Adolescent HIV and pregnancy rates in Southern Africa are amongst the highest in the world. Despite decades of sexual and reproductive health (SRH) programming targeting adolescents, recent trends suggest there is a continued need for interventions targeting condom use for this age group.This review synthesises evidence from qualitative studies that describe the determinants of condom use among adolescents in Southern Africa. We conducted systematic searches in four databases. Data were extracted, appraised for quality and analysed using a ‘best-fit’ framework synthesis approach.unequal gender norms and restrictive masculinities favouring male sexual decision-making and stigmatising condom use in committed relationships; 2) other social norms reflecting negative constructions of adolescent sexuality and non-traditional family planning; 3) economic and political barriers including poverty and a lack of policy support for condom use; 4) service-level barriers including a lack of youth-friendly SRH services and comprehensive sex education in schools; 5) interpersonal barriers and facilitators including unequal power dynamics in sexual partnerships, peer influences and encouraging condoning condom use, and inadequate communication about SRH from parents/caregivers; and 6) negative attitudes and beliefs about condoms and condom use among adolescents. A conceptual model was generated to describe determinants of condom use, illustrating individual-, interpersonal- and structural-level barriers and facilitating factors.We coded deductively findings from 23 original studies using an a priori framework and subsequently conducted thematic analysis. Synthesised findings produced six key themes relating to: 1) pervasive SRH programming targeting barriers and facilitators of condom use at multiple levels is recommended in Southern Africa. We present a multilevel integrated model of barriers and facilitators to guide adolescent SRH decision-making, programme planning and evaluation. Given the existence of multilevel barriers and facilitators, interventions should, likewise, take a multilevel approach that incorporates locally relevant understanding of the individual-, interpersonal- and structural-level barriers and facilitators to condom use among adolescents in the region.The online version contains supplementary material available at 10.1186/s12889-021-11306-6. In sub-Saharan Africa, consistent use of condoms among adolescents is low . This isMuch research has attempted to uncover determinants of condom use among adolescents that might be targeted by sexual and reproductive health (SRH) programmes. A complex array of individual-, interpersonal- and structural-level influences are at play –14, inclThis review aims to describe the individual-, interpersonal- and structural-level determinants of condom use among male and female adolescents in Southern Africa and then develop an integrated conceptual framework. The findings provide clear recommendations for future research aiming to test causal pathways explaining condom use among adolescents, and for SRH programme development and adaptation in the Southern African region.The synthesis reported here is part of a larger research study to adapt an SRH intervention for adolescents in Southern Africa . The proWhat are the individual-, interpersonal- and structural-level barriers and facilitators of condom use among adolescents in Southern Africa? 2) How can these multilevel barriers and facilitators be conceptualised within an integrated framework?For the present review, the ENTREQ   guidelin‘Best-fit’ framework synthesis , 27 was If I Were Jack (JACK) for the Southern African context  know everything [about HIV] and may pass people in the street and even say ‘so and so is infected’. But the boys say, why are you afraid of HIV and not flu? They have become unafraid because it’s so normal.”There was also evidence suggesting that social norms may act as a moderator of risk perception relating to HIV. In one Tanzanian study , it appe“It’s if you have two girlfriends, your steady and your secret lover. You can never use a condom with your steady but you can use one with your secret lover because you don’t know if she has a disease.”  window and no questions were asked [of adolescents who took them]’ ’ .Several studies mentioned the absence of sex education in schools and communities as a barrier to condom use , 55, 57.Discomfort among teachers presenting SRH material was noted by one Tanzanian study  as a posReligious organisations and their representatives were mentioned by several studies as barriers to condom use , 53, 54.“Nor were adolescents given full information, even about the menstrual cycle, on the grounds that it might encourage sexual liberties”  have sex in an unfinished house (…) they are not using condoms because they are in a hurry and they do not have time.” [Two studies noted that a barrier to condom use was that young people did not carry condoms with them and therefore did not have them readily available when needed , 57. Rele time.”  Similarle time.”  adolescee time.” , 52, guee time.” , and shoe time.” , 46, 52 Across studies, interpersonal networks including sexual partners, peer influences and parent/caregiver communication presented as barriers and facilitators of condom use.Heavily influenced by unequal gendered norms, condom use within a sexual relationship was seen as dependent on the status of the relationship, with condom use in casual relationships more widely accepted than in committed relationships. For people in committed relationships, not using condoms appeared to be linked to trust, faithfulness and respect for one’s partner , 52, 53 Young women argued that for a steady partner to insist on condom use is seen as indicating a lack of respect and trust that could destroy one’s reputation within the peer group. If a boy wants to use a condom she will say it is because he disrespects her, because he wants to use ‘a plastic’.’ [Some studies mentioned the importance of peer influences on condom use, noting that negative peer norms relating to condom use acted as a barrier, particularly for young men , 47. It astic’.’  One Botsastic’.’ .A lack of communication and guidance from parents and primary caregivers about SRH was indicated as a possible barrier to condom use by four studies , 51, 57,Attitudes that condoms negatively affecting pleasure or sexual satisfaction were noted as barriers to their use , 56, 57,It also appeared that attitudes about condoms were strongly influenced by inaccurate knowledge. Studies reported that adolescents did not use condoms because they believed they were ineffective against STIs/HIV or pregnancy because they had ‘little holes’ in them allowing sperm (and HIV infection) to pass through , 53, 57.If Were Jack theory of change [This review aimed to synthesise qualitative evidence relating to the individual-, interpersonal- and structural-level barriers and facilitators of condom use among adolescents in Southern Africa. We identified and mapped relevant qualitative literature onto an a priori framework incorporating three theoretical models – the social ecological model , 32; an f change –30 – andThe findings provided evidence to support all 12 a priori themes in the original ‘best-fit’ model depicting the multi-level determinants of condom use among adolescents in Southern Africa. The combined three-model framework was able to capture more determinants than any one of the models could accurately achieve on its own, thus suggesting that a multilevel conceptual model as outlined in Fig. In line with previous reviews , 62, 63,The findings of our review are consistent with other studies , 62–64 wThe findings suggest that valuable and limited resources should be best used in coordinated effort to increase condom use by implementing multilevel interventions at all levels of the social ecological system. This could be informed by emerging broad-based guidance for improving uptake and access to contraception . ProgramThe findings of this study indicate the need for easily accessible and free condoms, especially in resource-poor and rural settings. Importantly, they equally emphasise the need for evidence-based adolescent SRH strategies that provide health professionals and educators training and resources needed to provide youth-friendly SRH services and education. The findings also highlight the influence of social norms reflecting negative perceptions of adolescent sexuality, and non-traditional sex education and methods of avoiding HIV, STIs and unintended pregnancy. The strength of these prevailing norms suggest that programme developers need to involve local stakeholders in co-design and co-production processes. Interventions that can engage wider community members where these negative norms are played out are also critical. Community mobilisation interventions have shown positive impacts in relation to other SRH interventions, particularly those that involve comprehensive SRH education and positive role modelling by community members such as community elders, religious leaders, healthcare professionals and educators –67. CoupCentrally, comprehensive sex education delivered to adolescents in school and community settings should include gender transformative components; directly challenge stigma and myths surrounding condoms and condom use; and harness the facilitating effects of promoting female agency in sexual decision-making , 72. TheCore strengths of this review include the systematic process by which we integrated and analysed rich contextual data from a broad range of qualitative studies conducted with adolescents in Southern Africa, and used them to develop an integrated conceptual framework that might be of value for intervention developers and decision-makers.Limitations include the possibility that we did not identify potentially relevant articles despite our comprehensive search. In particular, due to resource constraints, we excluded studies not reported in English as well as grey literature. We may therefore have missed studies that were relevant to the review. In particular, over the past two decades, ministries of education and health in many Southern African countries have worked to implement comprehensive relationships and sexuality education policies and programmes in schools and communities that have not been captured by this review. Further, while we report findings from 11 countries in Southern Africa, five other countries in the SADC region included in our search  were not represented in the review. These omissions mean that the findings may not be entirely representative of the experiences of young people across the region. Additionally, due to uneven reporting of sample composition and age range, it was difficult to determine what findings might apply to sub-populations of adolescents. Further, because some factors were only reported on by studies in some of the included countries, we cannot assume that the findings are generalizable to all countries or populations in Southern Africa.Finally, despite promising findings regarding quality in other domains, the lack of reflexivity related to theoretical and/or cultural positionality of the researcher is important to address in qualitative research, especially regarding sensitive content such as condom use and sexual practices. While bias can be mitigated in straightforward ways in quantitative research, researcher positionality is often not clearly stated, which can negatively influence the rigour and accuracy of the findings. Indeed, while we ourselves are an international, multiracial, mixed gender, multidisciplinary research team, we recognise that our interpretation of the findings represents but one among other possible interpretations. The data synthesis and drafting of this paper was led by the first author, a white, Irish, female, PhD, who positions herself as a social psychologist heavily influenced by interpretivism and realism. While we are confident that reflexive journaling as part of the analysis process, as well as team discussions drawing out various interpretations of the findings, have increased rigour, unconscious bias may have been inadvertently introduced.Our findings suggest that programmes should address the wider structural influences through both individual- and structural-level interventions, in addition to targeting individual-level socio-cognitive factors. It is especially important to understand the key barriers and facilitators of condom use that act as moderators on the pathway towards consistent condom use among adolescents. In Southern Africa, as in many other regions of the world, these barriers include unequal gender norms and restrictive masculinities that stigmatise adolescent girls; social norms that restrict positive sexualities among adolescents and perpetuate negative perceptions of condoms and condom use; and the pervasive impact of poverty on access to condoms, SRH education and the power to negotiate condom use freely. SRH programming targeting barriers and facilitators of condom use at multiple levels is urgently needed in Southern Africa. Such programmes should pay particular attention to the key gaps in knowledge and evidence-based interventions highlighted by this review, for example: promotion of female agency in SRH decision-making; increasing positive parent-child communication about SRH; increasing accessible youth-friendly SRH services; and encouraging the widespread adoption and implementation of strategies to improve SRH.Additional file 1. Search Terms.Additional file 2. Coding Framework.


