Pediatric integrative medicine (PIM) is of significant interest to patients, with 12% of the general pediatric population and up to 80% of children with chronic conditions using PIM approaches. The field of PIM has evolved over the past 25 years, approaching child health with a number of guiding principles: preventive, context-centered, relationship-based, personalized, participatory, and ecologically sustainable. This manuscript reviews important time points for the field of PIM and reports on a series of meetings of PIM leaders, aimed at assessing the state of the field and planning for its future. Efforts in the first decade of the 2000s led to increased visibility in academic and professional pediatric organizations and through international listservs, designed to link those interested in and practicing PIM, all of which continue to flourish. The PIM leadership summits in recent years resulted in specific goals to advance PIM further in the following key areas: research, clinical practice, professional education, patient and family education, and advocacy and partnerships. Additionally, goals were developed for greater expansion of PIM professional education, broader support for pediatric PIM research, and an expanded role for PIM approaches in the provision of pediatric care. Integrative medicine is defined as relationship-centered care that focuses on the whole person, is informed by evidence, and makes use of all appropriate therapeutic approaches, healthcare professionals and disciplines to achieve optimal health and healing, including evidence-based complementary and alternative medicine. Pediatric integrative medicine (PIM) develops and promotes this approach within the field of pediatrics ,2.The field of pediatrics is at a crossroads. The health of our children—our future—is at stake. The prevalence rates of myriad chronic pediatric health conditions continue to rise at an unprecedented pace ,4. ChronPediatric integrative medicine (PIM) represents an evolution in pediatric care, a paradigm that embodies a philosophy consistent with long-standing holistic principles of quality medical care. As Dr. Kathi Kemper noted in her Presidential Address to the Ambulatory Pediatric Association nearly 20 years ago, “Holistic medicine is really just good medicine. It means caring for the whole child in the context of that child’s values, their family’s beliefs, their family system, and their culture in the larger community, and considering a range of therapies based on the evidence of their benefits and cost”  (p. 214)Preventive: True primary care pediatrics is proactive rather than reactive. Prescribing lifestyle solutions to prevent disease is generally preferable to costly and potentially risky treatments. Lifestyle prescriptions may include food, activity, nature, creativity, rest, mindfulness, and connection with others.Context-centered: Children must be nurtured within the context of healthy families, communities, and schools. Health in mind, body, and spirit depends on how suitable the environment is for the child.Relationship-based: Only through open communication and building trust are we best able to work together to ensure each child’s optimal health. The connection between health professionals and families has its own healing potential.Personalized: Health is not a one-size-fits-all proposition. Each child carries a unique potential based on a complex interplay of genetic and environmental factors. There is no medical treatment that can be guaranteed as safe for 100% of any population. Each family has the inherent right to make health care decisions for their children, keeping in mind the best interests of the child as well as legitimate public health concerns that ethically inform these decisions.Participatory: Creating health should be a collaborative process, actively encouraging participation and putting children and families back in control of their own health. Patient-centered care creates hope and empowers families to make sustainable changes, inspiring children to create the future they deserve.Ecologically sustainable: How we practice healthcare affects the environment, which has a measurable and cyclical impact on our health. The health and well-being of all the Earth’s inhabitants are intimately tied to the health of our planet.Evidence-informed: Therapies that are evidence-informed while using the safety-effectiveness rubric  are consPIM is defined by several core guiding principles ,11:PreveThe field of PIM has developed organically over the last 25 years owing to pressing need and interest from pediatric health professionals, parents, and children. We have clear and compelling data that complementary therapies are of great interest to parents . Use of Critics maintain that integrative therapies do not have sufficient evidence to support their use in pediatric populations. We recognize that all health interventions would benefit from more high quality pediatric research to assess both effectiveness and safety. We do not agree that, by definition, all conventional care is evidence-based and that complementary therapies, by definition, lack evidence, or else they would be incorporated as part of conventional care. Research published in reputable journals has shown over the last 30 years that myriad complementary therapies are safe and effective for a variety of pediatric conditions and symptoms. Pediatric health professionals are encouraged to ask their patients and families about complementary therapy use . In a naAs demonstrated in the graphic, use of therapies should be recommended if the intervention is known to be safe and effective based on best available evidence. If the therapy is known to be safe but efficacy has not yet been conclusively established, it is reasonable to tolerate use while monitoring response. If a therapy is known to be effective but its safety is questionable, after a careful informed consent discussion, use may be considered if monitored closely. Finally, a therapy is to be avoided and discouraged if it has no proven efficacy and known adverse effects. Relative risks and benefits should always be considered in light of best available evidence, and professionals can use the graphic to help guide decision-making in collaboration with patients and families. It is important to note that this rubric applies to all therapies—not just those deemed complementary—as complementary therapies may not apply to all pediatric conditions.We recognize there are pediatric health professionals who would like to know how to discuss and apply these therapies in clinical practice, where to seek further training, and when to refer patients for these therapies. In addition, several barriers may exist for both professionals and families, such as adequate coverage of therapies and availability of PIM resources for the underserved or for those living in resource-poor locations ,20. The The field of PIM has evolved tremendously over the past two decades. The sentinel events that have shaped the current PIM landscape are noted below.1995 Ambulatory Pediatric Association establishes Holistic Pediatrics Special Interest Group1996 “The Holistic Pediatrician” published (Kemper)1998 Boston Children’s Hospital establishes Center for Holistic Pediatric Education and ResearchHolistic Pediatrics = Good Medicine)1999 First PIM Conference hosted by University of Arizona; Dr. Kemper’s APA Presidential Address  and University of Minnesota, AAP Task Force on CAM established and AAP NCE CAM sessions start2004 First PIMLI Summit in St. Paul, MN; Pediatric Complementary and Alternative Medicine Research & Education (PedCAM) Network (Vohra) and International Pediatric Integrative Medicine (IPIM) Network (Rosen) started2005 AAP Provisional Section on Complementary, Holistic, and Integrative Medicine (CHIM) and Integrative Pediatrics Council (IPC) established2005–2008 International PIM/Pangea conferences hosted by IPCPediatrics in Review series on PIM debuts 2006 Pediatric Clinics of North America volume on PIM published 2007 The Use of Complementary and Alternative Medicine in Pediatrics AAP Clinical Report published in Pediatrics, IPC dissolves2008 AAP Section on CHIM official ; 2009 “Textbook on Integrative Pediatrics” published Pediatric integrative medicine: pediatrics’ newest subspecialty? Vohra S, et al.); University of Arizona Center for Integrative Medicine launches Pediatric Integrative Medicine in Residency (PIMR) curriculum; AAP SOCIM name changed to Section on Integrative Medicine (SOIM)2012 PIM program survey published 2014 2015 PIMLI Summit II in Boston, MAMind-Body Therapies in Children and Youth AAP Clinical Report published in Pediatrics2016 PIMLI Summit III in Hackensack, NJ; “The Holistic Pediatrician, 20th Anniversary Edition” published (Kemper); 2017 “Integrative Pediatrics: Art, Science, and Clinical Application” textbook published (McClafferty)Pediatric integrative medicine timeline, 1995–2017:All events are listed to the best of the PIMLI’s Summit collective knowledge and may not include all international PIM events.As noted, the first official meeting of PIM leaders in the United States was held in 2004 and termed the Pediatric Integrative Medicine Leadership Initiative (PIMLI) Summit. The first PIMLI Summit spawned several major initiatives: A Section on Integrative Medicine within the AAP, an interprofessional PIM nonprofit (the IPC), and two international online resources (the IPIM-Network and PedCAM). These entities spearheaded numerous educational programs, including (1) PIM content at the AAP’s National Conferences and Pangea PIM Conferences; (2) publication of key PIM books and scholarly articles; and (3) the establishment of the PIM in Residency (PIMR) training program. The decade of significant progress following this first PIMLI Summit coupled with the desire to nurture sustainable growth in the field prompted PIM leaders to systemically revisit the vision for the future of PIM ,22.Supported by a generous grant from the Marino Health Foundation, Drs. Kathi Kemper and Lawrence Rosen—in partnership with the AAP—developed the second PIMLI Summit held in Boston, MA in June 2015 to accomplish the following objectives: (1) develop a long-term vision for PIM addressing gaps and future needs for clinical, educational, research, and advocacy domains; and (2) develop future PIM leaders who can achieve the vision through practical strategies and partnerships.A group of fifteen PIM leaders from the United States and Canada were invited to attend the Summit. These physicians had a varying range of expertise in PIM with different stages of career development, and practiced in a variety of settings. They also represented the AAP Section on Integrative Medicine, Academy of Integrative Health and Medicine, University of Arizona Pediatric Integrative Medicine in Residency program, various North American pediatric academic programs, and the PedCAM and IPIM Networks. An intentional effort was made to incorporate a balance of early career and established leaders. Representatives from many other professions and partner organizations were consulted during meeting preparation to optimize long-term sustainability and success and to embody the interprofessional philosophy inherent in integrative care. Specifically, with organizational support by John Weeks, a pioneer in collaborative interprofessional IM efforts over several decades, representatives from the Academic Consortium for Integrative Medicine and Health (ACIMH) participated in a comprehensive pre-Summit survey.In May 2015, more than 30 integrative health professionals provided feedback on the definition of integrative medicine, the state of child health, and a vision for PIM through a pre-Summit survey developed by Drs. Kemper and Rosen (unpublished data). In addition to pediatricians, these professionals represented expertise in Ayurvedic Medicine, botanical medicine, chiropractic, education, energy medicine, family medicine, health policy, massage therapy, mental health, naturopathy, Traditional Chinese Medicine, and yoga. Drs. Kemper and Rosen coordinated a conference call with John Weeks and a specially-designed 15-member interprofessional task force to discuss the survey and provide guidance for the Summit. A wordcloud  was creaRegarding the current state of children’s health, respondents noted that while pediatric acute care is ‘good’, both the quality and quantity of medical care for children and youth with chronic conditions often is not optimal. Survey participants felt the current conventional health care system is failing to adequately address the rising prevalence of chronic illnesses