Theoretical and methodological issues are addressed with the aim to instigate greater conceptual and operational clarity in future investigations of expression authenticity.People dedicate significant attention to others’ facial expressions and to deciphering their meaning. Hence, knowing whether such expressions are genuine or deliberate is important. Early research proposed that authenticity could be discerned based on reliable facial muscle activations unique to genuine emotional experiences that are impossible to produce voluntarily. With an increasing body of research, such claims may no longer hold up to empirical scrutiny. In this article, expression authenticity is considered within the context of senders’ ability to produce convincing facial displays that resemble genuine affect and human decoders’ judgments of expression authenticity. This includes a discussion of spontaneous vs. posed expressions, as well as appearance- vs. elicitation-based approaches for defining emotion recognition accuracy. We further expand on the functional role of facial displays as neurophysiological states and communicative signals, thereby drawing upon the  The accurate recognition of emotions plays a crucial role in communication and social interaction. Knowing what another person is feeling is relevant for predicting their psychological state, likely future behavior, and interaction outcome . Howeverexpression authenticity.Humans have great control over their facial behavior , with th1 the ability to distinguish the authenticity of such expressions is much poorer  innate cues reflecting genuine affect or (b) communicative signals of affect and intent.encoding-decoding perspective (decoders) “decode” the meaning behind emotional displays of others . Facial expressions are considered to be innate, neurologically activated, fixed facial muscle patterns that occur in response to emotion-eliciting stimuli . Evolutionary there is no reason why facial expressions and emotion perception could not have co-evolved as part of a social signaling system  and deliberate  expressions. It is important to note, though, that the argument for clear differences in expression authenticity  is neithspontaneous and posed. These are generated in various ways, ranging from emotion-induced exemplars to directed facial muscle activations . For encoding-decoding scholars, genuine and spontaneous reflect similar concepts, namely, the absence of modulation and intentionality in the emotional display . Yet, foEmotional experiences are often difficult to measure, with some scholars even arguing that they are empirically unverifiable . Most investigations rely on proxies such as self-report or bodily measures  and posed (deliberate) displays. By contrast, emotion categorization ability and emotion communication accuracy. Such interchangeable use in terminology may lead to confusion or misleading conclusions and interfere with attempts to synthesize research , where genuine expressions reflect responses to an emotion-evoking event and non-genuine expressions are voluntarily produced displays in the absence of such an event. It makes no assumptions as to what constitutes a veridical emotional display and merely refers to the congruence between the eliciting event and the external behavior. Natural variations in displays between senders are considered relevant for the judgment process by decoders. Exemplars are selected based on the elicitation technique, allowing researchers to explore how differently produced displays affect people’s judgments. Under this approach, labels such as “genuine” and “deliberate” apply only to the inferences made by judges. While elicitation-based approaches introduce more variability in judgments, they capture the diversity of facial displays and mirror the emotional inferences made in real life. This is in stark contrast to the appearance-based approach in which facial exemplars must adhere to a strict morphological or dynamic criterion regardless of the production method being used.The congruency , in decoders’ ability to detect specific facial configurations, and how alterations of such patterns impact perception and judgment. The elicitation-based approach permits investigations of the variability in human responses to emotional events, how such behaviors are affected by context or experimental manipulation, and how people infer meaning from such displays. Noteworthy, measures of accuracy have a different meaning under the two approaches. According to the latter, judgment accuracy is more akin to cy as in , where aFor future investigations of expression authenticity, we recommend the use of advanced statistical analyses, such as Bayesian mixed-effects models, to account for individual differences in senders and judges as sources for variability see . For exademeanor bias – the finding that some senders produce general impressions of (dis)honesty irrespective of their veracity (truth-bias may impact expression judgments. Overestimating others’ truthfulness results in inflated accuracy scores which do not reflect true detection ability but a response preference (see authenticity bias; Separate from the sender-judge variability within and between studies, considerations should be given to biases in authenticity judgments. For sender-specific biases, the veracity  – plays ence see . People Future research should also embrace the wide range in which facial expressions occur. Studies concerned with authenticity typically employ one set of spontaneous and posed stimuli, pre-selected from many exemplars and based on specific criteria see . Rarely Finally, it would be desirable to aim for greater transparency and consistency in the use of operational definitions, urging researchers to be explicit, comprehensive, and transparent in their methodology. While some scholars may be aware of the nuances and shortcomings of specific terminology , over-laDeciphering what another person is feeling is a complex task. Here, we address the role of facial expressions as innate cues and communicative signals, proposing a shift from accuracy measures to judgments in expression authenticity. This includes a comparison of encoding-decoding and affective-induction perspectives to offer insights into the process of emotion expression recognition. We conceive of senders as strategic performers who utilize their full expressive capabilities in social interaction and judges as attempting to infer meaning and intent from emotional displays. To help accelerate progress in the field we encourage researchers to carefully consider theory and methodology in how they operationalize facial expressions.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.MZ: conceptualization. MZ and EK: writing and revision. Both authors contributed to the article 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.


Manufacturers have a significant stake in the vaccine supply chain as their reputations rest on the effectiveness of their vaccines at the point of vaccination. The risks of low performing supply chains are detrimental for the safety and effectiveness of vaccines, with potential consequences to future supply in the case of adverse events. For this reason, a study was set up to explore the involvement of developing country manufacturers in the vaccine supply chain over the next decade to determine the areas where innovations could have a positive impact on the supply chain, focusing on the secondary stages of production where formulation, filling and packaging take place. An expert desk review identified eight areas of interest for the vaccine supply chain and informed the development of a survey to assess the relevance of the areas identified. The review also conjectured whether the overall effect of the identified areas is cost-neutral or resulting in net savings to countries. Overall, respondents identified five areas as of highest interest and subsequently an expert working group of representative manufacturers prioritized three of them. Specifically, traceability in the context of global digital health initiatives, stockpiling in the context of addressing vaccine shortages, stock-outs, outbreaks and epidemic prevention, and new packaging technologies are discussed in this report. It is important that vaccine manufacturers be actively engaged in global stakeholders' forums, as equal partners in determining the best ways for improving the vaccine supply chain. Innovative vaccines have been developed, that are already pre-qualified by the World Health Organization (WHO), and newer vaccines are coming to market, expanding the global supply capacity.Vaccine manufacturers from emerging countries, both publicly- and privately-owned, established a public health driven international network, the Developing Countries’ Vaccine Manufacturers Network (DCVMN) with a mission of protecting people from infections by supplying high-quality and affordable vaccines. DCVMN follows the United Nations classification of developing countriesWhile manufacturers' management of vaccine supply mostly stops at shipment or factory exit, except in the case of some national shipments, vaccines then start a long road to vaccination in country distribution chains which are fraught with challenges The risks of low performing supply chains are detrimental for the safety and effectiveness of vaccines at time of vaccination, with potentially negative consequences to future supply and reputation. For this reason, DCVMN initiated a study to explore the involvement of members’ manufacturers in the vaccine supply chain over the next decade to determine the areas where their engagement could have a positive impact on the supply chain, focusing on the secondary stages of production where formulation, filling and packaging take place See , Fig. 9.2Initially, an expert desk review identified eight areas relevant to the vaccine supply chain. This review informed the development of an anonymous survey to assess among DCVMN members the relevance of the areas identified. The survey was composed of 36 questions on manufacturers' general supply capabilities, actions and understanding of global standards. In addition, eight questions asked manufacturers' interest in pursuing each area through a vaccine supply chain expert group. Regulatory issues were not included as they are assessed separately by DCVMN Answers to the survey questions could only be YES or NO, to provide a quantitative snapshot of the areas identified. The anonymity of the survey meant that the profiles of respondents were unknown. The survey was circulated only in English, which may have limited responses from manufacturers without a reasonable command of the English language. It was open for 3 weeks from 7 to 28 March 2019, resulting in 26 respondents, a 60% response rate.Following the survey, phone interviews, which delved deeper into the areas, were held by an independent consultant with nine manufacturers, of eighteen contacted, from Africa, Asia and the Americas, including six with vaccines pre-qualified by WHO, to seek feedback on qualitative aspects of the surveyed areas. Five representative manufacturers , constituting a working group, then met in Geneva, on 25th June 2019, and reviewed the results of the survey and subsequent interviews and determined the initial priorities proposed as the DCVMN members focus, taking into account initiatives being undertaken by the global immunization community.Areas addressed by the survey and interviews1.Traceability determines the ability to track vaccines through the supply chain from factory to point of vaccination including key information such as the Global Trade Item Number (GTIN), lot number and expiry date. With appropriate systems in place these data support inventory management, consumption history, wastage and demand forecasting, as well as being key for vaccine safety monitoring.2.Sharing supplier audits can, in principle, reduce the cost burden for manufacturers and their suppliers in ensuring the continued quality of inputs they purchase for manufacturing, including equipment, vials, stoppers, and other supplies/accessories.3.Vaccine temperature monitoring tools, including vaccine vial monitors (VVMs), freeze indicators and electronic temperature recorders, can detect product exposure to high temperatures or freezing during the transportation and storage of vaccines 4.oC. An additional determination for using vaccines out of the cold chain is an extended controlled temperature chain (ECTC) which can consider any temperature/time setting above the traditional + 2–8 °C cold chain that might facilitate vaccine distribution and where CTC is one specification Heat stability testing of all vaccines determines the shelf