While price increases and targeted cessation support have been found to reduce inequalities in smoking by socioeconomic status (SES), evidence on other measures is mixed. We aimed to update the most recent (2014) previous review by identifying and appraising evidence published since 2013 on the equity impact of population tobacco control measures.Systematic searching of 10 electronic databases and hand-searching of four key journals identified 68 primary research articles published since 2013 that sought to examine the equity impact of population tobacco control measures in high-income countries with a negative socioeconomic gradient in smoking. Reported equity impacts were categorised as positive (greater impact among lower SES), neutral (no difference by SES), negative (greater impact among higher SES) or mixed/unclear.There was substantial growth in research seeking to evaluate the equity impact of tobacco control interventions, but the majority of new studies showed mixed/unclear results. Findings for price increases and targeted cessation support continue to suggest an equity-positive impact, but limitations in the available evidence make further assessment difficult. Substantial differences in the context, scale and implementation of tobacco control policies make straightforward comparison of findings from the previous 2014 and current reviews problematic.Researchers need to adopt more sophisticated, multidisciplinary approaches in evaluating the equity impact of tobacco control measures—developing robust measures of equity effect and using frameworks that take account of context, existing systems/processes and the likely mechanisms of action. Socioeconomic differences in intervention impact within low-income and middle-income countries require evaluation. The development of effective tobacco control measureset al included evidence published up to February 2013.Several systematic reviewsGiven the evolution of both tobacco control policies and related research over recent years, it is timely to update these reviews by examining evidence published since 2013.Summarise current evidence on the equity impact of tobacco control measures on socioeconomic inequalities in smoking and compare findings with the most recent previous reviewExplore the challenges of assessing changes in intervention equity impact within a complex and evolving policy context;Illustrate these challenges via a case study and detailed synthesis of the evidence for one exemplar intervention, namely, smoke-free policies.et alhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=96686) and the review written in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA): Equity Reporting Guidelines.This systematic review draws on the conceptual framework used by Brown Studies were eligible for inclusion if they evaluated a population tobacco control intervention, comparing a smoking-related outcome across two or more SES groups, with relevant outcomes reflecting the full spectrum of potential mechanisms via which tobacco use might be reduced . EligiblStudies were identified through electronic searches of 10 bibliographic databases  on 10 Ma10.1136/tobaccocontrol-2020-055874.supp1Supplementary dataStandardised data extraction sheets were used to record basic design details for each eligible study , with fiet alWe present our findings via narrative synthesis in three parts, mirroring our review aims. First, we provide an updated assessment of equity impact by intervention type, using the rating scale developed by Brown Bibliographic database searches identified 43 367 papers which reduced to 19 894 once duplicates were removed . Of theset alStudies were split fairly evenly across the five main intervention types, with 16 evaluating the equity impact of tobacco price/taxation increases,The quality of the available evidence was mixed, with a mean ‘value to review’ score of 4.0 out of 6. Only half the included studies (35 out of 68) were designed with a primary focus on assessing intervention impact by SES; consequently, many studies were under-powered to detect differences by SES , and in some cases the study design and/or analysis was not optimised for assessing impact by SES. A reliance on retrospective, self-report data drawn from existing population surveys cast doubt on the validity of some outcome measures . The common use of observational rather than experimental or quasi-experimental designs made it difficult to attribute observed changes to the intervention. Study quality was broadly similar across intervention types . While direct comparison of quality scores was not possible across the two reviews  and an equity-negative (16) effect, broadly matching the pattern seen in the previous review . Only onEquity impacts varied by intervention type, but were mostly in the same direction as those reported in the 2014 review. Among studies showing a clear equity result, findings for price/taxation measures and population-level cessation support continued to suggest an overall equity-positive effect, with greater impact among lower SES groups. Equity-negative findings continued to dominate studies examining smoke-free policies, while evidence around mass media campaigns remained mixed. Our review did though find a shift in evidence on sales and marketing controls, with findings weighted towards an equity-negative impact—compared with a predominantly neutral effect in the previous review. Looking beyond the overall summary measures, it appears that this shift may be partly explained by a change in the specific types of control evaluated.Our summary findings point to two key issues concerning the use of overall equity impact scores—such measures are no longer robust in the face of increasingly complex patterns of equity effect and they obscure the evolution and innovation that has occurred since the last review. These issues are further compounded by substantial diversity, complexity and change within the evidence base, and particularly in relation to intervention context, scale and implementation , which makes straightforward interpretation and comparison of summary measures problematic. We now explore this complexity in more detail.As in 2014, studies were heterogeneous in the populations covered. There was a predominance of US papers, with half (35 of 68) being carried out in America. Most of the rest (24) focused on Europe, looking primarily at the UK (10), Spain (3), the Netherlands (3) or multiple European countries (5). Six studies were undertaken in Australia, and two in Canada, with the final paper covering Australia and Canada. Most studies used individuals as the unit of analysis, drawing variously on members of the general population as well as more specific groups such as smokers and ex-smokers, pregnant women, employees and multi-unit housing residents/owners. Other units of analysis included households, organisations and geographical areas. Study sample sizes ranged from 4 to 17.7 million (most between 500 and 500 000). Data collection intervals were varied, with some studies gathering data over several weeks but others using multiple waves of data collection over many years (the longest being 24 years)—and, while a number of studies included data from as far back as 1984, most data were gathered between 2000 and 2017.et alet al,Across both reviews, approximately three-quarters of studies focused on policies and interventions delivered at national or state level although evaluation was not always undertaken at the same geographical level as delivery. For example, Choi and Boyleet alet alet alet alFor nearly all intervention types, we found a shift in the specific variants of the tobacco control measures studied. Evaluations of smoke-free policies (see objective 3 below for more detail) broadened from a sole focus on restrictions covering indoor public spaces and workplaces to include measures covering outdoor publicTo further illustrate the diversity, complexity and change inherent to the evidence base, we next provide a detailed account of studies assessing smoke-free policies. We saw earlier that the weight of evidence across both reviews pointed to an equity-negative effect, with around half the studies finding a greater impact in high compared with low SES groups. More specifically in the current review, seven studies suggested an equity-negative impact,et alet alFirst, the 2014 review almost exclusively focused on smoking restrictions covering workplaces and/or indoor public spaces, demonstrating a clear distinction between national comprehensive policies that were largely equity positive or neutral, and voluntary, partial and regional bans that were predominantly equity negative. In the latest review, only three studies evaluated national comprehensive policies,et alet alet alIn addition, Huang or hospitality venues) in the USAet alFour papers in the current review focused on partial smoke-free regulations that applied to a more restricted range of locations, with one evaluating regional legislation covering hospitality venues in Geneva (Switzerland),et alAlongside this increasingly complex picture around workspaces and indoor public places, other changes in the evidence also began to emerge, reflecting the evolution of smoke-free regulation and its expansion into new spaces, such as outdoor public places and private areas. Two US papers explored smoke-free park policies, both focusing on partial bans that applied to some rather than all of the parks in a jurisdiction, with one national study showing an equity-negative effect on coverage at the county levelOur review finds substantial growth and increasing complexity in the evidence assessing the impact of population tobacco control interventions on socioeconomic inequalities in adult smoking. Average annual publications almost doubled between 1995–2013 and 2013–2018, suggesting greater research interest in this understudied area,We encountered several challenges in assessing changes in intervention equity impact. First, reports of complex equity effects—where the direction of equity impact varied across different population