in children. They believed there is a need for a larger workforce of PIM health professionals to meet the challenges of complex childhood conditions while also promoting wellness. They also highlighted the importance of educating families about lifestyle approaches including healthy nutrition, physical activity, sleep, and stress coping skills. A need for more effective advocacy for improving children’s health globally was mentioned, including a push for healthier modes of transportation, sustainable agriculture and food sources, and addressing health related environmental factors.When asked how pediatricians can more effectively work with other stakeholders to best serve children’s needs, survey participants responded that collaboration with other health professionals, parent groups, third-party payers, and community organizations is key. PIM stakeholders’ vision for what pediatric integrative medicine would look like in 10 years included the wish that “decisions regarding a child’s healthcare would be made from an integrative perspective, taking all possible healthcare options into account”. Pediatric clinics would provide integrative care as part of the medical home with respect for all members of the patient’s health care team. In addition, schools that train health professionals will incorporate integrative medicine training and provide interprofessional learning environments to build trust and facilitate patient-centered collaborative care. Finally, increased public and private funding would be available to support the investigation of all evidence-informed approaches that are personalized to the individual, given their health, preferences, and goals.https://momsmeet.com, unpublished data) answered questions regarding their knowledge of PIM, PIM therapies they’d like to see offered in pediatric practices, and their willingness to advocate for insurance coverage of PIM therapies. Of note, even in this sample of natural health oriented parents, nearly one in four respondents were not familiar with IM. Fewer than one in seven definitively consider their pediatrician integrative while approximately 60% of parents believe having an integrative pediatrician for their children is important. Information about therapies is most commonly found online, and the two most desired in-office therapies are nutritional counseling and behavioral/mental health services. Key survey findings are shown in Parents are key PIM stakeholders and, therefore, a national parent online survey was conducted just prior to the PIMLI Summit to guide the meeting, with the logistical support of Kiwi Magazine, a publication focused on healthy lifestyle approaches for families. A sample of 1500 parents solicited through Kiwi’s Moms Meet network  by adapting existing Develop an online video series featuring children and families discussing integrative care success stories.Develop a robust library of PIM patient handouts for widespread use in the clinical setting.Advocacy and PartnershipsEstablish an online presence to serve as a strong independent voice advocating for PIM as mainstream pediatric healthcare, including a repository for research, clinical, and educational resources.Partner with disease-specific organizations to spread knowledge of PIM therapies that may improve quality of life for their stakeholders.Cultivate strong relationships with specialties also serving children, such as family medicine, medicine/pediatrics, and obstetrics/gynecology.Work with federal and state organizations to develop and promote preventive lifestyle policies for children and families.Contribute to resource development and advocacy efforts that support payment for PIM services and models of care.Explore sustainable resources for philanthropy to support ongoing growth of the field.Sustainable support for the AAP SOIM research and education grant program.http://www.cpsp.cps.ca/uploads/publications/Posters-CAM.pdf) to pediatricians.Re-printing and redistribution of the “Talk with Your Doctor” PIM poster . Survey participants were recruited from two professional listservs: the IPIM Network and the AAP Section on Integrative Medicine listserv.A total 93 health professionals completed the survey.Approximately 75% identified as pediatricians (MD/DO) with a total of 17 professional disciplines represented.Approximately 50% had been in practice more than 20 years, and more than 80% had been in practice more than 10 years.Over 75% stated that currently available PIM resources online are not sufficient to support their pediatric practice.The top two most valuable current online PIM resources were the two listservs noted above; no current website was rated as valuable by more than 25% of respondents.Membership for pediatric healthcare professionals providing specialized access to educational and community-building resources, including integrating existing interprofessional and international PIM networks .Consumer and policymaker engagement via media tools and the development of short promotional videos profiling PIM “success stories”.Educational and Research Resource Repository, including professional presentations and a searchable PIM publication bibliography.Continuing education online conferences and webinars.Professional consultative service assisting the development of academic PIM centers and clinical practices.Coordination of PIM efforts with the AAP SOIM and other reputable national/international organizations.Conversations with key stakeholders and advisors confirmed the need and desire for an independent organization focused specifically on PIM education and advocacy, directed at the broad ‘middle’ of the professional and consumer populations. Challenges identified included: (1) prioritizing PIM both within a larger pediatric organization and within a larger integrative organization; (2) securing funding for administrative support given the significant ongoing clinical, research, and educational commitments of PIM leadership—creating a balanced interprofessional leadership group; and (3) nurturing leadership development to ensure sustainability of the organization. Understanding these obstacles, the PIMLI steering committee evaluated and debated potential partners to host this initiative, concluding that no existing group ideally met our needs. They proposed exploration of hosting an independent nonprofit organization as the first option. Paramount to the success of this organization would be the design and launch of a robust multimedia website that serves as a hub for all PIM activities, including:Organizational structure and funding needs were discussed including potential funding partners and self-sustainable sources of support and leadership. Given the huge scope of the proposed activities above and the clearly expressed needs in the 2016 professional survey, the scope was initially narrowed to online PIM professional education, because opportunities to fill the gap of online educational resources currently exist. At this time, PIM education exists through the University of Arizona Center for Integrative Medicine: Pediatric Integrative Medicine in Residency (PIMR) curriculum for pediatric resident physicians, various continuing education conferences, and online resources . The PIMPIM exemplifies a mainstream model of comprehensive care that emphasizes a personalized, participatory, and evidence-informed approach to the whole child.PIM emphasizes preventive health, understanding of the etiology of underlying illness, and exploration of all appropriate treatment options to optimize health and well-being.PIM promotes a cohesive, respectful, and interprofessional team approach focused on the well-being of the child as a growing, developing individual in the context of the family.Professionals collaborate across disciplines and geographic boundaries in advocating for the needs of patients and families from all socioeconomic and cultural backgrounds.Integrative professionals embrace self-care as a cornerstone of health.Integrative professionals support identification of and access to reliable PIM educational, clinical, and research resources for all those interested in maximizing patient health and wellness.Based on work at the 2015 and 2016 Summits, long-range visions for PIM’s next decade are outlined:Establishment of an international and interprofessional pediatric group to coordinate and advance the work of PIM in collaboration with the AAP SOIM. This two-pronged approach ultimately represents the optimal strategy to ensure the sustainable growth, evolution, and impact of PIM within the field of Pediatrics.Medical schools, residencies, and other professional training programs teach PIM routinely and widely.Hospitals, clinics, and academic centers promote co-located PIM services .Pediatric training programs implementing the PIMR curriculum and PIM fellowship programs experience high enrollment and active participation of alumni.A yearly interprofessional symposium is established and brings together PIM professionals for collaborative learning.PIM materials  are compiled and hosted on an independent website for ready access by professionals, patients, and institutions.PIM research is adequately funded to develop the science of utilization, safety, efficacy, and cost-effectiveness of PIM therapies, and a multi-center research network is established to facilitate the acquisition of this knowledge.Safe, effective, and cost-effective PIM therapies and health care systems receive endorsement from national organizations, hospital leadership, and other decision makers to judiciously expand PIM as appropriate.To achieve this vision, proposed tangible outcomes include:


Eight years have passed since the launch of PhytoKeys  – PensofIn a very short time period after its inception, PhytoKeys became one of the most popular and appreciated Open Access journals in botany. The journal started with only 48 submissions in 2011; by 2017 that number quadrupled to 187 manuscripts submitted annually (Table IPNI)  , 2016. IOver the years PhytoKeys has attracted a diverse range of botanical researchers from all parts of the world, with the highest numbers coming from the United States of America (193), Brazil (93), China (80), United Kingdom (53) and Germany (49). Altogether 939 scientists from 67 countries have published in the journal from its launch until 1 June 2018 CNKI (China)CINIPIEC (China)eLibrary (Russia)ORCID Dryad Data Repository Open Citations Corpus Since 2016 PhytoKeys has been using Altmetric – a technology providing article level metrics which enables authors to track the online shares and discussions of their published articles. Figure PhytoKeys site have received 147,865 views. Four species described in PhytoKeys – the flowering tree named as a new genus Sirdavidiasolannona, the dragon tree Dracaenakaweesakii, the orchid Telipogondiabolicus and the bush tomato from northwestern Australia, Solanumossicruentum made it to the top 10 new species nominated by the State University of New York College of Environmental Science’s International Institute for Species Exploration (IISE) .Pensoft continues to invest in the popularization of PhytoKeys via media campaigns. Some examples of press releases on articles published in the journal that grasped the attention of journalists and received large media coverage are listed in Table Over the eight years of the existence of PhytoKeys, the journal has positioned itself among the world’s leading journals in systematic botany. Started by the editors primarily as a taxonomically-oriented journal, the journal has since extended its scope to enable publications across other botanical disciplines, such as plant ecology, genomics, evolutionary biology, paleontology, bioinformatics, ethnobotany, etc.As the chief editors of PhytoKeys we have worked hard to expand the journal’s editorial board, which has grown significantly and today is comprised of more than 80 experts from various scientific disciplines and geographical areas. The journal has achieved an international reputation by publishing milestone works that will affect all botanists, such as the changes to publication requirements made at the XVIII International Botanical Congress in Melbourne , b, the With its continuous technological innovation and support from subject editors and reviewers, PhytoKeys continues to receive recognition by the international community of plant researchers. This success would not have been possible without our authors, reviewers, subject editors, production staff, readers, and supporters, to which we express our sincerest gratitude and thanks! We cannot wait to see what the 200th issue will look like!


