There is uncertainty about the influence of diet during pregnancy and infancy on a child’s immune development. We assessed whether variations in maternal or infant diet can influence risk of allergic or autoimmune disease.n = 26), infant (n = 32), or combined (n = 22) interventions. Risk of bias was high in 125 (48%) milk feeding studies and 44 (25%) studies of other dietary exposures. Evidence from 19 intervention trials suggests that oral supplementation with nonpathogenic micro-organisms (probiotics) during late pregnancy and lactation may reduce risk of eczema , and 6 trials suggest that fish oil supplementation during pregnancy and lactation may reduce risk of allergic sensitisation to egg . GRADE certainty of these findings was moderate. We found weaker support for the hypotheses that breastfeeding promotion reduces risk of eczema during infancy , that longer exclusive breastfeeding is associated with reduced type 1 diabetes mellitus , and that probiotics reduce risk of allergic sensitisation to cow’s milk , where GRADE certainty of findings was low. We did not find that other dietary exposures—including prebiotic supplements, maternal allergenic food avoidance, and vitamin, mineral, fruit, and vegetable intake—influence risk of allergic or autoimmune disease. For many dietary exposures, data were inconclusive or inconsistent, such that we were unable to exclude the possibility of important beneficial or harmful effects. In this comprehensive systematic review, we were not able to include more recent observational studies or verify data via direct contact with authors, and we did not evaluate measures of food diversity during infancy.Two authors selected studies, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. We searched Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Web of Science, Central Register of Controlled Trials (CENTRAL), and Literatura Latino Americana em Ciências da Saúde (LILACS) between January 1946 and July 2013 for observational studies and until December 2017 for intervention studies that evaluated the relationship between diet during pregnancy, lactation, or the first year of life and future risk of allergic or autoimmune disease. We identified 260 original studies  of milk feeding, including 1 intervention trial of breastfeeding promotion, and 173 original studies  of other maternal or infant dietary exposures, including 80 trials of maternal  during late pregnancy and breastfeeding may reduce risk of eczema, and fish oil supplementation during pregnancy and breastfeeding may reduce risk of sensitisation to food allergens.We found more limited data that longer duration of breastfeeding may reduce risk of eczema and type 1 diabetes mellitus.A mother’s diet during pregnancy and lactation may influence her child’s risk of developing allergic disease. Immune-mediated health conditions such as allergic and autoimmune diseases appear to have increased in prevalence in many countries and are leading causes of chronic illness in young people . There iThis review is reported in accordance with PRISMA guidance. The review is part of a series of systematic reviews commissioned by the UK Food Standards Agency in order to inform UK dietary recommendations for infants and their pregnant or lactating mothers, under the title ‘Review of scientific published literature on infant feeding and development of atopic and autoimmune disease'. The protocols for the systematic reviews were registered with the International Prospective Register of Systematic Reviews  on 5 August 2013, prior to title screening or selecting any studies from the search results. This manuscript reports findings from the majority of the project, comprising Reviews A and C, ‘milk feeding’ and ‘maternal and infant diet’. Review B, regarding timing of introduction of allergenic foods, and one part of Review C, regarding use of hydrolysed infant formula, have been published separately ,13. ThusStudies of total breastfeeding duration, exclusive breastfeeding duration , and timWe included all intervention trials, and observational studies described as cohort, case control or cross-sectional analytic studies. Intervention trials were classified as randomised controlled trials (RCTs), where the method of treatment allocation was random, and as controlled clinical trials (CCTs), where treatment allocation was nonrandom and likely to lead to significant imbalance between treatment groups. CCTs were analysed separately from RCTs. Prospective and retrospective observational studies were analysed separately. We included studies of diet during pregnancy or lactation and of infant feeding between birth and 12 months of age. We excluded studies in which participants or their mothers were defined by the presence of a preexisting disease state, including very low birth weight or very premature infants.Allergic and autoimmune outcomes were selected on the basis of their population prevalence in children and young adults . We inclhttp://apps.who.int/trialsearch/. Both peer-reviewed publications and abstract publications were included. We reviewed the bibliography of eligible studies for possible additional publications and included all eligible publications, regardless of the language. Study authors were not contacted for original data. The search strategies were extensively piloted and refined to optimise sensitivity, comparing search results with those of other systematic reviews. The search strategies are shown in We searched The Cochrane Library , Excerpta Medica dataBASE (EMBASE) (1947 to July 2013), Literatura Latino Americana em Ciências da Saúde (LILACS) (1982 to July 2013), Medical Literature Analysis and Retrieval System Online (MEDLINE) (1946 to July 2013), and Web of Science (1970 to July 2013) on 25 July 2013. We reran the searches for intervention trials and systematic reviews on 26 February 2017 and for intervention trials again on 15 December 2017. We included all studies published up to that date and studies in progress or completed but unpublished studies identified through Title and abstract screening was undertaken by a team of 9 trained researchers . Two researchers undertook title screening independently and met to agree upon included and excluded titles. Their screening was checked by a third person, and uncertainties were resolved at a weekly team meeting between February and April 2014, 2015, and 2017 . The full texts of all potentially eligible studies were reviewed.Risk of bias assessment was undertaken in duplicate, using modified versions of the Cochrane Collaboration Risk of Bias tool for intervention trials and the National Institute for Clinical Excellence methodological checklist for cohort and case–control studies . Risk ofData extraction was undertaken in duplicate. Disagreements and uncertainties about data coding and risk of bias were discussed within the team. For foreign language studies, data were extracted by VGL together with a native speaker of the relevant language (see Acknowledgemnts section). We extracted all relevant data from included studies, including data not able to be meta-analysed. Data were extracted using either raw frequencies or crude or adjusted effect estimates. Random effects meta-analysis was undertaken, and where this was not possible, study results were summarised in a narrative table.For intervention trials, we extracted outcome data that adhered to the intention-to-treat principle in preference to data based on per protocol analyses. Where studies included multiple intervention groups, we performed pairwise comparisons where we split the number of events and no events in the unexposed/control group to prevent double counting. Where studies reported data at multiple timepoints, we extracted the most complete dataset available beyond the intervention period ; this is the dataset with the largest denominator or, where the denominator is identical for multiple time points, the largest numerator (number of events). Where studies reported multiple assessments of the same outcome at the same timepoint, clinical assessments were selected in preference to serological assessments, and skin prick in preference to sIgE assessment of allergic sensitisation. For observational studies of breastfeeding or timing of solid or other food introduction to the infant diet, data were only included in meta-analysis where the reference group was complete, i.e., ‘less than’ a certain duration or, in some cases, ‘never’. Where more than one exposure group was compared with the reference group, we analysed data for the latest exposure group. For all observational studies, adjusted effect estimates were used in preference to unadjusted estimates for meta-analysis if both were reported.www.r-project.org). For continuous outcomes measured using similar scales, data were summarised as mean differences with 95% CI. Key findings are presented in a Summary of Findings table with Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of certainty of findings . Sec. SecL. rcumented . It was This comprehensive and wide-ranging systematic review has highlighted key dietary interventions that may reduce risk of allergic outcomes, information which will be useful for pregnant women and their healthcare providers. However, for many dietary exposures, data were inconclusive or inconsistent, such that we are unable to exclude the possibility of beneficial or harmful effects. One limitation of this study is the 2013 search date for observational studies, such that review findings that are derived from these studies may benefit from an update in due course. We included abstract publications, since their exclusion can lead to publication bias; however, their inclusion carries a risk of methodological bias due to the lack of peer review. While the list of dietary exposures included was comprehensive, we did not evaluate food diversity during infancy, which has been suggested as an important factor in relation to allergic outcomes, and we did not evaluate objective markers of nutritional status, with the exception of blood vitamin D level . This meThese findings, together with our previous findings regarding hydrolysed formula and allergenic food introduction to the infant diet, suggest that current infant feeding guidance needs revision. Guideline committees will need to carefully consider the key findings together with an evaluation of the safety, acceptability, and cost implications of advising probiotic or fish oil supplementation for pregnant and lactating women.S1 PRISMA Checklist(DOC)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S2 Text(DOC)Click here for additional data file.S3 Text(DOC)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S1 Data(ZIP)Click here for additional data file.S2 Data(ZIP)Click here for additional data file.S3 Data(XLSX)Click here for additional data file.