groups, SES indicators and/or outcomes—were increasingly common. The reasons for this were not immediately apparent  but could suggest less substantive developments in some intervention areas  and/or an increased willingness to publish studies where equity findings are less clear cut.Both reviews were characterised by considerable heterogeneity in intervention context and scale, with studies focusing on different units of analysis , different periods of intervention and evaluation , and different jurisdictions . Given this high degree of heterogeneity, it is far from certain that the two reviews are comparing like with like—a problem further compounded by high levels of intervention innovation, with shifts in the specific formulation of policies/measures employed across most intervention types. The WHO, moreover, recognises that measures such as smoke-free policies, mass media campaigns and marketing controls can be introduced with different degrees of comprehensiveness,et al,et al,Taken together, our findings highlight the difficulties of trying to synthesise findings from evaluations of complex policy approaches where the available tools for evaluating and systematically reviewing intervention impacts are largely derived from individual-level interventions. We argue that the complex mechanisms via which population tobacco control interventions have their effects—combined with diversity in their implementation, scale and effects in different population groups—require the development of more nuanced approaches to evaluating their impacts on socioeconomic inequalities in smoking. Encouragingly, we saw initial evidence of attempts to reflect these subtleties in the analysis and interpretation of equity effects, with researchers beginning to consider how SES might interact with other aspects of social location and context, to discuss how different tobacco control measures might interact with one another, and to explore how the impact of particular policies may change over time. Thus—for example—Huang and colleagueset al.While we sought to update the most recent previous review,While we appraised the quality of individual studies identified in this review, we did not consider it relevant or appropriate to set a minimum quality threshold for inclusion since our primary finding relates to the increasing complexity and diversity of the evidence base around intervention equity impact. Our review therefore includes studies of lower quality and/or of modest value to our aim.Our initial data synthesis summarises the evidence base by counting reported study outcomes by categories of ‘equity impact’, giving numbers  indicative of ‘positive’, ‘neutral’, ‘negative’ or ‘mixed/unclear’ equity impacts. While these numbers provide a crude summary of the available research in terms of equity effects, we emphasise that these figures should not be interpreted as a robust evaluation of the balance of evidence since (1) a single study might contribute more than one finding (where more than one measure of SES or outcome is used); (2) these figures do not account for study quality; and (3) the results of individual studies are not directly comparable, given differences in indicators of exposure  and outcome , differences in assessment of intervention impact by SES  and differences in study context.While our review reflects increased research interest in impacts of tobacco control on socioeconomic inequalities in smoking, there are several areas where the value of such research could be enhanced. The quality of the available evidence is limited by weaknesses in study design and power, often reflecting a lack of focus on equity impacts in the initial study aim. There is a clear need for more studies evaluating the equity impact of tobacco control interventions to be specifically designed and powered to be able to detect any shift in inequalities. Stronger study designs include those that collected data before and after the introduction of an intervention and/or those with a control group, and those that used study instruments (such as surveys) specifically designed to assess the equity impact of the relevant intervention. Alongside this, research is also required on differential intervention impacts by SES in low-income and middle-income countries where smoking inequalities are still evolving.A key implication of our review is the need for researchers to develop more sophisticated and multidisciplinary approaches to evaluating the impact of tobacco control measures, particularly with reference to their potential impact on socioeconomic inequalities in smoking. Several researchers have recognised the need for a broader range of tools in evaluating complex health interventions, with suggested approaches including process evaluation,We argue that health researchers need to make greater use of these approaches in exploring the impact of tobacco control interventions by SES. This almost certainly precludes further attempts (such as ours) to synthesise evidence across diverse approaches and contexts. Instead, we recommend reviews focusing on specific interventions that can take account of evidence from a range of methods and disciplines, applying this to an underlying theory of the relevant mechanisms via which the intervention is thought to have its effect. Such an approach requires a narrower but deeper evaluation of relevant evidence, in contrast with the more comprehensive approach employed in most systematic reviews. This may involve some adjustment in the expectations of readers, reviewers, editors and research funders who may be more familiar with the empiricist assumptions underlying most systematic reviews of health interventions. However, the advantage of these more theoretically informed and multidisciplinary approaches is a more nuanced understanding of how tobacco control interventions interact with existing regulations and social structures, and thus a better understanding of how they might be adjusted or tailored to meet the needs of less advantaged groups. Ultimately, this understanding is necessary if we are to reduce socioeconomic inequalities in smoking and make genuine progress towards a tobacco endgame.Previous systematic reviews suggest that price increases and targeted population-level cessation support are the interventions most likely to decrease socioeconomic inequalities in smoking, while other interventions have mixed effects.We updated the most recent systematic review (from 2014) on the impacts of population tobacco control measures on inequalities in smoking by socioeconomic status (SES).While a growing number of studies have sought to evaluate the equity impacts of tobacco control interventions, the majority of new studies show mixed or unclear results. Price increases and targeted population-level cessation support continue to be the only interventions where there is consistent evidence of a greater effect among low-SES smokers.In order to assess the equity impacts of tobacco control interventions in the real world, researchers need to develop more sophisticated and multidisciplinary evaluative approaches (including robust measures of equity effect) which take account of variations in context, the interaction of specific tobacco control interventions with existing systems and processes, and the mechanisms via which interventions produce their effects.


Oral diseases still pose a significant health burden affecting over 3.5 billion people worldwide. Dental caries is a major contributor to the global burden of oral diseases. Particularly, over half a billion children worldwide experience untreated caries in deciduous teeth  which coThis special issue offers a selection of original articles and systematic reviews about the burden of oral diseases and behaviors, their determinants, the impact of these conditions on quality of life, and preventive and therapeutic approaches for their prevention and treatment in children. We have a variety of publications: two systematic reviews, one case report, and seven original research manuscripts.Three articles were related to dental caries and its determinants. Even though the number of people with untreated oral conditions is decreasing in some countries, dental caries is still highly prevalent in other countries. For example, a study from Mexico demonstrated that over half of 6–12-year-old school children from agricultural manual worker households had caries in either or both dentitions, and a considerable proportion were untreated lesions. However, the authors noted that the prevalence levels in their study were lower than other reports from Mexico in similar age groups . AnotherTwo studies were related to dental service utilization. Representative data from a large child population were used by Tiwari et al. (2021) to explore the association between the medical well-child visit (WCV) with preventive dental visit (PDV) among adolescents from 13 states in the US. More PDVs were made by children who participated in WCVs. Girls, Hispanics, and those aged 5–9 years had higher PDVs after a WCV . AnotherA study from Australia evaluated an outreach mobile dental service targeted at Australian children with low household income. The authors found that the program reduced mean costs, restorations, and extractions in the subsequent year . Oral diIn this issue, we also had a good collection of articles related to malocclusion and orthodontic treatment procedures. Abate et al reported findings using retrospective data on Rapid Maxillary Expansion (RME) safety on temporomandibular joints of growing patients with Juvenile Idiopathic Arthritis (JIA). They found that usage of RME in these special needs children with maxillary constriction is safe when JIA is in the quiescent phase, similar to healthy children . ChildreWe hope that the readers will find the diversity of the content published in this special issue interesting and valuable. We had systematic reviews and original research reports, ranging from population-based studies to patient-centered clinical studies evaluating the effectiveness of treatment and preventive regimens.