life under normal conditions of storage from + 2–8 °C, and for VVM specification at + 37 5.Stockpiling of finished product, either through rotating buffer stocks or static stockpiles, can help to mitigate uncertain demand forecasts and stock-outs, which continue to affect many countries 6.Environmental impact assesses the carbon footprint of vaccines and the potential for reducing waste. The increasing numbers of vaccines significantly add to the risk of increased waste and wastage in countries. Using biodegradable or recyclable secondary and tertiary packaging and insulation materials is one consideration, as are reusable shipping containers.7.New packaging and delivery technologies are being developed to improve the vaccine supply chain and vaccination. There is increasing attention to new packaging technologies including blow-fill-seal (BFS) tube technology, multi-component containers and smart packaging, while intradermal delivery devices, microarray patches (MAPs) and sublingual delivery represent new delivery technologies 8.Direct participation in the vaccine supply chain may help countries address the constraints existing in vaccine supply chains through assessing the need for new structures and policies and applying system design techniques The desk review assessed the areas where manufacturer interventions could have a positive impact on the supply chain:3Predicted costs and savings for manufacturers were based on specific drivers for each of the eight areas . In examIf these additional costs to manufacturing hold up in reality, then vaccine prices could rise, but could be offset by increased efficiency and savings in other areasThe survey has been analyzed from the perspective of manufacturers' self-reported knowledge, capabilities and actions relevant to the eight areas identified, providing qualitative rather than quantitative data. Results are reported as a percentage of 'yes' answers to 36 questions, among the 26 respondents.Half the respondents indicated familiarity with GS1 standards, 2D barcoding and radio frequency devices (RFD) technology . Only 36Almost all respondents are engaged in auditing suppliers but less than half audit every supplier, rather focusing on those considered critical to their operations . Quite aRespondents indicated that electronic temperature indicators placed in shipping cartons are the monitoring tool most widely used, both for national and international shipments . VVMs arA third of respondents indicated that they had vaccines meeting the minimum temperature–time requirements of CTC, but only a third of those had vaccines that exceed CTC requirements . The avaAround 60% of respondents indicated that they keep finished products in stock in the anticipation of orders, but indicated current remaining shelf-life requirements is an on-going constraint to managing stockpiles effectively . Almost While half of respondents indicated having a specific strategy for minimizing their environmental impact, only a quarter are using biodegradable or recyclable secondary and tertiary packaging, indicating that environmental concerns are more focused on country-level action . Only onMost respondents indicated it was important for DCVMN members to be consulted and provide feedback on new packaging and delivery technologies, especially with regard to cost and practicability . Less thHalf of respondents indicated that they deliver vaccines to sub-national levels in their countries even though several more have the capability to do so . This deAn additional eight questions asked respondents their interest in DCVMN pursuing each of the eight areas .•Vaccine temperature exposure monitoring (85%);•Traceability (77%);•Stockpiling (77%);•New packaging and delivery technologies (77%);•Environmental impact (73%).Overall, respondents' interest in pursuing the eight areas identified was highest in 5 of them with more than two-thirds indicating their interest in:Direct participation in the supply chain was of interest to 62% of respondents, but less interest was indicated in sharing supplier audits (46%) and in adding heat stability data to labels or inserts (38%).41.Stockpiling is a concern given both the cost of storage and the potential financial risk if stockpiled vaccines are not used or do not comply with the required remaining shelf life for shipment. Prepayment of stockpiles or at least a financial incentive to hold stock was specifically indicated by three manufacturers while all manufacturers stated the need for countries to accept lower requirements for remaining shelf life for stockpiled vaccines;2.New packaging and delivery technologies had in the past not been perceived as a high priority for manufacturers due to the probable high costs involved; however they are now aware of the research being undertaken and all considered it important to actively evaluate such innovations relevant to vaccine supply to developing countries;3.Effectively tracking vaccines through the supply chain (traceability) is important to all manufacturers especially related to AEFIs4.Vaccine temperature monitoring tools are used by manufacturers, mainly according to customer demand, such as VVMs on all UNICEF shipments but not on national shipments or other exports unless demanded. All manufacturers recognize that temperature monitoring tools provide significant security in distribution, which is a priority concern given low performance levels of many supply chains, but fell short of suggesting a greater standardization due to increased costs and lack of global demand;5.Changes in heat stability labeling would require specific protocols from regulators (countries or WHO) and demand from countries. Two manufacturers indicated pursuing CTC for stable vaccines and one manufacturer noted that a wider range of heat stability data on each vaccine could be positive for marketing;6.Environmental impact was seen by all manufacturers interviewed to be mainly in the hands of customers receiving vaccines, with secondary and tertiary carton packaging able to be recycled. One reference was made to the use of envirotainers which eliminate the use of plastic ice packs which are considered an environmental hazard;7.Sharing supplier audits was indicated as potentially useful for reducing auditing costs but all manufactures pointed to significant challenges in establishing complex legal agreements between suppliers and manufacturers' quality assurance personnel across diverse jurisdictions, and to concerns around possible breaches of confidentiality;8.Direct participation in the supply chain happens in the case of national shipments in producing countries with the potential for added services being provided by manufacturers. For international shipments, the customer essentially determines the point of disembarkation.Following the survey analysis, phone interviews took place with nine manufacturers, a 50% response rate, of 18 selected. The lower response rate compared to the anonymous survey may be due to some manufacturers preferring to remain anonymous in providing feedback or the higher investment in time. Interviews elicited detailed feedback on each area and determining which should be given priority by DCVMN. Five of the 9 interviewed manufacturers prioritized the areas. Despite the fact that only 5 manufacturers expressed their prioritization choices at the interviews, four of the five priorities coincided on traceability, vaccine exposure monitoring, stockpiling and new packaging and delivery technologies; environmental impact was therefore discarded as a priority, to narrow down the common priorities for the DCVMN. Noteworthy, the following main points were expressed in the interviews:5A three-step prioritization process was followed: the survey, the interviews and the final selection of priorities. An expert working group of representative manufacturers reviewed the survey results and the subsequent in-depth interviews held with selected manufacturers, with the mandate to select 2–3 priority areas, where DCVMN can contribute globally. A key factor in the deliberations was related to feasibility and impact of each area, recognizing that opportunities for vaccine manufacturers are of higher impact when aligned with the global immunization community investments in specific initiatives. The four areas prioritized in both, the anonymous survey and the interviews, were then considered by the working group. The group deprioritized delivery technologies, as these need extensive R&D, thus not related to supply chain only, while maintaining new packaging technologies as priority. Temperature monitoring was considered a product specific development and requiring complex field studies, and engagement at this level was not feasible. Most pertinent areas were traceability in the context of global digital health initiatives, stockpiling in the context of addressing vaccine shortages, stock-outs, outbreaks and epidemics, and new packaging technologies. These three areas were, as a consequence, agreed as the initial priorities of the working group of DCVMN members, engaging actively in future analysis around the appropriateness, cost and adoptability of innovation related specifically to the functioning of the vaccine supply chain.6The opportunities facing vaccine manufacturers in developing countries have to be considered against a significant degree of uncertainty, which can include weak demand forecasting, erratic ordering schedules, dependence on material and supplier relationships as well as the configuration and infrastructure of the supply chain. Added to this are externalities such as disease dynamics including outbreaks and epidemics, greater demand for data, environmental factors and tender procurement methods. Such uncertainties and externalities are confounded by a sustained under-investment in preparedness in countries for outbreak and epidemic response The ability and capacity to embrace opportunities remain a goal for many emerging vaccine manufacturers, but they often lack resources for significant changes to their operations There are two significant constraints. Firstly, emerging country vaccine manufacturers are diverse both in location across all developing regions, and in set-up with both privately-owned and state-owned companies, so seeking commonalities is not straightforward. Secondly, innovation and price pressure are competing goals and requires the understanding of international stakeholders that a balance is necessary for sustaining a healthy vaccine industry These constraints should be seen in a context where some manufacturers started supplying vaccines within the last decade and do not have significant experience in global supply chain.1.TraceabilityDCVMN members’ feedback indicates their interest in pursuing ways to improve the vaccine supply chain, increasing their visibility and efficiency in the international immunization community by developing specific proposals and innovations pertinent to emerging countries.Traceability is a key feature in the implementation of immunization information systems, helping to plan and manage immunization activities and resources and ensuring that adequate quantities of vaccines are always available to meet demand Health systems are increasingly integrating digital health which can lead to positive impact on immunization information systems, with immediate access to data on vaccine inventory, shortages and stock-outs. Gavi is already engaged in blockchain technology to track funds and vaccines. Within digital health there is a strong focus on mobile health  using smartphones, which would enable health workers at all levels to track vaccines with mobile-phone applications, when packaging includes 2D barcoding; smartphone technology’s expanding sphere of influence could enable it to become the future of global health The World Health Assembly has broadly determined that the use of appropriate digital devices for public health can increase access to quality services, reduce maternal, child and neonatal mortality, increase health security and increase patient, family and community engagement While over 120 countries have reported having national digital health strategies So far, mHealth interventions have been largely on a pilot scale, many spearheaded by non-governmental bodies. The total market size of mobile health was estimated at US$23 billion by 2017, of which 42% was in the Asian Pacific, Latin American and African regions, with scaling up likely when governments embrace constructive policy for mobile health Barcoding significantly facilitates traceability and allows unit level data connection from manufacturer to end user, and is recommended by WHO on all vaccine packaging, except for primary packaging, following GS1 standards There have been divergent views on barcodes on primary packaging ; posing a technical challenge that could take several years to overcome, while a majority of manufacturers indicated implementation could occur much quicker. Some DCVMN member manufacturers are already pursuing barcoding on primary packaging to increase product security, given concerns about vaccines being diverted to parallel markets. This would also address secondary packaging being often discarded well before vaccination sessions, causing traceability to be lost before individuals are vaccinated. 