MicroRNAs (miRNAs) are a class of small non-coding RNAs that have recently emerged as important regulators of gene expression, mainly through cleavage and/or translation inhibition of the target mRNAs during or after transcription. miRNAs play important roles by regulating a multitude of biological processes in plants which include maintenance of genome integrity, development, metabolism, and adaptive responses toward environmental stresses. The increasing population of the world and their food demands requires focused efforts for the improvement of crop plants to ensure sustainable food production. Manipulation of mRNA transcript abundance via miRNA control provides a unique strategy for modulating differential plant gene expression and miRNAs are thus emerging as the next generation targets for genetic engineering for improvement of the agronomic properties of crops. However, a deeper understanding of its potential and the mechanisms involved will facilitate the design of suitable strategies to obtain the desirable traits with minimum trade-offs in the modified crops. In this regard, this review highlights the diverse roles of conserved and newly identified miRNAs in various food and industrial crops and recent advances made in the uses of miRNAs to improve plants of agronomically importance so as to significantly enhance crop yields and increase tolerance to various environmental stress agents of biotic—or abiotic origin. Plants form an important part of the ecosystem and may be used by humans as shelter, medicine and food. Major threats to plant productivity are human activities, abiotic stresses like drought, soil toxicity, climate change, and biotic threats like insects, herbivores, microbial pathogens, etc. The growth in human population with the concomitant increase in demand for plants and plant products warrants an increase in crop yields. One such method involves reducing the yield penalties by designing and adopting environmentally friendly crop protection measures. Advancement in molecular biology demonstrated the involvement of microRNAs (miRNAs) in regulating essential plant metabolic processes at the post-transcriptional level  are typically found in intergenic areas but can be also found in antisense—or sense orientation within introns of genes. Some miRNAs are clustered in the genome and are most likely to be transcribed together as long polycistronic RNAs. The biogenesis of miRNAs thus occurs in the nucleus  and serrate (SE) into miRNA precursors (pre-miRNAs). These hairpin-looped structures are further processed by DCL1 to generate miRNA:miRNA* duplexes in the nucleus rather than in the cytoplasm . The modes of action of miRNAs as important regulators of gene expression have been increasingly investigated  locus, which produces a microRNA (miR-JAW) that can guide the cleavage of mRNAs of many TCP genes (TFs) controlling leaf development  analysis of the known miRNA sequences against potential nucleic acid sequences  of cotton  and microarray data processing  which is a comprehensive and searchable miRNA database based on miRNA name, keyword, references, and annotation  contains a large amount of information for plant miRNAs, such as the miRNA and their target(s), secondary structure, expression profiling and genome browser , AthaMap (http://www.athamap.de/)    . Recently, the technique of degradome sequencing was developed. This is a modified version of 5′-RACE using a high-throughput, deep sequencing method . Voluminous literature is present on the identification of miRNAs from rice NGS data and several conserved miRNAs are known to be involved in the response to abiotic stresses , which targets two rice auxin receptor gene homologs (OsTIR1 and OsAFB2), was highly expressed under drought conditions. Its overexpression resulted in the reduction of tolerance to drought as well as salt  in response to the heat stress and adaptation of rice , disease resistance (miR-10), transcription (miR-4), metabolism (miR-5) etc. , a plant-specific TF family involved in development and stress regulation  and 23 were novel  and a high content of oil (20%) and is important for both human consumption and animal production. The interest of miRNAs in soybean began in 2008, when for the first time, 55 families of miRNAs of which 20 conserved  and 35 new miRNAs  were identified  pathway of this study revealed that 34 miRNA families could be involved in 52 different biological processes such as carbohydrate metabolism, fatty acid biosynthesis, plant-pathogen interactions, response to stress, oxidation/reduction, and signal transduction  is widely cultivated and is one of the five most important oil seed crops in the world. In 2010 the first miRNA-related research was performed on peanuts using high-throughput Solexa sequencing. Currently 14 novel miRNAs (miRn1 to miRn14) families (of these 13 are peanut-specific) and 75 conserved miRNAs  which belong to 22 families are discovered  wilt disease which reduces production significantly  were first identified and predicted to target 186 genes involved in floral, leaf, root, and stem development, signal transduction, metabolism pathways and stress responses  repository , vitamins  and proteins. Sweet potato produces two types of roots, fibrous roots, and storage roots. The storage roots have high starch content with a sweet taste and are the portion of the plant consumed by humans. In addition to its use as staple food, sweet potato is used as a source of starch, animal feed, and also as a raw industrial material for alcohol production. Similar to other crops, numerous miRNAs have been discovered in sweet potato. The plant responds to wounding, by inducing the expression of miR828 which controls lignin and HGrapevine is one of the most economically important and widely cultivated fruit crops in the world with good nutritional and processing properties. It is the first fruit crop to have its genome completely sequenced, attracting much interest from scientists for investigating miRNAs  of which 135 were conserved and 11 were novel miRNAs  in leaves, stems, flowers, and fruits and predicted their corresponding target genes. About 124 orange miRNAs were identified in miRbase 21. The control of miRNA expression in orange root development can promote root growth and partially improve root absorption of more water and nutrients and also improve plant tolerance to abiotic and biotic stresses, resulting in increased plant biomass and yield  domain genes which confer resistance to F. oxysporum , metabolism (NADPH-cytochrome P450 reductase regulated by miR1128), protein degradation (ERD1 protein regulated by miR827), RNA processing (exonuclease RRP41 regulated by miR1439), stress response , and transportation  was recently published . These identified coffea miRNA families regulated potential target genes involved in various biological processes and they strongly influence growth patterns, such as plant development, hormonal responses, mature mRNA formation, stress responses, and cellular signaling pathways  is an important cultivating measure for flue-cured tobacco which switches the plant from reproductive to vegetative phase. It is used to increase tobacco leaf production and to encourage leaf ripening. Since many genes had been found to be differentially expressed in response to topping, it had been proved from a previous study that miRNAs (136 conserved miRNAs belonging to 32 families and 126 new miRNAs belonging to 77 families) were differentially expressed in flue-cured tobacco roots before and after topping and regulated transcripts distinctly involved in response to topping  which targets quinolinate phosphoribosyltransferase-2 encoding a quinolinate phosphoribosyltransferase  which control plant growth, development and response to abiotic and biotic stress in plants. Therefore, miRNA-based genetic modification technology is one of the most promising solutions which can contribute to agricultural productivity in order to produce superior crop cultivars.Transgenic approaches toward manipulating the miRNA-based control on gene expression include the overexpression of miRNA-resistant targets as well as the creation of artificial target mimics . Thus, development of transgenic plants which express miRNAs associated with these physiological processes is growing as a new approach for improving plant architecture, grain yield, fruit improvement and enhanced shelf life. In tomato overexpression of miR319 resulted in larger leaflets and continuous growth of leaf margins  present in cells, as well as that needed for visible effects, before designing the artificial miRNAs directed toward obtaining plants with desirable agronomical traits. Although this artificial miRNA method is already used as an effective tool (Khraiwesh et al., The ability of engineered decoys to modulate miRNA regulatory networks through modification of miRNA activity is also an approach for achieving a desired outcome (Ivashuta et al., With the realization of the potential of miRNA manipulation as a plausible tool in plant crop improvement, it is also important to be aware that such genetic modification approaches can lead to unintended side effects (Kamthan et al., AD, NS, KN, and ID conceived and designed the review. All authors contributed to writing and editing 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.