Genetic instrumentation has been suggested as a tool for aiding causal inference in nutritional epidemiology.et al.,A recent work by Cole ,et al.SLC23A1) gene is robustly associated with circulating vitC levels,Mendelian randomization is a form of instrumental variable analysis used to assess causality of exposures using genetic data and it has become increasingly popular in epidemiology over the past decade.et al.The complex relationships between genetics, dietary exposures and potential causal pathways with health outcomes were recently elaborated by Pirastu et al. analysed the potential causal effects of morning-evening diurnal preferences on food intake.In another recent study using the UK Biobank data, Dashti et al.It is important to note that genetic pleiotropy is an established and pervasive characteristic of the human genome. Consequently, we should not think as simply as ‘one gene, one function, one trait’, but be aware that many single genetic variants influence a plethora of different traits.et al.et al.et al. tackled the inconsistencies in observational associations between the consumption or circulating concentrations of micronutrients and breast cancer risk. Of the 11 micronutrients studied, higher concentrations of magnesium were causally related to the increased risk of breast cancer.et al. challenged the contradictory observational evidence on associations between folate and the risk of several common cancers. Their results gave little evidence that serum folate would be causal for pan-cancer or various site-specific cancers, suggesting that increasing levels of circulating folate is unlikely to lead to population-wide increase in cancer risk.The studies by Papadimitriou ,,In spite of the above-mentioned methodological complexities, and even some unfounded resistance expressed by some prominent researchers,,,A particularly fruitful area of research may lie at an intersection of RCTs and Mendelian randomization analysis. Instead of attempting to stretch nutritional trial durations long enough to cover clinical endpoints, a more practical approach may be to first conduct a smaller and shorter RCT followed by Mendelian randomization. This ‘two-step randomization’ approach has been performed to investigate potential clinical benefits of lycopene supplementation on prostate cancer risk.,Recent years have provided a cautionary exemplar of over-reliance on observational epidemiology, namely circulating high-density lipoprotein cholesterol (HDL-C), the so-called ‘good cholesterol’ for many years. Since the early days of cardiovascular research, low HDL-C has been seen as an unquestionable risk factor for CVD, but the situation has become intricate with modern genetics.In nutritional epidemiology, a story with similar features is unfolding around vitamin D (vitD). The observational evidence for the association between low circulating vitD and multiple disease outcomes is strong and long-lived. However, recent RCTs of vitD supplementation in the prevention of canceret al.A recent genome-wide association study of vitD concentration in the UK Biobank (which identified 143 independent loci), together with bidirectional Mendelian randomization analyses, is an elegant exemplar of how the causal role of a biomarker can be extensively evaluated.The long-term nutritional research on the potential direct health effects of dietary fats is an exemplar of the vast difficulties in acquiring robust causal evidence. The early research suggested that the reduction of saturated fats, especially when replaced with polyunsaturated fats, would be beneficial for cardiometabolic health.,,Recent observational findings from the large-scale Prospective Urban Rural Epidemiology study, with over 125 000 participants from 18 countries from five continents, have been interpreted to be at odds with current recommendations to reduce total fat and saturated fats.et al. were able to assess the causal associations of relative macronutrient intake on the risk of chronic kidney disease (CKD).A partial solution to the above-mentioned instrument problem has been recently provided by a GWAS of relative macronutrient intake.et al., suggesting that higher vegetable intake may be causally associated with better kidney function.The Mediterranean diet is generally seen favourable for cardiometabolic health. In a recent study, Li and co-workers developed a quantitative score for the adherence to a traditional Mediterranean diet and further linked the score to a systemic metabolic signature.Determining reliable and specific biomarkers for food intake is extremely challenging, if not impossible. It should also be noted that diet naturally has effects on multiple biomarkers and thus a single one would be highly unlikely to capture the physiological effects successfully. However, with Mendelian randomization analysis we now have a potentially powerful tool to assess causality of various biomarkers. Dietary behaviours and individual nutrients are most likely linked to several biological mediators in the human (patho)physiology. Although we may never know or be able to measure all of them, striving to identify causal mediators allows us to make stronger causal inferences for dietary exposures. If none are available or instrumental variable analyses disagree with the observational findings, wider exploration of alternative hypotheses, including methodological shortcomings related to study designs, are warranted. Overall, we highlight the importance of appraising known causal biomarkers before any causal interpretations of observational dietary data.Food and nutrient intakes are largely influenced by environmental factors with minimal or no genetic contribution. However, when it comes to dietary behaviours, the role of genetics is plausible.PO is supported by the Emil Aaltonen Foundation. MAK is supported by a research grant from the Sigrid Juselius Foundation, Finland.


Primary cilia direct cellular signaling events during brain development and neuronal differentiation. The primary cilium is a dynamic organelle formed in a multistep process termed ciliogenesis that is tightly coordinated with the cell cycle. Genetic alterations, such as ciliary gene mutations, and epigenetic alterations, such as post-translational modifications and RNA processing of cilia related factors, give rise to human neuronal disorders and brain tumors such as glioblastoma and medulloblastoma. This review discusses the important role of genetics/epigenetics, as well as RNA processing and post-translational modifications in primary cilia function during brain development and cancer formation. We summarize mouse and human studies of ciliogenesis and primary cilia activity in the brain, and detail how cilia maintain neuronal progenitor populations and coordinate neuronal differentiation during development, as well as how cilia control different signaling pathways such as WNT, Sonic Hedgehog (SHH) and PDGF that are critical for neurogenesis. Moreover, we describe how post-translational modifications alter cilia formation and activity during development and carcinogenesis, and the impact of missplicing of ciliary genes leading to ciliopathies and cell cycle alterations. Finally, cilia genetic and epigenetic studies bring to light cellular and molecular mechanisms that underlie neurodevelopmental disorders and brain tumors. The primary cilium is a ubiquitous cellular organelle that resembles an antenna whose main function is to sense extracellular signals through a wide repertoire of receptors present on its surface and linked signaling pathways. Once overlooked as an evolutionary vestige, the cilium has recently emerged as the sensory antenna of many pivotal signaling pathways, such as Sonic Hedgehog (SHH), G-protein coupled receptor (GPCR), platelet-derived growth factor receptor (PDGFR), WNT and TGF-β signaling . PrimaryCilia are microtubule-based structures that emanate from the cell membrane. Whereas motile cilia are found in specialized tissues such as in the respiratory tract and brain ventricles, one primary cilium can be present in every cell. The process to generate a cilium, ciliogenesis, involves several centrosomal proteins and it is tightly coordinated with the cell cycle . PrimaryCentrosomes are microtubule organizing centers formed by centrioles that are cylindrical structures formed by microtubules that serve as a platform for microtubule polymerization. During mitosis the centrosomes are duplicated and migrate to opposite poles of the cell. After cell division the mother centriole, formed in the previous mitosis, can be dislocated to anchor to the ciliary membrane through the distal appendages. This is an important step to initiate ciliogenesis and, at this point the modified centriole is called a basal body . The basDuring ciliogenesis ciliary proteins produced in the Golgi can be delivered to the base of the cilium by vesicles as they carry a ciliary target sequence that is recognized by a group of proteins such as Arf4 that regulates the vesicle traffic toward the basal body and the cell membrane. There are other proteins that also participate in this trafficking of vesicles to the cilium such as Rab11, Rab8 and a protein complex called Bbsome that controls IFT assembly and cilia-mediated Hedgehog signaling pathway .Once vesicles reach the basal body and the cellular membrane, they can be transported along the cilium by IFT proteins that serve as adaptor proteins connecting vesicles to motors that navigate along the axoneme. This process then creates the primary cilium that is a very small and dynamic microdomain in the cell. We will present how primary cilia are involved in different signaling events controlling several processes within the cell such as cell–cell communication, differentiation and cell division .Neuronal development is a complex process requiring neural stem cell activity, lineage commitment and neuronal maturation. These events are controlled by signaling pathways that have been shown to be mediated by the primary cilium and ciliary defects are observed in several human genetic syndromes that are characterized by neurological symptoms highlighting the importance of cilia in neuronal development .Primary cilia participate in neuronal development as they are crucial for early brain patterning, neurogenesis, neuronal maturation, and survival mostly through regulating cell cycle progression and key developmental signaling pathways such as SHH and WNT . MoreoveThe SHH signaling pathway guides brain development and SHH signals depend on proper primary cilia IFT machinery to be carried in and out of the cilium. The SHH pathway regulates cell fate and self-renewal, and it is activated in the cilium. In the presence of SHH ligand, the receptor Smoothened is recruited to the cilium promoting the formation of activated forms of GLI (GLIA) that migrate into the nucleus and modulate target genes . It was Besides the SHH signaling pathway that is modulated by the primary cilium, WNT signaling also plays an important role in brain development. The WNT pathway controls cell proliferation, differentiation, migration, apoptosis and tissue morphogenesis . The invNeuronal formation requires proliferation of neuronal stem cells, cellular migration, and differentiation. There are different models of cell division observed in neuronal progenitors such as self-amplifying division to produce two progenitors, self-renewing division to produce one progenitor and one