2D matrix barcoding allows for fast and simple readability by downstream supply chain implementers and is already on primary packaging for vaccines used in developed countries The demands on manufacturers to support traceability down to the individual being vaccinated will become pressing as countries scale digital health, and it is an opportune time for manufacturers to:• understand the specific demand of country immunization systems, including digital health systems, in terms of the traceability of vaccines down to individuals being vaccinated;• model the options for including barcodes using GS1 standards at the primary packaging level;• estimate the potential capital and operating costs involved;• articulate financing options, which could include third-party grants to subsidize investment costs, advance market commitments to guarantee vaccine purchase volumes, the raising of vaccine costs, or potentially new financing innovations;2.Stockpiling• showcase pilots in improving traceability.Stockpile investments are an integral part of comprehensive disease control strategies, providing countries with the capacity for rapid response to vaccine shortages or emergency situations The shift in the global health landscape, with increased pressure from climate change, population increases and mass urbanization, heightens the risk of large-scale outbreaks and urban epidemics, continuously re-defining the role and size of vaccine stockpiles Gavi, which already supports cholera, yellow fever (YF) and meningococcal vaccine stockpiles, is working to mitigate the risk of outbreaks including creating the right market conditions to bolster vaccine stockpiles. Gavi provided an advance purchase commitment for an Ebola vaccine, ensuring its immediate availability and the eventual creation of a stockpile for future outbreaks. WHO has stated that the cholera stockpile has transformed a vicious cycle of low demand, low production, high price and inequitable distribution to a virtuous cycle of increased demand, increased production, reduced price and greater equity of access.9UNICEF manages four stockpiles for outbreaks and humanitarian emergency situations – measles and measles & rubella (MR), oral cholera, YF and meningococcal vaccines - as well as a monovalent Oral Polio Vaccine (mOPV) stockpile for both bulk and finished product. The advantage of global stockpiles is common governance with an accountability framework based on good partnership to overcome a “first-come, first-served” approach Some stockpiles are static, not shipped until an outbreak or epidemic occurs. Rotating stockpiles are shipped for routine immunization programmes and specific volumes should be available within 72 h, as stipulated in UNICEF tenders While there is considerable investment in vaccines tied to elimination strategies and on outbreak response, short-term shortages and stock-outs of vaccines disrupting routine immunization activities are widespread. Between 2010 and 2015, countries in all regions of the world and of all economic levels experienced regular stock-outs of key vaccines The likelihood of vaccine stockpiling becoming more prominent impels manufacturers to assess and determine their capabilities, conditions and best practices for retaining and expanding stockpiles, specifically to:• collect more information on global and regional stockpiling policies for both creating and financing stockpiles;• determine main contributions for manufacturers in creating, financing and maintaining stockpiles;3.New packaging technologies• identify potential efficiencies and financing options in stockpile management.Gavi, WHO, Bill and Melinda Gates Foundation, PATHVIPS has prioritized 5 upstream and 4 downstream innovations, of 24 assessed, based on health impact, coverage and equity impact, safety impact, economic costs and potential breadth of innovation use, with cost issues of upmost importance from country perspectives MAPs may be a priority as a case has been made for the MR vaccine The benefits of cPADs include delivering a correct dosage, low vaccine wastage, reduced logistics workload and reduced time by health workers to deliver vaccination. These benefits have been verified in Indonesia and Timor Leste where hepatitis B is delivered in a cPAD out-of-the-cold-chain in hard to reach areas Dual-chamber delivery devices for lyophilized vaccines can simplify the reconstitution process. MR dual-chamber injection devices reduce open vial wastage at any volume and can lead to an increase in MR vaccine availability While not an immediate priority of VIPS, BFS polymer containers have been shown to be the least expensive option for oral vaccines in terms of total cost of delivery and second to glass vials for injectable vaccines in multi-dose forms Improved packaging and presentation reduce stress on vaccine supply chains, through reduced volume packaging. There may be opportunities to reduce the packaging footprint in the cold chain. A smaller box for the safe delivery and storage of vaccines has been developed, halving the size of packaging, allowing twice as many doses to be shipped at once and occupying half the storage space, while removing all plastic to make it eco-friendly From surveys and interviews with DCVMN members during 2019, it was observed that many member manufacturers had not actively participated in the prioritization processes of VIPS, and would welcome to be engaged more actively in discussions around packaging innovations. This is particularly important as manufacturers will bear the costs of innovations and need to have the opportunity to voice the options they see on the practicalities, costs and financing of adopting innovations.The development of new packaging technologies requires partnership between vaccine and technology manufacturers, with key considerations being programmatic suitability include cold chain volume, costs, IP rights and health impact Innovations in packaging are largely aimed at increasing the ease of vaccination by health care workers while reducing vaccine wastage and in some reducing storage volumes. DCVMN manufacturers have to be more active in partnering with innovation developers to ensure that innovations are feasible and cost-comparable with current technologies, specifically to:• review the multiple innovations being developed by global stakeholders;• become fully familiar with MAPs, cPADs, dual-chamber delivery devices, reduced packaging footprints and BFS;• determine if additional innovations might be pursued by manufacturers;• intervene in design, prototyping and piloting phases;• identify any IP issues;• estimate the projected capital and operating costs of selected innovations;• signal potential financing options for the introduction of innovations.7Manufacturers have a significant stake in the vaccine supply chain as their reputations rest on the effectiveness of their vaccines at the point of vaccination. Manufacturers from developing countries are diverse in nature, being from distinct regions of the world and being either privately or state-owned. They agree, however, on finding ways to positively impact the vaccine supply chain through advances they can bring to vaccine production stages. This study provided an opportunity for manufacturers to express their views and served to identify areas where strengthening is warranted Traceability, stockpiling and the introduction of new packaging technologies have been selected as the initial priorities of a DCVMN vaccine supply chain expert group to engage manufacturers in a movement towards collective improvements.In looking at the next decade, the overall context includes a global move to digital health which can provide significant opportunities for improving the traceability of vaccines. Here, the labeling of primary packaging to include 2D barcodes will likely become a requirement in the near future and manufacturers adopting this first may likely gain considerable market share. It is considered that major opportunities lie ahead for digital health innovators A second driver will be the increased demand for stockpiling vaccines, both as a measure to address shortages and stock-outs as well as for preparedness for outbreaks and epidemics. A third driver will be technological innovations that significantly improve the workload and time investment of health workers in vaccination and reduce vaccine wastage.Key aspects for manufacturers to consider are the wider use of barcoding to enhance traceability, including the application to primary packaging, the increased use of stockpiling including buffer stocks, and new packaging technologies that include new primary containers. DCVMN manufacturers have to be more active in partnering with innovation developers to ensure that innovations are feasible and cost-comparable with current technologies. This implies to engage more actively in global stakeholders' forums, not as information recipients but as equal partners in determining the best ways forward for improving the vaccine supply chain.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


The association between dysregulated metabolic processes and development of pericyte pathologies will be highlighted. Despite ongoing debate regarding pericyte classification and their functional capacity for trans-differentiation in vivo, pericytes are increasingly exploited as a cell therapy tool to promote tissue healing and regeneration. Ultimately, the efficacy of therapeutic approaches hinges on the capacity to effectively control/optimize the fate of the implanted pericytes. Thus, we will identify knowledge gaps that need to be addressed to more effectively harness the opportunity for therapeutic manipulation of pericytes to control pathological outcomes in tissue remodeling.Pericytes are mural vascular cells found predominantly on the abluminal wall of capillaries, where they contribute to the maintenance of capillary structural integrity and vascular permeability. Generally quiescent cells in the adult, pericyte activation and proliferation occur during both physiological and pathological vascular and tissue remodeling. A considerable body of research indicates that pericytes possess attributes of a multipotent adult stem cell, as they are capable of self-renewal as well as commitment and differentiation into multiple lineages. However, pericytes also display phenotypic heterogeneity and recent studies indicate that lineage potential differs between pericyte subpopulations. While numerous microenvironmental cues and cell signaling pathways are known to regulate pericyte functions, the roles that metabolic pathways play in pericyte quiescence, self-renewal or differentiation have been given limited consideration to date. This review will summarize existing data regarding pericyte metabolism and will discuss the coupling of signal pathways to shifts in metabolic pathway preferences that ultimately regulate pericyte quiescence, self-renewal and  Pericytes are a heterogeneous population of mural vascular cells that typically reside within the basement membrane on the abluminal surface of most capillaries and some larger blood vessels. The pericyte basement membrane is contiguous with that of the endothelial cells and is composed of extracellular matrix proteins (predominantly collagen IV and the glycoprotein laminin) secreted by both cell types. Morphologically, pericytes are characterized by numerous cytoplasmic processes that emanate from a prominent cell body, tracking along several endothelial cells and occasionally spanning adjacent capillaries . PericytDuring development, pericytes are first attracted to newly formed capillaries via the endothelial-secreted chemoattractant platelet-derived growth factor (PDGF)-BB, which binds to PDGF receptor β (PDGFRβ) on pericytes . IntegriTo date, there is no molecular marker known to be unique to pericytes. Thus, a combination of general criteria are commonly used to define pericyte populations, such as perivascular localization, morphology and the expression of one or more recognized molecular markers such as Neural/glial antigen 2 (NG2), PDGFRβ or