Experience of early life stress (ELS)  is highly prevalent in the general population and constitutes a major public health problem  and their unfavourable outcomes  has been associated with a history of ELS in several retrospective but also prospective studies, while the moderating interaction of ELS and pre-existing genetic vulnerability in these disorders has been extensively discussed in recent literature. Nevertheless, the chronic physical health consequences of childhood adversities may be as substantial as mental health consequences. Prior research suggests an association of ELS with cardiovascular, pulmonary and metabolic diseases, chronic inflammatory and pain syndromes, frequency of medical consultations and number of medical diagnoses. In addition, risk behaviour patterns such as substance use, and especially tobacco and alcohol consumption, are considered significantly increased in individuals with experience of ELS. Consequently, many studies have reported a negative impact of ELS on adult general mental and physical health-related quality of life, while recognizing the additive effect of the number or different types of childhood adversities is important for understanding their cumulative effect on later life adjustment (Agorastos, Pittman et al., The distinct impact of ELS may lie in enhanced plasticity mechanisms during this period that lead to persistent functional and epigenetic alterations and to higher allostatic load over time. Experience of ELS has been shown to lead to an increased neuroendocrine stress response and vulnerability to stress, hypothalamic–pituitary–adrenal axis dysregulation, long-lasting alterations in emotional and psychophysiological reactivity, impaired adaptive functioning, malfunction of fear response circuits and structural changes in the central nervous system. ELS can also lead to epigenetic modifications in response to environmental influences through stress-related gene expression and, thus, play a central role in the long-term biological trajectories leading to stress-related disease, and may explain interindividual variation. In addition, ELS represents an independent risk factor for neuroendocrine–immunological abnormalities with the development, to some level, of a proinflammatory phenotype in adulthood. Finally, recent literature has focused on the potentially fundamental role of sleep and circadian rhythms in the development of ELS-related disorders. Central and peripheral circadian disruption after severe stress in childhood could engrave pathophysiological trajectories of ELS through impaired homeostatic balance, with overall neuroendocrine, immune, metabolic and autonomic dysregulation (Agorastos, Kellner et al., Taken together, persistent structural, functional and epigenetic changes in neural circuits after ELS could foster chronic chronodisruption and thus mediate the risk of disease and resilience in adults, following a distinct dose–response relationship. The long-term effects of ELS may be conceptualized as a common developmental risk factor triggering a health-related risk cascade with high public health impact. Future studies should focus on prospective investigation of potential predictors and mediators, their temporal sequence and combined effects at epidemiological, biological and epigenetic levels, while taking into account the potentially delayed time-frame for the expression of their effects. Screening strategies for ELS need to be improved, as they would help to identify an individual’s risk level for disease development and predict the response to treatment, towards a better understanding of the relationship between gene and environmental exposures that impacts resilience.


