The emergence of porcine epidemic diarrhea (PED) in commercial swine in North America and growing concerns about the potential for the introduction of African swine fever (ASF) from China, the European Union, or other affected regions has put a spotlight on the possible role of contaminated feed and feed ingredients in the introduction and transmission of viral swine pathogens. This paper systematically reviews the scientific literature regarding whether non-animal origin ingredients of commercial swine feed could introduce or transmit viral pathogens of swine into or within the United States. The purpose of this review is to identify, evaluate, and summarize the relevant scientific knowledge, published through March 2018, and to identify information gaps and research needs, thereby making the available evidence more accessible to policy makers, the swine industry, and the scientific community. A total of 26 documents were selected for the final review process, which included experimental studies, case reports, epidemiological investigations, and scientific opinion, among others. The review found that the scientific literature has addressed some critical experimental questions pertaining to transmission of swine viruses via feed and feed ingredients, but the current body of scientific knowledge lacks conclusive evidence of virus contamination of non-animal origin feed ingredients of commercial swine feed, particularly for imported commodities, and further investigation into the epidemiology of virus transmission via feed to swine under field conditions through natural feeding behavior is warranted. Additional studies of how imported ingredients of commercial swine feed are sourced, processed, transported and, thus, contaminated prior to importation into the United States are needed. Moving forward, studies designed to examine the likely source(s) of contamination and subsequent virus mitigation steps in processing and post-processing may be the most fruitful focus of research. Over the past three decades, the swine industry in the United States has experienced several significant disease outbreak events with highly pathogenic viral pathogens, including porcine reproductive and respiratory syndrome virus (PRRSV), porcine circovirus type 2 (PCV2), and, most recently, the swine enteric coronaviruses, including porcine delta coronavirus (PDCoV) and porcine epidemic diarrhea virus (PEDV) –4. TheseDuring the 2013–2014 outbreak of porcine epidemic diarrhea (PED) in North America, contaminated feed and feed ingredients were suspected as a potential introduction and/or transmission route for spread as early cases of PED in Canada were associated with a common feed source containing spray-dried porcine plasma (SDPP) –9. AdditDespite extensive investigative work in the field and the laboratory, the specific mode of introduction of exotic viral pathogens such as PEDV into the United States and, subsequently, into domestic swine premises remains unknown. In order for feed or feed ingredients to be a route of disease introduction into the United States, they must become contaminated with the causative agent; avoid inactivation through (trans-oceanic) transport, feed manufacturing, processing, and distribution; and be ingested at a dose sufficient to cause infection in a susceptible pig.Salmonella are known to be transmitted via swine feed —and the occurrence of emerging swine diseases in new geographic ranges  and/or with increased pathogenicity  suggests that the critical production inputs along with existing biosecurity and mitigating measures that have historically delivered an acceptable level of protection may need to be re-evaluated.In order to better inform policy makers, swine industry stakeholders, and the scientific community, a literature review was conducted on the scientific evidence regarding whether non-animal origin ingredients of commercial swine feed could introduce or transmit viral pathogens of swine into or within the United States. The goal of the literature review is to understand the current scientific knowledge and to identify information gaps. The results may support future scientific research for evaluating the risk of entry of exotic viral pathogens via specific feed ingredients from source countries and mitigation measures to prevent exposure to U.S. swine populations.This literature review aims to answer the following research question:What evidence is available in published scientific literature regarding whether non-animal origin ingredients of commercial swine feed could transmit viral pathogens of swine into or within the United States?The methodology of this literature review follows the framework of a qualitative systematic review . The litA search of the National Library of Medicine/PubMed, National Agricultural Library/PubAg, National Agricultural Library/Navigator  and Google Scholar was conducted to identify published scientific literature pertaining to evidence regarding whether non-animal origin ingredients of commercial swine feed could transmit viral pathogens of swine into or within the United States. Studies published any time through March 2018 were identified.Focus on non-viral pathogensFocus on disease transmission routes other than feed and feed ingredientsAnimal origin feed ingredientsFocus on mitigations/treatment/disinfection of equipment or sanitizing feedNo English translation availableFull text not availableDuplicate publicationSubject matter outside the scope of the review.The study selection process was performed in two stages. In the first stage, an initial screening of search results was performed based on title and abstract. In the second stage, the full text of the preliminary list of studies was evaluated. Additional articles were obtained through manual review of reference citations in the relevant literature. The most common reasons for exclusion, in descending order, were: focus on disease transmission routes other than feed or feed ingredients; focus on mitigations/treatment/disinfection of equipment or sanitizing feed; subject matter outside the scope of the review; and focus on animal origin feed ingredients. The two-stage study selection resulted in retention of 26 included studies. The studies included for the qualitative analysis are reported in The data extraction component is the process by which research reviewers obtain the necessary information about study characteristics, methods, and findings from the included studies. The quality assessment component aims to identify internal and external validity of the selected studies. Standardized data extraction provides consistency in a literature review, thereby reducing potential bias and improving validity and reliability .A fillable, pdf data extraction form template was created for the purpose of this literature review. Twenty-six published articles were included in the data extraction and quality assessment process. Reviewers worked in pairs to perform the data extraction and quality assessment. Each article was reviewed for general information, study characteristics, and outcome results. For the quality assessment portion, the reviewers reported on potential sources of bias, shortfalls in the statistical and analyses methodology, the quality of reporting, and the generalizability of the study to the commercial swine industry in the United States. The data extraction form template is provided in the supplementary information A qualitative, narrative approach was used for the data synthesis and report writing. The information extracted in the data extraction process was summarized into a data synthesis table. This table is provided in The 26 studies included in this literature review were collated into three categories: background information on risk factors for transmission and virus survival on fomites, epidemiology and outbreak investigations, and experimental studies with swine bioassays. Information extracted from these studies may overlap into more than one category and, thus, may be discussed in more than one section. Additionally, the study summaries provided in this section are not meant to be detailed and fully comprehensive but rather are focused on the information pertinent to this literature review, namely, non-animal origin feed ingredients.post-hoc outbreak investigations, and experimental studies of the survival of viruses in contact with fomites. The studies are grouped into two categories: risk factors for virus transmission and virus survival in contact with fomites. The virus scope of these studies includes African swine fever virus (ASFV), porcine high fever disease virus, highly pathogenic PRRSV, pseudorabies virus (PRV), Aujeszky's disease virus, and blue eye disease virus.Numerous investigators have reviewed the epidemiology and impact of swine viral pathogens and analyzed industry expert opinion and outbreak information to identify risk factors for transmission of swine pathogens. Additionally, several studies have looked at the survivability of viruses on various fomites related to swine production and husbandry, including feed and feed ingredients. Methods used by these investigators include expert elicitation, questionnaire-based Three studies examined the epidemiology of specific swine pathogen(s) or outbreak events in various regions of the world –17. The Le et al.  conducteA retrospective case-control study by Fasina et al.  sought tA review by Guinat et al.  summarizBrookes et al.  elicitedThree studies examined virus survivability on various swine-related fomites, including feed and feed ingredients –23. The Schoenbaum et al.  conductePirtle and Beran  conducteMartínez-Gamba et al.  conducteIn summary, most of the reports and studies summarized above were not designed to focus on non-animal origin feed and feed ingredients as a potential vehicle for virus transmission; however, feed and feed ingredients were included in the study design or discussion. Similarly, some findings in this group of studies may not be generalizable to other viruses or virus families or the commercial swine industry in the United States. Given these limitations, several key points are highlighted below.Le et al.  identifiSeveral investigators have examined the persistence of viral activity in the presence of various fomites, including non-animal origin feed ingredients. In experiments in which they spiked fomites with stock virus, they found, in general, that viral activity did not persist for long periods of time under the experimental conditions used. Schoenbaum et al.  found thAmong the knowledge gaps identified in these studies are the need for a comprehensive evaluation of potential transmission pathways involving non-animal origin feed ingredients and swine viruses. The scientific literature regarding the survival times  for various non-animal origin feed ingredient/pathogen combinations as well as determination of infectivity is incomplete and warrants further studies along with documented replication of studies. Furthermore, the likelihood of non-animal origin feed ingredients incurring contamination and documented scenarios in which cross-contamination occurs under field conditions is unknown.In 2013, swine enteric coronaviruses, such as PEDV and PDCoV, emerged as pathogens of significance for the swine industry in the United States and several other countries. Efforts were made to describe the epidemiology of the outbreaks which included a focus on the sources of virus introduction and transmission. Among other things, feed and non-animal origin feed ingredients were suspected as one possible route of virus introduction and spread. Studies reviewed in this section were separated into two major categories: epidemiological reports, reviews, and surveys; and feed and feed ingredient experimental studies. These studies are primarily focused on PEDV and PDCoV; however, other swine pathogens are included such as transmissible gastroenteritis virus (TGEV), PRRSV, and PCV2.Eight epidemiological reports examining the