cluster of differentiation 146 (CD146) . HoweverPericytes that reside within an established microvessel network are dominantly quiescent. However, physiological expansion of the capillary network and a variety of pathological conditions trigger their activation and proliferation, which may result in self-renewal or in differentiation. During sprouting angiogenesis, pericytes initially detach from the vessel wall and assist in remodeling the basement membrane to enable endothelial cell sprout formation . ProlifeThe differentiation of pericytes into multiple lineages  is observed when these cells are cultured . This mutrans-differentiation capacity in vivo in multiple tissues assessed, including skeletal, cardiac and adipose tissues  failed to display  tissues . Notably tissues . As well tissues . This idssues , which generates oglycans . The HBPoglycans  and, theFatty acid oxidation is estimated to contribute to ∼15% of human placental pericyte ATP production . PericytIt is well-recognized that the differentiation of multipotent cells is accompanied by shifts in cellular metabolism. Glycolysis is associated with stem cell pluripotency  as it fuThe metabolic programing that supports pericyte status is under the control of signal transduction pathways that in turn are governed by local levels of stabilizing and mitogenic factors. Below, we will discuss molecular mechanisms that enforce quiescence, favor proliferation or induce commitment and differentiation of pericytes by driving changes in cellular metabolism. These pathways are summarized in The quiescent state of pericytes is preserved by cell-intrinsic programs but also by cell-cell interactions. This is achieved in large part by the cell adhesion protein N-cadherin, which mediates heterotypic cell contacts between endothelial cells and pericytes . Human pBesides the regulation imposed by cell adhesion molecules, pericyte quiescence is promoted by Notch signaling. Notch3 on pericytes interacts directly with Jagged-1 on endothelial cells to promote pericyte-endothelial cell adhesion while also inhibiting pericyte proliferation and migration . Notch sA similar enforcement of quiescence may be promoted by the Forkhead box O (FOXO) transcription factors. This family of transcriptional regulators maintains cellular quiescence in adult stem cells through repression of metabolic pathway genes and cell cycle activators . FOXO3A Growth factors that stimulate pericyte proliferation increase the uptake and utilization of available nutrients. For example, insulin promotes glucose uptake and induces glucose-mediated proliferation of bovine retinal pericytes . PDGF-BBGenerally, “stemness’ of pericytes is retained through cycles of proliferation. Maintenance of the stemness and multipotent state of pericytes is highly dependent on interactions with the basement membrane protein laminin. In the absence of this protein, brain pericytes develop the properties of a contractile cell . Stemnes+ human umbilical cord perivascular cells (presumptive pericytes), allowing them to proliferate and maintain their multipotency  is a hallmark of pericytes that are poised to undergo osteogenic or chondrogenic differentiation . Osteo-iic genes . During ic genes . Interplic genes .Metabolic state may contribute to determining pericyte fate decision toward osteogenesis. Runx2 expression itself is glucose-dependent  and its +) pericytes exhibit adipogenic potential and were shown to contribute to the generation of adipocytes when transplanted into glycerol-injured muscles (in vitro) and several studies point to additional roles of PPARγ beyond driving adipogenesis. In hematopoietic stem cells, PPARγ suppresses self-renewal while promoting cell differentiation, in large part through strong suppression of glycolysis (The peroxisome proliferator activated receptor gamma (PPARγ) transcription factor is recognized as a master regulator of pre-adipocyte differentiation and metabolism and its expression is strongly stimulated by exposing cultured pericytes to adipogenic factors . C/EBPβ  muscles . Further muscles . PPARγ aycolysis . Howeverycolysis .Nutrient availability can impact pericyte state in several ways. Hyperglycemia acutely increases glucose metabolism . In the O-GlcNac-modification of proteins, including insulin receptor and PDGFRβ, interferes with mouse retinal pericyte migration  . The resigration . FOXO1 migration . This suigration .Prolonged exposure to increased levels of fatty acids causes insulin resistance and lipid toxicity in many cell types . To datetrans-differentiation and interstitial fibrosis in mouse models of kidney disease , hypoxia-induced retinopathies (characterized by excessive neovascularization), and kidney and liver fibrosis . Studiestrans-differentiation of PDGFRβ+ pericytes into fibroblasts occurs within a tumor environment, which causes alterations to capillary structure and interstitial matrix components that ultimately enhance tumor invasion and metastatic potential (In vivo pathological activation of osteogenesis/chondrogenesis within pericytes can lead to ectopic ossification (Excessive differentiation of pericytes into smooth muscle cells also occurs in PAH and contributes to the pathogenesis and severity of the disease . In geneotential . In vivofication . This alfication . While efication , it is pThe capacity to fine-tune pericyte metabolism may provide mechanisms to optimize the function of pericytes used in regenerative medicine, through enhancing the survival and participation of these cells despite the unfavorable conditions found within the host ischemic or injured tissues. Pericytes, and related cell populations that have been referred to as ‘pericyte-like adventitial cells,’ ‘fibro-adipocyte progenitors’ and ‘mesenchymal stromal cells’ have been tested in various types of cell-based therapies and as tools for tissue bioengineering . To dateThe value of pericytes as a tool for cellular therapy is highly dependent on their capacity to survive and function within the environment to which they are delivered. The relative reliance of proliferating pericytes on glycolytic vs. oxidative metabolism may help to support pericyte survival when they are injected into ischemic cardiac or skeletal muscle . Howeverin vitro could be used to correct these deficiencies and to condition the cells for more effective functions once transplanted.Moreover, the success of pericyte-based therapies may be limited by the patient’s pre-existing disease. Although autologous transplantation is preferable to use, these cells may be deficient in number and/or function . For exaAn ongoing challenge in the field of pericyte biology is the inherent heterogeneity of this cell population. This has led to substantial study to study inconsistencies in the classification of pericytes, which in turn confounds the interpretation of research on pericyte functions. Thus, a comprehensive characterization of pericyte subtypes and validation of appropriate identifying markers for these populations are crucial next steps for advancing our knowledge of pericyte functions and differentiation potential. Single cell sequencing offers tremendous promise in establishing global gene expression signatures and novel molecular identifiers of pericytes, as well as enabling the discovery of subtype, tissue and disease-specific patterns of pericyte gene expression. With this knowledge, it will be possible to evaluate the extent to which pericyte subpopulations are pre-programed with discrete and tissue-specific lineage potentials and to identify which pericyte subgroups have the most favorable characteristics for use in regenerative cell therapies.in vivo, it will be important to determine if there is variability in metabolic programing that coincide with specific gene expression signatures. With the evolving advancements in metabolomics technologies, there is now unprecedented opportunity to map the metabolome of pericytes even to the single cell level and to identify the metabolic pathways that are integral to transitions in pericyte state and lineage commitment. Lastly, it is crucial to consider the impact of various pericyte isolation and culturing conditions on the signaling and metabolic pathways that regulate activation and differentiation potential, since this could greatly influence the reproducibility and efficacy of cell-based therapeutic treatments. Addressing these avenues of research not only will provide valuable insight into the contribution of specific metabolic pathways in shaping pericyte phenotype but it may also reveal new tools for the optimization of pericyte characteristics in pathological conditions and when used in cell therapies.Emerging evidence indicates that the regulation of metabolic pathways may offer the potential to manipulate the cell-state and fate decisions of pericytes, which could enable the development of novel strategies to control pericytes contributions to pathological conditions and their use in regenerative medicine. However, knowledge of pericyte metabolism is rudimentary to date and the overall understanding of how pericytes integrate signal transduction, metabolic programing and cell state/fate decisions currently lags far behind the state of knowledge of these relationships in other vascular and stem cells. Therefore, many fundamental questions remain to be answered. Considering the extent of pericyte heterogeneity All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


The body of research examining the validity of food addiction and eating addiction far exceeds the research examining their clinical utility. Although neither food addiction nor eating addiction are officially recognized diagnoses, many individuals self-identify as “food addicts” and/or exceed the cut-offs on measures of addictive-like eating. To be clinically useful, a diagnosis should inform the treatment plan and predict clinical outcomes. This special issue presents a collection of articles, contributed by renowned experts, researchers, and clinicians spanning different disciplines, that adds to the knowledge on the clinical utility of food addiction and eating addiction. The articles in this collection include reviews ,2,3,4,5 Oliveria et al.  examinedIn their international survey of health care professionals who potentially work with patients presenting with addictive eating behaviour , Burrows et al.  reportedWiss & Brewerton  contribuA number of authors contributed papers to this special issue that emphasize the need for individual-level and societal-level interventions for food addiction. In a sample of post-operative bariatric surgery patients, Cassin et al.  found thIn his review and commentary, Lustig  providesOther authors examined the similarities between food addiction and other forms of addiction, or the presence of addictive-like eating in other clinical populations. Zawertailo et al.  conducteCollectively, the articles included in this special issue suggest that individuals with food addiction, and particularly those presenting for treatment of food addiction, often have comorbid psychiatric diagnoses, body image concerns, and impaired quality of life, and that many health care professionals who potentially work with such patients feel that they need additional knowledge of, and training in, assessment and evidence-based treatments for food addiction. Similar to other addictions such as tobacco use disorder, a multi-component approach including both individual and societal intervention is warranted to reduce the personal and public health impact of food addiction.As research attention shifts from examining the validity to the clinical utility of food and eating addiction, many questions remain to be answered. What factors predict treatment seeking among individuals with food or eating addiction? What are the treatment preferences of individuals with food or eating addiction? Are existing evidence-based treatments for eating disorders or substance-related and addictive disorders effective among individuals with food or eating addiction? What can be done to improve the durability of treatment effects of those interventions that have already been examined and found to improve only short-term outcomes? What is the evidence for abstinence-based versus moderation approaches? How do patients experience each of these interventions? What do they find helpful and unhelpful, and what do they attribute any changes to? Recognizing that “one size will not fit all”, how can we move to personalized approaches to food addiction treatment ? We hope that the articles included in this special issue will provide the impetus to explore these important questions and generate knowledge to inform clinical practice guidelines.