Women with chronic medical conditions, such as diabetes and hypertension, have a higher risk of pregnancy-related complications compared with women without medical conditions and should be offered contraception if desired. Although evidence based guidelines for contraceptive selection in the presence of medical conditions are available via the United States Medical Eligibility Criteria (US MEC), these guidelines are underutilized. Research also supports the use of decision tools to promote shared decision making between patients and providers during contraceptive counseling.MiHealth, MiChoice project is to design and implement a theory-driven, Web-based tool that incorporates the US MEC (provider-level intervention) within the vehicle of a contraceptive decision tool for women with chronic medical conditions (patient-level intervention) in community-based primary care settings (practice-level intervention). This will be a 3-phase study that includes a predesign phase, a design phase, and a testing phase in a randomized controlled trial. This study protocol describes phase 1 and aim 1, which is to determine patient-, provider-, and practice-level factors that are relevant to the design and implementation of the contraceptive decision tool.The overall goal of the This is a mixed methods implementation study. To customize the delivery of the US MEC in the decision tool, we selected high-priority constructs from the Consolidated Framework for Implementation Research and the Theoretical Domains Framework to drive data collection and analysis at the practice and provider level, respectively. A conceptual model that incorporates constructs from the transtheoretical model and the health beliefs model undergirds patient-level data collection and analysis and will inform customization of the decision tool for this population. We will recruit 6 community-based primary care practices and conduct quantitative surveys and semistructured qualitative interviews with women who have chronic medical conditions, their primary care providers (PCPs), and clinic staff, as well as field observations of practice activities. Quantitative survey data will be summarized with simple descriptive statistics and relationships between participant characteristics and contraceptive recommendations (for PCPs), and current contraceptive use (for patients) will be examined using Fisher exact test. We will conduct thematic analysis of qualitative data from interviews and field observations. The integration of data will occur by comparing, contrasting, and synthesizing qualitative and quantitative findings to inform the future development and implementation of the intervention.We are currently enrolling practices and anticipate study completion in 15 months.This protocol describes the first phase of a multiphase mixed methods study to develop and implement a Web-based decision tool that is customized to meet the needs of women with chronic medical conditions in primary care settings. Study findings will promote contraceptive counseling via shared decision making and reflect evidence-based guidelines for contraceptive selection.ClinicalTrials.gov NCT03153644; https://clinicaltrials.gov/ct2/show/NCT03153644 (Archived by WebCite at http://www.webcitation.org/6yUkA5lK8) Access to family planning services to prevent unintended pregnancies is one of the leading health indicators for Healthy People 2020 . UnintenWomen with chronic medical conditions  have a higher rate of pregnancy-related complications -11 and dWomen with chronic conditions most frequently see primary care providers (PCPs) for their health management ; these vIn 2010, the CDC released the United States Medical Eligibility Criteria (US MEC), which was adapted directly from the World Health Organization’s MEC to meet the unique needs of US patients. The US MEC provides guidance to clinicians regarding the selection of contraceptive methods in the presence of specific chronic conditions  and personal characteristics   and is rStudies have shown that provider recommendations have a significant and positive impact on patient initiation and selection of a contraceptive method -40. HoweThe underlying rationale for collecting, integrating, and analyzing both qualitative and quantitative data are multifold: (1) quantitative data collected from self-administered survey items will provide descriptive statistics to allow for comparison with other practice settings and populations, (2) qualitative interviews will provide a deeper understanding of the lived experiences of women with chronic conditions and their primary care teams with respect to receiving and providing contraceptive services, respectively, (3) qualitative interviews provide an opportunity to immediately expand upon close-ended quantitative survey items that warrant further investigation , (4) levTo ensure the development of a patient-centered tool that explicitly upholds patient autonomy in decision making, we created a conceptual model that draws upon principles from reproductive justice theory and health behavior theories. This conceptual model will provide a preliminary prototype for the decision tool, which will be modified iteratively during this study phase. To develop an intervention that is contextualized for use in real-world clinical practices, our study design is informed by implementation science, an emerging field of methods and approaches that address the challenges of implementing health interventions in usual practice settings. We use sMiHealth MiChoice study, is to design and implement a theory-driven, Web-based contraceptive decision tool that can be accessed on an electronic tablet or computer before a clinical visit by women with chronic conditions who are seen in primary care settings. The feature of this tool that sets it apart from prior decision aids is that it will be tailored to factor in the personal preferences and medical history of a specific individual in a manner that also reflects evidence-based guidelines. The development and testing of this tool will occur over 3 phases . The aim of this study protocol for phase 1 is to identify multilevel contextual factors that should drive the design and implementation of the contraceptive decision tool and explain subsequent study outcomes [The overall goal of this mixed methods implementation project, the outcomes .This mixed methods implementation study consists of 3 phases. This protocol focuses on phase 1, which is to identify the most critical patient-, provider-and practice-level factors that should inform the design and implementation of the decision-support tool. In phase 2, we will work with an expert health informatics team and an advisory council comprising patients, providers, and decision aid experts to build the Web-based decision tool that is accessible via a secured weblink from a computer or handheld tablet. Findings from phase 1 and a novel conceptual model  before their qualitative interviews. The quantitative survey items complement the qualitative interview guide with the goal of obtaining maximal depth and breadth of understanding of each construct. Semistructured field observations in practices and collection of practice artifacts  will further diversify our data sources and optimize data triangulation, which in turn will reduce the risk of systematic biases based on reported behaviors and experiences alone .or provide LARC methods on site. To achieve maximum variation in practice attributes that are associated with variations in contraceptive practice [To balance similarity and variation across practices, providers, and patients, we will use a combination of purposeful sampling techniques as described by Palinkas and colleagues . Eligiblpractice ,64, clinpractice . We willpractice .To achieve the depth and variation in practices as described above, we aim to enroll 6 clinical sites. For individual qualitative interviews, prior literature has documented that 6 to 12 interviews per homogeneous group provide sufficient qualitative data to reach saturation, the point at which analysis produces no new information, or disconfirming or confirming evidence ,66. On tdo not insert LARC devices, or (3) provide prescription contraception and insert LARC devices. For practice staff members other than PCPs, we aim to gather staff perspectives regarding contraceptive services and interventions that may differ based upon their primary responsibilities and context of patient interaction: (1) director or manager , (2) work with PCPs during clinical visits , and (3) other services . A designated practice liaison  will assist the study team to identify eligible practice members and extend invitations for study participation.Eligible practice members must be aged 18 years or older, English-speaking, able to give informed consent, and be indirectly or directly involved with patient care. PCPs must be physicians, nurse practitioners, physician assistants, or certified nurse midwives, who currently provide preventive health and management of chronic conditions to reproductive-aged women . To compactively managed (on medication or requiring at least 2 visits a year), (2) a documented past medical condition or multiple medical conditions which would pose a significant risk to health during pregnancy , or (3) current use of any drugs that are Pregnancy Category D or Category X medications. This definition expands upon guidance provided by the Department of Health and