global outbreaks of PED and PDCoV infection were reviewed. The geographic scope of these reports include Europe, Asia, and North America , 24–30. High levels of infectious PEDV are shed in feces, contributing to contamination of various fomites, including vehicles, humans, and feed.The transmission of PEDV via feed has been shown but more data are required to assess its epidemiologic importance.Food waste fed to pigs (swill) can contain PEDV but epidemiologic role of this finding is unknown.In 2014 and 2016, the European Food Safety Authority published two reports pertaining to PED and PDCoV , 30. In In 2016, the European Food Safety Authority published a scientific report of PEDV epidemiology and impact as reported in the scientific literature in 2014 and 2015, together with an analysis of PED cases in the European Union . TransmiAlthough PEDV was first identified in Japan in the 1990s, Japan experienced renewed outbreaks of the disease in 2013. In a retrospective questionnaire-based case-control study, Sasaki et al.  focused In a report by Davies , the autThe author also discussed the risk of feeding animal products to swine and whether or not the risk warrants excluding animal origin products (or other ingredients) from swine diets. The author argues that complete bans on certain ingredients in swine feed may not be the solution. Rather, he suggests that one must take into consideration all contributing disease transmission pathways, the cost-benefits of mitigating risks associated with feed and feed ingredients, and the nutritional needs of commercial swine .In a review by Lowe , the autIn 2014, the United States experienced the emergence of a second novel swine enteric coronavirus, PDCoV. McCluskey et al.  administpost-hoc investigations, epidemiologic surveys, a case-control study, brainstorming, and speculation. They used previously collected epidemiologic data to develop scenarios and identify hypothetical routes of PEDV introduction into the United States and conducted follow-up studies to gather evidence for the most plausible scenarios. The follow-up studies included testing organic soybeans and pet jerky treats imported from China and archived serum samples opportunistically collected from feral swine; all results were negative. The authors did not identify a proven source or route of PEDV introduction into the United States. However, it was suggested that incomplete farm feed/ration records negatively impacted investigators' ability to thoroughly evaluate the potential epidemiologic role of feed or feed ingredients. The authors identified totes used to transport bulk feed or feed ingredients as providing “the simplest explanation” for the investigation findings  for the presence of virus and/or to conduct assays testing the ability of feed to serve as a fomite for virus. The following summarizes the reported findings.Associated with the U.S. outbreak of PED in 2013, an epidemiological investigation was conducted at an affected Ohio swine operation to determine the source of virus introduction . The timA retrospective case study by Greiner  investigTrudeau et al. , 34 condIn summary, the epidemiologic investigations and outbreak studies did not definitively link or exclude transmission of PEDV or PDCoV with non-animal origin feed or feed ingredients. Inconsistent findings impart uncertainty toward feed or feed ingredients as a transmission pathway , 32, 35.Two studies conducted environmental sampling of feed, feed facilities, and feed transport vehicles to determine whether these items contributed to the cause of the outbreaks of PED and PDCoV infection in the United States , 32. ColAmong the knowledge gaps identified in these studies are the identification of critical control points for pathogen contamination of feed and/or non-animal origin feed ingredients and consensus on the feed-based transmission pathways for PEDV and PDCoV. The potential point source(s) of virus contamination of non-animal origin feed or feed ingredients have not been identified nor clearly defined.in vivo biological assays (bioassays) to be conducted. The bioassays were used to assess the biological activity or potency of the pathogen(s) of interest by measuring the magnitude of response such as observed clinical signs consistent with the study disease(s) and/or positive findings to diagnostic testing and necropsy examination. Most studies included in this section of the literature review used swine bioassays to determine the infectivity of the pathogen(s) of interest in feed or feed ingredients subsequent to detection by polymerase chain reaction (PCR) of virus nucleic acid in the matrix (feed or feed ingredients) under examination.The rapid spread of PED in commercial swine in North America in 2013–2014 prompted several non-randomized, experimental studies with ad libitum  feeding , PRRSV, porcine sapelovirus (swine vesicular disease virus surrogate), PCV2, ASFV, and influenza A virus of swine in selected virus-ingredient combinations. Pigs were inoculated by various methods, including orally via syringe, intramuscularly, and intranasally. A positive bioassay was observed for the following virus-ingredient combinations: PRRSV and conventional SBM; PRRSV and DDGS; Senecavirus A and choline; and PCV2 and lysine, choline, and vitamin D .n) included conventional SBM (n = 7), lysine (n = 5), vitamin D (n = 4), choline (n = 4), organic SBM (n = 3), and DDGS (n = 2). The findings suggest that viruses can survive in non-animal origin feed ingredients but survival duration is variable and dependent on virus properties and feed matrix , and bovine herpesvirus-1 (PRV surrogate). The non-animal origin feed ingredients that supported survival of multiple viruses  , 37, 40.Among the knowledge gaps identified in these studies are the identification of vulnerable non-animal origin feed ingredients for viral contamination, ingredient (matrix) characteristics that support or hinder virus survival, and identification of the critical point(s) in the transboundary feed production and distribution continuum where viral contamination of non-animal origin ingredients could occur. There is a lack of field data demonstrating whether, how, and when non-animal origin feed ingredients may become contaminated with swine viruses. Further, although some field epidemiological investigations have associated contaminated (PCR positive) feed with the source of virus introduction on affected farms, to date, experimental studies of virus transmission via feed and feed ingredients have yielded inconsistent data. Additionally, the development of diagnostic assays and sampling techniques capable of detecting small amounts of virus in large volumes of non-animal origin feed ingredients is necessary to allow more accurate estimation of the frequency with which these materials are contaminated with virus, which viruses are present, and, if present, at what concentrations. Subsequent assays to determine the level of virus in the final, processed feed product would be useful to estimate the likelihood that contaminated non-animal origin feed ingredients could serve as a transmission pathway for swine viruses and to what degree feed should be prioritized as a biosecurity risk.The objective of this literature review was to gather and analyze the evidence in published scientific literature regarding whether non-animal origin ingredients of commercial swine feed could introduce and transmit viral pathogens of swine into or within the United States. The goal was to understand the current scientific knowledge and to identify information gaps to better inform policy makers, swine industry stakeholders, and the scientific community. To achieve this, relevant literature was reviewed and findings were qualitatively summarized.The results of the literature review demonstrate that a limited number of studies currently address swine viral pathogen transmission through non-animal origin feed and feed ingredients. Despite the small number of published studies, there is relevant evidence in the literature that contributes to the on-going discussion regarding the potential role of non-animal origin feed ingredients in the transmission of swine pathogens, including:A subset of the studies reviewed provided experimental evidence that swine viruses can survive in non-animal origin feed ingredients under various experimental and laboratory conditions –39, 41. A subset of experimental studies provided evidence that feed contaminated with virus can transmit disease to naïve piglets , 37–41.◦ choline chloride◦ D/L methionine◦ dried distillers grain with solubles◦ lysine HCL◦ soybean meal◦ vitamin D.Further, a subset of experimental studies attempted to identify individual feed ingredients that may be more likely than others to support virus survivability , 39, 41.Extended survival of PEDV was observed in conventional SBM . Similar◦ PEDV-contaminated choline chloride , 39◦ Senecavirus A-contaminated choline chloride ◦ PRRSV-contaminated conventional soybean meal ◦ PRRSV-contaminated dried distillers grain with solubles ◦ PCV2-contaminated choline chloride ◦ PCV2-contaminated lysine HCL ◦ PCV2-contaminated vitamin D A subset of experimental studies concluded that duration of virus survival (and infectivity) is ingredient-dependent. Virus viability as determined in swine bioassay was observed with the following virus-ingredient combinations:Under the laboratory-simulated model conditions, both LA and MCFA were concluded to be effective chemical mitigants against PEDV in individual feed ingredients stored under simulated shipping conditions, suggesting they might be useful for reducing viral load in feed ingredients , 39.n = 4); experimental methods which do not mimic natural feeding behaviors of swine or large-scale commercial swine production; and environmental scenarios which cannot be easily extrapolated to other seasonal variations or geographical regions.Limitations in several studies hindered generalization to real-world commercial swine scenarios. For example, studies were limited by small feed sample volumes  which does not directly equate to the quantities (tonnage) in actual swine production and feed scenarios; small sample sizes (2 replicates) which reduced statistical strength and confidence of findings; low sensitivity of swine bioassays  for swine viruses onto the index farm may differ from the transmission route(s) among housing units within the index farm and between secondary farms. Similarly, the entry route for swine viruses into the United States may differ from the transmission route(s) among domestic swine farms. Thus, if swine viruses contaminate non-animal origin feed ingredients, a multi-modal transmission mechanism is likely to occur. When considering non-animal origin feed ingredients as potential fomites for swine virus transmission, it is important to understand how the primary transmission pathways  interface with one another, in particular, how the production and distribution of feed interacts with other potential or known sources of virus contamination  to contribute to disease transmission both into and within the United States. Similarly, it's important to understand the relative risks of various transmission pathways and where feed ingredients fit in among broadly accepted risk pathways such as movement of infected pigs and fecal contamination of fomites . By understanding the magnitude of the risk of feed ingredients, one can better balance the costs of sourcing “safe” feed ingredients and the nutritional needs of pigs with the costs of applying various mitigation strategies to potentially contaminated feed .Over the past several decades, the U.S. commercial swine industry has improved biosecurity measures on commercial premises to prevent transmission of economically significant viruses such as PCV2, PRRSV, and, most recently, PEDV. Commercial swine operations may use the absence of PRRS on the farm as an indicator of thorough implementation and enforcement of biosecurity measures. In