at least one Choosing Wisely recommendations, most New England EDs had a guideline/policy/clinical pathway related to at least one of the recommendations. However, only a minority of them were using provider-specific audit and feedback or computerized decision support. Few EDs have embraced the opportunity to implement the multiple evidence-based interventions likely to advance the national goals of improving patient-centered and resource-efficient care.One year after release of the ACEP  Choosing Wisely® recommendations for emergency department (ED) use of diagnostic tests and treatments,Choosing Wisely recommendations, a number of tools, including clinical pathways,In 2013, the American College of Emergency Physicians (ACEP) published 10 evidence-based Reduce Avoidable Imaging InitiativeChoosing Wisely recommendations.” The initiative is a laudable endeavor meant to emphasize the many tools available to assist with adherence to these recommendations. However, there are sparse data on whether EDs have implemented any interventions to improve adherence to guidelines since their initial publication in 2013. Our objective was to investigate whether New England EDs implemented evidence-based interventions to improve adherence to ACEP Choosing Wisely recommendations after their release, and also whether provider-specific audit and feedback for imaging had been implemented in these EDs.In June 2016, ACEP’s Emergency Quality Network (E-QUAL) began its Choosing Wisely recommendations). These initial mailings included cover letters denoting the endorsement of each state’s ACEP chapter, and were followed up twice with repeat mailings to non-responders.This survey study was exempt from institutional review board review. In 2015 we used the 2012 National Emergency Department InventoryChoosing Wisely imaging scenarios: head computed tomography (CT) studies (for minor traumatic brain injury [MTBI] and in asymptomatic adults with syncope); chest CT for low-risk pulmonary embolism (PE); lumbar spine magnetic resonance imaging (MRI) for atraumatic low back pain; and abdominal CT for renal colic. For each of the scenarios, respondents were asked dichotomous yes/no subquestions regarding whether they had implemented either a guideline/policy/clinical pathway and/or computerized decision support. Pediatric EDs and EDs without CT/MRI capability to which individual questions might not apply were asked to indicate “NA” (not applicable). “Guideline/policy/clinical pathway” and “computerized decision support” were not further defined to allow respondents flexibility in deciding which of their interventions fell into each category. Respondents were also asked whether their clinicians received provider-specific audit and feedback regarding use of advanced imaging .The survey included a total of 30 questions, of which two focused on interventions that EDs had implemented targeting the five What do we already know about this issue?ACEP has recommended a number of tests that can be avoided as part of the Choosing Wisely initiative.What was the research question?Do EDs have guidelines, policies, pathways, decision support, or feedback regarding ACEP Choosing Wisely Initiatives?What was the major finding of the study?57% have guidelines, policies, or pathways, 40% have decision support, and only 28% provide feedback regarding Choosing Wisely.How does this improve population health?Adherence to Choosing Wisely requires more than just education - the use of the evidence-based tools we studied should improve adherence to Choosing Wisely.Choosing Wisely imaging scenarios, as well as the use of provider-specific audit and feedback. Data analysis included descriptive statistics and a comparison of state differences using Fisher’s exact test.The outcomes were the presence or absence of at least one reported intervention for each of the five Choosing Wisely imaging scenario; a guideline/policy/clinical pathway (57% of EDs) was more frequently reported than CDS (28%) (Responses were received from 169/195 (87%) of New England EDs; all individual state response rates were >80%. Overall, 101 (60%) of responding EDs had implemented an intervention for at least one DS (28%) . In addiChoosing Wisely targets had interventions implemented for them.The most common interventions were for chest CT in patients at low risk of PE (47% of EDs), and head CT in patients with MBTI (45% of EDs) . By statChoosing Wisely recommendations, most New England EDs focused their interventions on only two imaging scenarios: patients with suspected PE and those with MTBI. While most EDs had a guideline/policy/clinical pathway related to at least one of the Choosing Wisely recommendations, only a minority had implemented CDS related to one of the recommendations. In addition, fewer than half of New England EDs were providing provider-specific audit and feedback about imaging utilization to their clinicians.One year after release of the ACEP Choosing Wisely recommendations are largely evidence-based and meant to target likely unnecessary and overused imaging studies. Translating these recommendations into clinical practice to reduce low-value care is the next needed step. A recent analysis of the effectiveness of the publication of several Choosing Wisely recommendations on outcomes (including head and lumbar spine imaging) found mixed results.Reduce Avoidable Imaging Initiative will be key to broad implementation of tools targeting the established Choosing Wisely targets.The Reducing Avoidable Imaging Initiative to succeed, understanding current ED interest and practice in imaging re-education is essential to guiding future efforts. From our data, it is evident that a number of EDs, at least in New England, are already focusing on reducing imaging in patients with suspected PE and suspected MTBI. Both conditions have a broader evidence base to guide imaging decisions, including widely disseminated ACEP clinical policies, likely making provider engagement in quality improvement (QI) easier. Conversely, clear evidence gaps remain for two of the other targets —CT for syncope and abdominal CT for renal colic —for which no clinical practice guidelines or many large clinical trials exist. In the case of lumbar spine MRI for back pain, which is supported by the Choosing Wisely campaigns of numerous medical specialty societies and clinical practice guidelines, lower rates of ED QI interventions may reflect that many of the guidelines are still based on expert consensus rather than evidence-based decision instruments. As national efforts such as E-QUAL continue to expand, resources must be dedicated to developing an evidence base and the associated clinical practice guidelines necessary to engender physician trust in recommendations to reduce imaging use historically considered necessary to exclude high-risk, life-threatening diagnoses.For campaigns such as the E-QUAL Choosing Wisely recommendations. Poor adoption of CDS is surprising given the rapid adoption of electronic health records (EHR) in the ED as a result of the CMS Meaningful Use program. However, not all EHRs have easily-customized CDS capabilities, and ED staff may not have had the opportunity to readily implement CDS to address Choosing Wisely recommendations. As our survey preceded implementation of the 2014 Protecting Access to Medicare Act (PAMA) that mandates physician use of CDS, increased adoption of CDS is likely to be reflected in future surveys of EDs.Our work also demonstrates wide variability in the implementation of evidence-based QI strategies, with a notable lack of CDS and provider-specific audit and feedback. There is evidence that both of these interventions can improve the appropriateness of imaging use in the EDThis study has two main limitations. The first is that it was conducted only in New England, and therefore results may not generalize nationally. We used a survey methodology that relies on self-reporting and we did not assess any potential differences in actual “on the ground” implementation. However, we have no reason to believe that respondents were untruthful, particularly as they were told in the survey instructions that no identifying information would be used and responses would be reported only in aggregate.Choosing Wisely recommendations shows broad interest in reducing avoidable imaging. However, the QI practices are largely limited to select interventions and certain clinical scenarios. Few EDs have embraced the opportunity to implement multiple evidence-based interventions likely to yield synergistic gains necessary for emergency care to advance the national goals of improving patient-centered and resource-efficient care.10Our assessment of initial ED efforts undertaken after publication of the