Purpose: Racism is an essential factor to understand racial health disparities in infection and mortality due to COVID-19 and must be thoroughly integrated into any successful public health response. But highlighting the effect of racism generally does not go far enough toward understanding racial/ethnic health disparities or advocating for change; we must interrogate the various forms of racism in the United States, including behaviors and practices that are not recognized by many as racism.Methods: In this article, we explore the prevalence and demographic distribution of various forms of racism in the United States and how these diverse racial ideologies are potentially associated with racialized responses to the COVID-19 crisis.Results: We find that among white Americans, more than a quarter express traditional racist attitudes, whereas more than half endorse more contemporary and implicit forms of racist ideology. Each of these types of racism helps us explain profound disparities related to COVID-19.Conclusions: Despite a robust literature documenting persistent patterns of racial disparities in the United States, a focus on the role that various forms of racism play in perpetuating these disparities is absent. These distinctions are essential to realizing health equity and countering disparities in COVID-19 and other health outcomes among people of color in the United States. COVID-19 merely follows the existing pattern of racial/ethnic health disparities that sets the United States apart from many other countries. Public health scholars have made vital contributions to understanding these disparities, in particular documenting how segregation, institutional racism, and racial bias have contributed to excess morbidity and mortality for Americans of color. However, racism takes a myriad of forms, and these nuances have particular implications for how we address COVID-19 and other health disparities.2Many public health scholars, activists, and leaders were not surprised to learn of dramatic racial and ethnic disparities in COVID-19 morbidity and mortality.Racism can be defined as the ways in which individuals are privileged or disadvantaged, overtly and covertly, on a macro and micro level, based on perceived biological and cultural differences between groups, most often relative to skin color. Based on this definition, racism can result from the actions of individuals or institutions and can unfold in ways that are both intentional and unintentional. These distinctions may seem unnecessarily precise, but they have enormous implications for the promotion of health equity. Although many Americans still envision racism as individual prejudice, reminiscent of the Jim Crow era, racism has evolved to take on many different forms, some of which may be barely recognizable as racism. Each form has critical implications for understanding and addressing public health challenges such as COVID-19.3–10 These studies have helped to explain the shift from old-fashioned Jim Crow era biological explanations of racial inferiority to modern justifications for blacks' subservient group position. In addition, they have contributed to developing a better understanding of the harms of contemporary racial ideology that downplays the existence of racism at all.Sociologists have developed various theories of racism that seek to explain how and why whites have continued to preserve their power.old-fashioned racism—characterized by the belief that blacks are inherently inferior to whites; institutional/systemic racism—inequities rooted in the practice of social and political institutions; symbolic racism—the belief that black people are responsible for their disadvantaged social position; laissez-faire racism—the notion that blacks' cultural inferiority is to blame for racial inequality; and color-blind racism—the belief that racism and discrimination are no longer a problem and that equal opportunity exists.11 Understanding how different types of racial ideology may impede efforts to achieve equity is a necessary step to counteracting the effects of racism and developing antiracist ideology that reduces health disparities such as those found with COVID-19. In this article we explore (1) the prevalence and demographic distribution of each ideological type and (2) how these diverse racial ideologies are associated with COVID-19 disparities.Building on these theories, Adrienne Milner developed an operational typology of white racial ideology that encompasses N=2530). This survey of United States-based citizens aged 18 years and older  2016 Time Series Study . The institutional racism scale consisted of four indicators of how much influence respondents perceive white, black, Hispanic, and Asian people to have in politics (Cronbach α=0.82). The symbolic racism scale consisted of four of the eight indicators used in Henry and Sears's Symbolic Racism 2000 Scale (Cronbach α=0.86).12 The laissez-faire racism scale consisted of six indicators about whether respondents feel that blacks, Hispanics, and Asians were lazy or violent (Cronbach α=0.79). The color-blind racism scale consisted of three indications of whether respondents think there is discrimination against blacks, Hispanics, and Asians (Cronbach α=0.79). Because this analysis only employed secondary data, this study was not considered human subjects research by our institutional research boards.A combination of factor analysis and scaling techniques was employed to develop constructs based on the theoretical rationale for each type of racism: the The majority of white Americans possess more racist than less racist attitudes . AlthougThis profile highlights that those holding old-fashioned racist attitudes on average have a lower socioeconomic status in terms of education and household income than those exhibiting other types of racist attitudes. Conversely, those adopting color-blind racist attitudes tend to have a higher socioeconomic status than those who exhibit other types of racist attitudes. Across all types of racism, self-identified Republicans are much more likely to hold more racist attitudes than Democrats, with independents falling in the middle. Republicans are nearly three times as likely to adopt institutional racist attitudes, and more than two times likely to adopt symbolic and color-blind racist attitudes than their Democrat counterparts.How do different forms of racism shape COVID-19 disparities?13 Old-fashioned racism has become less prominent, although this form of racist ideology is still expressed by more than a quarter of the white population.It is logical that old-fashioned racism was the least adopted form of racism by white participants in our analysis. Before World War II, old-fashioned, or Jim Crow, racism was the dominant racial ideology in America. Characterized by the belief that blacks are inherently inferior to whites, old-fashioned racism promotes overt endorsement of nonegalitarian beliefs, such as support for racial segregation and open discrimination.14 Old-fashioned racist attitudes have also been evident in terms of responses to COVID-19 infection rates among black Americans with many white Americans blaming genetic differences, rather than social conditions for differences in outcomes.15 In addition to the short-term effects of discrimination, activation of the stress process16 and unemployment and poverty17 are strongly linked to a host of chronic disease outcomes, suggesting that COVID-19 might not only reveal existing disparities, but also create new patterns of racial inequality altogether.Although old-fashioned racism is no longer the dominant racial ideology in the United States, in the presence of a health threat brought forth by COVID-19, this type of racism seems to have been activated. Reports of harassment toward people of East Asian descent have skyrocketed. In addition to harassment and violence, Asian Americans are currently facing a disproportionate rate of unemployment in New York that stems at least partly from customers avoiding Asian restaurants and businesses.Not all racism occurs on the individual level, as racist ideology has shaped the structure and operation of major social institutions in ways that limit opportunity and perpetuate racial inequality. Racial ideas and ideology shaped US law, and through historical and governmental processes, functioned to create and dominate various racial groups. For example, scholars point to real estate practices such as redlining, voting laws, and educational policies that limit economic, political, and social opportunity for nonwhite Americans coming into contact with these institutions. This form of racism is particularly insidious because it is difficult, if not impossible to pinpoint the individual prejudice or racial ideology that is responsible for discrimination. As a result, this type of racism is often invisible to those not affected by it, and through downplaying its existence, whites can perpetuate existing inequality.18 Disparities in chronic disease have been tied consistently and causally to historical processes such as real estate practices, mass incarceration, and discrimination in educational settings.20 Redlining, for example, created widespread disinvestment in communities of color, and contributed to growing neighborhood racial segregation.21 Today you can view old redlining maps, which guided where banks were willing to invest, in comparison with rates of asthma, diabetes, and hypertension and see the historical connection