the studies reviewed, Bowman et al.  stated tArguably, the most crucial pieces of missing information are that neither the contamination routes of swine viruses into non-animal origin ingredients of commercial swine feed, leading to virus transmission to swine, nor the pathways of entry of exotic swine viruses into the United States have been definitively identified. A major knowledge gap exists in sources of potential contamination and where feed or feed ingredients may become cross-contaminated. Very little information is available on how non-animal origin feed ingredients are produced and sourced outside the United States and current studies have produced little scientific evidence of whether, how, or when non-animal origin feed ingredients become contaminated with swine viruses in regions outside the United States. The critical point(s) of susceptibility to contamination along the entire feed supply chain, from harvesting of plant-derived feed ingredients in the field to on-farm delivery of feed to swine premises, have not been identified. To compound this issue, reliable and validated assays and sampling techniques capable of detecting small amounts of virus in large volumes (bulk) of non-animal origin feed ingredients are not available. Taking a systematic approach to the entire (transboundary) feed production system, similar to the hazard analysis and critical control points process used in food safety, may help to identify vulnerabilities in the production process, better inform the development and application of mitigation measures to reduce viral contamination risks, and help stakeholders allocate resources toward mitigation measures based on the likelihood of virus contamination.While investigators have addressed some critical questions pertaining to transmission of swine viruses via feed and feed ingredients, the current body of scientific knowledge has yet to provide conclusive evidence of virus contamination of non-animal origin feed ingredients with swine viruses and the epidemiology of virus transmission to swine via feed and feed ingredients under field conditions. If the primary concern lies in the importation of contaminated feed and feed ingredients, then additional research and investigative studies of how ingredients are sourced, processed, and transported prior to importation are needed. However, the lack of validated feed and feed ingredient diagnostic assays and sampling techniques capable of detecting small amounts of virus in large volumes of material limits the ability to determine whether and at what point non-animal origin feed or feed ingredients may become contaminated with viruses and limits the ability to identify critical control points in feed production, distribution, and storage to mitigate risk. Although LA and MCFA were shown to be effective chemical mitigants against PEDV, additional mitigation strategies should continue to be explored, including other chemical treatments, the application of heat or pressure (pelleting) to feed, and holding times for feed or feed ingredients. Moving forward, studies designed to examine the likely source(s) of contamination in the feed supply chain and virus mitigation steps in processing and post-processing may be the most fruitful focus of research.Currently, the role of feed in the transmission of swine diseases is experiencing intense scrutiny and research from U.S. Federal and State government agencies, the swine industry, and the scientific community. The pool of knowledge is rapidly changing; thus, future consideration should be given to conducting an updated literature review to incorporate more recent findings (April 2018 to present).RG, IK, and AM performed the literature searches. RG, KC, IK, DL, and AM reviewed the articles identified via the literature search, determined which articles met the inclusion criteria, and performed the data extraction and synthesis steps. RG, KC, IK, and DL authored the manuscript. All authors reviewed the manuscript, contributed to the design and research purpose statement of this review.The authors declare that the literature review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The views expressed in this article do not necessarily reflect the official policy of the U.S. Department of Agriculture or the U.S. Government.


Engineering of biologic skin substitutes has progressed over time from individual applications of skin cells, or biopolymer scaffolds, to combinations of cells and scaffolds for treatment, healing, and closure of acute and chronic skin wounds. Skin substitutes may be categorized into three groups: acellular scaffolds, temporary substitutes containing allogeneic skin cells, and permanent substitutes containing autologous skin cells. Combined use of acellular dermal substitutes with permanent skin substitutes containing autologous cells has been shown to provide definitive wound closure in burns involving greater than 90% of the total body surface area. These advances have contributed to reduced morbidity and mortality from both acute and chronic wounds but, to date, have failed to replace all of the structures and functions of the skin. Among the remaining deficiencies in cellular or biologic skin substitutes are hypopigmentation, absence of stable vascular and lymphatic networks, absence of hair follicles, sebaceous and sweat glands, and incomplete innervation. Correction of these deficiencies depends on regulation of biologic pathways of embryonic and fetal development to restore the full anatomy and physiology of uninjured skin. Elucidation and integration of developmental biology into future models of biologic skin substitutes promises to restore complete anatomy and physiology, and further reduce morbidity from skin wounds and scar. This article offers a review of recent advances in skin cell thrapies and discusses the future prospects in cutaneous regeneration. Advances in burn care during the recent past have included improvements in fluid resuscitation, early wound excision, respiratory support and management of inhalation injury, improved nutrition and modulation of the hypermetabolic response, infection control and enhanced immune function, incorporation of aerobic exercise during recovery, and development of anti-scarring strategies . These aCutaneous burns can generate a continuum of injuries with increasing depth into the skin. Partial-thickness burns often do not require grafting and, if debrided and treated with antimicrobial dressings, will heal spontaneously from regrowth of epithelial appendages  to cover the wounds. However, deep partial-thickness burns which do not heal within ~ 3 weeks and full-thickness burns require replacement of the epidermal barrier by transplantation of autologous keratinocytes. Transplantation can be accomplished by either conventional split-thickness skin grafts (STSG), applications of keratinocyte suspensions or sheets, or dermal-epidermal skin substitutes –5. AutolWound closure after full-thickness burns requires reestablishment of stable epidermis as a minimum requirement. Stability of the epidermis depends on reformation of the basement membrane and vascularized connective tissues to anchor the outer skin to the body. Split-thickness skin satisfies these requirements but does not replace the epidermal adnexa  or regenerate a full complement of sensory or motor nerves. Table Table Transplantation of cellular skin substitutes has had wide-ranging results for temporary or permanent wound coverage. Temporary cellular dressings include direct harvest of split-thickness skin, available as either fresh or cryopreserved human cadaver skin , 29, or Preclinical investigations have reported more complex models that also include melanocytes –45, micrAlthough great progress has been made in reductions of morbidity and mortality in management of burn wounds, some of the most exciting advances remain ahead. These prospective advances include, but are not limited to, (a) complete restoration of skin anatomy and physiology, (b) gene therapies for specific applications, (c) automated and robotic fabrication of engineered tissues to increase efficiencies and reduce costs, and (d) quantification of wounds with non-invasive biophysical instruments.Table Gene therapies for the skin have been studied extensively over the years and have met with limited success –64. RiskIn addition to unique compositions of cells, gene expression, and scaffolds to construct analogs of skin, a critical and limiting factor to greater availability of skin substitutes is manual fabrication of these complex materials. To address this limitation, numerous methods for robotic fabrication of skin and other tissue substitutes have been described . Many ofAssessments of skin wounds have progressed from subjective examinations by clinicians to more objective measures with non-invasive instruments for both diagnostic and prognostic evaluations. For diagnostic purposes, scanning laser Doppler flowmetry has been shown to provide accurate assessments of burn depth and color with simultaneous image capture –82. AccuSafety and efficacy of skin substitutes are regulated in the USA by the US Food and Drug Administration (FDA). Biologic skin substitutes have increased in complexity from models that replace either dermis or epidermis, to dermal-epidermal models, to those that deliver combinations of biopolymer scaffolds, multiple cell types, or multiple cell sources, to those that express gene products for prospective improvements in wound healing. This spectrum of unprecedented materials presented questions regarding the regulatory framework within which each model would be evaluated for consideration of permission to market. Traditionally, the FDA has consisted of three centers for evaluation of human therapeutics: the Center for Devices and Radiologic Health (CDRH), the Center for Biologics Evaluation and Research (CBER), and the Center for Drug Evaluation and Research (CDER). Availability of cadaveric allograft has been provided under regulations for tissue banking, which are administered by CBER. As the spectrum of research models of skin substitutes broadened during the 1980s and 1990s, several investigative therapies had components that required consideration by multiple centers at FDA. The agency responded proactively with two initiatives that have contributed to greater clarity of the regulatory process and with Guidance for Industry , 87 on hAn early initiative was FDA’s participation in establishment of definitions and standards for tissue-engineered medical products (TEMPs) through formation of a Division IV of Committee F04 for medical devices through the American Society for Testing and Materials (ASTM) . BeginniMore recently, the 21st Century Cures Act (Cures Act) was signed into law in the USA in December, 2016. As the name implies, this law is intended to facilitate and expedite the availability of novel therapies to patients with serious, or potentially life-threatening, conditions. The Cures Act provides for expedited therapeutic development programs including the Regenerative Medicine Advanced Therapy (RMAT) designation for eligible biologics products, and the Breakthrough Devices program which is designed to facilitate the review of certain innovative medical devices . These nFuture prospects for biologic skin substitutes are extensive and diverse. Advances in use and regulation of stem cells in the skin are highly likely to lead to autologous skin substitutes with greater homology to uninjured skin by providing restoration of skin pigmentation, epidermal appendages , a vascular plexus, and subcutaneous tissues. Genetic modification of autologous cells opens tremendous opportunities for regulation of wound closure, reductions in scar formation, and correction of congenital diseases. As these advances in biologic skin substitutes translate into clinical care, it can be predicted with confidence that reductions in morbidity from acquired and congenital skin diseases will also be realized.