Human Services [other group to capture women with less common conditions that nevertheless have a significant impact on pregnancy-related morbidity and mortality and contraceptive eligibility. The principal investigator (JW), who is a primary care specialist and a family planning expert, will review each participant’s medical history and medications, in conjunction with the designated practice liaison, to ensure that eligibility criteria have been met.Eligible patients must be women aged 18 to 50 years, fertile, English-speaking, and able to provide informed consent. They must also meet at least one of the following criteria: (1) a documented medical condition or multiple medical conditions being Services  as well Services , conditiServices . The folThe designated practice liaison in each practice will assist the study team in identifying patients who meet the eligibility criteria. With the permission of their PCPs, recruitment letters will be sent to potentially eligible patients followed up by up to 3 phone calls.Dehlendorf and colleagues recently described the development and testing of a tablet-based contraceptive decision aid that underwent rigorous cognitive testing  among paConceptual Model to Guide Development of the Decision Tool (Patient-Level)In a systematic review, Wyatt and colleagues identified 32 unique characteristics among 19 decision aids and classified them into 4 overarching categories: method effect, mechanistic, social/normative, and practical . Among tand indicates she is ready for contraceptive education, she will proceed through a responsive algorithm based upon her personal preferences, concerns, and prior contraceptive experiences. Constructs from the health beliefs model [Adapting a principle from the transtheoretical model , the patfs model  will be If the patient indicates she desires pregnancy, she is advised to return to her PCP for preconception counseling and exits the study at this time. If the patient expresses ambivalence regarding pregnancy, the decision aid assesses if she is ready for contraceptive education, and if so, she proceeds through the contraceptive algorithm as outlined above.Trained research assistants (RA) will spend 2 to 3 days at each clinical site to collect practice-specific data using a Practice Environment Template (PET), a semistructured checklist adapted from prior work by Crabtree and colleagues  and JaénAll participants  will fill out a written or electronic  quantitative survey before the face-to-face in-depth interview. There are 3 surveys: (1) a 34-item Patient Survey, (2) a 19-item Provider Survey (for PCPs), and (3) a 13-item Staff Survey (for practice members other than PCPs). Participants will be interviewed in a quiet, private space designated by each practice. Interviews are audiotaped with the participants’ permission and informed consent. We will conduct “member checking” with participants who agree to be contacted after the interview. This qualitative technique, also referred to as respondent validation, helps improve the accuracy, credibility, and transferability of research findings as well as empower participants to verify or modify the final interpretations of the data . Member-All interview audiotapes will be transcribed verbatim. Qualitative analysis is an iterative process during which investigators go through cycles of reading, summarizing, and re-reading data ,84. The Enrollment of patients and providers in community-based primary care practices in Michigan is underway. Upon completion of this first study phase, the findings will be used to inform design of the contraceptive decision tool for testing in a future randomized controlled trial. The results of this study will be published in a peer-reviewed journal and presented at scientific conferences.The study design and proposed intervention have several strengths. First, we are collecting multilevel qualitative and quantitative data to gain a comprehensive and deep understanding of the experiences of and interactions among patients, providers, and staff. Constructs from implementation science theory and behavioral health theories drive data collection and analysis. To organize this large volume of data, we employ a rigorous mixed methods design and data integration procedures. A potential weakness of this study is that practices are limited to Michigan, which has a lower prevalence of ethnic and racial minorities than more populous states. However, we will recruit practices that have greater representation of underrepresented groups to mitigate this concern. We also anticipate challenges associated with practice-based research, including efficient recruitment and coordination of research practices with multiple practices outside our institution. The support of a locally based and established state-wide primary care network and previously established relationships between our institution and community partners will be critical to these processes.This protocol describes the first phase of a multiphase design and implementation of a theory-driven intervention that incorporates customized decision tool attributes and embeds targeted US MEC recommendations to meet the contraceptive needs of women with chronic medical conditions in primary care settings. The study findings will provide critical knowledge regarding the feasibility and best approaches to implement the intervention in real-world primary care settings with the goal of promoting shared decision-making and evidence-based guidelines.


In order to enhance patient safety during resuscitation of critically ill patients, we need to optimize team communication and enhance team situational awareness but little is known about resuscitation team communication patterns. The objective of this study is to understand how teams communicate during resuscitation; specifically to assess for a shared mental model (organized understanding of a team’s relationships) and information needs.We triangulated 3 methods to evaluate resuscitation team communication at a tertiary care academic trauma center: (1) interviews; (2) simulated resuscitation observations; (3) live resuscitation observations. We interviewed 18 resuscitation team members about shared mental models, roles and goals of team members and procedural expectations. We observed 30 simulated resuscitation video recordings and documented the timing, source and destination of communication and the information category. We observed 12 live resuscitations in the emergency department and recorded baseline characteristics of the type of resuscitations, nature of teams present and type and content of information exchanges. The data were analyzed using a qualitative communication analysis method.We found that resuscitation team members described a shared mental model. Respondents understood the roles and goals of each team member in order to provide rapid, efficient and life-saving care with an overall need for situational awareness. The information flow described in the interviews was reflected during the simulated and live resuscitations with the most responsible physician and charting nurse being central to team communication. We consolidated communicated information into six categories: (1) time; (2) patient status; (3) patient history; (4) interventions; (5) assistance and consultations; 6) team members present.Resuscitation team members expressed a shared mental model and prioritized situational awareness. Our findings support a need for cognitive aids to enhance team communication during resuscitations.The online version of this article (doi:10.1186/s12245-017-0149-4) contains supplementary material, which is available to authorized users. Effective team communication is crucial in the resuscitation of critically ill patients. A team has been defined as two or more people who interact dynamically, have a common goal, a specific task and possess complementary skills . During When analyzing the root cause of adverse events, team communication has been a frequent theme , 4. ReceThe overall goal of this study was to understand how teams communicate during resuscitation, whether they endorsed a shared mental model and their information needs. We defined a shared mental model as an organizing knowledge structure of the relationships among the team . SpecifiThis was a mixed methods observational study with three components: (1) stakeholder interviews; (2) observations of recorded simulated resuscitations; (3) live observations of resuscitations in the emergency department (ED). The study was conducted at The Ottawa Hospital, a tertiary care academic center and level 1 trauma center in Canada where the dual campus EDs have a census of 150,000 ED visits per year. The Ottawa Hospital Research Ethics Board approved the study.We engaged in purposive sampling in order to represent all potential professions of stakeholders in resuscitation teams in an ED setting. These included attending physicians, trauma team leaders, emergency medicine residents, registered nurses, respiratory therapists, advanced care paramedics, patient care assistants, registration clerks, and social workers. We excluded medical students who do not tend to take an active role in resuscitations, but rather serve as observers. We also excluded patients who are often too ill to be aware of resuscitation procedures.We included all emergency medicine residents and registered nurses who provided informed consent to have their simulated