Integr Environ Assess Manag 2018;14:344–357. © 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC)The Global Horizon Scanning Project (GHSP) is an innovative initiative that aims to identify important global environmental quality research needs. Here we report 20 key research questions from Latin America (LA). Members of the Society of Environmental Toxicology and Chemistry (SETAC) LA and other scientists from LA were asked to submit research questions that would represent priority needs to address in the region. One hundred questions were received, then partitioned among categories, examined, and some rearranged during a workshop in Buenos Aires, Argentina. Twenty priority research questions were subsequently identified. These research questions included developing, improving, and harmonizing across LA countries methods for 1) identifying contaminants and degradation products in complex matrices (including biota); 2) advancing prediction of contaminant risks and effects in ecosystems, addressing lab‐to‐field extrapolation challenges, and understanding complexities of multiple stressors ; and 3) improving management and regulatory tools toward achieving sustainable development. Whereas environmental contaminants frequently identified in these key questions were pesticides, pharmaceuticals, endocrine disruptors or modulators, plastics, and nanomaterials, commonly identified environmental challenges were related to agriculture, urban effluents, solid wastes, pulp and paper mills, and natural extraction activities. Several interesting research topics included assessing and preventing pollution impacts on conservation protected areas, integrating environment and health assessments, and developing strategies for identification, substitution, and design of less hazardous chemicals . Finally, a recurrent research need included developing an understanding of differential sensitivity of regional species and ecosystems to environmental contaminants and other stressors. Addressing these critical questions will support development of long‐term strategic research efforts to advance more sustainable environmental quality and protect public health and the environment in LA.  The Global Horizon Scanning Project aims to identify timely research needs around the world that are necessary to achieve more sustainable environmental quality.Twenty priority research questions for Latin America were identified, following input from multidisciplinary scientists and engineers from academia, government, and business and a synthesis workshop.Addressing these critical questions will support development of a long‐term strategic research effort to advance more sustainable environmental quality and protect public health and the environment in Latin America. The global goals specifically include 17 sustainable development goals and 169 targets, which aim to extend beyond and complete the previous Millennium Development Goals from 2000 . Many of these sustainable development goals depend on implementation of environmental management decisions. Identification of specific research programs to support environmental management goals often occurs within organizations in response to societal needs, and then is modified as priorities and resource availability change through time. Scientists and engineers have thus responded to numerous environmental issues, yet interdisciplinary efforts to prospectively identify specific research necessary to address environmental quality challenges have not occurred at the global level . Interestingly, a category related to chemicals and waste was included in GEO 5, which was published in 2012, for the first time. Ongoing efforts include development of GEO 6. Of particular importance to Latin America (LA), GEO reports target specific regions with the most recent report for LA and the Caribbean (LAC) published in 2016 (http://web.UNEP.org/geo/). The most pressing issues for LAC included threats to biodiversity, habitat degradation, pollution, climate change susceptibility, and unsustainable patterns of production and consumption (http://web.UNEP.org/geo/). Clearly these topics deserve immediate attention, yet no attempt has been made to identify key environmental research questions associated with these pressing issues for LA. Herein, horizon scanning, including “key questions” methods  reports  and the German Environment Agency's Environmental Specimens Bank  provide useful models that could be expanded to other regions.Identifying how naturally occurring and anthropogenic chemicals elicit adverse outcomes to humans and ecosystems remains a pressing research need. Determination of chemical residues in contaminated food, air, and water critically supports an understanding of the magnitude, frequency, and duration of environmental exposure and potential risks. Fortunately, technological advances provide new opportunities to determine the spatial and temporal patterns of parent compounds, metabolites, and degradation products in various environmental matrices, including plant and animal tissues, including human biomonitoring. In fact, when coordinated environmental specimen–banking programs are coupled with advanced analytical methodologies, such as high‐resolution, nontarget‐directed chemical analysis and innovative contaminant monitoring systems , it becomes possible to more rapidly identify risks and prioritize locations that require public health and environmental interventions. For example, the US Centers for Disease Control and Prevention National Health and Nutrition Examination Survey .Routine access to advanced analytical instrumentation and other innovative technologies remains elusive in many LA countries, where resources are commonly focused to face social issues  more than to tackle environmental problems. Building or consolidating a few strategically distributed, high‐complexity research centers devoted to providing services to large regional areas (even between countries) with shared environmental problems would help to optimize resources and capabilities. Production of chemicals for industrial, agricultural, and personal use is increasing with development and population growth. Moreover, in the megacities of many developing countries, access to and concentration of chemical use is occurring faster than public health and environmental management systems can be effectively implemented . In many cases, these data can be inadequate for LA ecosystems due to differences in environmental fate and native species sensitivities  responses to fitness at higher levels of biological organization,difficulty evaluating and predicting effects on populations and communities, andproblems associated with assessments of indirect ecological effects .The fields of ecotoxicology and ecological risk assessment have made considerable progress over the last 50 y, significantly reducing risks from acute and high‐volume pollution in ecosystems by providing basic information on the large number of chemicals introduced into the environment and by implementing waste management systems and technologies. Nevertheless, the scientific community now recognizes that the risk assessment procedures on which these disciplines normally rely can suffer from a lack of ecological realism and can be simply inadequate to characterize risks to ecosystems and human health following chronic exposures to low concentrations of an increasing number of contaminants  in fresh and brackish waters have become a major environmental issue and emerging human health threat at the global scale  efforts are allowing for unprecedented understanding of chemical attributes and associated biological properties with a goal of protection of human health and ecosystems . For example, influences of antibiotics in the environment on the development of antibiotic‐resistant microorganisms was recently identified as a priority research need by an expert workgroup  of the total LA and Caribbean municipal wastes are deposited in landfills  represent the most widely used approach by regulatory entities worldwide to derive acceptable environmental concentration limits for protection of structure and function of ecosystems . At the same time, it is the world's leading source of metals and the second most important source of oil ECLAC . The regWith 75% of its inhabitants living in cities, LA is the region of the world where the greatest proportion of the population lives in urban centers Bárcena . As suchThe pursuit of sustainable environmental quality to protect public health and the environment is a compulsory long‐term goal shared by most modern societies and civilizations worldwide. In the present study, we report findings of an innovative initiative aimed at identifying key priority environmental research needs in the fields of environmental toxicology and chemistry, which are necessary to achieve more sustainable environmental quality in LA. One hundred research questions were initially received from environmental experts in the academic, government, and industry sectors from numerous LA countries. Twenty priority research questions were identified during the LA GHSP workshop in Buenos Aires and organized in 6 categories: Risk Assessment; Environmental Chemistry; Ecotoxicology; Health, Contaminants of Emerging Concern, and Environment; Spotlight on LA; and Environmental Management and Policy. This exercise also identified limited communication and coordination among governmental, industrial, and academic sectors in LA. We hope this horizon scanning effort will provide a foundation from which future bridges can be built among these sectors to facilitate strategic research activities and implementation of policies that are more environmentally sound.Identified issues of concern included the development, improvement, and harmonization across LA countries of methods for 1) measuring concentrations of contaminants and degradation products in complex matrices ; 2) better predicting effects of contaminants on ecosystems, addressing lab‐to‐field extrapolation problems and the complexity of mixtures or multiple stressors (including climate change); and 3) estimating environmental risk  and improving management and regulatory tools  toward achieving sustainable development. In addition, those environmental contaminants frequently addressed in the questions were pesticides and emerging pollutants . Major and consistently identified environmental issues were related to agriculture (mainly pesticides), industrial and urban effluents, solid wastes, pulp and paper mills, and extractive activities . Several special topics of concern included assessing and preventing pollution impacts on wildlife protected areas, developing strategies for identification, substituting and designing less hazardous chemicals for human health and the environment, and the difficulty of establishing and implementing allowable limits for emerging contaminants in environmental legislation across LA. Finally, a recurrent research need included gaining more information and a better understanding of differential sensitivities among regional species and ecosystems to environmental contaminants and other stressors.The effort described in the present study is part of a larger effort to identify important international research needs to advance more sustainable global environmental quality (Brooks et al. The authors declare no conflicts of interest.This article has no metadata and calculation tools. All the raw data can be found in Table S1 in the Supplemental Data.Table S1. Questions submitted from Latin American scientists and engineers and examined during a synthesis workshop in Buenos Aires, ArgentinaThis article includes online‐only Supplemental Data.Table S1. Questions submitted from Latin American scientists and engineers and examined during a synthesis workshop in Buenos Aires, Argentina.Click here for additional data file.