Burns are caused by several mechanisms including flame, scald, chemical, electrical, and ionizing and non-ionizing radiation. Approximately half a million burn cases are registered annually, of which 40 thousand patients are hospitalized and receive definitive treatment. Burn care is very resource intensive as the treatment regimens and length of hospitalization are substantial. Burn wounds are classified based on depth as superficial (first degree), partial-thickness (second degree), or full-thickness (third degree), which determines the treatment necessary for successful healing. The goal of burn wound care is to fully restore the barrier function of the tissue as quickly as possible while minimizing infection, scarring, and contracture. The aim of this review is to highlight how tissue engineering and regenerative medicine strategies are being used to address the unique challenges of burn wound healing and define the current gaps in care for both partial- and full-thickness burn injuries. This review will present the current standard of care (SOC) and provide information on various treatment options that have been tested pre-clinically or are currently in clinical trials. Due to the complexity of burn wound healing compared to other skin injuries, burn specific treatment regimens must be developed. Recently, tissue engineering and regenerative medicine strategies have been developed to improve skin regeneration that can restore normal skin physiology and limit adverse outcomes, such as infection, delayed re-epithelialization, and scarring. Our emphasis will be centered on how current clinical and pre-clinical research of pharmacological agents, biomaterials, and cellular-based therapies can be applied throughout the continuum of burn care by targeting the stages of wound healing: hemostasis, inflammation, cell proliferation, and matrix remodeling. Currently, multiple strategies exist for the management of burn wounds depending on both the depth and extent of the burn. Burn wound care strategies aim to modulate the inflammatory response, accelerate re-epithelialization, and improve overall wound healing. Furthermore, combinatorial approaches that incorporate cellular-based therapies, pharmacological agents, and biomaterials are utilized to minimize infection and serve as burn wound coverage adjuncts with the goal of restoration of skin function . This review focuses on how therapies for burn injuries are currently being developed to address the array of issues that occur throughout the continuum of burn care. Specifically, this review investigates treatment modalities for thermal burns that are currently in clinical trials and pre-clinical animal testing. To accomplish this and ultimately illustrate the challenges that remain unmet, it is important to understand the current standard of care (SOC) for burn wound injuries. Next, the United States (US) Food and Drug Administration (FDA) approval process will be described to explain how current products have been approved in order to highlight the challenges that new ideas and technologies will encounter and how this affects the current design of new products. Finally, an analysis of clinical and pre-clinical studies utilizing the latest regenerative therapies will be presented that are addressing the different stages of burn wound healing.Skin is the human body's largest organ, encompassing ~1.5–2.0 square meters for an average adult. It functions as a defensive barrier against foreign materials, assists in thermoregulation, prevents evaporative loss of fluids, acts as a sensory organ, and plays a role in Vitamin D production. It is composed of three layers: the epidermis, dermis, and hypodermis. The epidermis is the outermost layer, while the dermis is between the epidermis and hypodermis. The papillary dermis  consists of rete ridges, capillaries, and loosely arranged collagen fibers. The reticular dermis  contains blood vessels, nerves, roots of hair follicles, sebaceous and sweat glands, densely packed collagen fibers, and provides nutritional and structural support to the epidermis. The innermost layer is the hypodermis which consists of subcutaneous adipose tissue and associated blood and lymphatic vessels. This layer provides insulation, cushion from traumatic insults, buoyancy to the body, and possesses some endocrine functions  cause a systemic inflammatory response that results in damage throughout the entire body including the immune system, gastrointestinal system, and muscle. This systemic damage is much more pronounced in burn injuries compared to other forms of trauma Tiwari, . A hallmThe annual burn incidence in the United States is ~486,000 according to the National Burn Repository of the American Burn Association. Approximately 3,275 people lose their lives and 40,000 require hospitalization due to burn related injuries , darker skin color (pigmentation), female gender, facial or neck injuries, and severity of injury (%TBSA and depth). Several studies report that from 32 to 72% of all burns result in HTS formation  expression  by one of the following mechanisms with the goal of evaluating the safety and efficacy of a new product: 1) Investigational New Drug (IND) and New Drug Application (NDA) or Biological License Application (BLA), (2) 510(k) Submissions, (3) Investigational Device Exemption (IDE) and Premarket Approvals (PMA), (4) Humanitarian Device Exemptions (HDE), and (5) HCT/P. Table  Investigwww.FDA.gov). Class III devices support or sustain human life thus must obtain a PMA after progressing through clinical trials to establish the device's safety. The HDE designation is for specialty diseases that affect a limited number of individuals  every year. The exemption is accompanied by very strict guidelines with the intent on getting these products to market in a quicker fashion. HCT/P products  are available through tissue banks much like blood through blood banks. The tissue banks must adhere to standards set forth by the FDA and the products must be screened and verified that no viral, such as human HIV and hepatitis, or bacterial contaminants are present  take the longest to acquire approval that begins with pre-clinical animal studies followed by three phases of clinical trials, which are required components for an NDA or BLA submission to the FDA. This entire process can take 7–15 years and the latest estimated costs are ~$1B  molecules, and a wide range of cell types. Acute wound healing follows a complex, overlapping cascade of events consisting of hemostasis, inflammation, cell proliferation, and matrix remodeling of the wound site  the development, maturation, and function of bioengineered and regenerating tissues”  refers to “the practice of combining scaffolds, cells, and biologically active molecules into functional tissue….that restore, maintain, or improve damaged tissue or whole organs” , TGF-α/β, and epidermal growth factor (EGF), which are trapped in the blood clot and recruit other cell types for wound repair  is a new hemostatic agent that has been developed to modulate the coagulation pathway to induce clotting. It consists of a lipid microvesicle with a modified version of recombinant human tissue factor that is lyophilized and applied as a spray. A phase 2 RCT of 78 patients was recently completed evaluating this product's ability to reduce donor site bleeding duration. TT-173 was shown to stop bleeding faster than placebo. No adverse events were observed and donor sites healed as expected. Other benefits of TT-173 reported were reduced cost compared to fibrin sealants, ease of manufacturing, and no human or animal components which decreases the risk of pathogen transmission  as a plasma-free alternative produced from mammalian cells for use during burn surgeries. The initial study demonstrated efficacy in achieving hemostasis with 91.5% of patients attaining it in 20 min and safety with only 1.6% of the patients developing antibodies to the rThrombin  and TGF-β, which induces cell proliferation and migration  Table , a categThermal injury is associated with altered systemic immune function while the wound exhibits perturbed patterns of immune cell infiltration due to alterations in tissue permeability and lack of functioning vasculature in areas of coagulation , resulted in early wound closure, increased TGF-β1, and increased vascularization in the burn wound area, without excessive deposition of collagen  and cyclooxygenase-2 (COX-2) inhibitors have been investigated as a method to attenuate the inflammatory response . The active triterpene glycosides within Centiderm® transforms by hydrolysis into asiatic acid, which has shown to reduce the incidence of wound infections. In a recent clinical study, no infections were observed in the Centiderm®-treated group of 40 burn patients while 4 of 35 patients in the SSD group developed infections at the treatment site  pathogens in a mature infection when applied twice daily when compared to SSD  are commonly cationic and have broad-spectrum antimicrobial activity, targeting bacterial cell membranes and disintegrating their lipid bilayer structure . New blood vessels are formed by invading endothelial cells throughout the ECM to supply nutrients to the newly forming GT. As the wound fills in with GT, keratinocytes at the wound edges migrate and proliferate over the top of the wound until wound closure takes place  that reside at the base of the hair follicle act as foci for re-epithelialization. Hair follicles extend through the entire depth of the dermis and some viable HFSCs are present even in DPT wounds. In the event of a PT or deeper burn, the entire epidermis is lacking and thus an epidermal replacement is needed. For FT burns, the entire dermis has also been lost and needs to be replaced; otherwise, the resulting quality of life may be impacted by contractures and scarring . The applicability of CEA to burn wounds was widely recognized following the introduction of Epicel™ in 1988. Since then, many studies show the benefits of CEA in providing coverage to extensive burn wounds  applied with a spray device produce acceptable clinical outcomes ] which could significantly ease the availability of clinically acceptable xenografts , and is a viable FT product developed for treatment of severe burns after excision. StrataGraft® skin tissue consists of a stratified epidermal layer with a fibroblast laden collagen dermal component, is less fragile than CEA, and