The task of English language and literacy education to define citizenship, and shape citizens, has rarely been more compelling or more challenging than it is today. Globally and nationally, our civic response to COVID-19 has catapulted us into a world where our rights as and responsibilities as citizens are being fundamentally re-negotiated at the same time as we come to rely on technologically mediated literate practice to connect a world that is more spatially and temporally separated than many of us have ever known it to be. We are challenged to remake our identities and commit to new kinds of personal and civic relationships—nationally and globally—as we try to navigate uncharted waters. Our focus here is on the role that literacy education plays in understanding and defining active citizenship in a turbulent context in which foundational literacy practices are transforming just as accepted understandings of active citizenship are under challenge. We direct our attention specifically to the distinctive role that literacy practice plays in the production of identities and relationships and consider new ways for literacy education to build active citizenship across the lifespan from early education through primary and secondary education through to workforce education. Australia’s civic response to the COVID-19 virus has propelled us into a world that relies on technologically mediated literate practice to an extent that we could not have imagined prior to the pandemic. As good citizens, we worked from home when we could and socialised with our friends and family largely at a distance. The ligatures of citizenship became textual in character: video-conferencing peer-to-peer software platforms  became ubiquitous (the variability in Internet access becoming obvious) and the literate practices of toggling between the reading and writing needed to navigate the technologies and the face-to-face human interaction it enables became a ‘basic literacy’ with a speed we could not have predicted. In the space of 3 months, all of our most fundamental human activities—learning, working, caring and connecting—were, in large part and for most people, accomplished remotely and relied for their accomplishment on our capacity to exploit existing literacy practices, and to learn and generate new literacy practices, to connect us with people and technologies we needed to keep our lives in motion. Living with COVID-19 has taught us what these literacy practices make possible; it has produced new ways of being a student, teacher, worker, employer, parent, friend, carer etc., and created new relationships between all of these identities. It is unlikely that we will relinquish these nascent identities and relationships, even as we resume the old. Full citizenship, which encompasses all these identities and relationships, is being produced and expressed differently.AJLL will be familiar with contemporary debates around the term literacy so we will not rehearse them here: when we refer to literacy, we are referring to the practices of reading, viewing, writing, listening and speaking about text.What are the challenges to citizenship in this brave new world? How can we fulfill our responsibilities to our fellow citizens and the next generation by providing education that supports active citizenship and prepares them to recognise and meet these challenges? These questions have profound implications for all sectors of education and for education across the lifespan. In this paper, we focus specifically on literacy, asking: What literacy practices and resources do we need to animate active citizenship in these new times? In addressing this question, we enter two distinct and connected arenas of febrile debate. Our two key terms, ‘literacy’ and ‘citizenship’, are hotly contested in both scholarly and contemporary political debate. Readers of The term citizenship requires slightly more extended discussion. From a strictly legal perspective, the definition of citizenship is straightforward. The term refers to an individual’s membership of a category conferred by a nation state. Its use in scholarship and in public debate, however, is both more malleable and more contested Young, . DebatesWe are particularly concerned with the distinctive role of literate practice in ‘establishing, maintaining and repairing relationships. .. between people  and between people and technologies’ . In a few short years, children have large and varied vocabularies, can produce complex sentences, understand increasingly abstract concepts and generate stories. These various oral skills are differentially related to literacy Snow, . Importainteractional, where language is used to connect and form relationships with others and the personal where language is used to express feelings and build children’s identity and agency.Sociocultural theory  DEEWR, . The EYLeffective communication as one of its core learning and development outcomes, the EYLF recognises the importance of children’s communication and language abilities to provide the fundamental skills for their interactions with others, play-based experiences, and capacity to express their feelings and opinions. Equally, children are connected with and contribute to their world addresses children’s’ developing sense of citizenship. This is observable when children participate in decision-making and begin to cooperate and negotiate roles and responsibilities through play-based activities.With belonging, being and becoming. Children’s interactions with others and participation in the world enable them to construct their sense of who they are and provide the first steps to citizenship . Finally, Becoming signals the substantial change that occurs as young children learn and develop, acknowledging that their understanding of the world, their capacity to negotiate or repair relationships, is an integral part of participating enthusiastically in society. Children’s use of language and their interactions with parents, peers, and educators provide them with a sense of who they are and that they are valued. When children’s ideas, questions and opinions are listened to, discussed and intrinsically respected, confidence and participation flourish.The EYLF articulates three important characteristics that emerge in children’s lives through their experiences with family, community and culture: In addition, the United Nations Convention on the Rights of the Child (UNCRC) , to negotiate and share, and recognise the achievements of themselves and others, they are developing the skills of active citizenship and participation in community. Children are learning about personal beliefs that build and shape their identity. Throughout, language and sustained interactions mediate this learning. Positive experiences and attitudes are critical to building competent communicators and citizens for now and the future, ensuring children’s strong sense of identity, wellbeing and motivation for life-long learning. The foundations of which are built through children’s earliest communication skills and language use in the first few years of life.From the initial development of a protolanguage through to learning the mother tongue, meaning ‘consists in simultaneously construing experience and enacting interpersonal relationships’  to show humility and politeness in arguments, and to lower feelings of opposition among readers or addressees’, a skill often overlooked or underdeveloped  citizens, particularly in the face of an expanding electorate.’  is inextricably bound, as far as governments are concerned, with citizenship education:While language, literature and literacy all form core components of subject English in Australia ACARA, , it is hPerhaps because of its apparent transformative potential, the teaching of literature itself remains both a prime motivator for individuals to become English teachers Goodwyn, , and mucThe use of literature to support the development of a homogeneous, law-abiding, moral and aspirational citizenry was famously championed by Matthew Arnold, who was an Inspector of schools, academic and poet in England in the nineteenth century. This position has routinely been attacked by Marxist critics such as Eagleton , and perAs a result of contemporary concerns about the deployment of English and literature to animate conservative and compliant citizens, English teachers have not necessarily privileged citizenship discourses, preferring to emphasise individual and personal growth models of working with texts Frawley, , or critIt seems clear that, in the context of global pandemic, social and environmental crises, it is time to rethink the ways in which secondary English contributes to citizen formation, and the ways we understand, speak, read and write about ourselves in the world. Literature, and the telling and receiving of stories, plays a key role, here, in the way we enact the present, and imagine the future . The broader requirement for more workers to be literate emerged around the time of the first Industrial Revolution, around about the time that literacy was becoming associated with political participation.Literate practice and work practice are inextricably linked to public perceptions of productive working identities. The claim that the literacy skills of the contemporary workforce are not keeping up with the literacy demands of the contemporary workplace is a familiar refrain in public debate and has been for decades  and Political Revolutions (dangerous from their point of view) Donald, . A literwill be automated; political, social and economic factors contribute to specific decisions to automate specific tasks. It is to say they can be, and probably will be, when politically, economically and socially hospitable conditions arise.We are now at the dawn of the Fourth Industrial Revolution, and this revolution, too, is making new demands on literacy and presenting new challenges to citizenship. The Fourth Industrial Revolution is marked by emerging technology breakthroughs in a number of fields, including robotics, artificial intelligence, nanotechnology, quantum computing, biotechnology, the internet of things, 3D printing and autonomous vehicles. Essentially, the fourth industrial revolution is about the convergence of these new technologies—technologies which can communicate with each other and learn from each other. This is changing what work is available, how that work is organised and how the work is accomplished. It is now the case that anything, anything at all, that can be described by a set of steps or actions—anything routine—can be automated. This goes beyond manufacturing, where it is well advanced, to include major tasks associated with professions previously considered to be impervious to automation, like accounting, law and scientific research; high status occupations which include highly specialised, and highly rule-governed practices. This is not to say that these work tasks places to workspaces—dynamic, fluid, often transient, working units defined and bounded by regular, routine information and communications technology routes  towards distinctively human, technologically enabled, customised forms of literate engagement to achieve problem solving, innovation and the establishment, maintenance and repair of all the relationships that make up contemporary workspaces. These kinds of literate practices require a distinctive approach to literacy education across the lifespan. As far as work-readiness is concerned, it is no longer plausible to confine literacy education to early childhood education and schooling. As work practice and work organisation changes in response digitisation, we will all need professional education across the lifespan that supports us in learning new ways of reading, writing, listening and speaking about the multimodal texts that constitute our working lives.These developments in the digitisation of work, and especially changes to the ways that work is organised, make new demands on the literate practices of active citizenship. The trend towards casual work arrangements, often although by no means always managed through general companies like Airtasker or more specialised companies like Script using peer to peer software, has eroded working conditions like sick leave and mandated occupational health and safety requirements, leaving workers—from the least skilled to the most skilled—to fend for themselves  foregrounds the interpersonal—the establishment, maintenance and repair of relationships—across all the domains of human experience, whether it be to express ideas and opinions, tell and then write our own stories, and through the literary, inhabit the lives and stories of others.Since its inception, literacy education has been shaped by productive tensions: the tension between the development of a skilled (and compliant) workforce on the one hand and the development of a robust citizenry on the other; and the tension between the inculcation of respect for established knowledge and traditional relationships on the one hand and the capacity to challenge established knowledge and forge new relationships between people and between people and institutions on the other. In that sense, the challenges we face are no different from the challenges faced by those who have gone before us. We are, however, confronted with circumstances that are distinctively daunting and urgent. The convergence of global climate crises, global health crises and the profound social, political and economic upheavals generated by technological transformations of work challenge the relationships between people, technologies and institutions that form the foundations of our communities and our institutions. Literacy practices are the ligatures that establish, maintain and repair these relationships, the relationships on which active citizenship, positive social, political and economic transformation depends.What can we, as educators, teacher educators and public policy makers, do to make and sustain an environment in which the literacy practices which generate, support and protect these ligatures are strengthened? First, we can break down the traditionally siloed education sectors to promote literacy education across the lifespan. Effective literacy education for citizenship starts at birth and does not end with formal education but extends through every stage of our adult lives. Second, we can take what we have learned about literate practice from past research and theorising on literacy and test it against the contemporary and emerging lived experience of people unlike ourselves. Specifically, we need to commit to engaging with new, literacy-saturated workspaces and other newly emerging literacy-saturated social, political and economic institutions and learning about how they work and what they mean for the lives of our students. Finally, we can attend to the stories we tell and the stories we ask our students to write, recognising that these are the resources that will help our students imagine new worlds, new ways of being and new ways to relate with each other.