Media representations play a crucial role in informing public and policy opinions about the causes of, and solutions to, ill-health. This paper reviews studies analysing media coverage of non-communicable disease (NCD) debates, focusing on how the industries marketing commodities that increase NCD risk are represented.A scoping review identified 61 studies providing information on media representations of NCD risks, NCD policies and tobacco, alcohol, processed food and soft drinks industries. The data were narratively synthesized to describe the sample, media depictions of industries, and corporate and public health attempts to frame the media debates.The findings indicate that: (i) the limited research that has been undertaken is dominated by a focus on tobacco; (ii) comparative research across industries/risk-factors is particularly lacking; and (iii) coverage tends to be dominated by two contrasting frames and focuses either on individual responsibilities  or on the need for population-level interventions .Establishing the underlying frameworks is crucial for the analysis of media representation of corporations, as they reflect the strategies that respective actors use to influence public health debates and decision making. The potential utility of media research lies in the insights that it can provide for public health policy advocates about successful framing of public health messages and strategies to counter frames that undermine public health goals. A better understanding of current media debates is of paramount importance to improving global health. Research shows that the mass media, including print, radio, television, internet and social media, play a crucial role in framing public and political debates , 2. TheyOne important aspect of media coverage relates to the way in which different kinds of stakeholders are portrayed since this influences their acceptability and legitimacy as societal and political players, and therefore, policymakers’ willingness to be associated with, or supportive of, them . CorrespIn recent decades, non-communicable diseases (NCDs) have moved upwards in the ranking of causes of global years of life lost , becominWhile research examining the tobacco industry has led the way in helping the public and policy makers understand the detrimental impact of commercial interests on public health , more reGiven the pressing nature of the NCD crisis, the involvement of corporations in framing NCD-related problems, drivers and potential policy solutions, and the importance of the media in public health debates, media analyses can provide valuable insights into factors which crucially shape public and political debates on NCD risks and policies and the roles of different stakeholders in the development and implementation of such policies. Such analyses would also illuminate attempts by corporate stakeholders to influence and shape media coverage.In this article, we review existing media studies on NCDs, focusing on how tobacco, alcohol, and processed food and soft drinks corporations (i.e. the industries marketing commodities that increase NCD risk) are portrayed in media coverage. We also examine how these corporate actors attempt to frame NCDs within this coverage, as compared to public health actors, and reflect on the underlying values that relate to different frames. The aim of this review is to identify gaps in the available research that seem useful to address, thereby setting the scene for future research which more fully examines media representations of industries that contribute to NCD risk and their impact, including how media representations might be shaping public and political opinion and, therefore, viable policy options.A scoping review was conducted to identify studies providing information on media representations of NCD risks, NCD policies and tobacco, alcohol, processed food and soft drinks industries. We searched Web of Science, Medline, Embase, and Google Scholar, using the following search terms in various combinations: tobacco, nicotine, alcohol, food, soft drink, beverage, nutrition, business, companies, company, industr*, corporate, corporation, commercial, communications media, mass media, media advocacy, document*, media, newspaper*, misinformation, policies, policy, policy maker*, policy actors, policy framing, public relations. All abstracts were read and studies were included in the final sample that met the following inclusion criteria: (i) published in a peer-review journal; (ii) applied media analysis as part of the methodology; (ii) provided information on: media representations of tobacco, alcohol, processed food or soft drink consumption; OR tobacco, alcohol or obesity policy; OR the tobacco, alcohol, processed food or soft drinks industry; (iv) published in English. No time or geographical limits were set. The bibliographies of included studies were checked for additional studies which met the inclusion criteria. The final sample was 61 studies, from which we systematically extracted the following data: primary product of interest of the study ; specific issue investigated; location of study; period of investigation; type of media analysed; methodology; aim of the study; and findings on the media representation of tobacco, alcohol, processed food and soft drinks industry. We then synthesised the data narratively by developing a preliminary synthesis of the findings of each included study, exploring relationships, similarities and differences in the data, and summarizing the accounts of the depictions of the tobacco, alcohol, processed food and soft drinks industry in a way which accounted for the heterogeneity of studies. In a next step, a conceptual frame derived from the literature theorizing about framing of public health issues was applied to the data . This con = 49) studies focused on the harms and health conditions caused by, and the regulation of, tobacco or alcohol or processed food and/or soft drinks consumption. Only six articles explicitly analysed the representations of corporations in the media (n = 2) or media coverage of litigation against corporations (n = 4), and all of these focused on tobacco companies , public health policies , industries , consumers , and products . Most (p < 0.000) , Australia (n = 12) and the UK (n = 7), possibly reflecting the fact that searches were undertaken in English. The remaining four articles focused on media coverage in Finland, Switzerland, Hong Kong and internationally. Only one study compared media across countries, focusing on US and Australian media coverage of tobacco.In terms of geographical focus, studies overwhelmingly analysed media in English-speaking countries, including the USA (n = 35) considered newspapers only. Other studies combined newspaper analysis with one or two other data sources, including TV programmes (n = 10), magazines (n = 8), trade or industry documents, websites or journals (n = 5), policy documents (n = 5), radio (n = 2), press releases (n = 1) or interview data (n = 1). Two studies investigated magazine articles only, and one article was unclear about the specific media sources that were included in the analysis. We found a striking dearth of studies taking account of online and social media. Only three studies which assessed multiple data sources compared reporting across, and associations between, different data sources, e.g. between newspaper coverage and industry documents, policy documents or personal accounts [More than half of the articles (accounts –40.n = 3 articles investigating media coverage during one month only); 30 studies investigated media coverage over a time period of 1 to 5 years; 11 studies investigated media coverage over a time period of 5 to 10 years; and 13 studies investigated media coverage over 10 years or more. In some instances, choosing a specific period of time was rationalised by the occurrence of specific events that were of interest to the subject of study, e.g. the release of a policy report or the adoption of legislation. More frequently, however, choices seemed to be for pragmatic reasons.Seven studies investigated media coverage over a time period of less than a year , or soda tax. In order to divert attention away from corporate actions as potential causes and oppose government regulation, corporate stakeholders presented arguments that such policies would have detrimental effects on the economy, were disproportionate, unnecessary, not feasible, or an example of ‘nanny state’ regulation and intrusion into personal freedom. They also promoted voluntary regulation as an alternative to legislation. The two studies which investigated industry reporting across different types of media found that the financial and trade press and media outlets which relied heavily on advertising income were more likely to present such arguments , 46.Examples of corporate framing strategies of NCD policy debates were identified in studies which analysed the alcohol industry’s use of the media. Katikireddi et al.’s  work anaIn contrast to the industry framing strategies on NCD-related debates, our review identified a similarly consistent alternative framing strategy most often promoted by public health advocates. Advocates used the media to advance arguments to emphasise the social and political determinants of health, the detrimental impact of industries producing and marketing tobacco, alcohol, processed food and soft drinks on NCD-related harm, and the need for regulation and population-based interventions. A number of studies, most prominently those that analysed tobacco debates, showed that some media depictions emphasised the tobacco industry’s mendacious conduct, corporate representatives’ ruthless marketing of a lethal product to children and vulnerable populations, and their focus on profits and economic interests ahead of any moral considerations , 55. SupNew York Times from 1985 to 2003, and described public health advocates’ attempts to advance “arguments emphasizing the social environment, including corporate and public policy”, tailored to denouncing corporate practices and calling for regulation of soft drinks. Similarly, two studies, one on media coverage of New York sugar-sweetened beverage portion-size cap policy [Several media studies showed that as well as drawing attention to industries as causal factors of tobacco, alcohol and nutrition-related health problems, public health advocates often called for structural changes or the regulation of the industry and its products. For example, Lawrence  examinedp policy  and anotp policy , mentionThis scoping review indicates that the framing of media debates on NCD risk and policy is an under-developed area of research, and that we know