can be sutured, stapled or secured with an adhesive and remains intact on the wound bed, providing the critical barrier function during wound healing  contain collagen-glycosaminoglycan substrates with autologous fibroblasts and keratinocytes, and they are currently under clinical investigation as autologous engineered skin substitutes (ESS) Table . CSS areUse of dextran and fibrin hydrogels are currently being pre-clinically investigated as options to treat PT or FT burn wounds  , tyrosine kinase receptor, PDGF-β, and Tie-2 to facilitate MSCs-host endothelial cell interactions and wound vascularization  levels at the wound site, and improved tissue re-vascularization  and anti-fibrotic factors, including hepatocyte growth factor, basic fibroblast growth factor (bFGF), and VEGF .According to the FDA, the use of homologous stem cells for skin regeneration—where donor cells or tissues match recipient cells or tissues and perform the same basic function(s)—is regulated separately from non-homologous cells or tissues. These non-homologous treatments are not regulated by the HCT/P exemption and instead are considered a “biologic,” requiring an IND, clinical trials showing both safety and efficacy, and BLA approval Table  FDA, 20. With thTo improve wound healing in burns, studies have investigated the application of growth factors derived from allogeneic sources, recombinant yeast, or bacteria. Treatment with these factors may occur alongside SOC . The existing body of literature on growth factor application to treat burn wounds is variable, though, with different burn pathologies and pre-clinical models studied. In contrast, a great deal of literature exists regarding the application of growth factors in other types of wounds that could be extrapolated to the burn wound  did not significantly improve epithelialization rates  contains extracted plasma purified with supraphysiological concentrations of platelets. Recent studies have yielded mixed results. A rodent burn model demonstrated that PRP accelerated wound closure and resulted in less GT compared to controls for PT burns but not FT burns  is non-chromosomal circular DNA which exploits the cell machinery to produce proteins for a transient amount of time  approved, and cell based substitutes requiring a clinical trial supported PMA Tables , 8. ThesThe final stage of wound healing is matrix remodeling which continues to progress for years after injury and when aberrant, can result in scar formation and contracture. As the proliferative phase of wound healing transitions into the remodeling phase, well organized type I collagen becomes more abundant and wound tensile strength improves, The remodeling of collagen fibers ultimately leads to ~80% wound strength by roughly 6-weeks after injury  strategies have advanced significantly over the past 30 years. Small interfering RNA (siRNA) and miRNA play a role in RNAi pathways by post-transcriptional regulation of gene expression for a period of time  lasers create microscopic dermal injuries that renew the healing process on a smaller scale (Tierney et al., While the technology is not new, lasers are currently in 11 listed clinical trials to determine their safety and efficacy for scar mitigation Table . Pulsed The area of scar prevention and mitigation is becoming more important with the increase in survivability of severely burned patients. There is a paucity of approved therapies aimed at improving the long term outcomes of this debilitating injury. Tables The current accepted practice for the treatment of burn wounds is early excision of the necrotic tissue followed by immediate autografting. This strategy reduces microbial colonization, improves survival, shortens hospital stay, and decreases HTS formation (Sterling and Heimbach, RS: wound healing cascade, hemostasis section, discussion, compilation of article, tables; SN: burn wound coverings and stem cells, figures; CK: infection, gene therapy, tables; LM: immune modulation; RMC: burn wound coverings; NC: growth factors; AC, DT, and RKC: scar prevention and mitigation; JR: current standard of care and clinical gaps; RJC: participated in preparation and revision of manuscript. All authors approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The dynamic nature of modern warfare, including threats and injuries faced by soldiers, necessitates the development of countermeasures that address a wide variety of injuries. Tissue engineering has emerged as a field with the potential to provide contemporary solutions. In this review, discussions focus on the applications of stem cells in tissue engineering to address health risks frequently faced by combatants at war. Human development depends intimately on stem cells, the mysterious precursor to every kind of cell in the body that, with proper instruction, can grow and differentiate into any new tissue or organ. Recent reports have suggested the greater therapeutic effects of the anti-inflammatory, trophic, paracrine and immune-modulatory functions associated with these cells, which induce them to restore normal healing and tissue regeneration by modulating immune reactions, regulating inflammation, and suppressing fibrosis. Therefore, the use of stem cells holds significant promise for the treatment of many battlefield injuries and their complications. These applications include the treatment of injuries to the skin, sensory organs, nervous system tissues, the musculoskeletal system, circulatory/pulmonary tissues and genitals/testicles and of acute radiation syndrome and the development of novel biosensors. The new research developments in these areas suggest that solutions are being developed to reduce critical consequences of wounds and exposures suffered in warfare. Current military applications of stem cell-based therapies are already saving the lives of soldiers who would have died in previous conflicts. Injuries that would have resulted in deaths previously now result in wounds today; similarly, today’s permanent wounds may be reduced to tomorrow’s bad memories with further advances in stem cell-based therapies.The online version of this article (10.1186/s40779-018-0154-9) contains supplementary material, which is available to authorized users. Wounds resulting from injuries suffered during active military service represent major challenges to defense health systems, accounting for huge military expenditures in the US, Russia, Ukraine, Iraq, Syria, Afghanistan, Yemen, Sudan and other areas around the world with active conflicts –4. The tTissue engineering is an emerging field representing potential alternatives to contemporary solutions. It is a science that combines stem cells, scaffolds with suitable growth factors, cytokines and chemokines to improve, replace or regenerate tissues and organs Fig.  6]. Thr. Thr6]. Stem cells (embryonic stem cells and adult stem cells) serve as the primary instrument of tissue engineering, a technology that has garnered a great deal of attention in civil and military research for providing possible treatment of many diseases and injuries Fig.  8]. Mes. Mes8]. Given the above functions, the inclusion of tissue engineering technology and stem cells in the treatment of battlefield injuries can bridge long-standing challenges in tissue repair and restoration. These possibilities provide promising therapeutic options to address the unmet needs of medical defense . For insIn this review, the treatments and potential applications of tissue engineering for injuries to the skin, sensory organs, nervous system tissues, the musculoskeletal system, circulatory/pulmonary tissues, and genitals/testicles, for acute radiation syndrome and for the development of biosensors are discussed. Search methods included references in the literature, cited sections of the most relevant articles, articles by authors of key references and science citation indexes, and other relevant web reports.The skin, the largest organ of the body, possesses a complex multi-layered structure that guards the underlying muscles, ligaments, bones, and delicate organs . It is mGunshot injuries, explosions, chemical exposures, nuclear heat, and any other agent of warfare can cause severe damage to the skin. Depending on the type and extent of an injury, the body regenerates itself through the process of wound healing, a dynamic process that involves stem cells, progenitor cells, parenchymal cells, extra cellular matrix (ECM), blood cells and soluble mediators in three phases: inflammation, proliferation and remodeling .The above processes can occur as long as any of the three layers of skin remain. Third- and fourth-degree burns are considered full thickness and are the most difficult to treat Fig. . These rSkin substitutes are defined as a heterogeneous group of substances that help in either temporary or permanent closure of any kind of wound. Skin substitutes help when standard surgical therapies are not desirable. The decision is case based, depending on the type and extent of burns, shallow or deep, and the area of the body affected .A good skin substitute should possess the following qualities: is flexible in thickness, is durable for long-term wound stability, conforms to irregular wound surfaces, resists infection, prevents water loss or dehydration, withstands shear forces and wound hypoxia, is cost efficient and easy to prepare, store and use, and has wide availability and a long shelf life. It should be devoid of antigenicity, provide permanent wound coverage, and recreate dermal, as well as, epidermal components . To dateMultiple preclinical models have demonstrated the efficacy of MSC-based treatments for promoting the repair and regeneration of thermal burns and radiation exposure –23. ThesIn 2008, the US Armed Forces Institute of Regenerative Medicine (AFIRM) began to harness stem cell technology to reconstruct new body parts, including skin. Over 2250 million dollars in public and private funds were allotted for the project’s first 5 years, with the National Institutes of Health (NIH) teaming up with three other public universities for a progressive developmental project. The results were encouraging . The US The invention of polycarbonate eye armor has ushered in an era of reduced injuries to the eye; however, recent increases in advanced explosive models have led to a reciprocal increase in devastating injuries to the eye Fig.  27]. Ne. Ne27]. Auditory impairments are the most typical sensory