differentiating cell, and self-consuming division to produce two differentiating cells. Importantly, cell proliferation and the exit of the cell cycle are crucial for neurogenesis as it determines the size of the brain and the formation of neuronal and glial cells .Primary cilia assemble and disassemble during the different phases of the cell cycle functioning as a barrier to cell cycle progression, therefore cilia defects affect proliferation and differentiation of neural progenitors leading to developmental malformations and diseases , notablyWDR62-deficient organoids displayed smaller brain sizes as a result of the depletion of neuronal progenitors  is one of the most common neurodegenerative diseases characterized by degeneration of dopamine neurons from the substantia nigra and accumulation of misfolded protein aggregates (Lewy bodies) in the brain . LRRK2 . LRRK2 iThe association of LRRK2 mutation and ciliogenesis disruption was observed in PD patient-derived iPSCs that fail to form a cilium in culture . MoreoveThe importance of LRRK2 in primary cilia formation was further tested in mouse embryonic fibroblast (MEF) cells expressing the pathogenic R1441C LRRK2 mutation. MEFs expressing R1441C LRRK2 at endogenous levels failed to produce a primary cilium, whereas cells treated with LRRK2 inhibitor MLi-2 were able to form cilia .Thus, accumulating evidence has uncovered a functional role for LRRK2 in primary cilia formation in murine and human models. These data highlight a molecular pathway involving cilia and SHH signals for proper neuronal function that is altered in Parkinson’s patients. Strikingly, these data show that primary cilia are important neuronal sensors not only during developmental stages but throughout differentiation and later stages of neuronal maturation and ultimately play an important role in neurodegenerative processes.Multiple recent studies have reported defects associated with primary cilia in various cancers . As primAre cilia functionally important in glioblastomagenesis? Functional studies revealed that primary cilia loss mediated by cyclin-dependent kinase 20  overexpression promotes GBM proliferation . CCRK beFurther support for the tumor-suppressing role of cilia in GBM was recently reported by PTCH1 mutations are the most common MB driver  enzymes . TubulinSHH signaling as it interferes with the translocation of GLi3 and tethering of Polycystic Kidney Disease 1/2 (PKD1/2)   and impa(PKD1/2) . Additio(PKD1/2) .Tubulin glycylation is specific to cilia  and glycAlterations of glycylation are linked to ciliopathies and cancer. Lack of TTLL3 reduces the number of ciliated cells and increases cell proliferation correlating to tumor progression in a mouse model for colorectal cancer (CRC) showing the importance of glycylation in cilia maintenance . AnalysiAcetyl-K40, one of the most conserved tubulin PTMs, is the most abundant tubulin PTM in cilia . Acetyl-HDAC6 is a histone deacetylase that deacetylates the Acetyl-K40 mark in α-tubulin and regulates microtubule-dependent cell motility . AccumulOther PTM enzymes involved in ciliogenesis are the methyltransferases EZH2 and WDR5. WDR5 regulates left-right patterning and controls ciliogenesis by acting as a scaffold rather than its histone methyltransferase activity . In addiGiven the role of primary cilia in neuronal differentiation and tumorigenesis, studies investigating the mechanisms underlying ciliogenesis and its impact on neuronal biology will tremendously benefit the development of therapeutic strategies for the treatment of ciliopathies and several neuronal pathologies including both neurodevelopmental and neurodegenerative diseases, as well as brain cancers. induced pluripotent stem cells (iPSCs) offer a unique platform to study human primary cilia formation and activity during neuronal differentiation, maturation and aging as primary cilia play important roles on neuronal tissue patterning, maturation, survival and tumorigenesis by orchestrating and coordinating important developmental signaling pathways such as WNT and SHH .in vitro using appropriate culture media, and (3) the possibility to obtain cells from patients allowing the investigation of cellular mechanisms in pathological contexts. Disease-related mutations can also be introduced by CRISPR-Cas9 technology mimicking various patient genetic backgrounds. In this context, large compound libraries can be tested on iPSC-derived cells allowing the screening for compounds that have an impact on ciliogenesis, maintenance and activity. Finally, (4) iPSCs can be used to generate tissue-specific 3D cultures called organoids to model human tissue development and disease. Organoids provide the opportunity to investigate architectural arrangement, cellular signaling events and molecular mechanisms involved in neurodevelopmental and neurodegenerative disorders, including Ciliopathies, using rare patient-derived samples.The advantages of using human iPSCs include: (1) to obtain human neuronal cells that are otherwise rare samples and difficult to obtain for research, (2) the opportunity to study developmental processes such as differentiation and maturation Brain organoids can be obtained by cultivating pluripotent stem cells in 3D suspension and are being used to model a great variety of organs including gut, retina, and brain . The genThe primary cilium plays crucial roles in modulating cellular signaling pathways that are essential for stem cell maintenance and neural development. Interestingly, ciliary defects are observed in developmental and neurodegenerative diseases, and brain cancers such as Glioblastoma and Medulloblastoma. Moreover, neuronal phenotypes such as microcephaly and intellectual disability are a common feature of human ciliopathies. Ciliogenesis is controlled by cellular processes such as the cell cycle, epigenetics factors, post-translational modifications as well as RNA splicing. This regulation has a strong impact on neuronal development as evidenced by the plethora of neuronal phenotypes observed in enzymatic deficiencies and mutations of epigenetics and PTM enzymes as well as RNA processing components. This role seems to be equally important as the more traditional roles of these enzymes on chromatin dynamics, gene expression and posttranscriptional control.Moreover, a growing body of evidence is unraveling the importance of the primary cilium in neuronal development, activity and maintenance as demonstrated by human iPSCs-based studies strongly implicating cilia in neurodevelopment, neurodegenerative diseases, and brain cancers. This emphasizes the importance of iPSCs studies in understanding human neuronal pathologies as they provide a platform for modeling human neuronal diseases. Thus, understanding the epigenetic and PTM mechanisms of how cilia are formed, maintained and disassembled is fundamental for neuroscience research and drug discovery.CR and PP contributed to conception, design, and writing of the review. Both authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Sensing changes in the environment is crucial for survival. Animals from invertebrates to vertebrates use both visual and olfactory stimuli to direct survival behaviors including identification of food sources, finding mates, and predator avoidance. In primary sensory neurons there are signal transduction mechanisms that convert chemical or light signals into an electrical response through ligand binding or photoactivation of a receptor, that can be propagated to the olfactory and visual centers of the brain to create a perception of the odor and visual landscapes surrounding us. The fundamental principles of olfactory and phototransduction pathways within vertebrates are somewhat analogous. Signal transduction in both systems takes place in the ciliary sub-compartments of the sensory cells and relies upon the activation of G protein-coupled receptors (GPCRs) to close cyclic nucleotide-gated (CNG) cation channels in photoreceptors to produce a hyperpolarization of the cell, or in olfactory sensory neurons open CNG channels to produce a depolarization. However, while invertebrate phototransduction also involves GPCRs, invertebrate photoreceptors can be either ciliary and/or microvillar with hyperpolarizing and depolarizing responses to light, respectively. Moreover, olfactory transduction in invertebrates may be a mixture of metabotropic G protein and ionotropic signaling pathways. This review will highlight differences of the visual and olfactory transduction mechanisms between vertebrates and invertebrates, focusing on the implications to the gain of the transduction processes, and how they are modulated to allow detection of small changes in odor concentration and light intensity over a wide range of background stimulus levels. This leads to a change in the membrane potential (Vm) of the primary sensory neuron that can be propagated to the sensory centers of the brain. Invertebrates appear to use a wider range of signaling cascades to detect odors or light. Their phototransduction is mostly mediated by a Gq-coupled pathway controlling transient receptor potential (TRP) and transient receptor potential like (TRPL) channels in the plasma membrane of the microvillar compartments of the photoreceptor neuron. However, there are some invertebrate species that also utilize the release of Ca2+ from intracellular endoplasmic reticulum (ER) stores via inositol triphosphate (IP3) pathway, or the same phototransduction pathway found in vertebrates. Some details of invertebrate phototransduction are unknown, most notably the second messenger gating their transduction channels remains to be resolved. Olfactory signal transduction in invertebrates is not understood in detail, however, it is often mediated by ligand-gated odor receptor (OR)/co-receptor (Orco) heteromer that may also be regulated by metabotropic pathway(s)  reminiscent of ionotropic glutamate receptors widely used in chemical synaptic transmission between neurons. In this review we will describe visual and olfactory transduction in vertebrates and invertebrates, focusing on how their differences contribute to the gain of the visual and odor transduction in vertebrates and invertebrates as well as how this gain is modulated to allow adaptation of vision and olfaction over a wide range of background light and odorant levels.Phototransduction and olfaction have been widely investigated in both invertebrate . Active rhodopsin can activate several G proteins, transducins (GT), by catalyzing the exchange of GDP for GTP on its α subunit . Therefore, vertebrate photoreceptors need to maintain a large inward cation current in darkness, which dominates their energy consumption. As light closes CNG channels, increasing ambient illumination decreases the energy consumption of photoreceptors  one R* activates many G*s, (2) PDE* hydrolyzes many cGMP molecules, and (3) co-operative binding of cGMP to the CNG channels   to produce inositol 1,4,5-trisphosphate (IP3), diacylglycerol (DAG), and H+ in a classical second messenger pathway mediating a multitude of functions across multiple species  and transient receptor potential-like (TRP-L) cation channels in vivo remain unknown  are odorant specific proteins . In addition, a recent study showed that the OR/Orco complex can also be activated by odor-induced Ca2+ influx via a calmodulin mediated pathway in Drosophila olfactory neurons  and maybe critical for increasing the sensitivity of the