resuscitations recorded and analyzed.We included any or all of attending emergency physicians and residents, consultant physicians, registered nurses, respiratory therapists, administrative clerks, patient care assistants, paramedical personnel and social workers. We included resuscitations for patients suffering from shock states , cardiac arrests , other unstable cardiac dysrhythmias, trauma resuscitations meeting institutional trauma team activation criteria, and other illnesses requiring an overhead Emergency Physician “stat call” as dictated by nursing discretion. Given the emergency nature of the care provided and the de-identified methods of data collection, the research ethics board waived the requirement of informed consent for this component of the study.We excluded cases involving patients less than 18 years of age as these are rare and not typical at our center. We also excluded cases where resuscitation is not as intensive, often requiring a smaller team: patients with stroke codes, respiratory distress not requiring intubation , uncomplicated acute heart failure, stable agitated patients, trauma not deemed to require trauma team activation. We also excluded transfers from outside hospitals directly to the care of admitting services.Our review of the literature could not uncover any survey tools designed to assess shared mental models of resuscitation teams. We designed the interview questionnaire using psychology and clinical resuscitation expertise of the investigative team. Questions were designed to determine team member roles and responsibilities, procedural expectations, and devices and artifacts used in resuscitation. The interview questionnaire is presented in Additional file The interviews were semi-structured and conducted by two of three investigators  in a hospital conference room. Interviewees were provided with an information sheet detailing objectives and nature of the study and written informed consent was obtained. Notes were taken and all interviews were audio recorded. Interviewers used pre-defined prompts, probes, and follow-up questions.We studied regularly scheduled critical care simulations which were part of the existing curriculum for those University of Ottawa Emergency Medicine residents who consented to participate in the study. Each simulation involved one to three residents at the post-graduate 1–5 year levels and 1–3 registered nurses. Emergency Medicine residents would also act as consultants in the simulations. Simulations were recorded with 3 separate cameras by the University of Ottawa Skills and Simulation Center for the purpose of education and delivering feedback during simulation debriefing sessions. Each group of videos were packaged together using Owl video player software. The video player allowed the viewer to observe four videos in four different windows at the same time. The videos were viewed and transcribed by a single investigator (MR). The transcriptions were entered into separate worksheets for each video, using Numbers and Microsoft Excel 2010 in four categories: (a) time and duration; (b) source and destination; (c) information conveyed; and (d) action. Verification of accuracy of data entry was performed by a clinician investigator (GM) for 10% of cases. The videos were permanently deleted at the end of the study.We prospectively observed a convenience sample of ED resuscitations based on the availability of a clinician investigator (GM). The investigator did not participate in the observed resuscitations. Observations proceeded from activation of the resuscitation team  patch, overhead “stat call”, or initiation of overhead “code” calls) until patients were deemed stable or deceased by the most responsible physician (MRP), or care was handed off to consulting services.We captured all instances of communication between team members in written notes using a structured and piloted data collection form based on concepts in other health-care communication research , 16. We Data were abstracted into a data collection form divided into five domains: (a) resuscitation event types; (b) flow and sequence of events: detailed explanation of a recent resuscitation; (c) people, tasks and information: team member interaction and linking for task completion; (d) problems, challenges or obstacles: any issues that could have led to communication breakdown; (e) communication network: list of team member interactions, events that could lead to such interactions. The outcome of the interviews was a perspective-based map of the workflow during resuscitations, including the role and responsibilities of each team member, expected coordination and information sharing processes.Using communication analysis we outlined and quantified verbal behaviors , content categories , situation awareness communications, sequential diagrams of communications (frequencies of communication sequences between team members), and mapping all of the above as a function of the event timeline.A qualitative communication content analysis method was used to identify, categorize, and aggregate items of information shared by the team during resuscitations to identify common thematic elements . We triaWe interviewed 18 stakeholders in resuscitation, nine women and nine men  and potential information loss in both verbal and written communication. The flow of information described in the interviews was reflected by the observations of simulated and live resuscitations. The most responsible physician and charting nurse were central in terms of volume of communication and the most common types of communication involved statements, requests, questioning and acknowledging. These types of communication were brief and direct rather than less frequent communication types such as suggestions and explanations which fits the need for rapid and efficient communication. These patterns also reflect the communication activity that is required for the acquisition and maintenance of situational awareness as well as teamwork processes such as coordination and cooperation. The categories of data conveyed during resuscitations were quite consistent among all 3 methods and we consolidated these into (1) time; 2) patient status; (3) patient history; (4) interventions; (5) assistance and consultations; (6) team members present. These elements, in addition to verbal behaviours such as statements and questions are all fundamental to establishing and maintaining situational awareness during resuscitation as they include information about the patient, environment, task, and time [ patient Our findings are consistent with a previously described integrative framework of task-related teamwork behaviours since we observed communication patterns consistent with team coordination, cooperation and information exchange . In termWe found that resuscitation team members share large volumes of critical information throughout a resuscitation event. A large proportion of communication is oriented around confirmation of clinical findings and patient status. We noted a high volume of communication between the MRP and charting nurse, reinforcing the shared mental model described in the interviews. Given the time constraints of these team communications, it is easy to appreciate the risk of information loss and degradation of situational awareness. This presents a potential threat to patient safety.Future research needs to consider solutions to enhance the acquisition of key information by all team members, maintenance of team situational awareness around dynamic elements and the sharing of information with relevant key members. Future directions could include incorporating a more in depth focus on these elements in team training and measuring the impact of such training on team situational awareness with validated measures . The devWhile this is the first mixed methods study to evaluate adult resuscitation team communication, it is not without limitations. Overall, this study was conducted at a single center and thus may only be generalizable to other urban academic tertiary centers but this is yet to be confirmed. For the interviews, since we relied on volunteers there is risk of self-selection bias, social desirability bias and recall bias. For the simulation observations, there were residents of varied levels of training which may have influenced the flow and sequence of events. In addition, there was the Hawthorne effect, and a risk that the fidelity of the simulation impaired authentic team communication. For the live observations, there was risk of data loss with the rapidity of case evolution and complexity of team communication and we attempted to verify this with the written health record. Video recording would have been helpful but would have required informed consent at our institution which is very difficult to obtain for emergency resuscitations. There is also risk of selection bias with the convenience sample we used for the live observations.Our findings across all three methods support a shared mental model among resuscitation team members. We identified clear information needs for resuscitation team members as well as a prioritized desire for team situational awareness. We observed consistent communication patterns whereby teams conveyed dense amounts of data in short periods of time. This study supports a need for cognitive aids to enhance teamwork and the acquisition and maintenance of situational awareness during resuscitations.