During the COVID-19 pandemic, distorted information about the COVID-19 vaccination is widely disseminated through social media. The present study examined the association between perceived information distortion about COVID-19 vaccination on social media, individuals’ functional and critical literacy, and addictive social media use (SMU), as well as the moderating roles of functional and critical literacy in the association between perceived information distortion and addictive SMU among social media users in Hong Kong. A web-based, cross-sectional survey was conducted among 411 Chinese citizens from June to August 2021. Findings showed that after adjusting for significant background variables, including age, gender, marital status, education, occupation, and income, functional literacy was negatively associated with addictive SMU. In addition, significant moderation effects of functional literacy and critical literacy were also observed, such that a positive association between perceived information distortion on social media and addictive SMU was significant among participants with lower functional literacy or higher critical literacy. Findings highlight the importance of improving functional literacy in addictive SMU prevention for social media users. Special attention should also be paid to the potential influence of critical literacy on addictive SMUs. COVID-19 has caused severe threats to public health globally, and vaccination is recognized as one of the most effective ways to curb this pandemic’s spread . Due to information distortion. Second, as lockdown policies were put in place to curb the pandemic, people spent more time on social media, which may be indicative of a rise in addictive tendencies [Social media platforms are internet-based applications that enable users to obtain, create, share, and communicate information with others and engage in public discourse . With thndencies ,12. Currndencies . Few havndencies . Yet verDespite the convenience provided by social media, previous research suggests that intensive online activity may lead to the development of addictive tendencies . During Information distortion refers to the tendency of information to be altered, omitted, or reorganized as it is communicated , which iMost studies regarding the factors behind addictive or problematic SMU focused predominantly on an individual’s personality  literacy refers to the ability to seek, find, understand, and appraise health information from electronic sources and apply such knowledge gained to address health problems , and itsFunctional literacy refers to basic skills in reading, understanding, and writing skills of online information . Some stHypothesis 2.Gaps in addictive SMU between high and low perceived information distortion would depend on functional literacy, such that those with high functional literacy would display lower addictive SMU than those who low functional literacy.Apart from functional literacy, we propose that critical literacy would be another potential moderator of the relationship between perceived information distortion and addictive SMU. Critical literacy involves more advanced cognitive skills to critically evaluate online information, discern the quality of platforms, and use quality information to make informed decisions . PreviouRQ1: How would critical literacy moderate the relationship between perceived information distortion and addictive SMU?A web-based, cross-sectional survey was conducted among social media users from June to August 2021 in Hong Kong. The inclusion criteria of the participants were as follows: (1) Hong Kong residents; (2) aged 18 years or over; (3) using social media platforms, such as Twitter, Facebook, Instagram, Snapchat, and TikTok, at least once a week in the past six months; (4) having been exposed to COVID-19 vaccine-related information on any social media platforms in the past month.Eligible participants were invited to participate in the web-based survey via social networking sites . The online survey was accessed through a hyperlink or a QR code for interested participants to log on to Google Forms, including the informed consent and study questionnaire. Participants were informed that the survey was voluntary and confidential, and only those who provided their informed consent could proceed with the following questions. Participants self-administered the online questionnaire, which took 15–20 min to complete. Each participant would receive an HKD20 (about USD2.56) coupon upon completion as a token of appreciation for their participation. Ethical approval was obtained from the ethics committee of the Chinese University of Hong Kong. A total of 411 completed responses were collected.Addictive SMU was assessed by the six-item Bergen Social Media Addiction Scale (BSMAS) [ (BSMAS) , which c (BSMAS) . The Chi (BSMAS) , which e (BSMAS) .Perceived information distortion about COVID-19 vaccination  was measured by two items adapted from a subscale of the media quality scale with vaccine-related context [ context . The iteFunctional literacy and critical literacy were measured by the functional and critical subscales of the 12-item eHealth literacy scale developed by Hsu et al. [u et al. . The iteDescriptive statistics were first used to present the characteristics of the study population. Next, Pearson correlation analysis was conducted to show the correlations between the key variables in this study. Univariate regression was performed first to examine the associations between background variables and addictive SMU. Then, hierarchical regression was used to examine the association between perceived information distortion and addictive SMU, with functional literacy and critical literacy as potential moderators in such association. All significant background variables in univariate regression were adjusted for in the hierarchical regressions.p-value < 0.05.Specifically, the main effects of perceived information distortion on social media and functional literacy on addictive SMU were first examined; to test the moderating effect of functional literacy, the two-way interaction term between perceived information distortion and functional literacy was computed and added to the hierarchical regression model. Such analyses were repeated for critical literacy as the second moderator to examine the effect of its interaction with perceived information distortion on addictive SMU. Both unstandardized (B) and standardized coefficients (β) with 95% confidence intervals (CI) in the hierarchical regressions were reported. All the above analyses were conducted using SPSS 26.0, and statistical significance was defined as a The descriptive statistics are presented in p < 0.05).The pairwise correlations among key variables are presented in p < 0.05). Demographic variables explained 5.30% of the variance in addictive SMUs. H1 posited that Perceived information distortion on social media would be positively associated with one’s addictive SMU. Block 2 showed that after adjusting for background variables, perceived information distortion had no significant association with addictive SMU, thus not supporting H1. H2 postulated that gaps in addictive SMU between high and low perceived information distortion would depend on functional literacy. The results in block 2 showed that functional literacy was negatively associated with addictive SMU , and block 3 further examined the interaction between perceived information distortion and functional literacy in explaining the variance in addictive SMU with a significantly negative interaction emerged , p = 0.046). The entire regression block explained 14.80% of the total variance in addictive SMUs. Results of simple slope analysis (p = 0.046) but not significant among those with higher functional literacy. Thus, H2 was supported.analysis  showed tp = 0.04). The entire regression block explained 6.60% of the total variance in addictive SMUs. Results of the analysis of the simple slope  may exist as the questionnaire was self-reported and self-administered, although self-reported measures are more feasible to implement. Third, the sample was made up of social media users who voluntarily participated in this study. In other words, the participants were more likely to be interested in social media use or acquiring COVID-19-related news on social media. Therefore, the current sample might not represent the whole social media user population in Hong Kong. Nevertheless, we have strived to recruit participants with socio-demographic characteristics similar to the census data for adults aged 18 or over in Hong Kong . Future The present study identified the relationship between perceived information distortion, functional literacy, and critical literacy on addictive SMU. Results showed that lower functional literacy contributed significantly to addictive SMU among social media users; in addition, findings suggested that in individuals with lower functional literacy or higher critical literacy, those with higher perceived information distortion regarding COVID-19 vaccination on social media appear more likely to develop addictive SMU. Interventions to prevent addictive SMU in the COVID-19 pandemic should seek to improve the functional literacy of social media users; special attention should also be paid to the potential influence of higher critical literacy on addictive SMU. In addition, a joint effort should also be made by the media news agencies worldwide against distorted information and elevate authoritative content to improve the information quality on social media.