between decades of discrimination and chronic illnesses that are primary risk factors for COVID-19 severity.22 Examples of how institutional discrimination shapes the current distribution of chronic health disparities are too numerous to count, but result from the proximity of nonwhite neighborhoods to factories and other environmental pollutants,23 poor housing stock that predisposes children specifically to lead and respiratory contaminants,24 and exposure to discrimination within white institutions that is associated with chronic stress and disease.26 The composition of America's communities, especially in urban areas, remains largely segregated and these patterns also shape where COVID-19 testing locations are present and the accumulation of political power that would allow for shared decision making in responses to the pandemic.27One of the early hypotheses of why COVID-19 has been associated with higher morbidity and mortality in predominantly black communities is that black Americans are more likely to have chronic diseases that are risk factors for severe COVID-19 infection.28 For example, disparities exist in insurance rates by race in the United States, but policies such as the Affordable Care Act (ACA) were heavily criticized for providing social welfare benefits without addressing the individual behaviors that were at the heart of insurance disparities.29 Lack of insurance is associated with poor health care access and the progression of chronic diseases that are primary risk factors for severe COVID-19 infection. Americans without health care coverage, who are disproportionately nonwhite, are not only at higher risk for infection from COVID-19, but also face considerable economic barriers if they need medical treatment in a hospital. The lack of support for policies to redress centuries of disparities in health care access is a direct result of racial stereotypes adopted within the framework of symbolic racism such as believing that black Americans themselves, rather than historic and persistent racism, are responsible for disadvantage.Symbolic racism involves the belief that black people are themselves responsible for any disadvantages faced. This contemporary version of racism includes downplaying the existence of historic and systemic racism and instead focuses on black people's perceived lack of ability to succeed compared with other racial minorities. This belief system can help us understand why many Americans are resistant to policies that would ameliorate racial inequality, especially in terms of widespread health disparities.30 Although the wealth gap is certainly a product of old-fashioned racism and discrimination built into systems and institutions, it is sustained by symbolic racism and the unwillingness of white Americans to support policies that target racial inequality.Beyond the health effects of COVID-19, Americans face a yet unknown economic future as businesses and local governments begin to recover from the effects of a near total economic shutdown. Unemployment due to COVID-19 is concentrated among nonwhite Americans, especially in the cities hardest hit by the virus. Again, COVID-19 did not create racial disparities in either health or wealth, but existing inequality makes it harder for people of color to weather the effects of COVID-19. Whites hold ∼10 times the wealth of black Americans and these resources are critical to surviving an economic recession.31 Laissez-faire racists do not feel that black people and other racial minorities are as capable as white people, especially in terms of employment because of the racial stereotypes they hold. Specifically, they feel that black people and other racial minorities should not be in positions that are thought to require intelligence, hard work, and composure or that provide racial minorities with power and responsibility over whites.Laissez-faire racism is the notion that blacks' cultural inferiority is to blame for the black–white gap in socioeconomic standing. Bobo and Smith argue that laissez-faire racism differs from symbolic racism in that it is rooted in a historical analysis of the changing economic politics of race.32 Jobs with less autonomy also activate the stress process in ways that make persons more vulnerable to severe illness and limit the ability to stay home during a pandemic or receive sick leave if one does become ill.33 In addition, laissez-faire racism results in a lack of racial minorities in decision-making positions. That is to say that white people, both as leaders in corporate and political settings, have been tasked with deciding when it is “safe” for their employees and constituents to end lockdown protocol. The result is that racial minorities who may also be at the most risk for COVID-19 severity are forced to go to work, use public transportation, and even vote in person against their personal safety preferences.34Laissez-faire racism is exemplified in people of color disproportionately working in jobs that are deemed essential or that require significant risk of exposure to COVID-19.9 argues that through the emergence of color-blind racism, whites have developed powerful explanations for contemporary racial inequality that exculpate them from any responsibility for the status of people of color. Color-blind racism allows whites to maintain their advantages without having to articulate at whose expense. For example, whites who say, “I don‘t believe in giving black people access to health care—they should get it themselves but are too lazy to get a job” is thought to reflect a laissez-faire racist ideology, an older form of cultural racism. In contrast, whites who say, “I do not believe in giving black people access to health care because no one should get anything because of their race” could reflect a new form of modern or color-blind racism (adapted from affirmative action example given in Bonilla-Silva9).Color-blind racism refers to a new racial ideology rooted in apathy and disagreement with government policy, ensuring the fair treatment of racial minorities. Bonilla-Silva10 Epidemiologists have uncovered patterns of premature aging or “weathering” among nonwhite Americans who experience subtle forms of interpersonal aggression by people who claim to not be acting with prejudice. This very type of chronic stress, however, has been linked to a vast array of illnesses, from premature labor to hypertension, and heart disease—all of which may exacerbate the severity of COVID-19 infection and mortality from the disease.Although the emphasis on cultural stereotypes epitomizes symbolic racism, a more covert, and perhaps insidious, form of racism operates among Americans who simply do not think that race any longer affects social, health, or economic outcomes. The result is racial apathy, or the feeling that race no longer is of consequence and as such the topic of racism can be avoided.35 Past studies have shown that black patients routinely wait longer for medical care, receive fewer pain medications, and are referred less often to the transplant list.36–38 In the context of COVID-19, unconscious or implicit bias likely shapes decisions for who gets medical treatments, especially when resources are scarce, such as being admitted to a hospital or receiving a ventilator. Other examples may extend to the receipt of personal protective equipment (PPE) for nonwhite medical professionals and essential workers or on who receives COVID-19 tests if presenting with symptoms. A teacher from New York is just one example of a black patient meeting the criteria for a test yet not receiving one until her illness had progressed to a point that it eventually killed her.39Evidence suggests that individuals who do not view themselves as racist often act in discriminatory ways, sometimes to their own surprise. There is growing evidence that physicians may unintentionally favor white patients and provide disproportionate time, warmth, and medical resources.Determining the manner in which different types of racism shape health disparities is essential for counteracting the effects of modern racist ideology and promoting health equity. Although racism is certainly at the heart of inequality in outcomes related to COVID-19, many white Americans do not see themselves as participating in or perpetuating a racist social system. As such, it is necessary to elaborate the myriad ways that racism persists in the United States and contributes to social and health inequality. It is simply not enough to state that racism exists.True antiracism and the elimination of health disparities will require interrogation of the different forms racism takes. Old-fashioned, systemic, symbolic, laissez-faire, and color-blind racist ideology, we argue, each help us understand how and why whites have continued to maintain their privilege and health advantage—especially during a global pandemic. Our descriptive analysis (1) illustrates that contemporary forms of racism are especially prevalent among white Americans and (2) provides examples of how these diverse racial ideologies are potentially with racial/ethnic disparities related to COVID-19. Thus, there is an apparent need to go beyond studying racial health disparities using broad classifications of racism and also focus on how specific types of racism contribute to differential outcomes. Only then can we develop antiracist countermeasures that address the complex ways in which various types of racism challenge the promotion of health equity in the United States.