OR-mediated olfactory transduction. In summary, it seems plausible that a combination of ionotropic and metabotropic signaling together with Ca2+ feedbacks and PPK25 channel can promote both fast and sensitive olfaction that is critical specifically for flying insects  was shown to mediate Caα/effector complex in vertebrate PR and OSN cilia since these processes are required for the cessation of the electrical PR and OSN response. Mechanisms that accelerate response recovery and/or regulate the sensitivity of the receptor cells to odors/light by modulating the homeostasis of second messengers and the affinity of cyclic nucleotides to CNG channels will be discussed below in the context of adaptation.Timely inactivation of transduction is key to maintaining the temporal relevance of information from primary sensory neurons. Each activated component of the signaling pathway needs to be inactivated and the concentration of secondary messengers restored to pre-stimulus levels to enable rapid and repeated detection of sensory stimuli. In this section we will focus on the inactivation of receptors and Gvertebrate phototransduction, the active receptor, R*, is inactivated through two processes: rapid initial phosphorylation through the activity of GPCR kinase 1 (GRK1)  is thought to play a role in rapid olfactory transduction termination potentially by phosphorylating the olfactory receptor  complex  in invertebrates involves Arrestins, two of which have been identified in Drosophila, Arr1 and Arr2  as discussed above. However, the molecular details of these metabotropic pathways remain unclear and controversial.As in vertebrate phototransduction, the effector enzyme PLC functions as a GTPase activating protein (GAP) for Gactivity . Inactiv2+ feedback mechanisms and adaptation characteristics across all four transduction modalities discussed in this review.Animals live in environments where sensory exposure levels can vary dramatically, for example from the low light levels of shaded forests and underground burrows to the bright sunlight of a field at noon. The ability to adapt to these very dramatic differences in light levels is crucial for survival. Adaptation is a universal feature of all sensory systems, including vision and olfaction  play a critical role in both light and odor adaptation. Thus, it is important to first understand how Ca2+ is regulated in the cilia or microvilli of the photoreceptors and OSNs in response to sensory stimulus. The channels mediating the influx of Ca2+ into vertebrate PR and OSN cilia are CNG channels which are not only permeable to Na+ but also to Ca2+ . However, vertebrate photoreceptors are a notable exception to this rule, their CNG channels are closed by light, leading to a decline in the outer segment [Ca2+]. Even if the details of how Ca2+ is regulated in these different transduction compartments may differ, the general principle of using the transduction channel to regulate Ca2+ influx seems to be a conserved strategy. This way Ca2+ level in the cilia or microvilli can be proportional to sensory stimulus level, an important feature for its ability to adjust the transduction gain in response to changes in ambient light or odorant level.Calcium ions   or CaM-binding myosin III (NINAC) is mutated . Initially, the lifetime of PDE* was thought to be independent of background light level or Ca2+  is the dominant mechanism for regulating sensitivity in vertebrate rods and cones  have Ca2+ bound to them and they cannot activate GCs. With light-induced decreases of Ca2+, Mg2+ replaces Ca2+ in GCAP proteins, and the Mg2+-GCAPs increase cGMP synthesis by activating GCs  causes several conformational changes in rhodopsin converting it to a physiologically active meta II form (or R*) which eventually decays to free opsin and all-trans retinal , Müller and photoreceptor cells. These pathways have been reviewed previously  to regenerate visual pigment are critical for vertebrate photoreceptors to escape saturation under continuous illumination or to restore full sensitivity after bright light exposure. Absorption of a photon by 11-trans-retinol (atROL) by retinol dehydrogenase (RDH) and transported to RPE by interphotoreceptor retinoid binding protein (IRBP). Lecithin:retinol acyltransferase (LRAT) esterifies the atROL to all-trans-retinyl-ester (atRE)  by retinoid Isomerohydrolase  monolayer Dowling, . Followicis retinyl palmitate from atROL  to form all-trans-N-retinyl-PE in the lipid membrane, and a blue photon then converts this to 11-Rgr in the mouse retina results in faster sensitivity loss in cones under constant bright background illumination. Morshedian et al.  in RPE . This allows invertebrates to detect single photons, and due to the large number of microvilli and bistable visual pigment, they can also sustain vision into bright daylight. Vertebrates developed an alternative strategy to see over a similar range of ambient light. During evolution, the molecular properties of ciliary cone photoreceptors became tuned to generate more sensitive rod phototransduction with high amplification, slower response termination and extremely stable visual pigment to enable single photon detection and vision at night. With a duplex rod/cone retina, vertebrates can also see both at night and in bright sun light in a way that is perhaps more energy efficient compared the invertebrate retina (Fain et al., Rhabdomeric phototransduction has extremely high amplification and fast response kinetics largely due to Catrans-retinal compared to cone pigments. In addition, cones can use several different visual cycles for faster and more efficient pigment regeneration, enabling vision in very bright light. Most of our information about the function of cones from the past 2–3 decades has been taken from mice, a nocturnal animal with rod-dominant retina. More details about biology of non-human primate and human fovea and para-/perifovea have emerged, but significant gaps in our knowledge remain. For example, the contribution or existence of the different pigment regeneration pathways for bright light vision in the human fovea and macula, specialized to promote high-acuity color vision in bright daylight conditions, are not known. Then again, significant gaps in knowledge about invertebrate phototransduction also remain, where even the identity of second messengers remains controversial.Unlike r-opsins in rhabdomeric photoreceptors, c-opsins in ciliary photoreceptors are not thought to be bistable and several enzymatic pathways to regenerate rod and cone visual pigments exist. The rod pigment is extremely stable with a low rate of spontaneous activation, and once activated it is also very slow to decay back to free opsin and all-olf is very low and, whereas rods and rhabdomeric PRs can detect single photons, ~40 odor molecules are required for olfactory sensation in mice. Where vision seems to have evolved in humans to enable high-acuity color vision during the day, mice seem to have retained a significantly larger number of functional olfactory receptors ~1,000, compared to ~400 in humans (Niimura and Nei, Although olfactory transduction in vertebrates also uses GPCR signaling cascade to transduce odorant signals, it has much lower amplification compared to phototransduction in either vertebrates or invertebrates. Indeed, the probability for activated olfactory receptor to activate GAll authors contributed to the writing of this review article to the work and approved it for publication. Figures were generated by FA.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Hospitalization is common among older adults. Prolonged time in bed during hospitalization can lead to deconditioning and functional impairments. Our team is currently working with Department of Veterans Affairs (VA) medical centers across the United States to implement STRIDE , a hospital-based walking program designed to mitigate the risks of immobility during hospitalization. However, the COVID-19 pandemic made in-person, or face-to-face, walking challenging due to social distancing recommendations and infection control concerns. In response, our team applied principles of implementation science, including stakeholder engagement, prototype development and refinement, and rapid dissemination and feedback, to create STRIDE in Your Room (SiYR). Consisting of self-guided exercises, light exercise equipment , the SiYR program provided safe alternative activities when face-to-face walking was not available during the pandemic. We describe the methods used in developing the SiYR program; present feedback from participating sites; and share initial implementation experiences, lessons learned, and future directions. Older adults are at higher risk for hospitalization compared to their younger peers. Many older adults spend extended periods of time in bed while hospitalized. These periods of extended inactivity can contribute to rapid deconditioning and the onset of new physical disabilities not present upon hospital admission ,2. assiSThe STRIDE program consists of an initial consult (submitted by a physician or nurse) followed by a gait assessment  early in a patient’s hospitalization and one to two daily walks supervised by a mobility assistant . An initial clinical demonstration evaluation of the program found that older adults participating in STRIDE were more likely to spend fewer days in the hospital and be discharged home rather than a skilled nursing facility . STRIDE As of Spring 2020, 18 VA Medical Centers across the United States had implemented STRIDE through a variety of channels including a clinical demonstration project (1 site), regional mandate 4 sites), funding via VA program offices (3 sites), system-wide “Shark Tank” innovation initiatives (2 sites), and participation in a cluster randomized stepped wedge trial sponsored by the VA’s Quality Enhancement Research Initiative (QUERI) (8 sites)  sites, f. All sitThe onset of the COVID-19 pandemic created unique challenges and made it difficult for some sites to continue offering STRIDE in-person walks in the face of social distancing and infection control recommendations. This paper describes the evolution and preliminary implementation experiences of STRIDE in Your Room (SIYR), a supplemental effort to support sites in maintaining an inpatient activity program during the COVID-19 pandemic. In this paper, we share the impact of COVID-19 on STRIDE programs and describe the process our team used to develop and evaluate the SiYR program in response to pandemic-related challenges. We offer lessons learned with the goal of using SiYR as one example of how to rapidly adapt and translate program enhancements to help promote activity of hospitalized older adult patients during a national emergency.Implementation science focuses on the methods to integrate effective programs into routine clinical practice . Since tOne feature of the national implementation of STRIDE, as described above, is a quarterly Diffusion Network Call. These optional calls are open to all STRIDE sites at any phase of implementation and are designed to serve as a learning collaborative. Calls are structured around one specific topic of interest  with ample time for discussion and exchange amongst attendees. In response to feedback received from sites, we dedicated our Spring call held in April 2020 to an open discussion of challenges and experiences related to the COVID-19 pandemic. Below, we report feedback from this