Background: Research in early childhood allergy prevention (ECAP) is flourishing and new intervention strategies have proven to be promising. Due to the dynamic nature of ECAP, gaps between what is known and how guidelines inform practice are likely. A living systematic review (LSR) can narrow this gap by incorporating new evidence as it becomes available. No efficacy comparisons across various ECAP interventions for similar outcomes have been carried out. Networks of randomised clinical trials can be evaluated in the context of a network meta-analysis (NMA). We aim to establish a LSR on the efficacy and safety of any intervention investigated in randomised controlled trials (RCT) to prevent the occurrence of allergic sensitisation (AS), symptoms or diagnoses of allergic diseases in infancy and early childhood (0-3 years).Methods: A baseline SR will synthesise the evidence from existing SRs of RCTs as well as RCTs not yet considered in these. After completion of the baseline SR we propose to conduct a LSR. Using this methodology, we aim to undertake constant evidence surveillance, three-monthly search updates, and review updates every three months, should new evidence emerge.Conclusions: The ECAP evidence landscape has undergone dramatic transformations and this process is likely to continue. As a response to this, a LSR offers the potential to allow more timely synthesis of new evidence as it emerges. Long gaps between updates of SRs makes it harder for guidelines and recommendations to be up to date. Users of information, such as parents, may be confused if they encounter new evidence that is not part of a trusted guideline. A LSR approach allows us to continuously search the literature and update the evidence-base of existing ECAP interventions resulting in a decreased timespan from evidence accrual to informing clinical practice. Around 10% of children are affected by FA and the incidence is still rising in developing countries. Food allergy impacts quality of life. Allergic diseases  are also highly prevalent and associated with decreased health-related quality of life (HRQOL).Allergy in children is common. Frequent food allergies (FA) in children include hen’s egg, cow’s milk and peanut.To counteract the large number of allergies and reduce their burden, a major shift from merely managing manifest allergy to preventing its occurrence has taken place. Previous prevention efforts revolved around avoidance of potential allergens , while more recently a new paradigm has been embraced whose focus is on early allergen exposure to induce immune tolerance. This new paradigm has been informing study designs for food allergy prevention. So far it has been established that oral tolerance induction is allergen specific and efficacious in single introduction trials of peanut and egg. However, one trial found no evidence that an orally applied bacterial lysate affected allergy development in at risk infants. It is however, expected that more research in this field will emerge soon.There is also research activity revolving around environmentally derived prevention paradigms . However, not all infections protect from allergy, resulting in criticism of the hypothesis. Further research has led to modifications of this hypothesis, suggesting that exposure to specific pathogens, commensals and symbionts protects against development of allergy. The dual-allergen-exposure hypothesis proposes that exposure to food allergens through the skin leads to allergy, while early consumption of these foods induces tolerance. While in the past it was advocated that avoidance of allergenic food would reduce the onset of allergy several recent trials have lent support to the dual-allergen-exposure hypothesis. The vitamin D hypothesis suggests that low vitamin D levels increase the risk of developing food allergy. There are, however, conflicting data on the relationship between vitamin D and the development of food allergy.In general, the design of preventive strategies has been informed by several hypotheses regarding the aetiology of allergy and allergic disease. The original hygiene hypothesis states that lack of exposure to common infections causes allergy. have been published, some of which provide useful insights. However, not all include a standardised evaluation of the quality of the evidence ) for randomised controlled trials (RCT). Risk of bias (RoB) assessment was done by a variety of different tools. Some used the National Institute for Health and Care Excellence (NICE) methodological checklist or the Strength of Recommendation Taxonomy (SORT) criteria. Thus, a homogenous RoB assessment and consistent evidence grading approach for each study type would be desirable.Research in early childhood allergy prevention (ECAP) is flourishing and more than 50 systematic reviews (SR) that exclusively or partly reviewed RCTsAs intervention effects may vary depending on whether at risk, not at-risk or children with manifest allergy are investigated, studies will be grouped accordingly. ECAP in the latter would still be considered primary prevention, rather than secondary or tertiary prevention, since we would look only at the prevention of new allergies.Many of the above SRs included observational studies as well as clinical trials. Studies examining the effect of breastfeeding versus no breastfeeding on allergy development cannot use an RCT design; however, for most other ECAP strategies, there are no ethical or other constraints that prevent the use of the gold standard RCT. Hence, we will only consider RCTs in our SR.Not all ECAP findings may yet be part of allergy prevention guidelines. As outlined above, due to the wealth of studies and new ECAP paradigms, more than 50 SRs have attempted to synthesise the evidence accumulated within the various approaches to ECAP. It is likely that there are gaps between what we know from the best available research and what happens in healthcare practice due to the dynamic nature of ECAP research. The incorporation of new findings into existing reviews or their updates is time-consuming and not always feasible. Hence, adapting prevention guidelines in light of new findings and providing health care providers and other information users with up-to-date evidence may be impeded. Recent advances in the presentation of systematically reviewed  data have led to the concept of a living systematic review (LSR). A LSR is defined as “a systematic review that is continually updated, incorporating relevant new evidence as it becomes available”.Furthermore, no efficacy comparisons across various ECAP strategies for similar outcomes have been carried out. Networks of randomised clinical trials can be evaluated in the context of a network meta-analysis (NMA). NMA refers to a procedure that allows inferences about the comparative effectiveness of interventions that may or may not have been evaluated directly against each other.We aim to establish an LSR on the efficacy and safety of any intervention to prevent the occurrence of allergic sensitisation (AS), symptoms or diagnoses of allergic diseases in infancy and early childhood (0-3 years).1.To identify all individual-level interventions using the oral, skin, environmental or pharmaceutical route for the prevention of allergy in allergy-free children or the prevention of new allergies in children with manifest allergy2.To identify all community-level interventions  which have thus far been investigated in RCTs to prevent the occurrence of allergy in infancy.3.To summarise the evidence regarding the effects (efficacy and safety) of these interventions in preventing the occurrence of allergy in infancy and early childhood.4.To judge the quality of this evidence.5.To provide a corresponding plain language summary (PLS) accessible for consumers.6.To develop a workflow for an LSR, which ensures that the evidence synthesis is continuously kept up-to-date.The specific objectives are: PRISMA  and its extension for application to NMA. A protocol registration will be made at PROSPERO. Any updates to the protocol will be made through PROSPERO. The protocol was developed closely considering the Prisma-P checklist. A baseline SR will synthesise the evidence available so far and then transformed into a LSR by regular updates.The review will be undertaken according to the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions,-Date of publication: 1980 onward-Types of study: Randomised controlled trials,-Population: expectant and/or breastfeeding mothers of and/or children 0 - 3 years (at time of intervention), at risk children (0 - 3 years) , not at risk children (0-3 years) , children (0-3 years) with manifest allergy -Interventions: any aimed at the individual or community level at preventing the onset of new allergy or allergic disease or allergic sensitisationoOral route , time and presence of allergenic food introduction , variation in condition  and/or amount of complimentary food introduction, avoidance of potential allergensoSkin route oEnvironmental interventions , avoidance of chemicals or allergens (e.g. mattress protector (mites))oPharmaceutical prevention , Bacillus Calmette-Guérin (BCG) vaccination))-Comparator: inactive comparator such as placebo, no intervention or usual care-Primary outcomes:oPhysician-diagnosed or parent-reported incidence of allergic asthma (AA), allergic rhinitis (AR), atopic eczema (AE), food allergy (FA)oPhysician-diagnosed or parent-reported recurrent symptoms of sneeze, wheeze, cough, itch, flexural eczema, or FA-Secondary outcomes:oincidence of AS measured by in-vivo tests such as skin-prick test (SPT)oincidence of AS measured by in-vitro tests such as fluorescently labelled anti-IgE antibody, enzyme-linked immunosorbent assay (ELISA), or Radio-Allergo-Sorbent-Test (RAST)oadverse events (AE), severe adverse events (SAE), withdrawalsStudies will be eligible for inclusion in the review should they meet the following (PICO) criteria:ECAP has revolved around antenatal and postnatal strategies targeting the mother and strategies targeting the child after birth . Strategies that have been explored in RCTs are illustrated inAny observational research  or quasi-experimental studies (matched controlled designs) will be excluded. We will not consider interventions aimed at treating allergy unless the intervention is also hypothesised to reduce the onset of a new allergic manifestation.We will use five approaches for the identification of studies for the baseline SR:1)Topic-based searches in databases and registriesClinicalTrials.gov, ISRCTN registry, Australian New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, EU Clinical Trials Register).We will search for all relevant RCTs regardless of publication status  in the following bibliographic databases: MEDLINE (Ovid), Embase (Ovid), CENTRAL (Cochrane Library), Science Citation Index Expanded & Social Sciences Citation Index (Web of Science), Cochrane Skin Group Specialized Register, GREAT , in clinical trial registries .ti,ab,kf. or (pre-school$ or preschool$).ti,ab,kf. or Nurseries/ or (nursery or nurseries).ti,ab,kf. or exp Parents/ or (parent or parents or mother or mothers).ti,ab,kf. or (infant or infants).ti,ab,kf. or infancy.ti,ab,kf. or toddler?.ti,ab,kf. or (baby or babies).ti,ab,kf. or newborn$.ti,ab,kf. or neonat$.ti,ab,kf. or Pediatrics/ or (pediatric$ or paediatric$).ti,ab,kf. or early childhood.ti,ab,kf. or  or pregnan$.ti,ab,kf. or Prenatal Exposure Delayed Effects/or Maternal Exposure/or  adj1 exposure$).ti,ab,kf. or .ti,ab,kf. or Fetus/ (Population)2exp Preventive Health Services/ or Preventive Medicine/or "prevention control".fs. or prevent$.ti,ab,kf. or prophyla$.ti,ab,kf. or Infant Formula/or (formula or supplement$).ti,ab,kf. or ((risk or protect$ or development or avoidance or exposure or introduction) adj6 ).ti,ab,kf. (Intervention)3exp Hypersensitivity/ or Allergens/ or allerg$.ti,ab,kf. or hypersensitivit$.ti,ab,kf. or prick test$.ti,ab,kf. or exp asthma/ or Dyspnea/or (asthma$ or dyspnea or wheezing).ti,ab,kf. or (difficult$ adj1 breathing).ti,ab,kf. or