On April 28, 2014, the World Health Organization (WHO) declared polio a “Public Health Emergency of International Concern” (PHIC) under the authority of the International Health Regulations. Although polio has been eradicated from nearly every nation on earth, Pakistan is one of three countries where wild polio and vaccine-derived polio strains remain, thwarting global eradication efforts.Polio eradication progress is complicated by security and conflict issues at the border area between Pakistan and Afghanistan. In addition to security issues, other critical challenges, such as maintaining cold supply chain for vaccines, active and sentinel surveillance, false beliefs about vaccines, distrust of healthcare workers, and accessibility to conflict areas due to terrorist activities, all play a role in the continued persistence of Polio. In response to these challenges, we assess the local and international policy environment and its impact on polio eradication in Pakistan.Based on our analysis of existing barriers and challenges associated with polio eradication in Pakistan, this study discusses why employing “vaccine diplomacy” represents a key policy and advocacy strategic approach to achieve the overall end game of polio eradication. Specifically, we identify a set of concrete public health, international development, and diplomatic and policy recommendations that can act synergistically under the umbrella of health and vaccine diplomacy to finally put an end to polio. In April 2014, an emergency committee organized under the International Health Regulations (IHR) of the World Health Organization (WHO), declared the spread of wild poliovirus a “Public Health Emergency of International Concern” . The representatives came together to discuss disease outbreaks in the Pakistan and Afghanistan border areas, mainly in parts of Hangu (KP), Bannu, Dera Ismail Khan (KP), and areas bordering South Waziristan (Pakistan) and Paktika/Bermal (Afghanistan). Most outbreaks occurred in border regions between Pakistan and Afghanistan and eradication efforts emphasized the critical need for stable relationships between the governments to contain disease spread . Health As an example of opportunities for increased military engagement in polio operations, the Pakistan Armed Forces can help improve polio vaccination coverage by training soldiers in polio vaccination techniques to be used during military operations in affected areas. More direct vaccination enforcement may also be an option though is less desirable. For example, in 2015, the Khyber Pakhtunkhwa government issued arrest warrants to 1200 parents and guardians for their refusal to permit polio vaccine administration .Hence, vaccine diplomacy activities need to be inclusive of both the multilateral environment, but also the national and regional military and security apparatus for affected countries. This is particularly important in the context of border and conflict areas that represent the final stronghold for polio.In November 2018, the WHO held its 19th meeting of the IHR Emergency Committee where it reviewed recent polio progress and also unanimously decided that the risk of international polio spread still constituted a PHEIC . The comHence, continued emergence of Polio indicates that Pakistan’s Polio Eradication Program requires continuous monitoring and surveillance in highly at-risk populations, policy action that is responsive to polio surveillance, and effective communication around the importance of polio vaccination as core interventions. Additionally, as we’ve outlined, there is a need for sustainable informative technology to deliver treatment, effective health communication and interventions, motivated religious leaders to engage with communities impacted, political commitment for funding and resource commitment, border stability to contain cross-border disease spread, and sustained global efforts to ensure adequate polio eradication funding.Though Pakistan has faced setbacks in eradicating polio, analyzing these challenges through the lens of vaccine diplomacy can address key challenges at the local, national, and international level. Global policy recommendations generated through diplomatic negotiations and multistakeholder organizations (such as the WHO) can then elicit inter-country coordination with Pakistan’s immediate neighbors, and also enable resources for safe drinking water, and enhance public health under the broader lends of international development and health security. Complete eradication of polio through international and intersectoral coordination could then become a milestone achievement for shared goals in public health, international affairs, shared security, and diplomacy, and finally send Polio to the archives of history.


Cholera remains a major public health problem in many countries. Poor sanitation and inappropriate clean water supply, insufficient health literacy and community mobilization, absence of national plans and cross-border collaborations are major factors impeding optimal control of cholera in endemic countries.In March 2017, a group of experts from 10 Asian cholera-prone countries that belong to the Initiative against Diarrheal and Enteric Diseases in Africa and Asia (IDEA), together with representatives from the World Health Organization, the US National Institutes of Health, International Vaccine Institute, Agence de médecine préventive, NGOs (Save the Children) and UNICEF, met in Hanoi (Vietnam) to share progress in terms of prevention and control interventions on water, sanitation and hygiene (WASH), surveillance and oral cholera vaccine use.This paper reports on the country situation, gaps identified in terms of cholera prevention and control and strategic interventions to bridge these gaps. Cholera represents an important public health problem in many settings. Annually, 2.8 million cases and 91,500 deaths occur in cholera endemic countries [In addition to poor sanitation and inappropriate clean water supply, insufficient health literacy and community mobilization, absence of national plans and cross-border collaborations are major factors impeding optimal control of cholera in endemic countries. Poor knowledge of the real burden of cholera due to substantial under-reporting is also another obstacle –5. PotenProgress towards better hygiene and sanitation will be faster if a multidisciplinary and multi-sectoral approach is developed and implemented. Implementation of such strategy requires action under two key pillars: 1) increase political and financial support for cholera control and; 2) strengthen multi-sectoral cholera prevention and control programs.In accordance with these pillars, the Initiative against Diarrheal and Enteric Diseases in Africa and Asia (IDEA) was born in 2011. IDEA is an independent and multidisciplinary network of professionals from cholera-prone countries in Asia and Africa, in collaboration with national and international stakeholders. IDEA’s main goal is to facilitate and support the implementation of relevant prevention and control interventions on water, sanitation and hygiene (WASH), and on the use of oral cholera vaccine (OCV) by sharing information and best practices and to raise awareness on the country specific cholera situation. Between 2015 and 2016, four IDEA workshops have been successfully achieved in Asia and Africa. The fifth IDEA meeting took place in Vietnam  and involved experts from 10 Asian cholera-prone countries  together with representatives from the WHO, the US National Institutes of Health, International Vaccine Institute, Agence de médecine préventive, NGOs , and UNICEF.Country representatives shared their respective country situation, and progress in terms of WASH, surveillance and OCV use. Representatives from different health agencies provided an overview of available initiatives, interventions and tools in Asia. Following the plenary sessions, participants worked in subgroups to identify gaps in terms of cholera prevention and control and to discuss strategic interventions to bridge these gaps.Update on cholera epidemiology, progress in the prevention and control of cholera and a mapping of country capacities were presented Table . SuboptiUNICEF chairs the WASH working group of the Global Task Force on Cholera Control (GTFCC). The WASH-GTFCC working group has developed technical briefs and set-up a study to estimate the effectiveness of households’ disinfection practices.WASH is also one of the main actions of StC, an international non-governmental organization that promotes children’s rights. The StC global approach to cholera includes emergency health units, prepositioning stocks in eight countries, and a multi-sectoral approach. The objectives are to i) keep fecal matter away from drinking water, ii) inactivate cholera in contaminated water and iii) provide WASH facilities for medical teams and patients.Another significant preventive tool available now is the global stockpile of OCV that was created in 2013 as an additional tool to help control cholera epidemics . The WHOThe dynamic creation by the establishment of stockpile has played a key role in increased use of OCV –11 Tabl. HoweverOther novel strategies including self-administration of the second dose (fisherman living in floating homes), out of cold chain use during distribution (Guinea 2012) and OCV delivery combined with other interventions  have also been tested and provide evidence of the feasibility of conducting OCV campaigns in a variety of scenarios.To help developing country vaccine manufacturers, the International Vaccine Institute (IVI) engaged in a technology transfer development strategy Table . Long-teTo elicit more consideration for the prevention and control of cholera in participating countries, a brainstorming breakout session was held. The first part of the session was focused on what should countries aim at in terms of cholera prevention and control. There were two clusters of countries in terms of mid-term objectives depending on where they currently stand in cholera prevention and control Fig. . CambodiParticipants identified five main areas of strategic intervention to bridge the gaps and hence to reach the objectives of countries in terms of cholera prevention and control.Currently, surveillance systems are patchy or minimal. Countries must strengthen the existing surveillance systems both in terms of coverage and capacity (e.g. laboratory diagnostic tests). This would allow early case detection and immediate response. Regular analysis and dissemination of data at the national and neighborhood level is also believed to act as a driver in the prevention and control of cholera.WASH is universally recognized as a major component of preventing several infectious diseases . ImplemeOCV is considered as a supplementary tool for cholera prevention and control . Pre-empTo be effective, community mobilization should be based on outreach and awareness campaigns that improve knowledge on the disease, prevention and existing treatment. They should provide transparent sharing of information and proper education about routes of transmission and prevention measures. Appropriate involvement of media and schools could ensure fast spread of the information.Cholera preparedness and responses should include inter-sectoral partnership between health authorities at national and international level, civil society and other stakeholders. Cholera epidemics commonly occur in a cross-border manner, emphasizing the importance of cross-border cooperation to control and prevent the spread of the disease.Cholera remains a continuous threat with high health and economic burden in several South Asian countries. Despite tremendous efforts, prevention and control of cholera suffers from a number of challenges and issues in Asia. Inadequate WASH was identified as a major barrier in the prevention and control of cholera. Countries believe that WASH responses were often reactive and the criteria to trigger WASH responses were often unclear. Funding of WASH priorities remains also a challenge. This might be due to the difficulties related to measuring quantitatively the effectiveness and sustainability of WASH, as compared to vaccination which is precisely measured and evaluated using immunological or surveillance data, or directly by determining vaccination status. The group recommended that priority WASH interventions in emergency situation should include: i) increased water supply, ii) improved quality of water supplied, iii) increased access to excreta disposal facilities, solid waste collection and disposal, hand washing facilities, soap and water storage vessels and iv) hygiene education and social mobilization.Weak surveillance systems, underreporting and limited laboratory capacities have been reported by country representatives who advocated for reinforcement of active and passive cholera surveillance system: capacity building, training, guidelines, and equipment facilities. Participating countries recommended that the Cholera Prevention and Response National Road Map should also be endorsed urgently.✓ A self-administered second dose for the fishermen in “floating homes” living on Lake Chilwa is carried out by MSF. The second dose is given together with first dose that will be home-based self-administration,✓ A community-led self-administrated second dose on the six islands of Lake Chilwa carried out by AMP. The second dose is given to community leaders and kept in large cool boxes to be administrated under direct observation of the leader.OCV have the added advantage of herd protection which further decrease significantly the number of cases. Thanks to technology transfer, the OCV stockpile will grow with more vaccines being manufactured by different companies. Vaccine price could also be positively impacted by multiplying manufacturers. The group concluded that OCV should be introduced and used in different ways according to the country situation . The use of one-dose OCV regimen could also be a promising solution during emergency situations. Other innovative OCV delivery strategies are also being tested. This includes:Evidence supports that killed whole cell vaccines are stable at high temperature for long periods , 18, 19.Provision of necessary supply will have the greatest impact on cholera burden if it is coupled with educational programs, community engagement and mobilization. The efficacy of a number of actions  has already been tested and ought to be sustained. Outbreaks should be investigated and controlled as rapidly as possible by means of communication. Low-cost nudges behavior changes with a preventive approach can could help to increase compliance to hand-washing. In a nudge-based intervention study (i.e. positive reinforcement to influence people’s behavior) carried in rural Bangladesh, hand-washing with soap increased from 4% at baseline to 68% the day after nudges were completed and 74% at 2 and 6 weeks post intervention .Cholera still causes stigma as it is said to be a ‘forgotten disease’ mainly affecting ‘poor people’. Outreach meetings including public and private stakeholders and the general population are warranted to recognize that cholera is not only a health problem but also the direct consequence of poor WASH, linked to various environmental, climatic and socio-economic situations. Cholera can be prevented and controlled via complementary, synergistic and multidisciplinary interventions including access to safe water supply, end of open defection, increased hygiene, political engagement, community mobilization, prompt case management and vaccination.Integrated multi-sectoral approaches have proven to be the best mechanism to implement effective strategies for the prevention and control of infectious diseases. Coordinated stakeholder activities are key components of disease control success. In this perspective Fondation Mérieux hosting organization along with present stakeholder during the meeting announces its full commitment to the coordinated strategy and join its cholera activities along with other partners within the Global Task Force on Cholera Control to implement the renewed strategy for cholera control while building on existing achievements.