call. Many VA Medical Centers made changes to facility procedures and clinic workflows upon the initial onset of the COVID-19 pandemic in March 2020. For example, some Medical Centers limited in-person interactions in facility hallways, no longer making supervised STRIDE walks feasible. Additionally, the VA Healthcare System’s fourth mission is to assist the nation in times of emergency, serving both veterans and nonveterans alike . In suppAs shared on this call, the impact of COVID-related restrictions varied across sites. Some facilities had limited COVID patients to restricted wards away from other patients, thus having minimal impact on STRIDE walks. Other sites reported facility-level restrictions in hallways. At one site, STRIDE therapists were able to advocate for continuing walks despite these restrictions. However, at least two sites were forced to temporarily suspend their STRIDE programs. As described above, total hospital census was down at all sites. For sites that were not on hold, the reduction in overall hospital census meant potentially fewer eligible STRIDE participants. However, sites also found opportunity in the reduced census. For example, some sites early in the STRIDE implementation process saw the reduced census as an opportunity to dedicate extra time and resources to ramping up their program while other more established programs found an opportunity to expand STRIDE to other wards.Several sites employed creative strategies to continue keeping patients active despite challenges associated with social distancing and infection control recommendations. At sites where patients were not permitted to leave their rooms, STRIDE staff utilized VA’s Video Connect platform to coach activity sessions over patients’ personal smartphones. However, this required advanced coordination so that a nurse could be present in the room for patient assistance and fall prevention. Other sites relied on existing activity programs that aired via the “GetWellTV Network” available in patient rooms. Despite these innovations, STRIDE sites expressed an interest in identifying more uniform and sustainable solutions to continue walking or exercising safely within the constraints of social distancing and infection control requirements.Social distancing requirements: At some sites, patients were instructed to remain in their rooms and STRIDE staff were prohibited from supervising face-to-face walks in the facility hallways.Rehabilitation support for COVID-positive patients: Patients hospitalized for COVID-19 were challenged by both respiratory symptoms of the virus and physical deconditioning.Supplemental tools for STRIDE: Providing patients and STRIDE teams with self-guided exercise could benefit teams during staffing shortages and/or could supplement existing walks for motivated patients who expressed an interest in additional activity.Support patients upon hospital discharge: At the height of the pandemic, admission to a rehabilitation and/or skilled nursing facility was complicated by a number of factors. First, some facilities had reduced capacity. Second, facilities often had extended waitlists due to requirements that potential admissions have one or more negative COVID-19 screens. Third, some patients and families preferred to be discharged home out of caution that residential and/or congregate settings may carry increased risk for COVID-19 exposure.In response to feedback received on our Spring 2020 Diffusion Network Call and in collaboration with the lead STRIDE Physical Therapist (JB), a new solution to enhance the in-patient walking program was developed: STRIDE in Your Room (SiYR). Financial support was made possible through supplemental funding from the VA QUERI program. SiYR was developed in response to four common experiences shared by STRIDE programs during the COVID-19 pandemic:Overview: SiYR was developed by the interdisciplinary research team with clinical guidance from STRIDE’s principal physical therapist (JB). The format and contents of the kit were also informed by the team’s prior work developing a “STRIDE at Home” program meant to encourage patients to continue walking after leaving the hospital. Finally, feedback from the STRIDE sites (as described above) and safety recommendations from VA Emergency Management and the Centers for Disease Control and Prevention (CDC) also informed the kit.Kit contents: The SiYR kit was designed to provide hospitalized patients with self-guided activities and light exercise equipment. Together, the components of the kit were designed to promote function and independence via exercises that targeted both large muscle groups and fine motor control necessary to carry out activities of daily living (ADLs). Consideration was given to both natural deconditioning that occurs during a hospital stay and potential respiratory effects of COVID-19. All kit components were developed based on evidence-based activities issued by the National Institute on Aging and COVID-19 safety recommendations issued by the Centers for Disease Control and Prevention (CDC). Together, the components of the kit included self-guided exercises to improve strength and balance, transfer, independent ambulation, activities of daily living, and overall endurance. Kits were designed for individual use and to be sent home upon discharge. All kits were packaged in plastic binders using page protectors that could be wiped down for infection control. Additional details of the kit components are displayed in Pilot testing of initial prototype: After developing the initial prototype, the lead STRIDE physical therapist (JB) completed pilot testing of the SiYR kit over a two-week period at our original STRIDE site in Durham, NC. The goal of this pilot testing was to gain preliminary experience in identifying appropriate patients, introducing the SiYR kit to patients, and documentation of kit distribution. Information gleaned from the pilot testing was then used to develop guidance for other STRIDE sites requesting SiYR kits, including content and instructional materials shared during the SiYR Orientation Calls described below.Launch of SiYR program: The research team introduced the SiYR program to STRIDE sites on a July 2020 Diffusion Network call. The purpose of this call was to describe the different components of the kit and to address any initial questions. A total of 20 participants joined from 7 different STRIDE sites. Call content was made available to sites unable to participate in the call.Orientation call: All sites requesting SiYR kits were invited to participate in an individual orientation call with the Function QUERI research team and lead Physical Therapist. The orientation call covered the following topics: (1) SiYR purpose; (2) kit contents; (3) identifying appropriate patients; (4) introducing the kit to patients, including how to match activities to patient’s discharge goals; (5) documentation of kit distribution; and (6) sharing feedback with the research team and other STRIDE sites. Although sites were given guidance on how to distribute and document kit use, a primary goal of the orientation call was to remind sites of the freedom involved in kit distribution. Similar to the implementation of the full STRIDE program, SiYR sites were encouraged to adapt the SiYR to best fit characteristics of their individual site, including staffing model and patient needs. The research team emphasized the collaborative, iterative nature of the SiYR program and the potential for each site’s feedback to inform best practices and guidelines for other STRIDE programs implementing SiYR in the future. Finally, the lead physical therapist also shared tips on motivating patients during the pandemic, adopting the phrase “walking all over COVID-19” to highlight the resilience of patients, providers, and staff in rising to the multiple challenges surrounding the pandemic, regardless of COVID status or exposure.Rapid feedback: As part of the rapid cycle assessment of the SiYR program, three sites volunteered to participate in further pilot testing (n = 3), which involved responding to a brief survey at regular intervals . Survey content is described in n = 18). Reach of SiYR was notable with 13 of 18 STRIDE sites (72%) requesting and receiving kits during the program’s initial rollout. Characteristics of participating sites are displayed in n = 7) and South Atlantic (n = 6) regions of the United States. Date of main STRIDE program launch ranged from Fall 2018 to Fall 2020. Just over one-half of participating sites are designated “mid–high complexity” facilities suggesting medium–high volume, medium-risk patients, some complex clinical programs, and medium-sized research and teaching programs [The SiYR program was officially introduced to STRIDE sites in July 2020 on a scheduled Diffusion Network Call (see description above); kit distribution began in September 2020. All STRIDE sites that had implemented a program prior to this date were invited to participate in this supplemental program , staff expressed concerns with patients having sufficient functional independence to safely participate in an independent activity program like SiYR. Kit distribution may also have been slower as sites were primarily focused on use for patients with a suspected COVID-19 infection or other immunocompromising condition(s). Some sites were impacted by competing clinical priorities, staffing shortages, and/or changes in staffing assignments during the pandemic.Across all sites, additional guidance on patient identification and SiYR enrollment was desired. More specifically, sites were unclear on when the SiYR kit should be introduced during a patient’s stay and whether patients who decline to participate in the full STRIDE program are still eligible for the SiYR program. Sites also desired more guidance around how to document distribution of the SiYR kit and whether additional uses of the kit should be indicated in the patient’s medical chart.As described earlier, SiYR was designed to be flexible, similar to the larger STRIDE program. During the Orientation Call, sites were encouraged to adapt both content of the kits and general procedures in distributing and documenting kit use to best fit the needs of their local site. Given the dynamic nature of the pandemic and the variation in COVID-19 cases across geographic regions, our research team was interested in observing how sites might implement a new program during a national emergency. However, our team also recognized the challenges faced by frontline healthcare workers during the pandemic and that, understandably, implementing a new program during this time might feel burdensome and/or less feasible without clear or sufficient guidance. Achieving the right balance between providing sites with clear guidance on how to implement SiYR and allowing flexibility for customization during a pandemic was challenging for the research team.STRIDE sites appreciated the tailored exercises provided in the SiYR kit. Some sites had been using established exercise programs  which required staff to modify exercises in order to prescribe an activity plan that was appropriate for patients’ functional levels. Although the self-guided exercise booklet was well received by STRIDE staff, sites expressed wanting additional examples that used the exercise equipment provided in the SiYR kit . Sites also shared that not all exercises were appropriate for patients and that more activity options could be