rhinoconjunctivitis.ti,ab,kf. or (atopic adj1 (dermatit$ or neurodermatit$ or eczema or disease)).ti,ab,kf. or Diaper Rash/or ((infant or infantile or diaper) adj1 (rash or rashes or eczema or dermatit$)).ti,ab,kf. or Disseminated Neurodermat$.ti,ab,kf. (Outcome)4.pt. or randomized.ab. or placebo.ab. or drug therapy.fs. or randomly.ab. or trial.ab. or groups.ab.) not  )51 and 2 and 3 (Combined concepts: Patients AND Intervention AND Outcome)65 and 4 (Combined concepts: Patients AND Intervention AND Outcome AND RCTs)We will search the conference proceedings (European Academy of Dermatology and Venereology (EADV), European Academy of Allergy and Clinical Immunology (EAACI), American Academy of Dermatology (AAD), American Academy of Allergy, Asthma & Immunology (AAAI), Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI) and Asia Pacific Association of Pediatric Allergy, Respirology & Immunology (APAPARI), World Allergy Organisation (WAO)) and Sociedad Latinoamericana de Alergia, Asma e Inmunología, Asunción (SLAAI). Additionally, we will review published documents from health technology assessment agencies . No restriction on status or year of publication will be applied. The search will be restricted to publications in English, German, French, Italian or Spanish. An initial draft search strategy for MEDLINE was developed by a medical librarian experienced in comprehensive searches for systematic reviews . The per2)Searches by trial registry numbersRegistry numbers of eligible trials will be collected to be used in follow-up searches with the aim to identify additional trial reports.3)Trials included in relevant SRsWe will search for relevant SRs in order to identify additional trials in these SRs.4)Reference lists of included trialsWe will screen the reference lists of all included study reports. To aid in this process the reference lists will be downloaded from Web of Science when available.5)Existing systematic reviewsFor the creation of the baseline SR previous SRs on ECAP will be systematically searched for.EppiReviewer (version 4.11.5.3) for deduplication and study selection. Assessment of eligibility, data extraction, risk of bias (RoB) evaluation and quality of the evidence assessment will be carried out by at least two researchers independently. The latter will be done according to the GRADE recommendations.Database search results will be imported intoThe following data will be extracted:Study characteristics: Author, year of publication, geographical region, study design, type of intervention, type of control, number of participants in intervention group and control group, study duration, time points of assessment, follow-up period, type of primary and secondary outcomes and safety indicators.Participant characteristics: Person in whom intervention took place , child, both), age, sex, ethnicity, allergic risk status, parental atopy, presence of allergic sensitisation and/or condition.Study outcomes: Efficacy outcomes (unadjusted/adjusted): Incidence of allergic sensitization and/or allergic disease; safety outcomes: proportions of AEs, SAEs, withdrawal due to AEs AMSTAR-2 is a critical appraisal tool for SRs that include randomised or non-randomised studies of healthcare interventions, or both. RoB assessment will be done by the use of A Risk of Bias Assessment Tool for Systematic Reviews (ROBIS). Findings of SRs whose quality has been judged adequate will be summarised. We intend to publish the results in one or several overviews (umbrella reviews). Conduct of these overviews will follow the methods outlined in chapter 5 of the Cochrane Handbook for Systematic Reviews. Only studies of the same intervention and outcome not considered in these SRs and summarised in the overviews will be individually assessed for RoB and quality of the evidence for the baseline SR.Existing systematic reviews will be incorporated into the baseline SR. Assessment of the quality of these will be carried out by A MeaSurement Tool to Assess systematic Reviews-2 (AMSTAR-2).et al.If no obvious qualitative heterogeneity within studies exists, we will perform meta-analyses across similar applications of interventions. Pair-wise meta-analyses between two intervention conditions (provided at least two eligible studies exist that are not too heterogeneous) for each different endpoint/outcome  will be conducted. These are to be updated in the LSR as relevant new studies emerge. To guard against potential type I error inflation and occurrence of type II errors which are a function of the number of analyses done with the same data (as new data is incorporated with each update) we will follow the recommendations outlined by Simmonds Pairwise meta-analysis allows for comparisons between pairs of interventions  for a specific outcome in a particular population or setting. It is, however, often the case that a variety of different interventions are available for any given condition. A single SR that includes all relevant interventions and presents their comparative effectiveness and potential for harm would help people to decide between alternative interventions. NMA affords an analysis option for such a review. A network of interventions consists of any set of studies that links three or more interventions via direct comparisons. Within a network, there can be numerous ways to make indirect comparisons between interventions. They refer to comparisons that have not been made directly within studies. Mathematical combinations of the available direct intervention effect sizes are used to estimate indirect effects. In NMA direct and indirect estimates across a network of interventions are combined in a single analysis.Pairwise meta-analysis is a statistical technique for quantitatively synthesising similar studies in a systematic review. Useful in its own right, it is, however, limited in that it can only compare two interventions simultaneously, and only those evaluated directly in head-to-head trials.CINeMA . This web application simplifies the evaluation of confidence in the findings from NMA and has evolved out of the GRADE approach. The GRADE approach offers an assessment of the confidence in the results from systematic reviews and meta-analyses. Many organisations, for example the World Health Organisation, have adopted the GRADE approach. Based on GRADE, two systems have been proposed to evaluate the credibility of results from NMAs, but the complexity of the methods and lack of suitable software have limited their wide adoption. CINeMA is based on six domains: within-study bias (referring to the impact of RoB in the included studies), across-studies bias (publication or reporting bias), indirectness (relevance to the research question and transitivity), imprecision , heterogeneity , and incoherence (if estimates from direct and indirect evidence disagree). Judgements across the six domains are then summarised to obtain four levels of confidence for each relative treatment, corresponding to the usual GRADE approach: very low, low, moderate or high.We also aim to conduct NMA to compare different interventions for the same endpoint/outcome , should assumptions for NMA be met. We will also perform a full evaluation of the confidence in the results from NMA by using the web applicationIf possible, we will also perform subgroup analysis . Prior to this, sources of heterogeneity across studies will be investigated and the impact of inclusion of studies at various risk of bias in meta-analyses will be examined. According to Cochrane’s Living Evidence Network transformation into a LSR is justified when the review question is a particular priority for decision-making, there is an important level of uncertainty in the existing evidence and there is likely to be emerging evidence that will affect the conclusions of the LSR. The review question is of particular priority for decision making because one SR on ECAP is among the Cochrane Priority Reviews and the rate of publications on ECAP interventions has substantially increased over the past years . A living systematic review is a cumulative synthesis that is updated regularly as new evidence becomes available.t years  and is eAn artificial intelligence algorithm for automated searches will be developed in collaboration with information specialists and software engineers. We will gradually incorporate more and more intelligent software tools for eligibility tests, data extraction, and analysis and synthesis presentation as they prove to be reliable in the subsequent update processes.This evolving search algorithm is to be run at three-monthly intervals and will be set up to notify the author team about studies with a high likelihood of being eligible. At the same interval manual searches will be conducted until the automated search algorithm is sufficiently reliable. The author team will review the search results, decide upon inclusion, and update the living SR’s web version after a new evidence synthesis is deemed necessary every three months. At the same time references of included studies and the corresponding tables and figures will be updated. Every three months the date of each subsequent search, the number of new included studies, and new summary of findings tables will be published on the LSR’s website along with an updated plain language summary.The LSR will be maintained in its ‘living’ form until no new evidence is likely to arise and/or so long as the certainty of the evidence for particular ECAP interventions remains unsettled. The necessary future funding will be sought.The baseline SR will be published in a peer-reviewed journal and indexed publication platform that allows the linkage of review updates through versioning of the review publication. A plain language summary will be provided on a project website. This website is intended to also contain graphical and other information for health care providers and the public.For the LSR, we will consider resubmission to the journal in which the baseline SR is published should the direction of the effect on the critical outcomes change or a substantial modification to the evidence’s certainty occur.At submission of this protocol the final search strategy is being peer-reviewed.The prevention of allergy in early childhood is important given the high personal burden and societal costs of allergic diseases. The ECAP evidence landscape has undergone dramatic transformations and this process is likely to continue. As a response to this, a LSR offers the potential to undertake a more timely synthesise of new evidence as it emerges. Long gaps in between updates of SRs may make it harder for guidelines and recommendations to be current and up to date. Users of information, such as parents may be confused if they encounter new evidence that is not part of a trusted guideline. A LSR approach allows us to continuously search the literature and update the evidence-base of existing ECAP interventions resulting in a decreased timespan from evidence accrual to informing clinical practice.It is also crucially important to assess whether an ECAP intervention is associated with harm. For instance, there is evidence suggesting that early egg white powder introduction at 4 to 6 months of age for the prevention of egg allergy in children from the general population may increase the occurrence of allergy.Further, a consistent assessment of the certainty of the evidence in line with the GRADE recommendation will be carried out across all included studies. This will allow a high level of concordance between the certainty of the evidence and future guideline recommendations.) will be able to conduct a comparison of multiple interventions . The latter provides information regarding the relative treatment effect and the ranking order for multiple treatments for a particular outcome irrespective of whether they were conducted in the same or different trials.Whilst our approach of including all interventions for the prevention of all allergies in early childhood may seem ambitious, none of the individual systematic reviews being undertaken at present .Data