loss experienced in a blast trauma. High-speed explosives and artillery result in mechanical and biochemical damage to the auditory system, especially to the sensory hairs. Severe injuries to hair cells in the cochlea, which lack regenerative capacity, can lead to permanent hearing loss and vertigo . To dateThere are 3 major kinds of injuries typically sustained in the nervous system. These include trauma/concussions to brain tissues, severed spinal cords and torn peripheral nerves Fig. . ProjectAccording to ongoing reports, blast-induced neurotrauma has been the signature wound of present wars around the globe. This is partly due to improved protective equipment against fragmentation and penetrative weapons –42. For Overall, close to 2,000 (23%) medically evacuated US troops sustained traumatic brain injuries (TBIs) during the previous war in Iraq. Closed traumatic brain injury (TBI) accounted for approximately 90% of 433 service men studied at Walter Reed Army Medical Center, highlighting that blasts are the signature injuries of contemporary conflicts .Hypotheses regarding how the brain becomes pressurized as a result of blast exposures have generated much debate. Researchers have concentrated on this phenomenon, although the developmental sequence and procedures to treat the resultant pathophysiology remain unresolved , 46.TBIs can be psychologically destructive, predisposing affected individuals to depression, substance abuse and personality disorders. In effect, they share many clinical features with post-traumatic stress disorder . The rolPeripheral and central nervous system trauma can pose problems on two fronts, causing both physical and psychological malfunction. Data exist that reveal peripheral nervous system trauma in approximately 20% of patients with limb injuries sustained in the Vietnam War . This fi6 cells per kilogram body weight into the sub-lateral ventricular zone, reported that 3 candidates maintained a consistent recovery in their Unified Parkinson’s Disease Rating Scale (UPDRS) “on and off” score. They also demonstrated recovery in Schwab and England, Hoehn and Yahr scores and in facial expression symptoms, episodes of gait imbalance and freezing . Ap. Ap77]. In hemorrhage and blood loss, emerging technologies have aided scientists in developing artificial blood that could treat wounded soldiers in far-flung battle fields. This procedure, named “pharming,” was launched by the US Pentagon for its Defense Advanced Research Project Agency (DARPA) in 2008 . Mass quThe US military has funded research into lab-grown testicles for soldiers whose battlefield injuries have left them unable to conceive children. This Pentagon-backed research at the Wake Forest Institute for Regenerative Medicine in North Carolina could fundamentally alter the prognosis of men with injuries impairing their procreative capability , 82. ThoOther works that have given hope to men and women with traumatic genito-urinary injuries from war include tissue engineering of a penis, tissue-engineered autologous urethras and tissue-engineered autologous vaginas , 86, 87.Strategies to solve potential threats posed by the incidence of ARS include, but are not limited to, enhancement of hematopoietic recovery and facilitation of healing of the gastro-intestinal tract and the skin.Hematopoietic complications are among the main causes of death upon exposure to radiation ranging from 1 to 10 Gy . The resIn another study, patients with serious burns from radiation, who were not benefitting from a conventional treatment course, were transplanted with 5 grafts of autologous cultured BMSCs. It was observed that these patients experienced significant decreases in their blood levels of C-reactive proteins for over 100 days post-stem cell treatment. They further observed overall reductions in pain, a disappearance of tissue necrosis and soft tissue regeneration, especially on the arm .For the advancement of civilian and defense responses to possible nuclear events, the US Department of Defense partnered with Osiris Therapeutics in the development of “Prochymal” for possible mass production. Prochymal, an allogenic stem cell therapy, was first approved by Canada for acute graft-vs-host disease (GvHD). MSCs derived from pooled bone marrow from healthy adults between the ages of 18 and 30 years were isolated, cultured, packaged and stored frozen until needed. These could be administered post-exposure or at the onset of symptoms, eliminating the need for a predefined treatment. The long-term storage capability of Prochymal makes stockpiling it for a mass-health event feasible , 91.Patients who are exposed to a level of radiation greater than 7 Gy will experience complications characterized by electrolyte imbalances, anorexia, malaise, dehydration, fever and severe diarrhea. The main root cause of the injuries to the gastro-intestinal tract is linked to sudden depletion and death of intestinal crypt cells, which are precursors to the epithelial layer cells that normally replenish them on a regular basis. This depletion causes a breach in the normal gastro-intestinal barrier and predisposes the subject to life-threatening infections. People diagnosed with this condition have low probabilities of survival; to date, there has been no specific medically approved response to this condition .Several studies have reported that MSC transplantation can aid regeneration and restoration of the intestinal epithelium by nurturing continuous replication of the remnant stem cells within the crypt. It is presumed that the mechanism by which MSCs elicit this support is by local secretion of cytokines and chemotactic signals that induce the migration of progenitor cells to injury sites. Animal studies of abdominal complications of ARS have shown increased survival with MSC transplantation, together with the regeneration of cells from the internal crypt, restitution of the stem cell bases, and increases in xylose absorption . The serIn modern warfare, the increased threats posed by chemical and biological weapons underscore the importance of the early detection of the presence of these agents .Due to their plasticity, stem cells have helped to diminish the concerns posed by various non-physical weapons, as well as to better appreciate their acute or extended effects via screening. These results have helped to develop biosensors with greater precision for detection .In preparation for risks to deployed forces, the US DARPA and several other military, academic and private institutions have developed classes of engineered tissue-based biosensors (TBBs) and biologically based biosensors with the capacity to detect almost any environmental chemical or biological hazard that can inflict acute  or chronic  health consequences on military or civilian populations. One example of this is the US Army Center for Environmental Health Research (USACEHR) ventilator system .The major agents of concern for deployed troops primarily include those with the capacity to be weaponized, including (a) neurotoxic agents ), (b) occupational chemicals , (c) environmental toxins (botulinum toxin), (d) industrial wastes, (e) military reagents and materials (propellants and refrigerants), and (f) combustion byproducts ). These agents can pose threats individually, in simple mixtures, or as complex mixtures with the potential for addition, synergistic or antagonistic reactions , 96.TBBs can be categorized into two groups: a) those with detector elements derived from higher animal cells and b) those with detector elements derived from simple organisms, which are occasionally genetically engineered for specificity  .They can detect significant concentrations of well-known biologically active agents or new potential lethal agents and send early warning signals to deployed troops. Biologically based sensors utilize biological components as sensing elements, which are compatible with chemical, electrical or optical transduction .Their detector elements include mammalian brain tissues, neuronal and glial cell cultures, spinal cord cultures, cardiomyocyte cultures, hepatocyte cultures, fish scale chromatophores and genetically engineered bacteria or biologically active cell processes , 98–101.Furthermore, military and civilian jet crews are continually in contact with higher doses of natural radiation from galactic cosmic rays at typical jet altitudes of 6.1 to 18.0 km. Exposure often occurs from sporadic solar flare activities, especially at higher supersonic jet altitudes. Isotropic particle fluence rates of primary cosmic rays, comprising 90% protons, 9% alpha particles and 1% heavy nuclei from carbon to iron, are derived from stellar flares and coronal mass ejections, pulsar acceleration, supernovas and explosions of galactic nuclei , 102. InOver the years, tissue-equivalent proportional counters (TEPCs) have been used to measure the ambient dose equivalents of the cosmic radiation exposure of aircrews during a solar cycle. Measurements performed at the International Space Station (ISS), ground-based neutron monitoring, Geostationary Operation Environmental Satellite (GOES) data and data from transport code analysis have been used to propose an empirical model for estimation of aircrew exposure during solar particle events. These data have been compared to results obtained during recent solar events . With reOrgan reconstitution and tissue regeneration have been the primary goals of tissue engineering in defense medicine. Virtually every tissue in the body is of military importance due to the diverse nature of injuries associated with war . More thIn war, it is difficult to have localized damage to a single tissue type from combat; injuries always reflect a mix of integrated wounded tissues. In the past, several techniques have been used to treat these defects, with varying degrees of success , 70, 71.Physicians at the United States Walter Reed Army Medical Center have reported that each war has its own characteristic wounds. World War I produced damaged lungs from poisonous gases, World War II inflicted cancers as a result of radiation from atomic bombs, and the Vietnam War produced skin disorders from Agent Orange exposure. In recent conflicts, blast-induced TBI has emerged as a signature wound .Tissue engineering has propelled the concept of regenerative medicine into promising realities. To properly engineer complex tissues, stem cells will need to be incorporated into biomaterials. This