beneficial. Specifically, some patients were too frail for independent exercise included in the SiYR kit while other more active and/or motivated patients could have benefited from more advanced exercises. Finally, some patients had difficulty using the equipment provided in the kit. For those patients not using a mobile phone to track steps, the pedometer’s display was too small to read. For some, utilizing a phone was helpful to track either distance or time walked and use this as a goal to adjust/increase each week. Other patients with dexterity limitations found the foam blocks difficult to use.As often shared during the COVID-19 pandemic, innovation arises out of necessity. The inability to safely conduct in-person walks prompted the Function QUERI research team to develop an innovative solution to continue optimizing patient activity in the hospital. Overall, STRIDE sites were eager to adopt the SiYR kit. Feedback from sites suggested that the SiYR kit was comprehensive and an acceptable alternative to face-to-face walks.However, the pandemic also demonstrated notable variability in impacts on participating sites. Some sites were overwhelmed by high COVID case counts, or regional surges, while other sites experienced lower case counts. Additionally, the ebb and flow of cases over the course of the pandemic also demonstrated a need for flexibility. Although SiYR was designed to be flexible in its initial implementation and to allow for adaptation over time, there were several areas in which sites wanted more direct guidance on how to implement SiYR. It is unknown whether additional guidance, including information on how to engage staff and leadership, may have contributed to wider adoption of SiYR kits.Beyond brief quantitative surveys and scheduled Diffusion Network Calls, obtaining additional feedback from participating sites was challenging, which may be attributed to a variety of reasons. First, dedicating time to complete quantitative surveys and other administrative tasks may have been difficult given patient care and safety priorities during the pandemic. Second, some sites felt as though they could provide more helpful feedback after distributing more kits. Third, as a rapid cycle improvement project, our research team was focused on addressing a gap in clinical care resulting from the COVID-19 pandemic, not focused on studying a priori research questions with clearly defined metrics of success. This lack of clearly defined goals may have complicated assessment and evaluation.Despite some of the challenges in distributing kits, some SiYR sites also demonstrated innovation at their local facilities. One team left a SiYR kit on their medical center’s dedicated COVID unit and provided instruction to the unit’s providers on how the kit might be used to promote activity among isolated patients. A second site utilized a “train the trainer” model, educating other facility physical therapists about how to use the SiYR kit and encouraging each therapist to distribute at least one kit. A third site produced a 10-minute video to be played in patients’ rooms that included supine and seated exercises, deep breathing exercises, and information on early mobility during hospitalization. Each of these innovations was presented to the larger STRIDE network as part of quarterly Diffusion Network Calls, further supporting the value of learning collaboratives as an effective implementation strategy, particularly in times of national crises.As implementation scientists, our team continues to engage in regular discussion around how the SiYR program can be refined to increase uptake, improve feasibility, and optimize patient use and outcomes. In addition to the lessons learned described above, we highlight potential directions our team may pursue in the future.Although the future trajectory of the COVID-19 pandemic remains unknown, the introduction of COVID-19 vaccinations has played a major role in slowing new cases. As the pandemic continues to shift, SiYR may be used for other immunocompromised patients who are unable to leave the hospital room and could benefit from a self-guided activity program. SiYR may also be used in times of staffing shortages and/or to supplement existing STRIDE walks. Identifying alternative uses for the SiYR kits may ultimately improve uptake. In addition, providing sites with clear instructions  on how to implement SiYR for different uses may also improve uptake and sustainability.Whether the SiYR kit is used during a future pandemic or to supplement existing STRIDE walks, our team has identified several tools which may further support self-guided activity. First, patients may benefit from educational and/or motivational text messages both during hospitalization and after discharge. Second, expanding the GetWellTV Network to include brief instructional videos may help patients learn and/or adapt the self-guided activities included in the SiYR kit. Third, postdischarge follow-up calls may be useful as some patients continue to use the SiYR kit after leaving the hospital. Finally, exploring the impact of SiYR on patient-level outcomes will be important in future work.The VA’s Office of Geriatrics and Extended Care (GEC) has expressed interest in identifying additional uses and/or plans for the dissemination of the SiYR kits. GEC currently leads initiatives to integrate principles of the Age-Friendly Health System  into VA The COVID-19 pandemic required our team to think quickly and creatively to identify alternative solutions for helping patients stay active at a time of unprecedented disruption in hospital operations. Inspired by feedback from frontline staff and informed by principles of implementation science, our team launched the STRIDE in Your Room (SiYR) program, an adaption of STRIDE, our existing evidence-based walking program. Although SiYR aimed to address a clinical gap, the challenging and changing circumstances of the pandemic made it difficult for clinical sites to adopt and sustain a new service. We recognize some of the inherent limitations in a rapid cycle assessment project, including implementation within a single healthcare system and prioritization of implementation outcomes over patient-level outcomes. Despite these limitations, lessons learned from this collaborative and iterative process may inform preparedness efforts for future pandemics or other emergency situations. In the meantime, our team will continue efforts to refine the SiYR program and identify how a self-guided exercise kit can serve as a tool to support patient activity both within the hospital setting and upon discharge.


As a result of significant recent scientific investment, the range of vaccines available for COVID-19 prevention continues to expand and uptake is increasing globally. Although initial trial safety data have been generally reassuring, a number of adverse events, including vaccine induced thrombosis and thrombocytopenia (VITT), have come to light which have the potential to undermine the success of the vaccination program. However, it can be difficult to interpret available data and put these into context and to communicate this effectively. In this review, we discuss contemporary methodologies employed to investigate possible associations between vaccination and adverse neurological outcomes and why determining causality can be challenging. We demonstrate these issues by discussing relevant historical exemplars and explore the relevance for the current pandemic and vaccination program. We also discuss challenges in understanding and communicating such risks to clinicians and the general population within the context of the ‘infodemic’ facilitated by the Internet and other media. As a result of a rapid and focussed international scientific response to the COVID-19 pandemic, an impressive array of vaccines against SARS-CoV-2 is now available and the largest vaccination program in history is now well underway. However, successful global implementation will be critically dependent on the public health response, with uptake of at least 70% required to achieve “herd-immunity”. However, it can be difficult to interpret large-scale safety data, and vaccines have been historically linked to a variety of notable adverse neurological events. Many of these still dominate the popular imagination, demonstrating how difficult it can be to change public opinion on safety and avoid vaccine hesitancy after seeds of doubt have been sown.When contemplating vaccination at such an immense global scale, it is particularly important to be vigilant for any iatrogenic harm, even when occurring at very low frequency. The precautionary principle warns against adopting new technology before sufficient evidence has accumulated about its effects. However, the risk of adopting a vaccine needs to be weighed against the population prevalence of disease, transmissibility, and the mortality and morbidity risk of the infection itself. Safety concerns should shift priority towards alternatives with similar efficacy and more robust safety data where possible but achieving an appropriate balance will depend on complex and dynamic contextual factors.There are currently 100 vaccines in clinical development and more at a pre-clinical stage. Data available from phase III randomised clinical trials of COVID-19 vaccinations have been largely reassuring, although real-world experience has identified important issues for selected vaccines. The phase III Oxford-AstraZeneca (AZ) (Vaxzevria) vaccine trial reported a single case of transverse myelitis thought to have been related to the vaccine .Fig. 3AThose who are critical or anti-vaccination will inevitably highlight the potential harms and down-play the benefits. This is a particular issue in the age of enhanced technological and social media accessibility. The general population is faced with a deluge of information rapidly disseminated over the Internet and media. Whilst this ‘infodemic’ may have distinct advantages in logistical organisation and effective public communication, it may also be countered by disinformation spreading “vaccine hesitancy” and threatening uptake , 92. PubAny new vaccine will have been carefully studied in large randomised trials before licencing. These can never be big enough to detect all possible adverse events and national surveillance systems are required to obtain post-marketing data and need to be combined using harmonised datasets that span international boundaries. Such analyses require appropriate governance data sharing and the necessary infra-structure to undertake anonymised individual patient data analyses. However, all post-marketing reports tend to be affected by bias and should be treated with caution with further well-designed and robust studies required to confirm or refute associations between vaccination and adverse events. Importantly, increased rates of adverse events may be due to the disease itself or a higher risk in the population targeted for initial vaccination, even without vaccination. Public messaging must be carefully measured, since the consequences of misreporting may be profound. Even where association is confirmed, contextualisation of risk is important, as risks of infection may far exceed those of adverse events, particularly in periods of high disease transmission. In addition, risks can be effectively mitigated by targeting strategies, timely dissemination of appropriate information, and effective public engagement.