particularly little about similarities and differences in the media strategies and portrayals of industries marketing commodities that increase NCD risk and how media coverage of these industries influences public and policy debates on NCDs. By undertaking a narrative review of a variety of studies, this paper enables us to make some comparisons and helps explain why the growing sense of caution regarding tobacco industry engagement with policy debates has not been expanded to other industries. Based on the review, we identify a need for a range of approaches to discourse analysis to support future research and practice on media coverage of industries involved in NCD debates. Our findings corroborate the call made by Australian academics more than two decades ago to take the framing of public health issues far more seriously , includiOur review found that media depictions of NCD risks and potential solutions to them seem to reflect broader societal tensions between two different viewpoints. Opponents of public health policies tend to promote frames which place the focus on unhealthy lifestyles as individual level problems and portray individuals as making more or less informed choices to smoke, consume alcohol or unhealthy food and drinks. Proponents of these frames tend to support voluntary policies and interventions targeted at changing individual behaviour (e.g. education campaigns), rather than regulatory and systemic changes . When this kind of framing dominates political and public debates about NCDs, corporations  tend to be portrayed as responsible, legitimate societal and political actors. Advocates of public health policies, on the other hand, often attempt to frame debates very differently, drawing attention to systemic, rather than individual, causes. They portray corporations as powerful, profit-driven actors who relentlessly market unhealthy products that undermine public health, and call on governments to assume responsibility to advance public health and protect citizens from dominant market interests by adopting regulation.These contrasting frames identified with regard to media depictions of NCDs resonate strongly with work by Beauchamp , who ideThe political implications of such different ways of framing are evident: Policymakers who are persuaded by ‘market justice’ framing are less likely to adopt policies that regulate corporate behaviour, whereas policymakers who follow ‘social justice’ framing will be more willing to restrict corporate abilities to market and sell products which contribute to the burden of NCDs cf. . DrawingRecent research on framing contests in alcohol and obesity policies provide emerging evidence of similar framing challenges: Public health advocates’ recent framing of UK alcohol pricing and promotion policy as effective means to tackle population-level harms were important in the passage of evidence-based policy measures . HoweverBeyond the finding that media coverage of NCDs and industries contributing to NCD risk occur within the tension of two rival frames, our review highlights considerable research gaps with regard to the values which underlie different frames; the contestations in media debates between industry and public health interests; the complex relationship between media coverage, public and political opinion, and policy debates and decisions; and the way in which changes to the media landscape may be complicating these interdependencies. Future studies could usefully investigate the kinds of questions outlined in Table Our review identifies a particularly urgent need to address the striking gap in terms of comparative research on the representations of different industries whose products increase NCD risk. The considerable variations in perceptions that public and political audiences seem to have of the tobacco industry compared to alcohol, processed food and soft drinks corporations  underlinThis scoping review also provides direction in terms of potential methodological approaches. Media studies scholars have employed a wide variety of approaches to analysing text and speech, including Critical Discourse Analysis , 73 and Existing media studies further show that researchers need to carefully tailor the selection of media outlets and outputs to the audiences that are the focus of investigation. Scholars who are interested in the role of media representations in policy debates should, for example, identify and select media outlets and outputs that are read, viewed, and listened to by the public officials, politicians and advocates in whom they are interested. This is likely to include some traditional print media sources, for which methodological approaches have been well developed –78. HoweStudies which analyse media coverage over time and relate findings to corporate or political discourses and outcomes by combining analyses of media coverage, press releases, policy documents and interviews are essential if we are to make any progress in identifying the influence of corporations on media representations or the contribution of media discourses to evolving policy debates. Such studies can illuminate the complex relationship among media coverage, public and political opinion, and political decision making. The broader social sciences provide an array of potentially useful additional methodological approaches, including innovative use of plagiarism detection software to analyse similarities between political statements , an apprIn conclusion, studies that investigate media debates on NCD risk and policy are important for developing a more nuanced understanding of the complex ways in which media representations of unhealthy commodity industries are shaped by, and contribute to shaping, public, corporate and political discourse. We urge those who are interested in this area of scholarship to consider the potential utility of media research for public health policy advocates. Media studies, including those about how highly skilled corporate stakeholders or successful public health advocates articulate their political messages, can provide insights into how to frame effective public health messages and counter frames that undermine public health goals. A better understanding of current media debates can improve the development and dissemination of framing NCD-related issues and is of paramount importance to improving global health. We have provided an overview of what is currently known about framing of NCD risks and policies in the media and media representations of industries that contribute to NCD risks, identified a set of important questions to consider in future media analyses looking at NCDs, and outlined implications for public health policy and advocacy. Our findings and reflections could support future research in this area, provide a crucial resource for those seeking to develop a common policy agenda to reduce NCD-related harm, and enhance public health advocates’ abilities to use the media to promote effective public health policy.


Different physiological as well as pathological stress conditions can, however, perturb ER homeostasis, giving rise to an accumulation of unfolded or misfolded proteins in the ER lumen, a condition termed ER stress. To deal with an increased folding demand, cells activate the unfolded protein response (UPR), which is initially protective but can become detrimental if ER stress is severe and prolonged. Accumulating evidence demonstrates a link between the UPR and ovarian development and function, including follicular growth and maturation, follicular atresia, and corpus luteum biogenesis. Additionally, ER stress and the UPR may also play an important role in the ovary under pathological conditions. Understanding the molecular mechanisms related to the dual role of unfolded protein response in the ovarian physiology and pathology may reveal the pathogenesis of some reproductive endocrine diseases and provide a new guidance to improve the assisted reproductive technology. Here we review the current literature and discuss concepts and progress in understanding the UPR, and we also analyze the role of ER stress and the UPR in the ovary.The endoplasmic reticulum (ER) is the principal organelle responsible for several specific cellular functions including synthesis and folding of secretory or membrane proteins, lipid metabolism, and Ca These include transient attenuation of translation to reduce the protein synthesis and folding load, activation of transcription of chaperone proteins and folding catalysts to expand the folding capacity of the ER, induction of ER-associated degradation (ERAD) to remove terminally misfolded proteins , and induction of apoptosis  and endocrine function . Follicles are the fundamental functional units of the mammalian ovary and consist of an innermost single oocyte, the surrounding granulosa cells (GCs) and the outer layers of theca interna cells, and theca externa cells. Beginning with the recruitment of primordial follicles from a reserve pool into the growing pathway, follicles develop through four major stages: primary, secondary, antral, and preovulatory -like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6α (ATF6α). In the absence of ER stress, these sensors bind to the ER-resident glucose-regulated protein 78 (GRP78) chaperones in their intraluminal domains  and thereby render the sensors inactive  domain  and pro-apoptotic   are expressed in GCs of late-stage follicles , and this expression is accompanied by activation of IRE1 and PERK  is the major stimulator of follicle growth and development in the final and preantral stages  and ovarian hyperstimulation syndrome (OHSS), a major complication during infertility treatment that is mainly characterized by increased capillary permeability (Elchalal and Schenker, In primary solid tumors, the UPR is activated as a result of aberrant regulation of protein synthesis in cancer cells and changes in the tumor microenvironment, such as hypoxia, nutrition deprivation, and low pH (Brown and Giaccia, The UPR, induced by ER stress, is an indispensable response for cells to restore cellular homeostasis; conversely, it may contribute to cell death when over-activated. The molecular pathways involved in the UPR have been clearly elucidated. Accumulating evidence suggests that ER stress and the UPR play a significant role in regulating ovarian structure and function, but our understanding of the molecular mechanisms involved remains incomplete. Future studies should further focus on the molecular mechanisms related to the dual role of the UPR in ovarian physiology and pathology to better understand changes in the ovarian cycle and provide new guidance to improve assisted reproductive technology.