The 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) sought to determine the prevalence of drinking, smoking, and associated disorders in the general population. This survey, which includes a large representative sample of the adult population of the United States, found that drinking rates were highest among young adults and declined with increasing age. Rates of smoking and co-use of alcohol and tobacco were highest among the youngest respondents and declined thereafter. Similar patterns existed for the presence of alcohol use disorders (AUDs), nicotine dependence, and comorbidity between AUDs and nicotine dependence. Among ethnic/racial groups evaluated, Whites were most likely to drink and Native Americans/Alaskan Natives were most likely to smoke and to have an AUD, nicotine dependence, or comorbid AUD and nicotine dependence. Finally, the rates of tobacco use, daily tobacco use, and nicotine dependence increased with increasing levels of alcohol consumption and the presence of an AUD. These findings have important implications for the development of prevention and intervention approaches. Thus, it is important to know the rates of alcohol and tobacco use and co-use in the general population and whether certain demographic subgroups are particularly at risk of using both alcohol and tobacco or being dependent on both substances. Studies of this nature are rare in the literature. In a previous issue of In addition to determining the prevalence of co-occurring alcohol and tobacco use and disorders in the general population and for certain demographic subgroups, it is important to understand how rates of tobacco use and nicotine dependence vary among people with different characteristics of alcohol consumption. Over the last 20 years or more, accumulating evidence has indeed pointed to a dose-response relationship between alcohol and tobacco use:Other analyses indicated that smoking rates and the number of cigarettes smoked increase with increasing alcohol consumption e.g., .Although data such as these strongly point to an association between drinking and smoking, the existing studies often have characteristics that, while making them useful for addressing specific research questions, limit their generalizability to the general population. These characteristics include the use of treatment samples, local community samples, or special subpopulation samples rather than nationally representative samples. Moreover, most comorbidity studies focused on smoking or cigarette smoking as the measure of tobacco use e.g., , ignorinThis article addresses these issues by updating the findings presented by The present study is based on data from the first wave of the NIAAA-sponsored NESARC, which was conducted in 2001–2002. NESARC is among the largest nationally representative comorbidity surveys ever conducted and includes extensive questions on alcohol and tobacco (as well as other substance) use and related disorders. The NESARC sample includes 43,093 respondents ages 18 and older, representing the civilian, noninstitutionalized adult population of the United States, including residents of all 50 States and the District of Columbia. Military personnel living off base and persons living in noninstitutionalized group-quarter housing, such as boarding houses, shelters, and dormitories, also were included . The samAll alcohol measures reflect consumption and diagnostic status during the past year . Although NESARC collected alcohol data separately for each of four beverage types , the results presented here are the aggregate across beverage types. The various alcohol measures are defined as follows:Lifetime abstainer—Never had one or more drinks of alcohol during the course of a lifetime, excluding small tastes or sips.Former drinker—Had at least one drink prior to the past year but no drinks during the past year.Current drinker — Had at least one drink of alcohol during the past year. Based on past-year consumption, current drinkers are divided into three drinking levels:– Light drinker—Had three or fewer drinks per week.– Moderate drinker—Had 4–14 drinks per week for men and 4–7 drinks per week for women.– Heavy drinker—Had more than 14 drinks per week for men and more than 7 drinks per week for women.AUD—Met the criteria articulated in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM–IV) ((DSM–IV)  for alco(DSM–IV) , an inte– Alcohol abuse (AA)—Met at least one of the following four criteria for DSM–IV alcohol abuse : continued use despite social or interpersonal consequences, hazardous use, alcohol-related legal consequences, or neglect of role responsibilities in favor of drinking.– Alcohol dependence  (AD)—Met at least three of the following seven criteria for DSM–IV alcohol dependence in the same 12-month period: tolerance, withdrawal syndrome or drinking to relieve/avoid withdrawal, impaired control over drinking, persistent desire or unsuccessful attempts to cut down or stop drinking, much time spent drinking, reducing/giving up important activities in favor of drinking, and continued drinking despite physical or psychological problems caused by drinking.Like the alcohol measures above, the tobacco measures employed in the present study also reflect past-year use and diagnostic status. NESARC collected data separately for each of four tobacco modalities ; however, the analyses presented here are an aggregate across all modalities. The various tobacco measures are defined as follows:Tobacco use—Had smoked at least 100 cigarettes or 50 cigars, had smoked a pipe at least 50 times, or had used snuff or chewing tobacco at least 20 times during the course of a lifetime and had used any tobacco modality at least once during the past year.Daily tobacco use—Had used at least one tobacco modality at least once every day during the past year.Nicotine dependenceBased on past-year alcohol and tobacco use and disorder status, two measures are defined:Co-use—Had used both alcohol and tobacco within the past year.Comorbidity—Had both an AUD and nicotine dependence in the past year.Data presented in this article are descriptive in nature. All prevalence estimates of alcohol and tobacco use and disorders are presented as percentages of the total adult population in the United States or of a subpopulation group. All analyses are carried out for men and women separately. Rates of alcohol and tobacco use, co-use, disorders, and comorbidity are estimated for four age-groups  and five mutually exclusive racial/ethnic groups . Furthermore, to evaluate the relationship between drinking characteristics and tobacco use, the prevalence of tobacco use, daily tobacco use, and nicotine dependence is presented by drinking categories . Current drinkers are further divided into five mutually exclusive subgroups . All estimates were weighted by sampling weights to represent the entire adult population of the United States. Standard errors for all estimates were generated using the software package SUDAAN, which takes into account the effect of the NESARC complex sampling design .The prevalence of alcohol use by age-group showed a somewhat curvilinear pattern for both men and women . AlcoholIn contrast, tobacco use declined monotonically for both genders, with the highest prevalence among the youngest group  and the lowest prevalence among the oldest group . Similarly, the prevalence of co-use of alcohol and tobacco declined steadily with age, from the highest rate among people ages 18–24  to the lowest rate among people ages 65 and older .The prevalence of alcohol use varied among racial/ethnic groups for both men and women. For both genders, Whites displayed the highest rates  and Asians/Native Hawaiians/Pacific Islanders displayed the lowest rates  . The preNESARC provides national prevalence estimates of AUDs, nicotine dependence, and their comorbidity, by age and race/ethnicity for men and women separately. According to these data, 8.4 percent of adults in the United States had an AUD and 12.8 percent had nicotine dependence during the past year . MoreoveFor both genders, the prevalence of AUDs, nicotine dependence, and comorbid disorders decreased with age . The preLike the rates of AUDs and nicotine dependence, the prevalence of comorbid disorders decreased with age, with the highest prevalence found among the youngest men and women  and the lowest prevalence found among the oldest men and women . Finally, for all diagnoses and age-groups evaluated, prevalence of AUDs and/or nicotine dependence was higher among men than among women.For AUDs, American Indians/Alaskan Natives displayed the highest prevalence  and Asians/Native Hawaiians/Pacific Islanders had the lowest rates  . The preFor comorbid AUDs and nicotine dependence, the rank ordering pattern among the racial/ethnic groups was similar for both genders: American Indians/Alaskan Natives displayed the highest prevalence  and Hispanics had the lowest rates .NESARC data also demonstrate how tobacco use is related with the characteristics of alcohol consumption. For all three tobacco measures—that is, tobacco use, daily tobacco use, and nicotine dependence— the rates increased monotonically with increasing levels of alcohol consumption and the presence of alcohol abuse and dependence . For insThis study presents updated epidemiologic data on alcohol and tobacco co-use and comorbidity in the adult population of the United States. With approximately 46.2 million American adults having used both substances in the past year, the sheer extent of co-use is high. The number for comorbid disorders is considerably lower, yet still significant, with approximately 6.2 million American adults having both an AUD and nicotine dependence. Furthermore, higher rates of co-use and comorbidity were found among certain demographic subgroups. For example, similar to In addition to quantifying the current rates of co-use and comorbidity in the United States, the present study also investigated the association between the characteristics of alcohol and tobacco use. Results showed a dose-response relationship between the two substances, with rates of tobacco use, daily tobacco use, and nicotine dependence increasing monotonically with increasing levels of alcohol consumption and the presence of AUDs. This dose-response relationship is consistent with findings noted in other epidemiological studies, although those studies mostly examined cigarette smoking rather than tobacco use in general. For example, in a national study, The present study improves on a significant portion of the existing studies by including all modalities of tobacco use rather than focusing only on cigarette smoking. The rationale for including all modalities of tobacco use is that all modalities have been shown to have detrimental health consequences when used in excess , 2005c.