was not discussed in detail here, but current developments in scaffolds have been captivating and impressive , 6, 27.The human body routinely regenerates liver and bone marrow cells. Fundamentally, all body parts, tissues and organs have a natural repository of cells that are available for replication when an injury occurs. Initially, efforts were focused on skin substitutes for treating burns, but an increasing number of tissue types, biomaterials and scaffolds used as delivery systems are now being engineered. Notable results have included tissue-engineered bone, cartilage, blood vessels, liver, muscle, and even nerve conduits , 106–108There are approximately 300 institutes in the USA and more than 80 in Europe that have embarked on stem cell, tissue engineering and regenerative medicine projects, both for military and civilian purposes . SeveralThe United States Army Medical Research Command (USAMRC) has focused on musculoskeletal tissue regeneration over the last several years. At the project initiation, it was acknowledged that recent wounds are more horrific; although death rates from injuries have dropped, more veterans face lives with broken limbs, which have increasingly called for efforts focused on regenerating them. This will help keep veterans on active duty and enable them to have normal lives . The UniSince 2012, apart from collaborations with notable academics, AFIRM collaborated with other tissue regeneration companies, such as Organogenesis, in Canton, and Intercytex, in Woburn Massachusetts, to create an “off-the-shelf” composite skin substitute. One of their most conventional projects was to optimize a skin-grafting technique with more modern skin spraying and printing technologies . Many reIn Russia, where tissue engineering was developed for the Defense Ministry in the era of the Soviet War in Afghanistan, scientists have attempted to use stem cells to cure psychological war traumas (PWT). The use of stem cells for PWT has progressively developed in Russia. In June 2014, the Russian Ministry of Defense announced its decision to continue research into PWT. A new scientific division within the Military Medical Research was formed and was subsequently divided into three units. These included the Biological-pharmaceutical, Medical-prophylactic, and Engineering-technical units. At first, they worked on the creation of a stem cell bank for soldiers who operated in risky assignments and in dangerous areas . In 2013As part of Britain’s preparations for a possible nuclear attack, their military partnered with the Pentagon on the production of Prochymal, which is believed to rejuvenate blood and repair damaged skin. Both the United States and the British government proposed investing millions of dollars in its purchase after approval from the FDA . The BriIn Malaysia, there is a pioneering center at the National University of Malaysia Medical Centre and other offshoots, among which is the Bio-artificial Organ Unit at the National Defence University, whose aim is to engineer bio-artificial organs for military medicine . With thIn China, there has been immense focus in both civilian and military research on stem cells and tissue engineering programs since the early 2000s. The application of stem cells in this area has mainly focused on hematopoietic stem cells and the use of MSCs in hematological diseases, vascular diseases, and diabetes mellitus. Among the major laboratories and centers for tissue engineering and stem cell biology are the Fourth Military Medical College Center for Tissue Engineering and the Institute of Basic Medical Science Academy of Military Medical Sciences. Several of the approved clinical trials that are monitored by the State Food and Drug Administration (SFDA) include: 1) autologous bone marrow mesenchymal stem cells for injection (X0407487); 2) recombinant stem cell factor for injection (CSL01037); 3) umbilical cord blood cell progenitor cells for injection (X0404120); 4) umbilical cord blood red blood cell precursors for injection (X0404119). All these were performed by the Institute of Transfusion Medicine, Academy of Military Medical Sciences of People’s Liberation Army . In 2007India is among the ten top countries deeply involved in tissue engineering and regenerative medicine research. The Indian stem cell industry, including both military and civilian research, was estimated to be worth approximately $500 million in 2010, with a projected annual growth rate of 15%. These research areas were originally a sub-segment of the biotechnology industry. The leading research institutes in India include the National Centre for Biological Sciences (NCBS), Bangalore; the Centre for Cellular and Molecular Biology in Hyderabad; the L.V. Prasad Eye Institute, Hyderabad; the Centre for Stem Cell Research, Vellore; the National Brain Research Centre, New Delhi; and the National Centre for Cell Science, Pune . SeveralThese stem cell companies and institutes have recently pursued trials on such diverse ailments as strokes, spinal injuries causing partial paralysis and cerebral artery infarction, among others . In 2009In Japan, there has been enormous progress with the use of stem cells and tissue engineering technology. The invention of induced pluripotent stem cells (iPSCs) in Japan 10 years ago served as a game changer for the study and potential therapeutic use of embryonic stem cells, which have attracted the wrath of moralists as well as religious evangelicals . Unlike In Australia, which has been among the world’s leading countries in stem cell research and tissue engineering, significant legislation has been put in place to keep hES cells, somatic cell nuclear transfer and therapeutic cloning out of active research areas. In 2010, the Australia spinal cord injury network , in collaboration with the US company Asterias Biotherapeutics, tried to develop stem cell technology that had successfully restored some movement in quadriplegics. This technology induced some recovery in arm and hand function in a patient paralyzed from the neck down after a low-dose injection of stem cell into the patient’s spinal cord. With a new protocol, when a higher injection dose was administered, there was a more robust return of arm and hand function, together with motor function, within 3 months following cell injections . RecentlDespite the advances described above, there are certain limitations with tissue engineering technology in defense medicine. One major concern is the cost of production, which could be discouraging. Over the years, the US Defense Ministry has invested millions of dollars in various projects that the Pentagon believed could 1 day help wounded veterans regain normal lives, but many expected products are far from deployment . AnotherDespite these challenges, there is the belief that scientists will 1 day select cells from human donors and process them to re-grow new tissues and organs within the same patient, thus avoiding rejection. Techniques are being developed by various defense ministries that can make new muscle and tendon and repair extremities, such as fingers, noses and ears , 4, 60.With the present progress of the use of stem cells in tissue engineering applications for defense medicine, future injuries in warfare may never be the same. Current developments in military medicine are already saving the lives of soldiers who would have died from their injuries in previous conflicts. This demonstrates that yesterday’s sure deaths have become today’s wounds; if extrapolated based on current trends, today’s permanent wounds may very well become tomorrow’s bad memories, when lost hands and feet can be successfully regenerated.Additional file 1:Notable stem cells and tissue engineering companies around the globe. (DOCX 30 kb)


Eighty-eight medicalrecords of CRA patients who had a return of spontaneous circulationsustained for more than 20 minutes were included and the post-CRA caremeasures performed in the first 24 hours were identified, as well as itsrelationship with survival and neurological status. the most frequent post-CRA care measures were use of advanced airway accesstechniques and indwelling bladder catheterization. Patients who hadmaintained good breathing and circulation, temperature control and who weretransferred to intensive care unit had a better survival in the first 24hours, after six months and one year after discharge. Good neurologicalstatus at six months and one year after discharge was associated withnon-use of vasoactive drugs and investigation of the causes of the CRA. the identification of good practices in post-CRA care may help to reduce themortality of these individuals and to improve their quality of life. In Brazil, circulatory diseases, including cardiorespiratory arrest (CRA), were themain cause of death in 2011-After the return of spontaneous circulation (RSC), defined as the maintenance ofmyocardial contractions capable of generating a pulse for more than 20 minutes afterthe completion of cardiopulmonary resuscitation (CPR), a severe clinical syndrome isstarted, which is responsible for about from 50 to 70% of deaths in the first 24 to48 hours after CRA. The post-cardiac arrest syndrome happens due to hypoxia andreperfusion lesions during the CRA and after the RSCPost- care has the potential to improve early mortality rates caused by hemodynamicinstability and multiple organ and system failure, and late morbidity and mortalityrates resulting from neurological damage. The main goals are to improvecardiopulmonary function and systemic perfusion; transport the CRA victims fromout-of-hospital settings to emergency or intensive care units; identify theprecipitating cause of the CRA and prevent its recurrence; and implement measures toimprove the long-term prognosis of patients and preserve their neurologicalfunction-The main measures to be adopted include: early reperfusion therapy for cases ofcoronary thrombosis; stabilization and maintenance of hemodynamic parameters;correction of arterial gas disorders; maintenance of normal glucose values; controlof water balance; administration of sedation and analgesia; prevention and treatmentof seizures and temperature controlThis study is based on the low survival rates found among CRA victims and on thegreat risk of neurological sequel to which they are exposed when spontaneouscirculation returns.Despite the advances in emergency cardiovascular care, the need for new techniques toreverse