are available under the terms of the This is an interesting approach.Network meta-analysis (NMA). It is interesting that comparative efficacy of interventions that have not been evaluated directed against each other can be compared. I think more information is required about this approach. Very simply, is it about comparing the efficacy of a prevention against placebo (or non-intervention) in two different trials showing for example that one intervention is twice as effective as another? More information should be provided about this interesting approach. Does it look at population heterogeneity from the two studies being compared, and how are different levels of risk in different populations adjusted for?Timing of an intervention for prevention in early infancy may be critical. Different studies will intervene at different time points, e.g. at birth, 3 months, and 6 months, and these few months can be critical. How will the NMA take these differences into account?Why is the LSR conducted every 3 months? Is this not too frequent? Most professional bodies will update their guidelines every 3-4 years. Is 3 months really necessary? Would once a year not be sufficient? Can the authors provide any evidence or compelling arguments that systematic reviews conducted at 3-monthly intervals are more valuable than those conducted at annual intervals?Why does the objective only study allergies during the first 3 years of life when most respiratory allergies develop at a later time point, and when food pollen syndrome develops at a later time point? Moreover, early interventions could potentially prevent allergies in the first 3 years of life and these preventative effects may disappear at later time points in life. I would strongly argue that any follow-on studies that go on beyond the first 3 years of life are taken into account. Such a long-term approach is well accepted in studies aiming to prevent cardiovascular events and I would recommend longer term follow up beyond the age of 3 where individual RCTs continue to follow the original population. I have a few questions:Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?PartlyAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:Food allergyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. In the study "The evidence for interventions in early childhood allergy prevention - towards a living systematic review: protocol" the authors propose a new, better and more objective intervention concept in early childhood allergy prevention (ECAP). The authors present concrete and objective methodology and metrics. In fact, living systematic review (LSR) requires regular and continuous updates with the implementation of new knowledge in guidelines and clinical practice. - However, there are several drawbacks to this concept; confusing and contradictory messages for the clinician in practice, as well as for patients (parents of children), giving guidelines for treatment that may not be applicable to every patient. It is therefore important to emphasize that evidence for interventions in early childhood allergy prevention, in fact, only "current guidelines" that can be changed or modified, and that they are not applicable to every patient. It is important for the authors to emphasize that personalized approach is still crucial in prevention strategy.Is the study design appropriate for the research question?YesIs the rationale for, and objectives of, the study clearly described?YesAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?YesReviewer Expertise:allergen immunotherapy,  environment and allergy developmentI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The present manuscript describes a project on future systematic reviews for interventions in early childhood allergy prevention. This is an interesting issue. However, some important points need to be clarified.et al. (2020). The rationale of the study is focused on dual-allergen-exposure hypothesis. It should be underlined that several strategies have been proposed to reduce the burden of allergic diseases as depicted in Table 1. For example, a multifaceted intervention that reduces exposure to allergens has been shown to be effective in preventing allergy onset. On the other hand, the list of “more than 50 systematic reviews” on early childhood allergy prevention is incomplete. For example see Mastrorilli Introduction:It seems that systematic reviews can only be useful for retrieving papers that have not been identified with other means. It is therefore difficult to understand why you should incorporate and assess existing systematic reviews. This point needs to be discussed and it should be providing possible explanations since it is not an objective of the current project. Study selection:It should be clarified whether a meta-analysis will be done when it results that heterogeneous studies with different design and outcome have been included. It seems that sometimes, this frequent limitation is not considered by meta-analysis. So, a statement on this issue is warranted. Meta-analysis:Is the study design appropriate for the research question?PartlyIs the rationale for, and objectives of, the study clearly described?PartlyAre sufficient details of the methods provided to allow replication by others?YesAre the datasets clearly presented in a useable and accessible format?Not applicableReviewer Expertise:NAI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. We thank the reviewer very much for having taken the time to critically review our manuscript. We have revised the manuscript taking your suggestions into account and hope to have improved the manuscript sufficiently.et al. (20201). The rationale of the study is focused on dual-allergen-exposure hypothesis. It should be underlined that several strategies have been proposed to reduce the burden of allergic diseases as depicted in Table 1. For example, a multifaceted intervention that reduces exposure to allergens has been shown to be effective in preventing allergy onset. On the other hand, the list of “more than 50 systematic reviews” on early childhood allergy prevention is incomplete. For example see MastrorilliThank you for this valuable comment. We agree with the reviewer, that there are several strategies within each route of administration. Table 1 lists the main routes of administration along with one illustrative example. Table 1 is not meant to be fully comprehensive of all strategies but instead meant to provide an indication of the hitherto used routes of intervention with an accompanying example. We would like to highlight, though, that for the purposes of the manuscript we had not intended to do a systematic search of all potentially relevant reviews. Thus, there may still be other reviews having examined randomised controlled trials of ECAP that are not listed in the manuscript. The suggested example by Mastrorilli et al., though a review, is not a systematic review. Introduction:It seems that systematic reviews can only be useful for retrieving papers that have not been identified with other means. It is therefore difficult to understand why you should incorporate and assess existing systematic reviews. This point needs to be discussed and it should be providing possible explanations since it is not an objective of the current project.We appreciate the reviewer’s comment very much. The respective section was revised to more fully convey the methodological approach to using existing SRs in the production of the baseline review. Study selection:It should be clarified whether a meta-analysis will be done when it results that heterogeneous studies with different design and outcome have been included. It seems that sometimes, this frequent limitation is not considered by meta-analysis. So, a statement on this issue is warranted.We are grateful for the reviewer’s comment and would like to stress that in the ‘Meta-analyses and network-meta-analysis’ section it is said, that only similar interventions (tested in RCTs only) and the same outcome will be considered in meta-analyses. We added another sentence  at the end of this section to clarify that we intend to examine the sources of heterogeneity and the impact of inclusion of studies at various risk of bias in meta-analyses. Meta-analysis:


Penetrating traumatic brain injury (pTBI) affects civilian and military populations resulting in significant morbidity, mortality, and healthcare costs. No up-to-date and evidence-based guidelines exist to assist modern medical and surgical management of these complex injuries. A preliminary literature search revealed a need for updated guidelines, supported by the Brain Trauma Foundation. Methodologists experienced in TBI guidelines were recruited to support project development alongside two cochairs and a diverse steering committee. An expert multi-disciplinary workgroup was established and vetted to inform key clinical questions, to perform an evidence review and the development of recommendations relevant to pTBI. The methodological approach for the project was finalized. The development of up-to-date evidence- and consensus-based clinical care guidelines and algorithms for pTBI will provide critical guidance to care providers in the pre-hospital and emergent, medical, and surgical settings. Penetrating (pTBI) traumatic brain injury (TBI) is a catastrophic primary wounding mechanism encountered in military and civilian settings and is characterized by the violation of the skull and brain by a foreign body. For those who survive, the constellation of cerebral injuries in the setting of either pTBI or blast-related pTBI creates complex management scenarios for pre-hospital and in-hospital healthcare providers. Recovery and rehabilitation are often protracted and complicated for these patients.2 The high lethality of civilian pTBI likely relates to the predominance of missile injury, including gunshot wounds, the absence of protective gear, and the violent circumstances that frequently surround the injury . From the military perspective, pTBI was prevalent in recent conflicts in Iraq and Afghanistan and most often results from a blast mechanism. pTBI outcomes in these modern conflicts are better than in past reports,3–10 most likely because of more aggressive clinical care.6 Before the conflicts in Iraq and Afghanistan, management in those who survived to reach care included limited surgical debridement and wound closure.11 In contrast, the new military model includes early cranial decompression and prevention of cerebrospinal fluid leak with skull base repair, causes of secondary brain injury are aggressively sought and mitigated , and a multi-disciplinary approach to cranial reconstruction is used.Civilian pTBI accounts for an estimated 20,000 deaths in the United States each year with mortality in up to 90% of victims.12 Topics addressed included antibiotic prophylaxis, antiseizure prophylaxis, management of cerebrospinal fluid leaks, surgical management, vascular complications, intracranial pressure monitoring, and prognosis. The 2001 guideline has not, however, been updated to reflect modern military experiences nor incorporate newer evidence- and consensus-based practices. There are no known published pTBI treatment algorithms informing patient management, despite the tremendous popularity of blunt TBI management algorithms13–15 and despite important changes to medical and surgical care over the past two decades. In response, the Brain Trauma Foundation (BTF) in collaboration with military and civilian TBI experts in the field, and with funding from the American Department of Defense  will generate an updated, evidence- and consensus-based pTBI clinical practice guideline and new care algorithms. The BTF has published numerous clinical practice guidelines for TBI care over the past quarter century17 and is undertaking this update with permission from the original pTBI guideline authors.pTBI clinical practice guidelines were first published in 2001 by an independent group.For this work, pTBI will be defined as a head injury with violation of, at