OBJECTIVES/SPECIFIC AIMS: The goals of this project are to: (1) Help research teams better understand, anticipate, and adapt research to address the needs of diverse communities. (2) Help clinicians and researchers develop patient-centered communication skills needed for more frequent and meaningful engagement of research participants. (3) Identify additional service support needs of clinical research teams not currently offered by other centers  so they can effectively recruit diverse communities. METHODS/STUDY POPULATION: Mixed methods evaluation approaches centered on obtaining community and academic input aimed at revising the tool to enhance its feasibility and relevance. Round one of focus groups were conducted (4), 2 with a diverse group of community stakeholders, 2 with a diverse group of academic stakeholders. Focus group feedback guided HLCR Assessment Tool revisions. This round of focus groups, served as an opportunity for community and academic stakeholders to discuss shared and divergent priorities related to the development and utilization of the tool. Feedback from these sessions guided a second set of revisions to the tool. Brief surveys were administered at each time point to gather participant demographic data. For the first round of focus groups with community stakeholders, 2 diverse groups totaling 19 people participated . Participants served a variety of populations including seniors, youth, underserved, Muslim Americans, Bangladeshi, Arab, South Asian, refugees, community health centers, service organizations, 1st generation students, Latinos, multi-ethnic groups, limited English speaking, people with lupus, un/underinsured, people with HIV, Korean Americans, African Americans, and the disability community. Data pending on the first round of focus groups with academic stakeholders. All participants of the first round of focus groups will be invited to return to a second round of focus groups (2), this time only 2 groups will be held, and these will combine community and academic participants in each focus group. RESULTS/ANTICIPATED RESULTS: Along with formatting and grammatical revisions, recurring recommendations focused on considerations/clarifications in 3 main areas: compensation for all stakeholders, developing a common language and clarifying terms, and aligning the research process with the community. Considerations around compensation was mentioned in discussions related to multiple tool domains. In particular, community stakeholders recommended inclusion and consideration of compensation not just for research participants but also community partners, sites, community representatives, and other academic partners. It was also very important to make sure the form of compensation for both community partners and participants aligns with what was being asked of them. Community stakeholders sited a few examples where they were involved in studies where the time and requirements for participation were not commensurate with the compensation they received or the study budget did not include compensation for community partner effort. Along with edits to questions in the HLCR Assessment Tool, community stakeholders also recommended education for budget/finance personnel on fair compensation for research participants and community partners. In both focus groups, there was also confusion around specific terms and an identified need to develop a common language and clarify terms among all those involved in the research process. More specifically, terms such as community, culture, community of focus, community partners, accessible, and convenient were identified as needing further definition or clarification. Through the focus groups, we learned the valuable lesson that it cannot be assumed broad terms or even seemingly specific ones will be interpreted the same by everyone or have the same meaning in different contexts. Therefore, it needs to be very clear what these terms mean and who or what they represent. Finally, the community stakeholders emphasized throughout both focus groups the importance of making sure that the HLCR Assessment Tool unpack and explicitly emphasize how the research process can align and should align with community needs, communication structures, influencers, and assets. Some factors community stakeholders suggested be considered were: (1) Where the researcher is in the research process; (2) How community members prefer to communicate with each other; (3) Stigma/biases  that may be pervasive in a particular community; (4) Identification of key community influencers/gatekeepers; (5) Learning about a community’s assets along with their needs. DISCUSSION/SIGNIFICANCE OF IMPACT: Currently, there is dearth of resources focused on increasing diverse engagement in clinical and translational research, and consequently, research teams have little or no knowledge or support for how or when to engage community partners in clinical or translational research. The goal of this project is to help fill that gap with a tool to guide clinical and translational research teams in assessing the health literacy and culturally responsive components of their research projects to improve recruitment of diverse populations. Feedback on the first iteration of the HLCR Assessment Tool helped us identify the priorities for community stakeholders and better understand their concerns and needs around engagement with academic partners in clinical and translational research. This understanding will help us enhance the relevance and usefulness of the HLCR Assessment Tool so that clinical and translational science researchers more effectively engage with community partners and help ensure the community’s needs are better aligned with. Therefore, developing and pilot testing this tool can offer a significant opportunity for clinical and translational sciences institutions to enable their researchers and their teams to teams better understand, anticipate, and adapt to the cultural and health literacy needs of diverse populations. More specifically, this tool can: (1) Help clinicians develop the patient-centered communication skills needed to facilitate more frequent and meaningful engagement of potential research participants during medical visits to truly make every healthcare encounter an opportunity for research. (2) Help clinical and translational sciences institutes identify additional service support clinical research teams will need access to in order to effectively recruit diverse communities, that are not currently not supported .


The editorial speaks to the Global Statement on Air Pollution and Health and How it may assist African countries to eliminate air pollution-related health impacts. The human health and economic costs of air pollution in Africa are high and rising. Between 1990 and 2013, deaths from ambient particulate matter on the African continent rose by more than one third, and by 2013 was costing the African economy approximately USD 215 billion annually [Sources of human exposure to air pollution in Africa include anthropogenic and natural sources and occur in urban, rural, industrial and residential settings. The main contributors are industry, power generation, agricultural burning, transport and traffic, the combustion of wood, coal, paraffin and dung for household energy needs Figure , unpaved2.5 mass in the cooking area, road dust and vehicle emissions comprised 12–33% of PM2.5 mass, and solid waste burning was also a significant contributor to household PM2.5 in low-income settlements [Certain vulnerable groups may be simultaneously exposed to air pollution from multiple sources – sometimes at highly elevated concentrations . For exa4tlements . Patriartlements .Tackling air pollution in Africa is undoubtedly important but constitutes a uniquely complex challenge. Unlike many OECD countries, African efforts to curb exposure to air pollution need to be implemented alongside actions to address competing health and economic challenges, including poverty and inequality, a process of rapid urbanization currently underway, housing shortages, unsafe water, inadequate sanitation and major epidemics such as HIV/AIDS. Poor people are exposed to higher concentrations of air pollutants, have access to inferior health services, and tend to suffer disproportionately from the effects of air pollution . In sett1In this regard, a fundamental concern is that air quality monitoring capacity in Africa is weak. One study reported that only 41 cities across 10 African countries measured ambient air pollution levels, and knowledge of the sources and pathways of human exposure to air pollution across is limited to well-resourced countries, providing a weak base for policy development and priority setting .As stated in the July 2019 Air Pollution and Health Statement jointly issued by the Academy of Sciences of South Africa (ASSAf), the Brazilian Academy of Sciences (ABC) and the German National Academy of Sciences Leopoldina as well as both the US National Academies of Medicine and Science (USNAM and USNAS), “the costs of air pollution to society and the economies of low- and middle-income countries are enormous” and “can undercut sustainable development” . AfricanThe Integrated High-Speed Train Network is a flagship project of the African Union’s Agenda 2063. The project aims to connect all African capitals and commercial centers through an African High-Speed Train Network thereby facilitating the movement of goods, factor services and people. The increased rail connectivity holds the potential for reducing transport costs, relieving traffic congestion and lowering traffic emissions . Emerginidentify co-benefits among policy instruments’. Renewable energy technologies that are increasingly deployed at grid- and household-level present another opportunity for policy co-benefits by reducing air pollution and greenhouse gas emissions from large fossil fuel-fired power stations and household fuel burning.While the challenges are complex, some novel solutions are emerging to overcome air pollution in some African countries. In South Africa, at a regional scale, the Greenhouse Gas and Air Pollution Interactions and Synergies or ‘GAINS’ model is a useful framework being considered to identify strong linkages between air quality and climate-relevant measures . The res