Despite achievements in the reduction of malaria globally, imported malaria cases to the United States by returning international travelers continue to increase. Immigrants to the United States from sub-Saharan Africa (SSA) who then travel back to their homelands to visit friends and relatives (VFRs) experience a disproportionate burden of malaria illness. Various studies have explored barriers to malaria prevention among VFRs and non-VFRs–travelers to the same destinations with other purpose for travel–but few employed robust epidemiologic study designs or performed comparative analyses of these two groups. To better quantify the key barriers that VFRs face to implement effective malaria prevention measures, we conducted a comprehensive community-based, cross-sectional, survey to identify differences in malaria prevention knowledge, attitudes, and practices (KAP) among VFRs and others traveling to Africa and describe the differences between VFRs and other types of international travelers.Three distinct populations of travelers with past or planned travel to malaria-endemic countries of SSA were surveyed: VFRs diagnosed with malaria as reported through a state health department; members of the general VFR population (community); and VFR and non-VFR travelers presenting to a travel health clinic, both before their pretravel consultation and again, after return from travel. A Community Advisory Board of African immigrants and prior qualitative research informed survey development and dissemination. Across the three groups, 489 travelers completed surveys: 351 VFRs and 138 non-VFRs. VFRs who reported taking antimalarials on their last trip rated their concern about malaria higher than those who did not. Having taken five or more trips to SSA was reported more commonly among VFRs diagnosed with malaria than community VFRs . Among travel health clinic patients surveyed before and after travel, VFR travelers were less successful than non-VFRs in adhering to their planned use of antimalarials  and employing mosquito bite avoidance techniques . VFRs who visited the travel health clinic were more likely than VFR respondents from the community to report taking an antimalarial , or to report bite avoidance behaviors .We observed heterogeneity in malaria prevention behaviors among VFRs and between VFR and non-VFR traveler populations. Although VFRs attending the travel health clinic appear to demonstrate better adherence to malaria prevention measures than VFR counterparts surveyed in the community, specialized pretravel care is not sufficient to ensure chemoprophylaxis use and bite avoidance behaviors among VFRs. Even when seeking specialized pretravel care, VFRs experience greater barriers to the use of malaria prevention than non-VFRs. Addressing access to health care and upstream barrier reduction strategies that make intended prevention more achievable, affordable, easier, and resonant among VFRs may improve malaria prevention intervention effectiveness. Despite global achievements in reduction of malaria morbidity and mortality , numbersCompared to other travelers to the same destinations VFRs have a disproportionately high prevalence of travel-related morbidity, particularly infectious diseases , includiHealth disparities and poor health outcomes among immigrant populations are associated with limited English proficiency and discordant languages between providers and immigrant patients –19, raciTo better characterize key barriers to effective malaria prevention among VFRs, we conducted a comprehensive community-based, cross-sectional, survey of US travelers to malaria-endemic countries in sub-Saharan Africa (SSA) informed by earlier qualitative research and community engagement . This stFor this cross-sectional survey, participants were recruited into one of three study arms: 1) imported malaria cases reported to a state health department, 2) the general population of VFR travelers originally from SSA, also referred to as “the community,” and 3) patients (both VFRs and non-VFRs) attending a travel health specialty clinic with upcoming trips to destinations in SSA .All cases of malaria diagnosed and reported to the Minnesota Department of Health  were reviewed for eligibility and inclusion in the imported malaria case arm of the study. Consenting US residents diagnosed with incident travel-associated malaria from January 1, 2016, through December 31, 2018, in Minnesota and reported to the state health department, and who traveled for any reason to SSA, were eligible for survey participation. When the case patient was under 18 years of age, only a parent or guardian proxy was eligible to respond on behalf of his or her child. Resettling immigrants, permanent residents of an African nation visiting Minnesota, or people surveyed after April 1, 2019, as a component of ongoing case investigation were ineligible. For the present article, only cases whose reported reason for travel was to visit friends and relatives were included in the analyses.The VFR general population (community) arm of the study consisted of surveys of past or prospective VFR travelers conducted at community events, online, and at a local emergency department (ED). Survey responses in the community arm were solicited from September 1, 2017, to April 1, 2019. For surveys of the community, eligible VFR travelers were defined as US-resident first- or second-generation immigrants from SSA; 18 years of age or older who had heard of malaria; capable of communicating in English, Amharic, French, or Somali; who either returned from travel to a country in the past 10 years, or plans to travel to a country in the next one year in SSA that is considered endemic for malaria . CommuniFor the travel health clinic arm of the study, patients preparing for travel to countries in SSA with endemic malaria  and seekA formal sample size calculation was not performed for each arm due to the limited number of eligible respondents in some survey groups, multiple study population subgroups, and lack of reference data in the literature. Within the malaria case arm, participation was limited to reported cases of imported malaria resulting from travel to SSA, and the ability to reach potential respondents through reported phone numbers. The target was to survey 75% of eligible travelers with confirmed malaria where a working phone number was available. The three-pronged approach  used in the community arm to solicit survey responses was designed to reach a broad VFR traveler population. Target sample size in the community arm was established at 100 West African VFRs and 100 VFRs from other countries of SSA. Finally, a target of more than 100 responses was established for each of the three groups in the travel clinic arm: West African VFRs, other VFRs, and non-VFRs. Although community-based participatory research has become a more commonly used method in public health studies, it has been used only rarely in travel medicine ,31 despiSurvey questions were constructed around malaria KAP, in addition to demographic characteristics. Trip and experiential characteristics were also queried, including destination, frequency of travel, length of stay, travel with children, and past experiences with malaria. Although mosquito coils are not recognized as an effective mosquito avoidance approach, focus groups performed identified that some VFRs use them to avoid bites ; a questA master survey, uniformly replicable across the multiple survey groups, was developed to allow for cross-arm comparison. Survey versions were modified for length and applicability for each setting as noted in Supplemental Materials online.Survey participants in all three arms were classified as VFR travelers if they met the US Centers for Disease Control and Prevention (CDC) definition for a VFR, “a traveler categorized as a VFR is an immigrant, ethnically and racially distinct from the majority population of the country of residence (a higher-income country), who returns to his or her home country (lower-income country) to visit friends or relatives…”  except wWest African travelers were defined as persons traveling to countries within the Global Burden of Disease (GBD) West Africa region . TraveleFor in-person and online participation, the informed consent process was documented with participants’ signatures or checking a box to indicate consent was granted. In the malaria case arm where participants were surveyed over the phone, the established, approved protocol for the interview of reportable infectious disease cases were followed and included summarizing the reason for the call, explanation of voluntariness, provision of the Tennessen Warning, and written documentation of verbal consent by the surveyor. In the travel clinic arm, the information and consent forms were read to potential participants, verbal consent was documented by the surveyor in the database, and participants received a copy of the information form by mail along with their incentive and educational material. In the malaria case arm, surveys developed for phone calls were not translated; professional telephone interpreters  assisted in live, bidirectional interpretation for case surveys when the participant had limited English proficiency. Surveyors attempted to contact cases weekly by telephone up to six times. Surveyors were trained to avoid prompting or validating certain responses while also allowing respondents to elaborate on their experiences as they wished to develop rapport.For the community and travel clinic arms, surveys, consenting documents, and post-survey informational handouts were professionally translated from English to French, Amharic, and Somali. Global Translator and Interpreter  translated, back-translated, and certified all translations. At the travel clinic and ED survey sites, surveyors proficient in Somali and French used translated study documents to conduct surveys in person or over the phone, directly in the patient’s preferred language, and later translated the responses back to English. Interpreters in the travel clinic and ED, guided by translated documents, assisted in in-person and telephone survey interpretation when a language-proficient surveyor was unavailable. When surveying the community, paper surveys translated into English, Amharic, French, and Somali were available for participants to self-administer the survey. The online survey was in English only. Participants in the community and travel clinic arms received travel health and malaria-related informational materials upon completion of the survey. Where not prohibited by survey site regulations or Institutional Review Board (IRB) stipulations, participants were eligible for a gift card honorarium for their time.A study team member monitored data collection for all arms throughout the survey period and conducted initial and iterative training sessions with surveyors and survey recruiters. REDCap databases  were developed and hosted within the Minnesota Department of Health, University of Minnesota, Hennepin County Medical Center, and HealthPartners Institute as approved by IRBs to collect survey responses and monitor recruitment.All data, including free-response prompts, were reviewed for protected health information by hosting organizations and completely de-identified before integration into a final data set. Variables corresponding to identical or largely identical prompts across the three survey arms were merged in the final data set for comparative analyses.Subgroups were formed among survey arms to facilitate comparisons of characteristics and outcomes. For analyses limited to participants meeting the VFR definition, a combined group was created that included VFRs in survey arms 2 (community) and 3 (travel clinic), and was termed “non-cases,” to allow for comparison with malaria cases reported to the health department . Within 2) for parametric relationships. Where goodness of fit statistics identified poorly fitting continuous predictors , predictors were transformed to improve normality and fit; transformations are described where performed. For Likert scale-structured responses, the nonparametric Mann-Whitney U test was used to evaluate pairwise statistical differences due to noncontinuous distribution, plus evidence of skew and non-normality. Odds ratios are presented for comparisons where relevant. The significance level was set for all analyses at α = 0.05. Statistical analyses were performed in SAS version 9.4 . Data are visualized in Excel version 2016 .Descriptive summary statistics of relevant outcomes and characteristics and comparative analyses stratifying outcomes by survey arm or traveler population were performed. Comparative analyses were performed using Wald’s Chi square statistic , University of Minnesota (STUDY00001189), Hennepin Healthcare Research Institute, formerly Minneapolis Medical Research Foundation of Hennepin County Medical Center (HSR#17–4350), and HealthPartners Institute (IRB0#A14-011). The study was funded by a cooperative agreement from the Centers for Disease Control and Prevention (CDC) (CK000357-01). CDC did not engage in data collection; human subjects review at CDC was not solicited.A total of 351 VFRs and 138 non-VFR travelers