minimum, the skull and likely dura and brain by a foreign body . Linear BTF leadership, alongside civilian and military clinicians with topical expertise in pTBI, comprise the pTBI Expert Workgroup. The workgroup and its efforts are led by two cochairs with guidance and governance provided by a core multi-disciplinary steering committee. Workgroup members were selected for diversity among disciplinary expertise relevant to the management of TBI, scientific expertise, and demographic and geographical representation. Represented medical disciplines include neurosurgery, plastic surgery, neurology, general/trauma surgery, orthopedic surgery, ENT  surgery as well as emergency medicine, physical medicine, pediatrics, pre-hospital care, and rehabilitation. A military medic and a patient (service member recovered from a pTBI) are included. Sex and ethnic diversity was also specifically sought.Workgroup members were divided into three areas of clinical focus: pre-hospital and emergent management; surgical management; and medical management, led by A.L.B., B.A., and J.G., respectively. Each workgroup will update the topics included in the 2001 guidelines and will develop clinically relevant key questions as well as inclusion and exclusion criteria using the Population, Interventions, Comparators, Outcomes, Timing, Setting and Study design (PICOTS) framework. The present effort will endeavor to only inform aspects of care in which pTBI care would be distinct from, or otherwise insufficiently informed by, the “umbrella” recommendations found in the fourth edition of the Severe Traumatic Brain Injury Guidelines, which largely focus on blunt head injury.Generated recommendations aim to be relevant to all patients with pTBI. However, evidence supporting distinct recommendations for key patient subgroups will be reported and may include differentiation by wounding mechanism , military versus civilian victims, and adult versus pediatric victims.We will search Ovid MEDLINE, EMBASE, and Cochrane CENTRAL without date limits. The search strategy will be developed and executed by a specialized medical research librarian with experience in systematic reviews with peer review by a second librarian.Review of abstracts and full-text articles will be informed by pre-specified PICOTS and corresponding inclusion and exclusion criteria. All abstracts identified by the literature search will be assessed by one reviewer and excluded abstracts confirmed by a second reviewer. Independent, dual review of the full text of any potentially relevant article identified at abstract level will be conducted. Disagreements will be resolved by consensus or with the addition of a third reviewer. Included and excluded articles, and reasons for exclusion, at the full-text level will be provided to the Guideline Panel for review and will be included as an appendix in the full Evidence report.Studies meeting inclusion criteria will be in children, adolescents, and/or adults with traumatic injuries that violate the skull and that provide evidence for a key question. Included outcomes of intervention studies consist of mortality, morbidity, function, and selected intermediate outcomes . We willWe will abstract data from all studies that include population characteristics , intervention and comparator characteristics , numbers enrolled and analyzed, relevant outcomes , and funding source.All included studies will be assessed for risk of bias using criteria specific for the type of study design. Randomized trials will be assessed for risk of bias based on the randomization process, method for allocation concealment, similarity of baseline characteristics, blinding, missing data overall and differences between groups, whether intent-to-treat analysis was used, and possible reporting bias. Assessment of non-randomized studies with a comparison group will include selection of participants, whether differences in prognostic factors between groups were present, missing data, pre-specification of outcomes, whether ascertainment of outcomes was unbiased, and adjustment for potential confounding. Assessment of single-group trials will include selection of participants, pre-specification of outcomes, whether ascertainment of outcomes was unbiased, and assessment of missing data. Case series and case reports are studies with high risk of bias and will not be individually assessed. Study risk of bias will be assessed by two independent reviewers.When there is more than one study of an intervention, data will be synthesized quantitatively if a meta-analysis is appropriate . When statistical heterogeneity is present in a pooled analysis, we will explore the reasons for this using stratified analysis and sensitivity analysis, as appropriate. We will also consider the potential effects of various participant subgroups  on intervention effects. When data cannot be pooled, we will provide a qualitative summary and analysis of findings.9 The quality of the body of evidence will be rated high, moderate, low, and very low. As an example, the highest-quality evidence (rated high) would come from multiple, well-conducted randomized trials with consistent findings, a precise pooled estimate of effect of the intervention on an included outcome, and be absent other bias. The lowest-quality evidence (rated very low) would come from expert opinion in the absence of any study data. We will generate a summary of findings table that includes ratings for quality of the body of evidence.We will assess the quality of the body of evidence by outcome using the GRADE  approach with the following criteria: risk of bias of included studies, consistency of effect, precision of the estimate, directness of the evidence, and potential publication bias.The development of recommendations is the next step after the evidence has been identified and synthesized and rated for risk of bias. Evidence-based recommendations are based on the quality of the body of evidence, applicability, and generalizability. For topics where there is little or no research, recommendations may be developed using rigorous Delphi consensus methodology.Level I recommendations are based on high quality of the body of evidence.Level II recommendations are based on moderate quality of the body of evidence.Level III recommendations are based on low quality of the body of evidence.Level IV recommendations are based on very low quality of the body of evidence.Level C: recommendations based on consensus in the absence of research evidence.Recommendations will be assigned a level based on the quality of the body of evidence. We will recognize five levels of recommendation based on the quality of the body of evidence:Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC) effort.18 A week-long in-person meeting will be held 18 months into the 2-year project to finalize the recommendations and algorithm. A private company will facilitate electronic, blinded voting at this meeting to enable the Delphi methodology.Blinded consensus voting will be conducted to establish consensus for key aspects of the project. This will be particularly important for consensus-based algorithm development. A vote of 80% will be required to declare consensus as having been achieved where at least 80% of the panel participates in the vote. This is the same threshold used for consensus in the recent 16 and their implementation has been credited with an ∼50% reduction in mortality.20 Because of their demonstrated benefit, compliance with the BTF guidelines is mandated for U.S. trauma centers to maintain trauma accreditation.Clinical practice guidelines evaluate and consolidate available literature into evidence-based recommendations designed to inform best care. Guidelines for the management of TBI created by the BTF were the first surgical clinical practice guidelines published,22 and TBI guidelines have been developed for numerous additional topics, including pediatrics,23 combat, pre-hospital care,24 and prognosis.25 The BTF's infrastructure has been key for disseminating and updating these important documents, with the most recent fourth edition TBI guidelines largely addressing closed head injury published in 2017.22Because of the success of the BTF guidelines and their demonstrated benefit, multiple editions of the BTF adult guidelines have been published,26 In contrast, no such algorithms for the management of penetrating and blast-penetrating TBI have ever been published.Algorithms for care bridge published evidence and its gaps with the realities of practice. Such care pathways were included with the first and second editions of the BTF adult guidelines, and they were the most popular aspect of these documents. These algorithms are inherently and necessarily consensus based, and their construction requires methodologies distinct from those for developing evidence-based clinical practice guidelines. To address the gap between evidence-based recommendations and patient care for severe blunt TBI patients, the SIBICC was recently convened, which led to two well-received and high-impact publications.Journal of Trauma more than two decades ago27–33 and, of course, do not reflect important subsequent advances in the literature and clinical standards of care (see Literature Search below).34 The combination of outdated pTBI guidelines and non-existent treatment algorithms may negatively impact morbidity and mortality because of the lack of consolidated clinician guidance on best practices for the medical and surgical care of pTBI. Because BTF did not lead the 2001 guideline, the organization sought permission to update the pTBI guidelines from the leadership of the original effort and this was granted.Guidelines for the management of pTBI were last published in the https://www.ncbi.nlm.nih.gov/pubmed) and the basic search term “penetrating brain injury.” A total of 968 references were identified when limiting the search criteria to publication dates between January 1, 1933 and December 31, 2001. This search time frame includes the references that formed the foundation of the existing and outdated pTBI guidelines referenced above and specifically includes all periods of armed conflict from World War II to 2001. When using the same search term and limiting publication dates from January 1, 2002 to the present, 2413 candidate references were identified. This suggests that the overwhelming majority of the existing information on pTBI has been published after the last guidelines were generated in 2001 and, in large part, reflect the experiences and care provided during the conflicts in Iraq and Afghanistan. This affirms the strong need for updated pTBI guidelines.To estimate the volume of new studies to be screened and assist resource planning, a preliminary literature search was conducted , using PubMed ; penetrating injury resulting from fragments propelled by blast (secondary blast injury); results of persons propelled or thrown by the blast wind (tertiary blast injury); and all explosion-related injuries . Given the importance of blast injury accompanying pTBI in the military, we have decided to include an analysis of such patients in this project. Given the risk of vasospasm inherent to blast-related pTBI, this patient subgroup mandates consideration of distinct management.35The recent conflicts in Iraq and Afghanistan have created renewed interest in blast as a mechanism of TBI. The Centers for Disease Control and Prevention (CDC) has defined blast injuries as “…characterized by the anatomic or physiologic changes from the direct or reflective over-pressurization force impacting the body's surface.”17 Future work will strategize and examine dissemination and implementation of the finalized guideline and algorithm to assess impact.A methodologically rigorous BTF effort, funded by the U.S. Department of Defense, is underway to update 2001 recommendations for the clinical care of pTBI. The vetted, multi-disciplinary workgroup will also develop the first treatment algorithms for pTBI to bridge gaps in published evidence with the practicalities of patient care.