Hallab and Jacobst), post-fracture inflammation and healing (Edderkaoui), their role in metastatic bone tropism (Coniglio), and their influence on PTH on bone remodeling (Siddiqui and Partridge)] there is a hypothesis and theory article discussing environmental factors that impact bone-relevant chemokines  and an original research article on how differentiation of preosteoblast cells to adipocytes is influenced by 1,25(OH)2 Vitamin D3 (Pendleton and Chandar).According to Webster's dictionary, equilibrium is a state of balance between opposing forces or actions. Bone provides a great example of why a dynamic equilibrium is important. The balance between bone resorption and bone formation is critical for the maintenance of bone mass and systemic mineral homeostasis. If there is excessive resorption by osteoclasts without a corresponding response by osteoblasts the result is osteoporosis, whereas the contrary may result in osteopetrosis. This equilibrium is dependent on a number of competing and complementary influences such as hormones, growth factors, biomechanical stimulation, and chemokines. Chemokines are a type of cytokine, defined by their ability to induce directional cell migration. Cytokines are a diverse group of soluble peptides and proteins including interleukins, interferons, colony stimulating factors, and chemokines that act as humoral regulators at nano- to pico-molar concentrations. The articles assembled for this Frontiers Research Topic focus on the chemokines and how they influence bone. In addition to four reviews covering a range of topics [orthopedic implant debris . While hip and knee replacements have become commonplace in part due to their success, the rate of failure grows each year following surgery due to a progressive inflammatory state that compromises the bone implant surface. The review covers activation of the innate and adaptive immune systems by implant debris , and how these events subsequently lead to loosening, a serious complication. They point out that aseptic implant failure due to inflammation is responsible for over 70% of total hip arthroplasty revisions and over 44% of total knee arthroplasty revisions . As delayed and non-union bone fracture healing are important clinical problems, the chemokines thought to play an important role in each of the three phases of fracture healing  are discussed. In addition, based on chemokine expression patterns and animal models utilizing knockout mice lacking select chemokines or their receptors, a hypothetical model for the contributions of chemokines in fracture healing is presented. While the importance of some chemokines seems clear , other chemokines  may also be involved in fracture healing.Dr. Bouchra Edderkaoui reviewed chemokine expression in response to bone fracture and the potential role of chemokines in post-fracture inflammation and healing (Siddiqui and Partridge). The contribution of CCL2 and its receptor CCR2 have been established for a number of pathological conditions that involve bone including rheumatoid arthritis, cancer-induced bone loss, and bacterially induced bone loss. The researchers provide the rationale for focusing on CCL2 and its receptor CCR2 given their prominence in bone remodeling and role in osteoclast recruitment, differentiation, and fusion. They point out their work establishing the robust increase in CCL2 following intermittent PTH(1-34) injections  and the involvement of CCL2/Monocyte Chemoattractant Protein 1 in the process of PTH-mediated bone remodeling (ent PTH1-4 injectiConiglio).That many tumors exhibit tropism with respect to metastasis has been recognized for over a century. Stephen Paget's “seed and soil” hypothesis  proposinSmith et al. reveals an extensive literature on environmental factors impacting bone-relevant chemokines and points out many potentially fruitful areas of research into the role of specific factors either as agents interfering with normal bone development and healing, or alternatively as potential bone therapeutic agents.A number of chemokines impact bone, having diverse effects on chondrogenesis, osteoblast differentiation, mineral opposition, fracture healing, osteoclastogenesis, and osteoclast activity, playing a role in the success and failure of implants, the bone loss in rheumatoid arthritis and the cancer-related bone loss and metastases . The com2 D3  were found to be widely expressed, including in cells of the immune system e system . Calcitre system , 8 and pe system , and thee system . Among re system , the anae system , and cale system . In perie system , calcitre system  and CCL2e system . A studye system . InteresAll 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.


Integrated knowledge translation (IKT) is a model of research co-production, whereby researchers partner with knowledge users throughout the research process and who can use the research recommendations in practice or policy. IKT approaches are used to improve the relevance and impact of research. As an emerging field, however, the evidence underpinning IKT is in active development. The Integrated Knowledge Translation Research Network represents a collaborative interdisciplinary team that aims to advance the state of IKT science.In 2017, the Integrated Knowledge Translation Research Network issued a call to its members for concept papers to further define IKT, outline an IKT research agenda, and inform the Integrated Knowledge Translation Research Network’s special meeting entitled, Integrated Knowledge Translation State of the Science Colloquium, in Ottawa, Canada (2018). At the colloquium, authors presented concept papers and discussed knowledge-gaps for a research agenda and implications for advancing the IKT field. We took detailed field notes, audio-recorded the meeting and analysed the data using qualitative content analysis.n = 11), trainees (n = 6) and knowledge users (n = 7). Seven overarching categories emerged from these proceedings – IKT theory, IKT methods, IKT process, promoting partnership, definitions and distinctions of key IKT terms, capacity-building, and role of funders. Within these categories, priorities identified for future IKT research included: (1) improving clarity about research co-production/IKT theories and frameworks; (2) describing the process for engaging knowledge users; and (3) identifying research co-production/IKT outcomes and methods for evaluation.Twenty-four participants attended the meeting, including researchers (The Integrated Knowledge Translation State of the Science Colloquium initiated a research agenda to advance IKT science and practice. Next steps will focus on building a theoretical and evidence base for IKT. Integrated knowledge translation (IKT) is a model of research co-production whereby researchers partner with knowledge users who can use or implement the research recommendations and/or findings . AccordiInvolving knowledge users, or individuals who can use the research evidence to inform policy and practice decisions, requires meaningful partnership in the research process as well as significant involvement and influence from knowledge users . Each stAlthough the research evidence underpinning IKT processes is promising, the field is in its infancy and several knowledge gaps remain. An evaluation of funding programmes to support knowledge translation showed that, compared to the traditional researcher-centred approach, co-produced research involving researchers and knowledge users was perceived to be more likely to improve the health of Canadians, create more effective health services and products, and strengthen the healthcare system . A scopihttps://iktrn.ohri.ca/aboutus/who-we-are/). The purpose of this Network was to establish a collaborative interdisciplinary team to improve conceptual clarity, assess IKT impacts, develop theories and measurement tools, create capacity-building resources, and train researchers and knowledge users in IKT. The research network includes 42 IKT researchers, 29 knowledge users, 11 implementation scientists and 17 trainees with national and international linkages and collaborations. This group is well positioned to make significant contributions to IKT science.To address knowledge gaps and improve the state of IKT science, the Integrated Knowlege Translation Research Network (IKTRN) was founded in 2016 [In 2017, the IKTRN issued a call to Network members to submit one-page proposals for producing concept papers of about 20–30 pages in length. The objective of the call was to further define the area of IKT, advance the understanding of IKT by focusing the IKTRN’s future research over the next few years, and inform the next IKTRN meeting. Proposals were reviewed by the executive committee  for alignment with the IKTRN’s mandate. The full papers were also peer reviewed. Authors who wrote a concept paper for the call  received a $1500 CAD honorarium. Authors who already had papers underway were invited to have their work discussed with the other concept papers and be published in a forthcoming special issue.In October 2018, the IKTRN hosted an invitational meeting in Ottawa, entitled IKTRN State of the Science Colloquium, of the lead authors of the concept papers and knowledge users. The purpose of the meeting was to share the ideas described in the concept papers, discuss their implications for advancing the field of IKT/research co-production and outline an IKTRN research agenda from the perspectives of researchers and knowledge users. Although research ethics board approval was not required for this report, all lead authors and knowledge users provided consent to publish their data, and reviewed and approved the final manuscript. Here, we report the proceedings of the 2018 IKT State of the Science Colloquium.n = 16) of their concept papers , knowledge users (n = 7) and trainees (n = 6)  improving clarity about IKT theories and frameworks; (2) describing the process for engaging knowledge users in the IKT process; and (3) identifying IKT outcomes and methods for evaluation.Attendees identified the need to develop a common understanding of theories and frameworks and how these are unique from, and overlap with, other collaborative or co-production approaches. IKT shares common principles with many collaborative research approaches, including co-production of knowledge, participatory research, linkage and exchange, knowledge production, engaged scholarship, patient engagement or involvement, and community-based research –17. GiveThe research agenda should also better describe the role, experiences and processes for partnering with knowledge users in IKT. As such, the contextual factors that hinder or enable knowledge user partnership in IKT processes, and the influence of leadership and power relations on knowledge users’ ability to meaningfully contribute to the research process or mitigating power imbalances, are key areas for investigation. Such research should lead to recommendations to guide researchers and knowledge users in the optimal use of IKT approaches.Another priority for the research agenda is to evaluate the impacts of IKT. This involves determining appropriate IKT outcomes that reflect a meaningful collaborative approach, identifying or developing valid and reliable instruments to measure IKT processes and outcomes, and establishing reporting standards for IKT.By partnering with knowledge users in the research process, the young field of IKT has potential to improve the relevance, impact and efficiency of research. The presentation of concept papers and subsequent discussion initiated a research agenda to advance IKT science and practice, both within the Network and for the broader community. Next steps for the IKTRN will include mobilising network members and other researchers around the identified research agenda.Additional file 1. List and bio-sketch of IKT meeting attendees.Additional file 2. Concept paper abstracts presented at the IKTRN meeting.