The legacy of polio in Africa goes far beyond the tragedies of millions of children with permanent paralysis. It has a positive side, which includes the many well-trained polio staff who have vaccinated children, conducted surveillance, tested stool specimens in the laboratories, engaged with communities, and taken care of polio patients. This legacy also includes support for routine immunization services and vaccine introductions and campaigns for other diseases. As polio funding declines, it is time to take stock of the resources made available with polio funding in Africa and begin to find ways to keep some of the talented staff, infrastructure, and systems in place to work on new public health challenges. The partnerships that helped support polio eradication will need to consider funding to maintain and to strengthen routine immunization services and other maternal, neonatal, and child health programs in Africa that have benefitted from the polio eradication infrastructure. The tragic impact of polio in Africa is borne by the many millions of disabled children and adults who have suffered from muscles weakened by the ravages of polio. However, there is a positive legacy of the years of polio eradication efforts in Africa—the African polio focal points, healthcare workers, surveillance officers, social mobilizers, laboratorians, and vaccinators who serve as a well-trained workforce prepared to fight other current and future public health battles. These dedicated staff have accomplished great things—not only in the fight against polio but also in improving health throughout the continent. They have enhanced routine immunization programs and perfected the use of mass vaccination campaigns against polio and other vaccine-preventable diseases (VPDs) to raise the immunity of large population groups, including nomads and persons living in insecure communities. They have emphasized the importance of having and using high-quality data for decision making. They have learned how to respond to a complex public health emergency using the Emergency Operations Center model. Awareness and trust were built as they engaged with the public, community and religious leaders, and traditional healers about healthy behaviors and the importance of childhood vaccinations. Finally, infectious disease surveillance was strengthened as laboratory expertise was decentralized and active searching for polio cases helped identify outbreaks .The Global Polio Eradication Initiative (GPEI) and its partners invest substantial funds in the polio program in Africa. These funds are used to hire and train many public health workers and have been critical to the polio eradication progress seen thus far. Funds allocated for eradication in the highest-risk African countries are detailed in As the Lake Chad region mounts an aggressive response to the wild poliovirus resurgence identified in Nigeria after 2 years without a reported case in Africa, public health systems in many African countries face the specter of decreased polio funding, which currently helps bolster the entire continent’s public health and immunization systems. Because of the success of GPEI globally, funding decreased in 2016 and may continue to decrease through the end of 2019 and beyond see  3]. The. The3]. This article summarizes areas where polio funding has made an impact on public health in Africa and highlights where continued funding is needed. When smallpox eradication finally succeeded in Africa, the program helped launch the Expanded Programme on Immunizations (EPI) . Now, inIt is not straightforward to isolate GPEI’s impact on routine immunization services, but it is clear that polio eradication–funded assets have supported systematic infant immunization, particularly in countries with the most polio eradication investments. The Boston Consulting Group survey  commissiThe Global Polio Eradication and Endgame Strategic Plan 2013–2018 places additional emphasis on strengthening routine immunization services . Gavi, tNigeria and Central African Republic have used polio campaigns to deliver an integrated health package that includes other routine vaccines. Many countries also deliver vitamin A and deworming during polio campaigns, with some areas extending this to include bed net distribution and promotion of handwashing. These “pluses,” as they are often called, help both encourage parents to have their child vaccinated and accomplish the distribution of other potentially lifesaving interventions. Polio campaigns have also provided a platform for vaccinations and other health interventions in hard-to-reach groups in remote and insecure areas.The Global Polio Eradication Initiative has a number of capacities that countries may leverage to strengthen routine immunization systems and improve coverage and equity. These include supply chain capacity; coordination and accountability; microplanning, including mapping of missed children and special populations; demand generation and engaging with communities; and working in areas of insecurity.As more detailed asset mapping of GPEI-funded assets becomes available in each country, this will inform the conversation on government-led transition planning. Funding from national governments, partners, and Gavi will be critical to allow countries to utilize GPEI staff and expertise to sustainably support routine immunization in the years after polio eradication.The Global Polio Eradication Initiative has made significant investments in health systems to help stop poliovirus transmission. Mapping of polio assets identified specific initiatives to improve leadership and governance, empower communities to engage and participate in polio and health issues, and strengthen information systems to facilitate the availability and use of quality data to guide local actions. However, the question remains whether GPEI has contributed to health system strengthening—defined as interventions that foster lasting changes to the main performance drivers of a functional health system , 9. PoliIn Chad, Republic of Congo, Democratic Republic of Congo, and Nigeria, polio-funded staff were given a broader mandate—to strengthen the human resource capacity of routine immunization programs. In Cameroon, Republic of Congo, and Democratic Republic of Congo, new public–private partnerships used mobile phone–based education to support supplementary polio immunization activities, which opened new horizons for the use of innovative technologies in creating demand and increasing social accountability for MNCH in general and routine immunizations in particular. In Chad, Democratic Republic of Congo, and Guinea, the use of lot quality assurance sampling in monitoring the performance of polio campaigns has brought in a new tool to strengthen data availability and quality in settings with weak health information systems.Countries have started using these promising polio eradication practices to strengthen health systems in MNCH programs beyond polio, including routine immunizations. Chad is 1 of the 12 countries accounting for 70% of unimmunized children globally. Only 50% of children receive 3 doses of polio vaccine, 25% are completely vaccinated, and 19% receive no vaccine doses . To imprThe ongoing polio transition planning process provides an opportunity for countries to shift polio-funded health system support interventions toward health system strengthening using domestic and other sustainable funding opportunities. This polio transition effort, combined with Gavi health systems strengthening support, will give African countries an opportunity to make much-needed improvements in their health systems.Acute flaccid paralysis (AFP) surveillance is 1 of the 4 pillars of GPEI; the others are routine immunization, supplementary immunization activities, and targeted “mop up” campaigns. The key steps in AFP surveillance are (1) finding and reporting children with AFP, (2) transporting stool samples for laboratory analysis, and (3) isolating and sequencing polioviruses, if present. An environmental surveillance system (testing sewage for polioviruses) is also operating in 11 African countries to supplement AFP surveillance .Stool and sewage samples collected through the surveillance network are tested in WHO-accredited laboratories within the Global Polio Laboratory Network (GPLN). The GPLN consists of 145 laboratories in a 3-tiered structure—national laboratories, regional reference laboratories, and global specialized laboratories. All laboratories are continually monitored for their adherence to quality indicators and have annual accreditation assessments .Certification of a WHO region as polio-free requires at least 3 years of timely and sensitive surveillance . Each coInnovations in surveillance are often needed because one approach does not fit all settings. In Somalia, an estimated 540786 (9%) and 1665027 (27%) of a total 5999444 children aged <15 years in the country live in inaccessible and partially accessible areas, respectively. During the 2013–2014 outbreak in Somalia, the polio program recruited and trained 635 village polio volunteers (VPVs) to identify and report AFP cases and collect stool samples. As of 12 June 2016, VPVs reported 75% of AFP cases in the inaccessible areas and 43% in the partially accessible areas. The cases were investigated in a timely manner, and the reverse cold chain was well maintained, as reflected by 100% and 93% of AFP cases being investigated within 48 hours and a nonpolio enterovirus (NPEV) isolation rate of 31% and 9% in the inaccessible and partially accessible areas, respectively [Polio assets include thousands of trained surveillance officers, WHO-accredited laboratory network staff and resources (including 20 polio laboratories in Africa), and surveillance procedures and lessons learned . Polio sGlobal Polio Eradication Initiative investments have created substantial communication assets over the years across Africa, which include social mobilization networks and multimedia platforms. Thousands of social mobilizers in Somalia, Ethiopia, South Sudan, Nigeria, Democratic Republic of Congo, Chad, and Cameroon are deployed to help reach every last child with the polio vaccine.Typically, trained community mobilizers and their supervisors constitute multitiered networks that are deployed in areas at high risk for polio. They raise awareness and educate parents about polio vaccination campaigns, engage communities, build relationships with religious leaders to garner their support, and create social acceptance of polio vaccination. Equipped with health education tools and interpersonal communication skills, 1078 social mobilizers in South Sudan, 3616 in Somalia, 14000 in Nigeria, 14467 in Cameroon, and >30000 in Democratic Republic of Congo conducted door-to-door visits and community group meetings aimed at reducing missed children. In Nigeria these networks are deployed on a full-time basis, and in other countries like Democratic Republic of Congo they are mobilized at the time of polio campaigns. They helped develop community profiles and social map and collect social data from sites such as schools, daycare centers, places of religious congregation, transit points, and playgrounds to enlist influencers and reduce noncompliance [Social mobilizers work during polio campaign days, but as part of the polio endgame strategy, they have also been active in accelerating routine immunization, reducing maternal and child deaths, and addressing malnutrition. Beyond development programs, these networks, which include groups of mothers, have demonstrated added value in emergency response—cholera and measles outbreaks in Democratic Republic of Congo, Cameroon, Chad, Somalia, South Sudan and drought in Ethiopia. In conflict areas, such as the Lake Chad region, they help displaced populations engage with camp dwellers and link them to social services. When Ebola cases were confirmed in Abuja in July 2014, polio community engagement networks were repurposed to actively find cases and track potential chains of transmission, helping Nigeria stop Ebola in 3 months , 18.As GPEI resources scale down, investments made in developing efficient community mobilization and health