Plasmodium falciparum and P. vivax malaria in pregnant women are limited to mefloquine or quinine plus clindamycin  approved AL for the treatment of uncomplicated malaria. At that time, this combination was not approved for use in pregnancy because animal research data indicated a potential association with poor pregnancy outcomes, and insufficient human data were available. Since then, global experience has contributed substantial evidence of the safety and efficacy of AL throughout pregnancy. Given the need for an additional option to treat uncomplicated malaria in pregnant women in the United States, a systematic review of the literature was performed to evaluate the safety and efficacy of AL use during pregnancy, and findings were used to update CDC recommendations.Each year, approximately 1,700 cases of imported malaria occur in the United States; approximately 630 (37%) of these cases occur in women, including 5%–6% who are pregnant at the time they are infected ; trimesters during which treatment occurred; medication dose administered; treatment duration; treatment outcomes; and pregnancy outcomes, which included miscarriage (pregnancy loss at <28 weeks’ gestation), stillbirth (pregnancy loss at ≥28 weeks’ gestation), preterm birth (<37 weeks’ gestation), low birth weight , congenital abnormalities, and any maternal adverse events reported.Systematic review results. In the initial search, 1,726 articles were identified. After excluding four articles during deduplication, 1,534 during title review, 94 during abstract review, and 73 after full text review, 21 articles remained and were included in the review.Efficacy. One meta-analysis . Second and third trimester safety. Data evaluating pregnancy outcomes in women taking ACTs during the second or third trimesters of pregnancy were available from 16 studies ( studies . No diff studies . One triFirst trimester safety. No randomized trials evaluating AL use during the first trimester of pregnancy were found (re found . HoweverMalaria infection during pregnancy can result in serious maternal and fetal complications. On the basis of the strength and quality of this evidence, CDC recommends AL as an additional option for treatment of uncomplicated malaria in pregnant women in the United States during the second and third trimesters of pregnancy at the same doses recommended for nonpregnant women. Women in the United States with uncomplicated malaria during the first trimester of pregnancy should be treated with the currently recommended options of either mefloquine or quinine plus clindamycin. However, when neither of these options is available, AL should be considered for treatment.P. falciparum infections acquired in regions with chloroquine resistance. To assess the implementation and impact of these updated recommendations in the United States, data from the National Malaria Surveillance System will be used to examine how antimalarials are used to treat uncomplicated malaria in pregnant women, as well as population-specific disease burden; in addition, the FDA Adverse Event Reporting System maintains adverse event and medication error data, which can be used to monitor adverse events associated with AL use during pregnancy.This update of CDC recommendations based on accumulated evidence of the safety of AL in pregnancy is in line with the malaria treatment guidelines of other countries without endemic malaria and WHO (


Background: Current literature supports the comprehensive health benefits of exposure to nature and green environments on human systems. The aim of this state-of-the-art review is to elucidate empirical research conducted on the physiological and psychological effects of Shinrin-Yoku (or Forest Bathing) in transcontinental Japan and China. Furthermore, we aim to encourage healthcare professionals to conduct longitudinal research in Western cultures regarding the clinically therapeutic effects of Shinrin-Yoku and, for healthcare providers/students to consider practicing Shinrin-Yoku to decrease undue stress and potential burnout. Methods: A thorough review was conducted to identify research published with an initial open date range and then narrowing the collection to include papers published from 2007 to 2017. Electronic databases  and snowball references were used to cull papers that evaluated the use of Shinrin-Yoku for various populations in diverse settings. Results: From the 127 papers initially culled using the Boolean phrases: “Shinrin-yoku” AND/OR “forest bathing” AND/OR “nature therapy”, 64 studies met the inclusion criteria and were included in this summary review and then divided into “physiological,” “psychological,” “sensory metrics” and “frameworks” sub-groups. Conclusions: Human health benefits associated with the immersion in nature continue to be currently researched. Longitudinal research, conducted worldwide, is needed to produce new evidence of the relationships associated with Shinrin-Yoku and clinical therapeutic effects. Nature therapy as a health-promotion method and potential universal health model is implicated for the reduction of reported modern-day “stress-state” and “technostress.”. Research conducted in transcontinental Japan and China points to a plethora of positive health benefits for the human physiological and psychological systems associated with the practice of Shinrin-Yoku (SY), also known as Forest Bathing FB (FB) ,2,3. SY Furthermore, SY may be considered a form of Nature Therapy (NT). Song, Ikei and Miyazaki’s present day model: Concept of Nature Therapy (CNT)  clearly Individuals living and interacting in green spaces (GS) report being more energetic, in good overall health and, have more of a sense of meaningful purpose in life . CurrentSeveral studies explored the therapeutic benefits of SY in Asian countries ,3,9,11. While exploring recent research about the health benefits associated with SY a dearth of scientific research conducted in Western populations was determined. Therefore, the increasing interest and the current published significant research findings surrounding the healing benefits related to SY, GS and the wilderness offers healthcare professionals an opportunity to delve deeper into this complementary modality for the prevention of disease and to assist with the potential healing of certain existing conditions in Western cultures. Revealing current research methods and subsequent research outcomes associated with SY practices may provide researchers, clinicians and students with an intervention that assists with preventative medicine and evidence-based practice (EBP). Therefore, the aim of this paper is to offer: (a) an in-depth inquiry of the current literature, (b) invite researchers residing in Western cultures to design and conduct empirical research regarding the therapeutic benefits associated with SY and, (c) to encourage healthcare providers/students to consider practicing SY to decrease undue stress and potential disconnection.The terms of this comprehensive review were to emphasize the core elements of the research proposition. The initial literature search was conducted with the intention of identifying publications that offered significant historic relevance to the practice of SY, included various populations, sample sizes and geographic locales, utilized evidence-based