the injury of ischemia and reperfusion is evident. In this context, it isvitally important to identify the post-CRA care measures so that strategies may beimplemented with the objective of reducing mortality associated with hemodynamicinstability, limiting brain damage and injury to other organs.Thus, the objectives of this study were to identify the post-CRA care measuresperformed in a university hospital and to relate them to the survival andneurological status of the patients in the first 24 hours, at hospital discharge,six months after discharge, and one year after discharge.Study approved by the Ethics and Research Committee of the Federal University of SãoPaulo (CAEE: 52531315.4.0000.5505).The study had a retrospective, analytical and quantitative approach, and it wascarried out in the Emergency Room (ER) of a university hospital in the city of SãoPaulo (SP), Brazil.All adult patients who had CRA in out-of-hospital settings and were taken forassistance at the ER of the above mentioned service in the year 2011, and whopresented RSC sustained for more than 20 minutes were included in this study,totaling 88 patients. We excluded from this study the CRA cases assisted in othersectors of the hospital.Data collection was performed in four different moments through the analysis ofmedical records. At admission, the following variables were collected: age, gender,skin color, presence of comorbidities, previous CRA events, pre-CRA neurologicalstatus, presence of consciousness, breathing and pulse at the arrival of the patientin the ER, place where the CRA occurred, if there were witnesses, presumed immediatecause, initial rhythm of CRA and interventions performed during care2partial pressure between 40 and 45 mmHg; monitoring of capnography; maintenance ofend-expiratory CO2 partial pressure between 35 and 40 mmHg; monitoring ofnoninvasive blood pressure (NIBP); maintenance of systolic blood pressure (SBP) ≥ 90mmHg; monitoring of invasive blood pressure (IBP); maintenance of mean arterialpressure (MAP) ≥ 65 mmHg; central venous access puncture; monitoring of centralvenous pressure; maintenance of venous pressure between 8 and 12 mmHg; monitoring ofvenous oxygen saturation; maintenance venous oxygen saturation > 70%;administration of saline solutions; administration of vasoactive and antiarrhythmicdrugs; in case of ventricular fibrillation and pulseless ventricular tachycardia;electrocardiographic tracing; 12-lead electrocardiogram (ECG); primary percutaneouscoronary intervention in cases of suspected acute coronary syndrome; realization ofechocardiography; identification and treatment of reversible causes of CRA;monitoring of body temperature; prevention of hyperthermia; monitoring ofelectroencephalogram; administration of anticonvulsants; monitoring of bloodglucose; maintenance of glycemia between 144 and 180mg/dl; chest X-ray; control ofgeneral exams every six hours; arterial blood gas analysis every six hours;indwelling bladder catheterization; monitoring of urine output; maintenance of urineoutput between 0.5 and 1 ml/kg/h; use of sedation in case of cognitive dysfunction;introduction of continuous enteral nutrition in the absence of contraindication andtransfer to an Intensive Care Unit (ICU)During the first 24 hours; the following post-CRA care measures were identified andrecorded: use of advanced airway access techniques; monitoring of respiratory rate;maintenance of respiratory rate between 10 and 12 rpm; monitoring of pulse oximetry;maintenance of oxygen saturation between 94 and 96%; maintenance of COGlasgow-PittsburghCerebral Performance Categories (CPC). The CPC is divided into fivecategories. Category 1 indicates complete independence and ability to work; Category2 indicates moderate disability, ability to work part-time and independence for theActivities of Daily Living; Category 3 indicates severe disability and totaldependence on the Activities of Daily Living; category 4 indicates persistentvegetative state; and category 5 indicates brain deathSurvival and neurological status of individuals were assessed at hospital discharge,six month later, and one year later and evaluated by the Data were analyzed in the softwares PSPP and R, version 3.3.1. Mean, standarddeviation, median, minimum and maximum values were calculated for the continuousvariables, and frequency and percentage for the categorical variables. Thenon-parametric Kruskal-Wallis test was used to correlate the survival and neurologicstatus in the first 24 hours, at discharge, six months after discharge, and one yearafter discharge. The non-parametric Kruskal-Wallis test was used for continuousvariables. The Pearson Chi-square test was used relate the response variable withthe categorical variables. The level of significance considered in all analyses was5%.Demographic and clinical data are presented in The characteristics of the CRA events and the interventions performed during CPR arepresented in The mean time between initiation of CPR and the first shock was 7.8 minutes; betweenthe initiation of CPR and installation of advanced airway access was 4.1 minutes;between the initiation of CPR and the first dose of epinephrine was 2.1 minutes; andthe mean duration of CPR was 11.1 minutes.Post-CPR care performed in the first 24 hours after the RSC is shown in Monitoring of capnography and venous oxygen saturation and electroencephalogram werenot performed in any patient.Of the 88 patients surveyed, 13 survived at discharge, 10 after six months, and 9after one year. The variables that were significantly associated with greaterpatient survival are presented in Realization of post-CRA care was not associated with greater survival of individualsat hospital discharge.When post-CRA care was related to neurological status at discharge, six months afterdischarge, and one year after discharge, none of the interventions were related topatients’ neurologic status within the first 24 hours or at hospital discharge.However, patients who did not receive vasoactive drugs and underwent investigationof the causes of the CRA presented good neurological status, CPC 1 and 2, in sixmonths (p = 0.04) and one year (p = 0.02) after discharge hospital.According to the guidelines of the American Heart Association, post-CRA care aims toreduce early mortality due to hemodynamic instability and to limit later multipleorgan failure and brain injury. This care includes adequate cardiopulmonaryconditions and perfusion of vital organs; safe transportation to intensive careunits; early recognition of the causes of the event, and treating and preventing itsrecurrence; controlled temperature to minimize neurological damage; diagnosis andtreatment of acute myocardial ischemia; ventilatory support with mechanicalventilation to limit lung injury; reducing the risk of multiple organ failure;assessment of neurological recovery prognosis; and promotion of rehabilitation ofsurvivorsThe mean age of the patients in this study was 66.2 years, as in a study carried outin Singapore by the National Emergency Ambulance SystemIn this study, maintenance of systolic blood pressure ≥ 90 mmHg, administration ofvasoactive drugs, investigation of causes of the arrest, maintenance of meanarterial pressure ≥ 65 mmHg, 12-lead electrocardiogram, central venous accesspuncture, crystalloid administration and bladder catheterization were the mostfrequent care measures. These actions aim at adapting the cardiovascular conditionsand organ and system perfusion, since death due to multiple organ failure isassociated with a persistent low cardiac output in the first 24 hours after CPR,Advanced airway access was frequently performed in the patients in this study. Inthese cases, ventilation and oxygenation should be immediately optimized, thusavoiding hyperoxia, which contributes to an increase in oxidative stress and isassociated with a worse neurological prognosisAs for prevention of brain injury, the most frequent care measure in this study wasthe prevention of hyperthermia and continuous sedation. Studies have shown thatpatients who reached temperature above 37.6ºC after the return of the spontaneouscirculation had lower survival chance and worse neurological prognosis in relationto the normothermic onesWhen post-CRA care and 24-hour survival were associated, the variables: respiratoryrate; oxygen saturation; IBP and NIBP; body temperature; maintenance of oxygensaturation between 94 and 96%; SBP greater than or equal to 90 mmHg; MAP greaterthan or equal to 65 mmHg; urine output of 0.5-1 ml/kg/min; 12-lead ECG and chestX-ray; indwelling bladder catheterization; continuous sedation; prevention againsthyperthermia; and transfer of the patient to the ICU were related to increasedsurvival when performed at intervals of 2 hours or less.2), greater than 300 mmHg, during CPR were associated withhigher rates of return to spontaneous circulation and better neurological outcomeswhen compared to normal or lower partial oxygen pressure (PaO2 of lessthan 60 mmHg)Six months after discharge, maintenance of oxygen saturation between 94 and 96%,non-administration of vasoactive drugs and transfer of the patient to the ICU wererelated to higher survival rates. In a study performed with out-of-hospitalcardiorespiratory arrest patients, it was observed that increased partial oxygenpressure (PaORegarding the administration of vasoactive drugs, studies evaluating specificstrategies to improve blood pressure comparing vasopressors and fluids are scarce. Astudy performed with patients who achieved a return to spontaneous circulation afterCPR found that MAP greater than 70 mmHg in the first 6 hours after CPR wasassociated with good neurological function-Transfer of post-CRA patients to the ICU may be related to greater survival ratesbecause an ICU is a safer and better treatment environment for critical patients inview of its infrastructure with more advanced materials and equipment, as well asqualified personnel to provide specialized assistanceIn this study, at one year after discharge, the variables that were significantlyassociated with higher survival rates were monitoring of respiratory rate; oxygensaturation; noninvasive blood pressure; electrocardiographic tracing; maintenance ofoxygen saturation between 94 and 96%; administration of antiarrhythmic drugs;performance of ECG and referral for hemodynamics in the case of acute coronarysyndrome; and transfer of the patient to the ICU. After the RSC, patients have ahigh probability