promotion platforms can be redirected to other public health priorities. For example, in Somalia, the plan is for these networks to be supported by Gavi health system strengthening; in Democratic Republic of Congo discussions are ongoing with the MoH to absorb a critical mass of community mobilizers as part of the new National Community Health Policy; and Cameroon is currently working toward an agreement with non-GPEI partners to absorb polio social mobilizers.Beginning in 2012, GPEI began establishing emergency management and control facilities in the 3 remaining polio-endemic countries. National and subnational Emergency Operations Centers (EOCs) were opened in Nigeria (8 during 2012–14), Pakistan (6 during 2014–15), and Afghanistan (4 in 2016). All remain in operation and provide an important framework for a heightened command-and-control response to complex public health emergencies.The EOCs addressed a particular problem in the polio program where management of program operations was spread across multiple institutions—government, United Nation agencies, and nongovernmental organizations—with each operating in relative isolation. The EOCs provide for the physical colocation of program resources under government leadership and are equipped with high-speed internet, printers, and computers for producing the analyses needed in real time to drive program decision making.Government MoHs provide a strong leadership team, creating the opportunity to strengthen accountability of health workers and managers for polio vaccination activities. The United States Centers for Disease Control and Prevention (CDC) provides epidemiological and virologic input to the EOCs to help identify areas at highest risk for sustaining transmission and supports field operations. UNICEF’s experts address social issues impacting the program, including misinformation, mistrust, and refusal to vaccinate, as well as vaccine management. WHO focuses on surveillance and operations and provides the backbone to the program response. BMGF and Rotary International provide funding and staff. Within each EOC, the government and its implementing partners have created teams organized along thematic lines, including strategy, operations, logistics, communication and advocacy, and data management. Once the EOC begins tracking performance of operations teams in campaigns and social mobilization, the EOC has the authority to sanction poor-performing field staff.Data-driven assessment of polio vaccination performance and local community health agency support before and during each campaign enables the EOC to shift focus to the highest-risk clusters and issues. Improved data collection from the field and use of satellite imagery allow the EOC to adapt new approaches rapidly and to experiment with interventions to solve complex vaccination and surveillance problems.Vigorous program management allowed the EOC to identify issues and intervene to mitigate specific challenges, such as reaching children trapped by the ongoing Boko Haram insurgency in northeast Nigeria. Examples include “hit and run campaigns” where vaccinators enter a village in a large group during periods of relative calm to rapidly immunize as many children as possible and “firewalling” Boko Haram–controlled districts by establishing intensive immunization activities in adjacent, government-controlled areas to increase immunity in areas surrounding inaccessible districts.Recent history provides evidence of the wider application of EOC processes and systems. From March to October 2014, the EOC structure in Nigeria was successfully leveraged for the response to the Ebola crisis. The rapid containment of Ebola transmission in Nigeria provided clear evidence of the wider application of the polio EOC model, a potent reminder of the legacy of the national polio program .The key lessons learned from the polio experience of EOCs—rapid synthesis of data to drive program choices, heightened accountability around action in the field, and the assembly of multifunctional teams to tackle priority issues in real time—all have meaningful application for outbreak and emergency response and for delivering critical health services to families and children in Africa.The Global Polio Eradication Initiative is a robust, multilateral, public–private partnership established to specifically attain the target of a polio-free world. The core global partners include WHO, UNICEF, Rotary International, BMGF, and the CDC. In Africa, this partnership has matured over time; the 5 core GPEI partners have collaborated in each endemic and outbreak country to ensure that WHO, UNICEF, MoHs, and local government are well supported. As Africa works toward becoming a polio-free continent, it is critical that the major partners, agencies, and donors continue to work well together to ensure a smooth transition into the postpolio era.The Global Polio Eradication Initiative operates within a broad framework of intergovernmental and interagency cooperation and participation at the global, regional, national, subnational, and district level. At the country level, Interagency Coordinating Committees are in place to improve coordination among partners in support of immunization programs—to include polio eradication activities. Crucial elements of an effective Interagency Coordinating Committee that harnesses a strong partnership include leadership and active participation from a high authority within the MoH, a coordinated work plan among all country-level stakeholders, coordinated implementation, and collective monitoring and evaluation of program performance.In security-compromised zones, GPEI partnered with a wide variety of stakeholders to negotiate access to conduct polio eradication activities. These partners included religious and community leaders, tribal elders, national and provincial governments (including the military and law enforcement authorities), and nonstate armed groups. Such partnerships allowed the program to proceed with conducting planned polio vaccination campaigns.The GPEI partnership finds itself at a crucial point in history. Once the eradication goal is achieved and the GPEI partnership ends, strengthening existing partnerships and creating new ones will be key to continuing to improve access to immunizations in Africa. Examples of such partnerships include cooperation among governments, investment institutions, charitable foundations, the private sector, and regional organizations. Governments, donors, and communities should begin to think about new partnerships and continue to build on the strong partnerships created to eradicate polio.The 54 countries in Africa rely to varying degrees on funds from donors to GPEI to support both polio immunization and other public health programs. In addition to helping fight polio, these funds have built capacity in health systems across the region critical for maintaining population immunity, as outlined in Boston Consulting Group surveys conducted in 2014–2015 . With GPThe process is designed to be led by national governments through mapping exercises that help to detail key assets and determine priorities for the future. Once these priorities are established, conversations with donors can begin, as budget cycles and appropriation processes must be considered. In several of the 16 African countries with the most GPEI funding, such as Sudan, Democratic Republic of Congo, and Chad, government leaders and partners have developed work plans to identify key polio assets, such as human resources, surveillance, and laboratory facilities, and have created budget projections for transitioning those critical resources. However, despite the completion of mapping exercises and the development of strategic plans, support from the global level for posteradication public health funding has not been secured. The Global Polio Eradication Initiative has provided tools to help guide the process , but in The Africa Health Strategy 2007–2015 points out that, although Africa has 10% of the world population, it bears 25% of the global disease burden and only 3% of the global health workforce . CurrentThe polio eradication program in Africa serves as an example of how collaborative efforts can impact the quality and reach of public health systems. This same collaborative effort among African countries and international donors has the potential to ensure that the resources built through polio eradication are effectively leveraged to benefit routine immunization services and other health priorities once polio has been eradicated. The timeframe to identify funding sources is short as polio budgets ramp down and the region faces the risk of losing the health gains made through the support of the polio eradication effort.Polio and other public health programs in Africa are at a crossroads. With progress in improving population immunity, sustaining a sensitive surveillance system, and strengthening outbreak response, Africa is moving closer to being polio-free. As a result, GPEI’s budget requirements are being systematically reduced in a manner to ensure the polio eradication gains to date are maintained and that the program globally remains on course to achieve eradication. The progress toward polio eradication invariably raises questions on how to best transition polio assets—people, infrastructure, processes, and knowledge—to other public health priorities as they are identified by national governments. This is of particular importance in Africa given its high child mortality and morbidity rates and the large investment by GPEI in several African countries. The transition planning underway provides an important opportunity to examine best practices and lessons learned, identify new possibilities for how polio assets can be used to support other public health priorities in the Africa region, and reinforce the unique partnerships that will help provide funding to strengthen routine immunization services and other maternal, neonatal, and child health programs.


Haemophilus influenzae type b) and pneumococcal vaccine. Unanticipated concerns emerged from countries over acceptability of multiple injections, sites of administration, and safety. We contextualized the issues surrounding multiple injections by documenting concerns associated with administration of ≥3 injections, existing evidence in the published literature, and findings of a systematic review on administration practices and techniques.In 2013, the World Health Organization’s (WHO’s) Strategic Advisory Group of Experts (SAGE) recommended that all 126 countries using only oral polio vaccine (OPV) introduce at least 1 dose of inactivated polio vaccine (IPV) into their routine immunization schedules by the end of 2015. In many countries, the addition of IPV would necessitate delivery of multiple injectable vaccines  during a single visit, with infants receiving IPV alongside pentavalent vaccine , site of injection, route of injection, and procedural preparedness. WHO and United Nations Children’s Fund data from 2013–2015 were used to assess multiple-injection visits included in national immunization schedules.Healthcare provider and caregiver attitudes and practices indicated concerns about infant pain, potential adverse effects, and uncertainty about vaccine effectiveness with multiple-injection visits. Published literature reinforced the record of safety and acceptance of the recommended schedule of IPV by the SAGE, but the evidence was largely from developed countries. Parental acceptance of multiple injections was associated with a positive provider recommendation to the caregiver. Findings of the systematic review identified that the intramuscular route is preferred over the subcutaneous route for vaccine administration and that the vastus lateralis muscle is preferred over the deltoid muscle for intramuscular injections. Recommendations on vaccine spacing and procedural preparedness were based on practical necessities, but comparative evidence was not identified. During 2013–2015, 85 countries added IPV to their immunization schedules, 46 (55%) of which adopted a schedule resulting in 3 injectable vaccines being administered in a single visit.The multiple-injection