The biased randomization and other quality concerns about the Canadian National Breast Screening Studies (CNBSS) were documented and criticized for decades, even by several individuals very close to the research. CNBSS were the outlier studies among several RCTs of the era and yet were given equal weighting and occasionally higher importance than the remainder of the canon of mammography RCTs. These studies have had an ongoing influence on subsequent evidence review, guideline formation, and, ultimately, patient access to screening. This article explores possible reasons for the ongoing inclusion of CNBSS in the body of mammography screening evidence, discusses the lack of expertise in critical healthcare guideline processes, and, ultimately, suggests several actions and reforms. People talk about evidence as if it could really be weighed in scales by a blind Justice. No man can judge what is good evidence on any particular subject, unless he knows that subject well.George Eliot (Mary Ann Evans), MiddlemarchRecent eyewitness accounts ,2,3 of tThe results of CNBSS have created ongoing doubt about the benefit of screening mammography, particularly in the 40–49 age group, where there was little other research at the time. CNBSS have been used in the formulation of guidelines worldwide for decades, including the Canadian Task Force on Preventive Health Care (CTFPHC) , EuropeaThe volunteer-based recruitment for CNBSS was fundamentally different from the remainder of the mammography randomized controlled trials (RCTs), which were population-based. As a result of the volunteer recruitment, there were high levels of contamination in CNBSS. Women allocated to the control arm of the trial, but who had volunteered because they were motivated to screen, were more likely to seek mammography outside the trial ,9. DiffiThe study data also pointed to non-random allocation of women between the mammography and usual care arms. In CNBSS1 , equal nSeveral articles were published criticizing the allocation and skewed statistics, including a calculation that the imbalance of late-stage cancers between the mammography and non-mammography arms could have occurred randomly only 3.3 times out of 1000 ,14,15. TUnfortunately, very few RCTs specifically addressed the 40–49 age group, and, therefore, CNBSS1 has had a large influence on breast screening recommendations for women in this age range. The statistical problems are obvious, so why was this study not excluded by the statistics and epidemiology experts writing guidelines? Several factors may be at play and point to a larger problem with the practical application of evidence-based medicine.CNBSS were criticized long before the results were published. The problematic implementation was questioned by external reviewers  and the Early criticism of CNBSS was so widespread that a forensic assessment was published in 1997. This review was limited. Only 3 of 15 sites were assessed, and, importantly, the study staff was not interviewed at that time, despite this step being mandated in the study design ,21.Interestingly, a recent modelling study used only CNBSS as the source material, choosing to focus on the outlier study and ignoring the remaining body of RCTs that converged on a significant benefit to screening . The 201Despite problematic recruitment and glaring statistical imbalances, recognized decades ago, CNBSS continue to influence research, guidelines, and worldwide guideline-based policy around breast screening. In Canada, CTFPHC guidelines strongly influence many provincial Clinical Practice Guidelines, which may, in turn, define patient access to screening through physician referral practices, programmatic screening structure, and billing restrictions.How does a study that has been plagued by extensive international criticism over its design and skewed data manage to continue influencing recommendations for decades?As a result of the evidence-based medicine movement, modern guidelines hinge on evidence review. This is performed by specialized bodies that conduct systematic searches for literature, decide which evidence is appropriate to include in the review, and then synthesize the data, often building upon older evidence reviews of the same topic. While this appears to be an ideal and objective way to expertly handle large amounts of research and perform the complicated statistical and epidemiological calculations involved, evidence review has some limitations.Content experts have little to no substantial influence on evidence review. For example, no radiologist is included on the list of contributors for the 2018 CTFPHC breast screening evidence review .Many members and frequently the chairs of evidence review and guideline bodies are non-physicians, and, thus, clinical experience and context are minimized. The continued inclusion of CNBSS in guideline evidence reviews is a stark example of the peril of minimizing content expert input. Had content experts been allowed appropriate input into the guideline processes, the well-documented imbalance in late-stage cancers and other significant problems with implementation could have been made clear to the reviewers.Evidence review is expensive, and evidence reviews are built upon older reviews to save time and money. Once an error has been made, however, it may be perpetuated by copying that error into future versions of the review. This is what is known in radiology as “alliterative error”, which is the tendency to perpetuate prior errors, particularly when the previous report has been viewed before assessment of the images—or evidence—one has been tasked with assessing .In addition to the evidence review process, guideline methodology and guideline oversight are problematic. While the evidence review tool, GRADE , recommeThe AGREEII  guidelinWhen is an expert not an expert? Perhaps the answer to this lies in the concept of epistemic trespassing ,32. ThisThe composition of evidence review teams and some guideline panels suggests that epistemic trespassing is a factor in current guideline formulation. For example, the CTFPHC produces guidelines largely intended for use by primary care providers, predominantly physicians and nurses. Until recently, however, it was chaired by a psychologist. The CTFPHC breast screening guideline panel was chaired by nephrologists in both 2011 and 2018, and a chiropractor was on the knowledge tools team for the 2018 guideline. There was, however, no breast surgeon, radiologist, technologist, physicist, pathologist, oncologist, or patient on these teams. The main opportunity for input from content experts was an emailed form, similar to that provided to all external stakeholders. There was no opportunity for dialogue or teaching by content experts. The urologists involved with the 2014 CTFPHC prostate guideline were so dismayed at the CTFPHC consultation process that they resigned in protest.In my conversations, with patients and even referrers, almost all of them are surprised to learn that the panels that form guidelines exclude the very experts they trust with their specialized healthcare. I suspect most people make the natural and trusting assumption that content experts make significant contributions to their healthcare guidelines. While the credentials of the authors of the CTFPHC guidelines are not hidden, they are not openly disclosed. The names of the authors of each guideline are provided, but their areas of expertise are not visible unless one specifically searches for their credentials. One could say that the lack of content expertise is hidden in plain sight.ad hominem, in this case attacking the motivation of the speaker and ignoring the substance of the argument.What is the reason for this counterintuitive guideline panel composition and lack of fulsome expert consultation? The stated reason seems to be an avoidance of conflict of interest (COI) ,35. TherWhile COI is an important concern, particularly in the case of industry-sponsored research, it is far less pertinent to practising Canadian medical specialists. Many, if not most, Canadian medical specialists are overwhelmed with waitlists  throughoUnfortunately, these unsubstantiated accusations of specialist physician COI lead to exclusion of content expertise. As we have seen with the continued use of CNBSS for guidelines, however, this is detrimental to the appropriate determination of scientific rigour. In fact, the implication of COI has specifically been used to dismiss valid concerns by experts, such as the excess deaths in the CNBSS screening arm .I posit that in a single-payor healthcare system, the largest financial COI is that of the payor. In Canada, this is the government, which also happens to fund the CTFPHC via the Public Health Agency of Canada (PHAC). Screening programs are expensive and create further downstream expenses. It is understandable that minimizing screening recommendations would be a desirable guideline outcome for the healthcare payor.In April 2019, when asked by NDP Health Critic, Don Davies, to halt the use of the 2018 CTFPHC breast screening guideline, the federal Health Minister at the time, Ginette Petitpas Taylor, absolved the ministry of any responsibility, stating, “While the government provides its support to the Task Force to the breast cancer screening work group [sic] its decision was totally done independently. As such these are not official government guidelines” . This stWhen asked about the news regarding the eyewitness accounts of misallocation of patients during randomization of CNBSS, PHAC issued a statement indicating that it provides funding to the Task Force and referred to the body as being an “arms-length from the government” , but tooThe current co-chair of the CTFPHC, when asked about the same eyewitness accounts, indicated that the group conducts “rigorous, detailed evidence reviews to formulate guidelines” and did not indicate that any further reviews would be performed, even in light