of developing multiple organ and system failure. Therefore,systemic perfusion should be adequate, metabolic homeostasis should be restored andthe function of the various organs should be maintained, aiming to increase survivalprospects without neurological damage over timeRegarding the neurological state of the individuals, those who did not receivevasoactive drugs had a better six-month and one-year neurological prognosis. Braininjury is an important cause of post-CRA morbidity and mortality. Recognition of itspathophysiological mechanisms and its correlation with patient characteristics, CPRmaneuvers, and post-CRA care may improve the prognosis of these individualsHemodynamic stabilization, MAP greater than 65 mmHg, can often only be achieved withthe use of vasoactive drugs and is critical for effective cerebral circulation aftera CRA. Good hemodynamic parameters are related to higher survival rates at hospitaldischarge and better long-term neurological outcomesDifferential diagnosis of the cause of CRA is paramount for establishing definitivetreatmentThe main limitation of this study was to have been performed in a single center,which may not represent other realities. In addition, because this was aretrospective study, there were difficulties during collection, such as medicalrecords with incomplete data and difficult to interpret.CRA is the most severe clinical emergency and with the worse prognosis, but it may bea transient, reversible stage with the possibility of recovery and returning toactivities. The identification of post-CRA care in a Brazilian referral hospital cansubsidize public policies aimed at the care of these individuals, reducing mortalityand limiting the occurrence of neurological damage and functional disability, aswell as adding key information for its prognosis and rehabilitation.The most frequent post-CRA care measures performed in the patients in this studywere: use of advanced airway access techniques; indwelling bladder catheterization;maintenance of SBP ≥ 90 mmHg and MAP ≥ 65 mmHg; investigation of the causes of theCRA; and administration of vasoactive drugs.Survival in the first 24 hours was greater in patients who received the followingcare measures: maintenance of good breathing and circulation, temperature control,continuous sedation, chest X-ray, and transfer to intensive care unit. After 6months, survival was significantly greater in cases where oxygen saturation wasmaintained between 94 and 96%, vasoactive drugs were not administered, and in thosepatients who were transferred to the ICU. After one year of hospital discharge,maintenance of good breathing and circulation, 12-lead ECG, patient referral forhemodynamic support, and transfer to ICU were the care associated with betterpatient survival.Regarding neurological status, patients who did not receive vasoactive drugs andthose who had the cause of CRA diagnosed survived with good neurological status atsix months and one year after discharge.


To assess women’s views on the acceptability of and satisfaction with non-pharmacological interventions to reduce the symptoms of anxiety in pregnant women. A systematic review and narrative synthesis (Prospero protocol number CRD42015017841). Fourteen included studies were conducted in Australia, Canada, Germany, New Zealand, UK and USA. Interventions were cognitive behavioural therapy, mindfulness, yoga, psychological assessment, supportive and educational based interventions. Studies included women from general antenatal populations and women with anxiety or depression symptoms or risk factors for anxiety or depression. The findings were limited due to the small number of studies evaluating different types of interventions using various study methods. Some studies had too little procedural reporting to allow a full quality assessment. Women’s views on the acceptability of and satisfaction with interventions were overwhelmingly positive. The review highlights women’s motivations for and barriers to participation as well as the benefit women perceived from peer support and individual discussions of their situation. Interventions need to be further evaluated in randomised controlled trials. The inclusion of women’s views and experiences illuminates how and why intervention components contribute to outcomes. Women’s initial concerns about psychological screening and the benefit derived from peer support and individual discussion should be noted by providers of maternity care. The Diagnostic and Statistical Manual of Mental Disorders (DSM-V)  NICE . Women uNon-pharmacological interventions were classified as (1) psychological, (2) mind-body, (3) educational and (4) supportive interventions.The primary outcome was women’s views on the acceptability of and satisfaction with interventions.Quantitative or qualitative studies which assessed women’s views on the acceptability of and satisfaction with an intervention.A systematic search of the following electronic databases was undertaken in January 2015 and updated in June 2018:Medline , CINAHL , Maternity and Infant Care database from MIDIRS (Midwives Information and Resource Service), PsycINFO, The Cochrane Library, EMBASE (Excerpta Medica Database), CRD (Centre for Reviews and Dissemination), SSCI , ASSIA , HTA  Library, JBI (Joanna Briggs Institute) Evidence-Based Practice Database and AMED (The Allied and Complementary Medicine Database). Visually scanned reference lists from relevant primary studies and reviews identified two additional studies for inclusion.The search was limited to studies conducted in countries with similar maternity care to the UK and published in English since 1990. This period reflects the time that non-pharmacological interventions have been recommended to support women’s mental health during pregnancy DOH . Search Potentially eligible papers were retrieved for full text assessment which was conducted independently by two researchers. Any disagreements were resolved by a third researcher.A pre-piloted data extraction form was completed independently by two researchers for each included study.The Critical Appraisal Skills Programme CASP  for asseData analysis and synthesis followed the suggested frameworks for conducting a narrative synthesis  approach was used to assess the extent to which the review findings from the qualitative studies represented the phenomenon of interest  were retrieved for full text assessment. Excluded papers (n = 3643) (1) did not report interventions delivered in pregnancy, include women’s views or report non-pharmacological interventions; (2) included women with severe mental health concerns or complex social factors. The literature search and inclusion process is detailed in the PRISMA Flow diagram   did not The 14 included studies, conducted in Australia, Canada, Germany, New Zealand, UK and USA, were reported from 2009 to 2015. Components of the interventions are detailed in Table In four studies, women were recruited from a general pregnant population. In eight studies, pregnant women with a history of mood concerns or elevated anxiety or depression scores were recruited Table . Two stuWomen were mainly recruited into studies while attending antenatal appointments in hospital and community locations. Women either self-selected into studies or were referred by healthcare professionals (HCP).RCT randomised controlled trial, IPT inter-personal therapy, CBA cognitive behavioural approach, CBT cognitive behavioural therapy, MBSR mindfulness-based stress reduction, MBCT mindfulness-based cognitive therapy, PND postnatal depression, NR not reportedFive studies evaluated psychological interventions: Cognitive behavioural therapy (CBT)   motives and barriers to participating in studies, (2) acceptability of interventions, (3) satisfaction with components of interventions, 4) overall satisfaction with interventions and 5) perceived benefit from participation. Table  overall  perceiveParticipants in studies of mindfulness interventions who had previous experience of anxiety and depression were motivated to participate ; many were feasibility studies or additional components to larger trials. Due to the limited reporting of the study methods in many of the included studies, a full quality assessment was not possible although methodological limitations were assessed and informed the overall CERQual findings. There was considerable heterogeneity between the intervention designs, participants and time frames in the included studies. Participation and experiences of interventions may differ for particular groups of women. The narrative synthesis explored and compared the different approaches to inform discussion and consideration of future intervention designs (Lucas et al. Studies not published in English were not included in the review. Most of the included studies had small sample sizes (The review findings are limited due to the small number of included studies, many with small sample sizes and limited reporting of methods. Women’s views on the acceptability of and satisfaction with a range of interventions were overwhelmingly positive. The review has highlighted the importance of creating a welcoming non-judgemental context for group interventions. Most women valued individual or group discussions about their symptoms of anxiety. Discussions helped women to feel supported and develop supportive networks.Responding to women’s views and experiences will help to inform the design of interventions which are acceptable to women and to develop an understanding of how and why intervention components may contribute to outcomes. Many qualitative studies accessed the views of women who had successfully completed interventions which introduced the potential for selection bias. Future studies need to access and report the views of women who did not participate or complete interventions to identify where further improvements are required. Researchers need to consider the acceptability of eligibility screening and identify ways to effectively communicate the purpose of screening to potential participants.Study reports should include the methodological approach, recruitment strategy, intervention provider details and data analysis procedures. The use of validated evaluation questionnaires, following quality frameworks and reporting process evaluations will help researchers compare intervention studies and assess whether interventions may produce similar or different effects in other settings.