experience identified gaps in guidance for future vaccine introductions. Global partner organizations quickly mobilized to assess, document, and communicate the existing global experience on multiple-injection visits. This evidence-based approach provided reassurance to opinion leaders, health workers, and professional societies, thus encouraging uptake of IPV as a second or third injection in an accelerated manner globally. Haemophilus influenzae type b [Hib]) and pneumococcal conjugate vaccine (PCV) [In 2013, the Global Polio Eradication Initiative (GPEI) launched the Polio Eradication and Endgame Strategic Plan 2013–2018 to comprehensively address both polio eradication and endgame objectives [ne (PCV) .The accelerated introduction of IPV globally between 2013 and 2016 posed many challenges for GPEI partners. In 2014, the managers of multiple countries’ national immunization programs expressed concerns during meetings and country consultations about the administration of an additional vaccine injection, including concerns about healthcare provider training as well as acceptance of the new vaccine schedule by both providers and child caregivers. While almost all countries had introduced new vaccines over the previous 15 years, these introductions were often facilitated by the use of new combination vaccines such as pentavalent vaccine . As suchIn the absence of existing guidance from the SAGE, the WHO provided the following provisional recommendations regarding the operational aspects of administering multiple injections at a single visit for IPV, PCV, and pentavalent vaccines. First, IPV (nonadjuvanted) can be given intramuscularly or subcutaneously, but because of reduced reactogenicity and easier administration, the WHO recommends the intramuscular route. Second, for intramuscular injections in infants <15 months of age, the deltoid injection site  should not be used, because of its inadequate muscle mass. Third, when 3 intramuscular injections are scheduled simultaneously in children <15 months of age, it is safe and acceptable to give 2 injections in the same thigh. The WHO recommendation is injection of PCV plus IPV, separated by 2.5 cm, in one thigh and injection of DTP-HepB-Hib in the other thigh.During regional meetings and personal communications, national immunization program managers expressed concerns about the increase in the number of injectable vaccines given to infants with IPV introduction  developed a multipronged strategy that included an expert review of the current evidence base, identifying and filling the gaps in evidence, and proactively communicating the findings to address country-specific concerns. In April 2015, SAGE reviewed the published and gray literature on healthcare provider and caregiver attitudes and practices regarding multiple injections; the safety and immunogenicity of administering IPV, PCV, and pentavalent vaccines during a single visit; and techniques for administering multiple injections. We review the multiple injections experience as it evolved during the implementation of the endgame strategy. We report results on the following topics: (1) provider and caregiver acceptance of multiple injections, (2) available evidence for guidelines when administering multiple injections, (3) communication messages on vaccine safety and acceptability, and (4) prevalence of recommended visits involving >1 vaccine injection during the 2013–2015 global IPV introduction.The methods used for each topic varied. The systematic review methods used for provider and caregiver acceptance are described in detail elsewhere .http://www.greylit.org), OpenGrey (available at: http://www.opengrey.eu), the Norwegian Satellite of the Cochrane Effective Practice and Organisation of Care Review Group (available at: http://www.epocoslo.cochrane.org), Google (available at: http://www.google.com), the WHO Institutional Repository for Information Sharing (available at: http://www.who.int/iris), UNICEF (available at: http://www.unicef.int), and the WHO (available at: http://www.who.int).For guidelines on administering multiple injections, we reviewed evidence from both the peer-reviewed and gray literature  that pertains to the recommendations on administering multiple injections in a single visit, with a focus on the administration of the most common Expanded Program on Immunization (EPI) vaccines for infants. Articles were identified through Medline (PubMed) and Embase databases. Five individuals reviewed a unique set of the resulting articles and abstracted relevant information, using a standardized Microsoft Excel–based data collection tool. In addition to this preliminary review, individual published and gray literature reviews were conducted for topics about which little or no peer-reviewed literature was found. Experts were contacted for comments on the topics and additional articles to review if no evidence was identified. Multiple-injection guidance documents and immunization guides were reviewed from selected national immunization programs, and other organizations were included if they were available online in English, Spanish, or French. The following sources were used to identify gray literature: Grey Literature Report  vaccine spacing, based on evidence for giving 2 injections 2.5 cm  apart; (2) site of injection, based on evidence on the suitability of using the vastus lateralis  versus other sites for intramuscular injections in infants; (3) route of injection, based on evidence favoring use of intramuscular delivery versus the subcutaneous route; and (4) procedural preparedness, based on guidelines for syringe- recapping procedures and preparation of multiple vaccines.Information on the route of injection summarizes the actions taken by the GPEI to develop a communications strategy when initial concerns were raised from immunization program managers about increasing the number of recommended vaccine injections per visit during global IPV introduction in 2013–2015. This information is derived from the multiple authors who were involved in development of this communications strategy. For procedural preparedness, data on national immunization schedules from the WHO/UNICEF Joint Reporting Form  and GPEIWith regard to acceptance of administering multiple injections at a single visit, a systematic review by Wallace et al found high caregiver acceptance of multiple injections in a single visit, even when the caregiver expressed concerns about the number of vaccine injections children received. Acceptance of all vaccine injections was markedly higher with a positive provider recommendation to the caregiver and high level of concern for the severity of the disease without vaccination . These sA preliminary systematic review of the safety and immunogenicity of administering IPV, PCV, and pentavalent vaccines during a single visit found that the vaccines were well tolerated and that there was a good immune response to each vaccine , 17. Of Official guidance in Australia, Canada, and the United States recommends a minimum distance of 2.5 cm between injections in the same limb; however, no published studies compared the spacing distances between injections  . This reFive literature reviews and 11 clinical trials or observational studies addressed the suitability of administering intramuscular injections in the deltoid muscle versus the vastus lateralis muscle in infants. These papers concluded that accurate identification of the injection site and adequate muscle mass are crucial to avoid nerve and muscle injury . BecauseThe vastus lateralis muscle  is the recommended intramuscular vaccination site for infants because its muscle mass is sufficient from birth, and study authors deemed it an appropriate site for children receiving multiple injections . The risIt was noted that, at all injection sites, intramuscular injections can cause complications such as muscle contracture, nerve injury, and abscess formation; however, these are rare occurrences.Fourteen articles met our inclusion criteria for the review; of these, 5 were clinical trials or systematic reviews that presented relevant results. One review noted that the practice of intramuscular versus subcutaneous administration for vaccines has been based on tradition . Two revFor a session with multiple injections, the Immunization Action Coalition (USA) recommends drawing up all of the vaccines indicated for 1 infant in a clean designated area, covering each clean needle with its cap, labeling each syringe, and then administering all the indicated vaccines to the infant in quick succession. While recapping used needles should be avoided to prevent needlestick injuries, unused needles have no risk of blood-borne pathogen exposure for the healthcare provider or the infant . A 2015 The SAGE was presented with key conclusions and recommendations based on this review . SAGE meThe SAGE’s recommendations reinforced the messages of the communication materials developed by the GPEI for health sector staff on the benefits of multiple injections, the safety of IPV when coadministered with other vaccines, and the ability to respond to parental concerns about IPV and multiple injections. Several key messages were communicated by the GPEI. First, multiple injections are safe when given at 1 visit, based on experience from many countries in which ≥3 injections are administered during a single visit. Second, delaying vaccination for concerns of multiple injections delays the infant from being protected against potentially life-threatening diseases, leads to more vaccination visits for caregivers, and reduces the efficiency of immunization programs. Third, with 3 injectable vaccines , IPV and PCV injections should be administered in one thigh, with the injection sites separated by at least 2.5 cm, and the pentavalent vaccine injection should be given in the opposite thigh because pentavalent vaccine is potentially the most reactogenic of the 3 vaccines . These rInformation was communicated through several strategies, including development of guidance and toolkits geared toward various audiences, such as decision-makers, technical staff, and vaccinators. Webinars and trainings for consultants and partners were held using evidence-based tool kits to address issues, concerns, and solutions related to multiple injections. All available information was broadly disseminated to partners, stakeholders, and countries. This strategy reinforced the evidence-based message on the safety and acceptability of multiple injections and emphasized the need for a strong healthcare provider endorsement of multiple injections, an essential means to increase caregiver acceptance of vaccines.Before 2013, 68 OPV-using countries had introduced IPV and 60 had done so using a combination vaccine that incorporated IPV alongside other antigens. Based on available data, of the 85 countries that introduced IPV during 2013–2015, 46 (55%) used standalone IPV and adopted a schedule with 3 injectable vaccines in a single visit, 26 (31%) used standalone IPV and adopted a schedule with 2 injectable vaccines in a single visit, 4 (4%) used standalone IPV and modified their pentavalent and/or PCV schedule to provide either IPV and 1 other injectable vaccine  in a single visit or only IPV in a single visit, and 9 (11%) used a combination vaccine and therefore avoided increasing the number of injections in a single visit . In the Access to IPV for all countries is a key component of the GPEI endgame strategy for phasing out use of OPV, starting with the globally synchronized switch from tOPV to bOPV in April 2016. Increasing concerns regarding the administration of multiple injections at a single visit emerged as a potential cause of delays in IPV introduction and the polio endgame strategy. The logistics and communications issues associated with the addition of another injection to the primary immunization schedule were complex for countries and national technical advisory groups, particularly given the short timelines and the sometimes concurrent introduction of PCV.Despite anticipated concerns over the acceptance of multiple injections, all 126 countries committed to introducing IPV as part of the endgame. By August 2016, 105 