participated across the three survey groups . Among tAverage and median trip duration among VFRs was 7.0 and 4.0 weeks respectively (range 0.3–72 weeks) . Non-norVFRs at the travel clinic were US residents longer than VFRs surveyed in the community . Having a primary care provider was reported among 88.3% (159 of 180) of VFRs; travel clinic VFRs  were more likely than community VFRs (surveyed in the ED only)  or travelers with malaria  to have a primary care provider.VFRs who reported taking an antimalarial on their last trip  were statistically significantly more concerned about malaria , but some differences across groups were observed : VFRs atSlightly fewer than half  of all VFRs were male; travelers with malaria were disproportionately male  compared to the community  or travel clinic  VFR respondents. Malaria case VFRs  had 2.7 times greater odds of having taken five or more trips than non-case VFRs  . Five or more trips to SSA while residing in the US were reported by 44.0% of malaria cases (11 of 25); fewer case respondents took two to four trips to SSA  or became ill on their first trip to SSA .Malaria case VFRs (= 0.035) . A statiOverall, non-case VFRs  had 3.9 times greater odds of using an antimalarial than diagnosed malaria case VFRs  . Nearly three-quarters  of community VFRs saw a health care provider before their last trip, whereas 41.9% (18 of 43) of malaria cases saw a provider (p<0.001). Community VFRs were more likely than travelers with malaria to use preventive behaviors , includiVFRs traveled statistically significantly longer  than non-VFRs  in the travel clinic (p<0.001). There was no difference in the number of prior trips between non-VFRs and VFRs.Before their trip, travel clinic VFRs were more likely than non-VFRs to plan to use certain malaria prevention approaches including: picking where they stayed to avoid mosquitoes , staying indoors when mosquitoes are out , and using mosquito coils  . Figs 3 While immigrant health outcomes are often studied in relation to assimilation to their new home country , establiThis is the first epidemiologically robust evaluation of malaria KAP and barriers to prevention with evidence to challenge many long-held beliefs around VFR behavior. In the travel clinic, non-VFRs reported statistically significantly lower concern about acquiring malaria than VFRs, while differences in level of concern were not observed between VFRs surveyed in the travel clinic and VFRs community. This challenges common assumptions that VFRs are less worried about malaria than other types of travelers , 33, 34.Although commonly described as a single population, VFR traveler subgroups may vary in their adherence to malaria prevention and in their interactions with health care systems ,12,27. SOur results demonstrated unique differences among VFRs from SSA, even among those residing in one area of the United States. Compared to West African VFRs, East African VFRs who made up most of the “other SSA” VFR subgroup, travel for longer duration, had a shorter length of United States residency, a lower likelihood of a postsecondary education, and have taken fewer trips as VFRs. As these newer arrivals to the United States become more settled, we expect that East African immigrants may become an emerging traveler population to destinations with malaria. Future interventions developed in anticipation of increased travel within this group that account for unique needs such as longer travel duration and lower education may be more impactful within this group.When comparing VFRs by location of pretravel care, VFRs at the travel clinic had a greater level of awareness that malaria can be prevented as compared to other VFRs surveyed in the community who may have had no pretravel health care or visited only a primary care provider. Travel clinic VFRs were also more likely to report having a primary care provider than malaria cases or VFRs surveyed in the community, suggesting travel clinic VFRs may reflect a sub-population more familiar with preventive health, better linked to, or better able to navigate the health care system. However, the findings for the community may be biased since emergency department users may be less likely to have a primary care provider. Maintaining an identified primary care provider has been shown to be protective for other preventable health conditions in US immigrant populations ,35, whilAlthough reported antimalarial use among community VFRs was greater  or similOne finding identified across all VFR subpopulations in this convenience sample of travelers from a variety of settings was that while malaria knowledge may not have been strongly associated with malaria prevention, attitudes and risk perception for malaria did correlate with preventive behavior. Taking an antimalarial or using insect repellent was associated with statistically significantly higher concern for malaria during travel. There are also potential structural barriers more likely to impact VFR travelers than others taking trips abroad. VFRs consistently report trips of long duration; in preparation for such travel, VFRs may face barriers in obtaining sufficient antimalarial medication to cover the entire length of their visits, especially when Medicaid or private insurance plans in the United States limit antimalarial dispensing to a 34-day supply and may not permit vacation overrides .By comparing the characteristics of post-travel malaria cases with the characteristics of a broader representation of VFR travelers from the same area, we can begin to form hypotheses about some of the behavioral and demographic risk factors related to prevention failure. Males were greatly overrepresented among surveyed malaria cases compared to VFRs surveyed in the community and travel clinic groups. This is consistent with international surveillance reports for imported malaria to nonendemic, high income countries . In otheIt is possible that multiple factors contribute to failure of malaria prevention in VFR travelers. Although having largely comparable knowledge about malaria, diagnosed case VFRs were more likely than other VFRs to list incorrect or non-existent methods of preventing malaria—most commonly, use of malaria vaccine. This suggests that misconceptions around being immunized against malaria could provide some VFRs with a false sense of protection, inhibiting their use of other (more effective) preventive measures.While participants surveyed in other settings were excluded if they had not heard of malaria before, this was not an exclusion criterion for malaria cases under the presumption that due to their diagnosis, cases had some knowledge of malaria at the time of the survey. Malaria cases may have been included that had not heard of malaria prior to becoming ill and thus may have been more likely to report incorrect methods of preventing malaria. Based upon the infrequency that this criterion excluded participants in other settings, the anticipated effect of this potential bias in baseline knowledge is hypothesized to be negligible or minimal. Overall, neither listing an incorrect prevention approach or method of contracting malaria were statistically correlated with decreased antimalarial use.Travelers who contracted malaria during their most recent trip appeared to be more frequent travelers than other VFR travelers and reported lower concern about malaria before travel. These differences suggest that risk perception and preventive behaviors may wane among VFRs after repeated healthy trips . RepeateThe three-arm approach used to survey VFRs demonstrated differences in stratified subpopulations and reflected a broad range of malaria prevention KAP. However, because of the lack of a known, representative VFR population or reliable census data describing this group, the representativeness of the study population cannot be estimated. The extent to which non-VFRs surveyed in the travel clinic reflect the underlying traveling population to malaria-endemic areas is unknown and was not explored in the study design. Non-VFRs were only surveyed through their engagement with pretravel care; for this reason, malaria prevention may be overestimated in this population. Expanded or targeted community-based studies would be necessary to achieve a more representative sample of the overall traveler population.Sampling techniques in this study targeted areas with large numbers of immigrants from SSA and may be representative of the Minnesota VFR population. The study may not be generalizable to other African VFR population centers in the United States or internationally. However, findings from focus groups performed with West African VFR travelers both in Minneapolis-St. Paul and New York City  do alignWhen identifying study participants with documented cases of malaria, we were limited to recruiting those diagnosed in Minnesota, and likely underestimated both persons who became ill and were treated abroad, as well as those who did not seek diagnosis and treatment at a United States hospital upon return from travel. A malaria-like illness on a past trip was self-reported by 11% of VFR travelers in community and travel clinic groups. As many illnesses present with similar symptoms to malaria, this is likely an overestimation of the malaria prevalence in the VFR traveler population, but it suggests that there may be unreported malaria cases in this population, especially if they self-treat their symptoms with antimalarials procured prior to travel or while abroad. During the study period, potentially eligible cases were lost to follow up as many had non-working phone numbers. Systematic and directional bias could affect case responses towards respondents more willing to talk to a state government representative, or towards those with more reliable phone accounts. Age and gender distribution of sampled cases was not statistically significantly different from all reported malaria cases in Minnesota during the same time period.In all populations, social desirability and correct answer bias could skew results toward the over-reporting of preventive behaviors or affirmative reporting of behaviors used inconsistently. Despite this, the differential between planned and adhered to preventive behaviors should theoretically remained constant and reliable, assuming prevention was overreported equally among travelers who had traveled and those who were planning to travel soon. Attempts to minimize this source of bias were incorporated into survey design, and techniques were used to develop rapport with respondents and pose the questions without prompting a preferred answer.As the gold standard for malaria prevention in travelers, correct use of chemoprophylaxis is critical. Consistent with recent literature, this study found that malaria knowledge alone did not translate to successful malaria prevention. Interventions that communicate to VFRs the severity of malaria illness, the importance of pretravel health care, and the necessity for chemoprophylaxis would address barriers identified in this study. Strategies to make intended malaria prevention easier, more affordable, and more accessible, can help improve the likelihood of adherence to recommendations.Although VFRs at the travel clinic may be better engaged with preventive and pretravel health care than their VFR peers surveyed in the community, specialized pretravel care does not appear to ensure chemoprophylaxis use among VFRs. Raising the level of concern for malaria and communicating its severity while also conveying the high level of effectiveness of malaria prevention when followed properly may be key messages that increase uptake of chemoprophylaxis among VFRs. Improving access to primary care and general preventive health in immigrant populations may have impacts on issues such as malaria and travelers’ health.Heterogeneity of barriers to malaria prevention exist within VFR groups and across traveler populations. Addressing access to health care and upstream barrier reduction strategies that make intended prevention more achievable, affordable, easier, and resonant among VFRs may improve malaria prevention intervention effectiveness. Future research needs include working to quantify the more impactful behavioral barriers proposed in the literature specifically in the VFR population instead of across traveler populations broadly. The detail of analysis and subgroup analysis presented in this study may serve as a model to be replicated in future work when examining the VFRs’ specific barriers to malaria prevention.S1 ChecklistChecklist of reporting guidelines for observational studies.(PDF)Click here for additional data file.S1 DatasetData set contains de-identified data for eligible records and an accompanying data dictionary.(XLSX)Click here for additional data file.S1 DocumentSurveys and consent materials are included for the five survey versions used across the three study arms. Materials are ordered as follows: S2.1) Consent and Survey– 2016 Case Interview—Pilot Instrument; S2.2) Consent and Survey–Final Case Interview; S2.3) Consent and Survey–Emergency Department; S2.4) Consent and Survey–Community Paper and Online; S2.5) Consent and Survey–Travel Clinic.(PDF)Click here for additional data file.