of the new information .The CTFPHC claims that its guidelines are ranked among the best in the world , but thiTo whom is this publicly funded government agency accountable? It would appear that CTFPHC answers to no one.Why might the government have set up an unusually unaccountable body to develop healthcare guidelines? As mentioned above, there is a large financial cost to screening, both directly and indirectly. Guidelines can be used to help control healthcare costs, and, ideally, good guideline recommendations will balance appropriate safe health care and judicious use of resources. Structuring a guideline body to be unaccountable, however, removes this balance and allows its recommendations to stand for years without correction of errors. There is another benefit to the arm’s-length status, however. According to National Cancer Institute Cancer Intervention and Surveillance Modeling Network (CISNET) modelling, 400 women may die each year as a result of the CTFPHC recommendation against screening women in the 40–49 age group . Arm’s-lWhen the rest of the evidence converges on the conclusion that screening saves lives, even for women aged 40–49, why continue to include the poorly performed outlier study in evidence analyses? One can certainly speculate that there is strong motivation to perpetuate the use of studies such as CNBSS. The outlier creates doubt around the benefit of screening women 40–49 and keeps the mammography screening controversy alive. In fact, the various techniques used to challenge the benefits of mammographic screening have been extensively discussed by Dr. Daniel Kopans in his analyses ,44.Have we seen this pattern of perpetuating doubt for financial benefit in the past? In fact, this strategy is known as “manufactured doubt” and has been employed for decades by large organizations ,46. In ihttps://ehjournal.biomedcentral.com/articles/10.1186/s12940-021-00723-0 (accessed on 26 May 2022). These have been correlated to examples of their use by the CTFPHC and other critics of screening. Keep in mind that the strategies were written with large commercial industries in mind, and the wording may not be fully applicable to government and screening scenarios. Additionally, I limit most of my examples to breast screening recommendations.Strategies for manufacturing doubt are well documented , as many1. Attack study design—Characterization of any studies that favour screening as flawed, frequently using CNBSS study as a comparator  in the prostate cancer field, the PLCO study  of PSA sDr. Laurence Klotz, MD, FRCSC, CMProfessor of Surgery, University of TorontoSunnybrook Chair of Prostate Cancer ResearchChairman, World Urologic Oncology FederationChairman, SI (Stability Index) UCare Research Office9Chairman, Canadian Urology Research ConsortiumSunnybrook Health Sciences Centre”We pointed out the flaw in their reasoning with our ‘stakeholders comments’ in 2014 and we received no response from the task force, and no evidence that they took our comments into account.Again, this indicates the pooling of poorly performed and well-performed research, creating doubt. Additionally, this demonstrates the lack of meaningful dialogue with highly qualified content experts. The use of the term “stakeholder”  is prejuIn fact, multiple other prominent specialists and specialist societies have written rebuttals to the CTFPHC guidelines, many of which are evidence-based ,67,68,69Is there any evidence that the government would deliberately suppress science? In fact, the Harper government did exactly that in the late 2000s. Climate change and environmental scientists were muzzled, and environmental research was inhibited, culminating in a 2012 protest on Parliament Hill, nicknamed the Death of Evidence March ,71. ClimThe lack of expert guidance in the performance of evidence review and the formation of guidelines is problematic. This requires urgent reform, but CTFPHC requires a robust accountability structure for any reforms to take place. As it currently stands, the lack of expert guidance constitutes a breach of the public trust. The public should insist on fundamental reform to the structure of the CTFPHC. A new national guidelines body should be formed with appropriate oversight and accountability built in.While COI is of serious concern, practising Canadian healthcare practitioners should not be conflated with “product defence” and other industry-funded experts. COI should be acknowledged for both content experts and for government agencies’ funding guidelines. COI should not, however, outweigh expertise and clinical experience. Ad hominem attacks on motivation should be avoided.Any CTFPHC guidelines formed without fulsome expert guidance, particularly if Canadian content experts have provided evidence-based rebuttals, should be suspended from use pending content expert review and, if necessary, revision. In the interim, many national specialty societies have their own guidelines, which can be substituted for suspended CTFPHC recommendations.Full disclosure of the credentials of personnel involved in evidence review and guideline formation is required for rebuilding trust in the processes.Process transparency should be emphasized, and satisfaction surveys of panel members should be a mandatory element of guideline quality assessment. A tool such as PANELVIEW  could beGuideline quality should not only be evaluated based on adherence to guideline methodology, but also by outcomes. Following the USPSTF recommendation against PSA screening in 2012, metastatic prostate cancer increased, as predicted by modelling . OutcomeEthicists should be involved in the restructuring process of the CTFPHC, the formation of guidelines, and ongoing oversight of methodological processes. The Precautionary Principle  should bWhere costs and other resource limitations are factored into guideline recommendations, this should be clearly disclosed. Science should not be manipulated to accommodate budgetary concerns.The ongoing use of the flawed CNBSS is the natural consequence of significant systemic problems with the application of guideline methodology and, in Canada, with the unaccountable structure of the CTFPHC. While the practice of medicine requires close adherence to evidence, common sense and clinical judgment are the lenses through which evidence must be filtered. The evidence-based movement has been criticized, even by its proponents, calling for a “return to real evidence based medicine”, including “increasing depth of knowledge and sensitivity to context when applying rules” .Making medical recommendations outside one’s area of specialty training is not accepted in clinical practice and should not be accepted in the formation of guidelines. Guideline oversight and methodology reform are required to provide appropriate expertise in guideline formulation. As a result of specialists’ career-long waitlists and resultant minimal COI, Canada is well positioned to produce excellent guidelines. To achieve these improvements, however, clinicians and patients must advocate for fundamental reform to guideline practices.


Crohn’s disease (CD) is a chronic relapsing inflammatory disease of the gastrointestinal tract. The etiology of CD may arise from complex interactions including host genetics, diet, and the intestinal microbiome. Increased consumption of saturated fats, characteristic of the Western diet, is a known risk factor for CD. Dietary fat (DF) is absorbed by the host through the release of primary bile acids (PBAs) and bio-transformed by the microbiome into secondary bile acids (SBAs). Altogether, bile acids (BAs) can act as signaling molecules involved in host immune regulation and potentially in CD onset.To investigate the relationship between CD risk, BAs, and DF, and evaluate the predictive performance of CD onset of these factors by developing machine learning models.We used samples healthy first-degree relatives (FDRs) recruited as part of the Crohn’s Colitis Canada- Genes, Environment, Microbial (GEM) project. Those who developed CD (n=87) were matched 1:4 by age, sex, follow-up time, and geographic location with control FDRs remaining healthy (n=347).Serum, urine, and stool BA were measured using ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy. DF types were derived from food frequency questionnaire data. We used conditional logistic regressions to identify associations between CD onset, BAs (n=93), and DFs (n=9). We further explored the relationships of significant CD-related BAs and DF via Generalized Estimation Equations. Finally, we used a tree-based machine-learning algorithm (XGBoost) with 5-fold cross-validation to assess the prediction performance of CD onset using BA from all sources as well as DF. Two-sided p<0.05 was considered significant.In total, 10 of 93 BAs, and two of nine DFs were significantly associated with increased odds of CD onset (p<0.05). Additionally, five BAs were significantly associated with DF (p<0.05). Serum-derived BAs had the best predictive performance for CD, with a mean AUC of 0.70 , followed by stool derived BAs with a mean AUC= 0.65 , and followed by urine derived Bas with a mean AUC= 0.57 . Lastly DF was not a predictive marker of CD onset with a mean AUC= 0.50 .This study suggests that BAs are associated with the pathogenesis of CD and the effects may be influenced by DF. Serum-derived BAs may be able to better predict the risk of CD than other stool or urine derived BA, while DF is not directly implicated in CD risk.Submitted on behalf of the CCC-GEM consortium.FundingCrohn’s and Colitis Canada Genetics Environment Microbial (CCC-GEM) IIIThe Leona M. and Harry B. Helmsley Charitable TrustKenneth Croitoru is the recipient of the Canada Research Chair in Inflammatory Bowel DiseasesThe International Organization for the Study of Inflammatory Bowel Diseases (IOIBD)Jingcheng Shao is the recipient of a Data Science Institute Summer Undergraduate Data Science awardNone Declared