countries had introduced standalone IPV, and many had adopted schedules that included the administration of 3 injectable vaccines at a single visit .Regional factors, potentially including differences in sensitivity to the costs of combination vaccines or additional immunization visits, cultural preferences regarding medical injections, or proclivities to follow WHO recommendations, may have influenced countries’ decisions to create visits with ≥3 injectable vaccines.To date, assessments of acceptance of the administration of 3 injectable vaccines in a single visit in countries that introduced IPV in 2014–2016 have indicated that the vast majority of healthcare providers and caregivers accept such schedules. In the Gambia, all children with an immunization visit at 4 months of age received the recommended doses of IPV, PCV, and pentavalent vaccine when all 3 vaccines were in stock . In AlbaOur systematic review of administration practices identified a need for comprehensive guidance for healthcare providers on preparing and administering multiple injections, as well as a need for research to support such guidance, as also documented by other studies . AdminisAlthough several recommendations state that vaccines should be spaced at least 2.5 cm apart when administered in the same limb, no evidence was found to support this or any other distance as optimal for vaccine spacing in terms of reactogenicity or immunogenicity; however, this spacing has become standard practice among healthcare providers. This recommendation is based on the practical consideration that it allows for local reactions to each vaccine to be distinguished by providers. Additional reactogenicity information on other vaccine combinations is needed to provide guidance on whether some vaccines may need spacing of >2.5 cm.Avoidance of the deltoid muscle for intramuscular injections in infants is based on the risk for nerve injury when infants have atrophied muscles . GuidancGuidance on the preparation procedures for multiple-injection visits is inconsistent across sources. When guidance was provided, it was vague and based on the best practices for prevention of used-needle recapping and needlestick injuries. National guidelines on provider preparation for a multiple-injection visit are needed to ensure that procedures adequately protect the patient and provider, as well as ensure that the correct vaccines are administered and recorded.There were several limitations with our analyses. Because of the variety and number of combinations of vaccines administered to an infant during a single visit, topics could not always be separated by type of vaccine. Very few studies were conducted in developing countries. Additionally, the findings of our literature review were focused on the effects of administering IPV, PCV, and pentavalent vaccines at the same visit. While we expect that administering other vaccine combinations would result in similar frequencies of adverse events, it is possible that administering other vaccine combinations at a single visit instead of at separate visits could increase the risk of adverse events following immunization. For example, administering inactivated influenza vaccine with either PCV or DTaP-containing vaccine to children at the same visit instead of separately has been found to be associated with a small increased risk for febrile seizures .As additional new injectable vaccines are introduced, the number of vaccine injections given at a single visit may continue to rise. Health care providers should be given information on the safety and value of providing all recommended vaccines in a single visit to infants, and national vaccination schedules should maximize the likelihood that children will be fully protected against vaccine preventable diseases by including multiple injections in a single visit while minimizing the risks of vaccine adverse events.In summary, existing evidence supports the safety of administering IPV, pentavalent vaccine, and PCV at the same visit, as well as the acceptability of including multiple-injection visits in routine immunization schedules. A review of administration practices and techniques offers guidance to countries based on the little evidence available or long-standing experience and expert opinion. On the basis of this evidence, the SAGE recommended that countries provide training to healthcare providers on vaccine coadministration practices, including techniques to mitigate pain at the time of vaccination, information about safety and effectiveness of vaccines when coadministered, information about the likely overestimation of parental concerns, and training on improved communication strategies with caregivers. Additionally, the SAGE concluded that unless there is contrary evidence, countries should not prevent multiple vaccine injection visits from being included in recommended immunization schedules. Most countries that have introduced IPV since 2013 have included multiple-injection visits in their immunization schedules. With the inevitable introduction of more new vaccines into the EPI schedule, research and operational evaluations in low-income countries are critical to address issues related to pain management and improvement of efficiency during vaccination and to interventions to overcome provider and parental concerns about administering multiple injections in a single visit. The SAGE developed a recommended list of key research topics and activities . The mul


Gryllus bimaculatus and by referring to the findings in honey bees and fruit-flies, we argue that comparable aminergic systems exist in the insect brain. We found that administrations of octopamine  and dopamine receptor antagonists impair conditioning to associate an olfactory or visual conditioned stimulus (CS) with water or sodium chloride solution , respectively, suggesting that specific octopamine and dopamine neurons mediate appetitive and aversive signals, respectively, in conditioning in crickets. These findings differ from findings in fruit-flies. In fruit-flies, appetitive and aversive signals are mediated by different dopamine neuron subsets, suggesting diversity in neurotransmitters mediating appetitive signals in insects. We also found evidences of “blocking” and “auto-blocking” phenomena, which suggested that the prediction error, the discrepancy between actual US and predicted US, governs the conditioning in crickets and that octopamine neurons mediate prediction error signals for appetitive US. Our studies also showed that activations of octopamine and dopamine neurons are needed for the execution of an appetitive conditioned response (CR) and an aversive CR, respectively, and we, thus, proposed that these neurons mediate US prediction signals that drive appetitive and aversive CRs. Our findings suggest that the basic principles of functioning of aminergic systems in associative learning, i.e., to transmit prediction error signals for conditioning and to convey US prediction signals for execution of CR, are conserved among insects and mammals, on account of the fact that the organization of the insect brain is much simpler than that of the mammalian brain. Further investigation of aminergic systems that govern associative learning in insects should lead to a better understanding of commonalities and diversities of computational rules underlying associative learning in animals.Revealing neural systems that mediate appetite and aversive signals in associative learning is critical for understanding the brain mechanisms controlling adaptive behavior in animals. In mammals, it has been shown that some classes of dopamine neurons in the midbrain mediate prediction error signals that govern the learning process, whereas other classes of dopamine neurons control execution of learned actions. In this review, based on the results of our studies on Pavlovian conditioning in the cricket  Elucidation of neural systems that mediate appetite and aversive signals in associative learning is an important subject in neuroscience. By associative learning, animals can acquire knowledge in their environments, which allow them, for example, to find suitable food, avoid toxic compounds, and escape from predators. Efforts have been made to elucidate neural systems mediating appetitive and aversive signals in associative learning in many animals, including mammals Schultz, , 2015, iThis review deals with results of our studies on the roles of biogenic amines in appetitive and aversive learning in crickets. Crickets are useful insects for the study of neurotransmitter mechanisms of learning and memory. First, they have excellent capabilities of olfactory and visual learning. For example, they exhibit lifetime olfactory memory  with odor CS and water or sodium chloride US, which allowed us to investigate the memory acquisition process /CRISPR-associated protein 9 (Cas9) system; Awata et al., Dop1 knockout crickets exhibited no obvious abnormality in behavior and external morphology. Our conditioning experiments showed that Dop1 knockout crickets exhibited no aversive learning with sodium chloride US but exhibited normal appetitive learning with water US or sucrose US  confirmed a significant reduction in the mRNA level of each gene 2 days after dsRNA injection. OA1-silenced crickets exhibited no appetitive learning, but they exhibited normal scores in aversive learning. In contrast, Dop1-silenced crickets exhibited no aversive learning but exhibited normal scores in appetitive learning. Dop2-silenced crickets, as well as control crickets injected with DsRed dsRNA, showed normal scores in both appetitive learning and aversive learning. We, thus, conclude that octopamine mediates appetitive signals via OA1 receptors, whereas dopamine mediates aversive signals via Dop1 receptors in crickets. The perfect agreements of the results of pharmacological, transgenic, and RNAi studies provide decisive evidence that neurotransmitters and receptors that mediate appetitive signals indeed differ in crickets and flies. Our findings in crickets are in accordance with the findings in honey bees, where it has been suggested that appetitive learning is mediated by octopamine neurons via OA1 receptors  after appetitive or aversive conditioning. Crickets were subjected to appetitive or aversive olfactory conditioning and then they received an injection of either octopamine or dopamine receptor antagonist before a retention test (Mizunami et al., Our findings were not in accordance with a neural model of classical conditioning proposed by Schwaerzel et al.  Figure , which wWe proposed a novel neural model of classical conditioning for the cricket (Mizunami et al., Finally, we address the question of what computational rules govern the learning process in crickets. In mammals, a discrepancy, or an error, between the actual US and the predicted US facilitates the classical conditioning for a stimulus paired with the US Schultz, , 2015. TWe performed experiments to investigate whether blocking occurs in classical conditioning in crickets (Terao et al., We revised our previous model Figure  for PavlMost animals possess neural mechanisms that allow modification of their behavior for receiving appetitive stimuli and avoiding aversive stimuli. We showed that some octopamine and dopamine neurons play critical roles in appetitive and aversive learning, respectively, and more specifically, the octopamine neurons mediate reward prediction error in appetitive learning in crickets. Moreover, we suggested that some octopamine and dopamine neurons mediate signals about the extent by which the CS predicts the US and such signals drive appetitive and aversive CRs, respectively. Those roles of aminergic neurons in crickets match the S-S learning theory (see Mizunami et al., In addition, our studies have demonstrated that crickets are one of most suitable animals for pharmacological analysis of learning and memory, and crickets may, thus, also be efficient model animals for screening drugs that affect motivational states of animals, and such screening may contribute to therapeutic applications in humans.MM and YM wrote the manuscript and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.