Health facilities form a central component of health systems, providing curative and preventative services and structured to allow referral through a pyramid of increasingly complex service provision. Access to health care is a complex and multidimensional concept, however, in its most narrow sense, it refers to geographic availability. Linking health facilities to populations has been a traditional per capita index of heath care coverage, however, with locations of health facilities and higher resolution population data, Geographic Information Systems allow for a more refined metric of health access, define geographic inequalities in service provision and inform planning. Maximizing the value of spatial heath access requires a complete census of providers and their locations. To-date there has not been a single, geo-referenced and comprehensive public health facility database for sub-Saharan Africa. We have assembled national master health facility lists from a variety of government and non-government sources from 50 countries and islands in sub Saharan Africa and used multiple geocoding methods to provide a comprehensive spatial inventory of 98,745 public health facilities.  However, these services are not accessible to everyone equally4. This inability to reach quality assured health services able to provide life-saving interventions contributes to the sustained high burden of communicable and non-communicable disease morbidity and mortality in SSA relative to other regions of the world6. The Global health agenda now aims to ensure Universal Health Coverage (UHC), to ensure that all people obtain the health services they need and underpins the health-related Sustainable Development Goals. Defining and planning for universal equity in access to health services demands better data on the location of both services and populations they are intended to serve.Defining the location of health services in relation to the communities they are intended to serve is the cornerstone of health system planning, ensuring the right services are accessible to the population and that no one is geographically marginalized from essential services. Across sub-Saharan Africa (SSA), health services are offered with increasing levels of medical sophistication, from community providers who handle basic care to hospitals which play a critical role in providing emergency care8 and censuses of service provision9, this has not been universal and most inventories lack coordinates. In Kenya in 2003, we began an exercise to compile and geocode a single, public health MFL from a variety of government, non-governmental (NGO), community-based (CBO) and faith-based organization (FBO) listings10, the first time a national map of service providers had been developed since 195911. Over the next 15 years we extended this approach across other countries in SSA, coinciding with a regional impetus to improve master health facility lists8.While countries have been encouraged to develop health Master Facility Lists (MFLs)14, then the emergence of Geographic information systems (GIS) in 1980s and 1990s led to the evolution of distance as a metric17 while network analyses, floating catchment area methods and cost-distance analyses are more recent21. By identifying top tier hospitals and lower tier facilities, it is now possible to estimate specific access to emergency care and surgeries24. Other extensions are application in defining access to Basic and Comprehensive Emergency Obstetric and Neonatal Care (BEmONC/EmONC) services25, evaluating public health sector service delivery26 and community-based interventions29. In the future, it is likely that this will be extended to understanding health care optimization. Georeferenced health service inventories, beyond defining equitable access, increase the epidemiological value of defining the evolution of emerging, epidemic pathogens30, antimicrobial resistance, and defining sub-national disease epidemiology as well as improving the potential of routine health data use31.Access to health care is a complex and multidimensional concept and can be defined in a variety of ways, however, in its most basic sense, it refers to geographic availability. Improved data metrics on health access demands at the very least a knowledge of where service providers are in relation to populations. Provider-to-population ratios were used to estimate availability in 1970s and earlierhttps://www.healthsites.io), there is no single, georeferenced and comprehensive public health facility inventory for sub-Saharan Africa. Building on a previous audit of public hospitals in sub Saharan Africa18, we provide a geo-coded inventory of 50 countries in sub-Saharan Africa, provided as an open-access resource. We have focused on public health facilities managed by government, local authorities, FBOs and NGOs. A wide variety of primary sources of information were consulted, from websites and data portals of ministries of health, national and international organizations, health sector reports, to sourcing data through personal communications. Facility types and numbers for each country were validated using reported data in national health sector strategic plans and other health sector reports.Notwithstanding previous efforts to extract health service providers from OpenStreetMap complimented by volunteered information  website was the first source of authoritative MFLs consulted. This was done through online searches and downloads of MFLs or maps hosted on the MoH website or on data portals managed by the MoH such as the National Health Map (Carte Sanitaire), health facility registries and online Health Management Information Systems (HMIS) including District Health Information Systems version 2 (DHIS2). In some instances, MoH publications with information on facility lists or maps were used. Occasionally, while the MoH sources did not have comprehensive lists of facilities or maps, other government agencies’ websites, for example national statistical agencies, hosted health facility listings and these were consulted. Where the governmental ministries and agencies had no facility listing information or was inadequate, other sources of data were consulted, including data hosted by the United Nations Office for the Coordination of Humanitarian Affairs’ (UNOCHA) Humanitarian Data Exchange (HDX) portal and websites of other UN agencies, and where relevant, websites of FBOs and NGOs working in each country. For countries where no health facility data were available online, we made attempts to directly contact people working with National Malaria Control Programmes, World Health Organization or other health-oriented agencies to aid in locating health facility listings. Often, more than one source of data was consulted for each country and assembled into a single list as illustrated in Online-only Table We undertook a data assembly process to compile a comprehensive health facility database across SSA, starting with Kenya in 2004Locations of existing health facility data for sub-Saharan African countries are fragmented. Half of the 50 countries had an MoH website/HMIS/data portal as the main source of data used; 4 (8%) had other governmental bodies, mainly national statistical agencies, as the main data source; 9 18%) countries had UNOCHA HDX as the main data source, while we used other sources like NGO and FBO websites for 7 (14%) countries. The main source of data for the remaining 5 countries (10%) is unpublished data obtained through personal communication. In total, 93 different sources of data were consulted to develop the first sub-Saharan Africa geocoded inventory of health service providers across all levels of service provision  centres, maternity and nursing homes, family planning clinics and specialist facilities  , where maps were available, facility locations were digitized in ArcGIS 10.5 , attribute information captured and converted to MS Excel.Facilities that had GPS coordinates from original data sources were 47,805 (48%), while 10,759 (11%) coordinates were obtained from digitizing health facility maps. For the remaining 40,181 (41%) health facilities with missing coordinates, we used a variety of existing location data and digital resources for geocoding. As a priority, where Global Positioning Systems (GPS) data for previously mapped infrastructure like schools were available, we used these to match to names of the health facilities in the same administrative zones to assign coordinates . The most useful digital resources were Geonames digital place name gazetteer , Google Earth/Maps  and other digital place name gazetteers including Encarta, OpenStreetMap, HereMaps, Bingmaps, iTouchMap and Fallingrain  . This involved finding descriptions of locations of villages matching health facility names in journal papers and news articles and using this information to triangulate these locations in Google Earth, or using shapefiles of the smallest administrative divisions of a country, matching these with the same administrative units in the facility databases and placing the facility location on a populated place in Google Earth, but only in administrative units that were roughly 5 square kilometers in area to minimize the location error. Within small administrative units in Google Earth, populated places were not always obvious to locate visually so we located them by tracing footpaths, roads, rivers or streams that led up to populated places. Facilities that could not be geocoded using any of the sources in Table 40 and through the World Health Organization’s Global Malaria Programme  in Microsoft Excel format. While the dataset available through figshare40 will be preserved in its published form, the one available through the World Health Organization’s Global Malaria Programme website will be updated through further in-depth validation and updating in collaboration with individual countries. The Database includes data from 50 countries in sub-Saharan Africa. Each data record represents a health facility and has 8 descriptive variables – Location identifiers including: country, first level administrative division, latitude, longitude and LL source (source of the coordinates). Coordinates are rounded off to four decimal places for uniformity, allowing an accuracy of 5–10 metres in decimal degrees coordinate format. We have included only the first level administrative divisions for each country that were in the primary data sources as they are least ambiguous and do not change much over time unlike second level administrative divisions which can change rapidly and are not consistent over time for most countries. The other pertinent details are the facility name, facility type and facility ownership. Facility types definitions vary between countries  facilities in the original lists having coordinates, some of the these plotted in wrong districts, on water bodies and or outside country boundaries. These were assigned new coordinates using Google Earth and minor shifts made in ArcGIS.Facility locations were validated in ArcGIS using two datasets and by visual inspection in Google Earth. In ArcGIS, the Spatial Join and Select by Location tools were used to identify facilities that fell slightly off international boundaries or slightly outside of their correct region and/or district. The Global Lakes and Wetlands Database (GLWD)Health facilities levels are defined based on the complexity of services they offer. Health facilities types, specifically at the primary level, vary between countries in their definitions, specialization, size of populations they serve and the essential services they provide, infrastructure and staffing. Health centres, medical centres, polyclinics, health posts, dispensaries, clinics, health huts, health units etc. may have similar functions but equally may represent different levels of service provision between countries. To cross-reference the completeness of our national inventories of facilities and to understand this variation, we first identified and defined service provision and health facilities at each level based on information from health sector policies and strategic plans for each country. We compared this against information in our database and for most countries, there was good concordance across all levels of service provision. Secondly, the number of health facilities at each service provision level for each country were compared with the corresponding number of facilities reported in the most current Health Sector Strategic Plans (HSSP) and other health sector reports and these were found to be largely similar with minor variations   who will henceforth facilitate further in-depth validation and updating in collaboration with individual countries covered. This will also bring the possibility of assigning the facility codes for future updating, data linkages and comparisons. We have focused this work on SSA countries as this is the region our previous work has focused on, is most lacking with respect to comprehensive MFLs and it’s the region under the World Health Organizations’ Regional Office for Africa, who we have collaborated with on this work.In addition to the data release through the figshare repositoryWe recognize that, despite our best efforts, this dataset is incomplete and will change over time. As such, we encourage readers to alert us via email to additional and/or newly available data so that we may add them, if appropriate.Download metadata file