practices, illustrated measurable physiological and psychological effect parameters, expounded upon practical frameworks and methodologies for the practice of SY, explicated unique measurable criteria for the application of SY and deduced limitations of previous research. The electronic databases searched included PubMed Central, PubMed, CINAHL, Scopus, and PsycINFO . Hand seTo remain prescient, the reference range utilized in this review included literature published between the years 2007 and 2017. Therefore, the inclusion criteria allowed for publications that were available in English, dated from 2007 to 2017, incorporated transparent evidence based practices in reviews or trials, included robust quantitative and/or qualitative data, offered unique frameworks and theories, and explored current trends in research. Studies not meeting the tenets of this criteria, specifically those that pertained to physical exercise, fitness, landscape architecture, and laboratory, or animal studies were withdrawn from considerations.The findings of all relevant studies were synthesized . The iniLivni  publisheOf the studies included within the PP section, and irrespective of study aims, there was a trend towards small sample sizes, gender and age homogeneity, and skewed ratios of females to males/vice versa, which by either methods of convenience, purpose and/or imparted bias to the research. An overwhelming number of studies included homogenous gender sampling ,25,26,27As changes in cardiac function, revealed by cardiac monitoring, are correlational to the physiological effects of stress regardless of environmental setting, it is coherently expected more than one third of the articles reviewed observe not only standard vital signs, including heart rate (HR) and pulse rate (PR), systolic and diastolic blood pressure (SBP/DBP) and ECG interpretation, but also heart rate variability (HRV), as well as left ventricular function and right ventricular function (LVF/RVF). While LVF is attributed to the ability of the left ventricle to perfuse the body, RVF is related to pumping blood to the lungs. HRV is defined as the variation in the time interval between heartbeats and is associated with the activation of the parasympathetic nervous system (PNS) through high frequencies (HF) and the sympathetic nervous system (SNS) through low frequencies (LF).The trends revealed by SY research over the past 10 years in relation to the cardiovascular and autonomic nervous systems (ANS) appears to have started with basic cardiac monitoring then shifted to the correlation of cardiac monitored data points with the PNS and SNS, and this started the development of a more in-depth study design to research the effects of SY on specific disease states, such as: hypertension (HTN), coronary artery disease (CAD), and chronic obstructive pulmonary disease (COPD). According to Kobayashi, Song, Ikei, Song, Kagawa and Miyazaki , 625 JapBlood pressure and PR also decreased while in the forest settings compared to the urban settings. In comparison to physical exercise tasks, Lee, Lee, Park and Miyazaki  measuredSignificant research has revealed the effects of SY and NT on specific physiological disease states, including HTN, CAD, COPD, and Diabetes Mellitus Type II (DMII). In a randomized control trial (RCT) of 24 adults with HTN, Mao et al.  found thMorita et al.  noted whFurthermore, Morita et al.  investigA hallmark of SY research has been the investigation of its’ relaxation inducing properties and application for ameliorating psychological distress. Within this review, 12 studies specifically addressed psychological disorders/disease states and relevant comorbid conditions with popular reference to stress and stress related heart disease, emotional distress and chronic depression, alcoholism, sleep disorders, and pain ,49,50,51Citing the impact of chronic stress on growing populations with insomnia and poor sleep patterns in Japan, Morita et al.  studied McCaffrey, Hansen and McCaffrey  investigGiven SY practices are relatively innocuous when compared with other more invasive procedures, Chun, Chang and Lee  studied p < 0.001) in a previous investigation [Han et al.  and Kangtigation , yet, giWith regards to human spirituality, Nakau et al.  noted inResearch on the cardiovascular effects of SY have precipitated a trend to discover how FB affects the ANS. At the level of the central nervous system (CNS) alone, marked changes in cerebral activity have been identified. Joung et al.  designedThis section, a further investigation into the physiological and psychological effects of SY or NT via the physiological metrics relevant to endocrine included 11 publications. These resources specifically measured the effects of SY or NT on specific physiological and psychological indicators of stress via measures of salivary cortisol (sCort), and/or emotional indicators of health and well-being ,49,52,53In the pilot study with a cross-over experimental design, investigators  addresseFisher  illuminaA subset of publications explicitly focused on sensorial stimuli, as a function of the effects of SY, which included time spent in forested outdoor environments, interactions with elemental aspects of natural environments and laboratory settings. Tsunetsugu et al.  synthesiResearch included within the SM theme invariably measured nervous system activity and emotional response of participants in relation to experiencing authentic aspects of forested environments by comparative means. Igarashi et al.  studied Igarashi et al.  looked aKoga and Iwasaki  investigPrevious research regarding the effects of SY explored elements of olfaction as a sense metric relevant to the biological effects of experiencing forested environments. Tsunetsugu et al.  noted inJo et al.  focused Following a systematic review of 25 articles from databases including, but not limited to PubMed, EMBASE, CINAHL, and PsychINFO, Bowler  found eaDuring the review of the literature, existing conceptual frameworks emerged that may be applied to SY practice and NT research. The first conceptual framework (CF) is Thomson’s “vis medicatrix naturae,” otherwise known as, “the innate ability of the body to heal itself” as presented in Logan and Selhub’s review of the effects nature has on the human brain . ThomsonThe second CF is by Berger . Berger The third CF is from a Threshold Concept and Transformational Learning perspective . The praLimitations of this review include the biases among the authors of the studies and articles culled, as well as the conceivable restrictions of SY as an evidence based practice within the traditional principles of Western medicine. While search criteria for the articles remained consistent across all database searches, publication bias must be acknowledged as most of the studies reviewed demonstrate a positive correlation among SY practice and NT with favorable physiological and psychological outcomes. In addition, original study sample sizes were often limited to less than 20 participants, with the inclusion criteria of primarily of healthy, young, male university students, making results difficult to generalize across entire populations. Other limitations within the studies include their inability to distinguish physical and psychological effects purely based on the participants’ surroundings versus the participants’ level of activity while present in either an urban or nature setting. Most studies offer little distinction among senses used, and which, if any, have a greater influence on positive or negative outcomes. While the current research has continued to trend toward the benefits of SY and NT on specific disease states and diagnoses, it has primarily focused on the short-term effects of the practice of SY and NT with little research to indicate the longevity of its benefits. This concept of permanence relates not only to the amount of time spent in a nature setting for short-term optimal results within a study timeframe, but the participants’ previous relationship with nature throughout their lifetime, and how a priming bias may influence the amplitude and frequency of corporeal effects. SY as a therapeutic practice to be exemplified by healthcare providers and recommended to their patients includes the limitations of theoretically defining SY for clinical use, the social and economic determinants of health which limit access to natural environments, and the correlation between the ever changing diversity of nature itself and the unpredictable physiological and psychological responses it may induce within the human body as noted by the Biophilia Hypothesis . In general, from a physiological perspective, significant empirical research findings point to a reduction in human heart rate and blood pressure and an increase in relaxation for participants exposed to natural GS ,40. EvenThe aims of this state-of-the-art review are to showcase and elucidate the existing research on the effects of the practice of SY and NT on human physiological and psychological systems, existing frameworks and sense metrics in order to assist researchers in conducting future empirical research to substantiate, gain a better insight and enrich the scholarly literature. Longitudinal research is recommended to investigate the powers of nature as a healer and preventative element in today’s modern/technological driven world over a long period of time. Proposed thoughtful and well-designed research would include both quantitative and qualitative approaches to identify specific SY and NT factors that influence disease and health promotion in Western Cultures. Furthermore, a systematic review of the current literature would honor the scholarly work completed to date and provide a higher level of evidence for the practitioner considering SY and NT as EBP interventions. This in-depth review illustrates, honors and supports the increased awareness of the positive health-related effects  associated with humans spending time in nature, viewing nature scenes via video, being exposed to foliage and flowers indoors and the development of urban green spaces in large metropolitan areas worldwide. Not only valid and reliable psychometrics have been implemented, but valid and reliable physiological measurements have been used to show significant and potentially healing and health promoting effects. Furthermore, physiological and psychological research, based on sound NT frameworks and hypotheses is needed in the areas of healthcare professional/student stress-reduction and life balance ,65. Process Eight: Creating healing environment at all levels, whereby wholeness, beauty, comfort, dignity, and peace are potentiated.Healthcare professionals and educators may turn to the SY and NT literature for simple, affordable and enjoyable complementary interventions to reduce stress, anxiety, and depression symptoms and enhance joy, relaxation, overall sense of well-being and balance in life. The founder and faculty member of the Association of Nature and Forest Therapy Guides and Programs, Amos Clifford, states the organization’s mission is to integrate FT into healthcare systems . MoreoveAdvancements in complementary and alternative medicine (CAM) are indicative of a time in history when researchers and practitioners are willing to look at how humans evolved over the past 6- to 7-million years. When one ponders humans existing less than 0.01% of the species’ history in modern surroundings and the other 99.99% of the time living in nature, it is no wonder some humans yearn and are drawn back to where human physiological/psychological functions began and were naturally supported. The Biophilia Hypothesis  supports


This study was aimed to investigate the acute effect of medium-distance running on bile acids concentration and composition, in order to verify whether the positive impact of physical exercise on cancer risk may also be mediated by variation of bile acids concentration and composition in serum.The concentration and composition of serum bile acids was analyzed in 30 middle-aged and healthy recreational athletes with a reference liquid chromatography-mass spectrometry technique, immediately before and shortly after the end of the running trial. The concentration of bile acids after the run was adjusted for plasma volume change.All athletes successfully completed the trial. After correction of values for the individual plasma volume change calculated after the run, the serum concentration of total bile acids was found to be significantly reduced by approximately 46%. A statistically significant decrease was observed for cholic, deoxycholic, chenodeoxycholic, ursodeoxycholic, glycoursodeoxycholic and hyodeoxycholic acids, whereas the concentration of the remaining compounds remained unvaried after the run. A considerable variation of bile acids profile was also observed. No significant association was found between running performance and variation of bile acids concentrations.These results show that middle distance running acutely decreases the concentration of total bile acids in serum, especially that of the more mutagenic and carcinogenic compounds, so providing an intriguing support to the favorable effects of physical exercise for lowering the risk of many gastrointestinal cancers. Bile acid exposure has been convincingly identified as a potential risk factor for many forms of gastrointestinal (GI) cancers . In factThe bile acids are 24-carbon steroids produced from cholesterol in the liver. These compounds are usually divided into those directly synthesized by the liver , and those produced by bacterial metabolism of the two primary bile acids in the intestine  and glycocholic acid (GCA), along with the conjugation of CDCA with glycine or taurine to produce taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) . NotablyThe bile acid levels in faeces and blood may be influenced by a number of variables such as total energy intake or the amount and type of dietary fats and fibers . BesidesTherefore, we designed this study to investigate the acute effect of medium-distance running  on bile acids concentration and composition in the serum of 30 middle-aged and healthy recreational athletes, in order to verify whether the positive impact of exercise on GI cancer risk may also be mediated by a variation of bile acids concentration and composition in serum.The baseline concentration of hemoglobin, hematocrit and bile acids is shown in Table All athletes successfully completed the 21.1 km trial, with a mean time of 1h52min42sec (range between 1h31min00sec and 2h31min11sec). The mean variation of hemoglobin, hematocrit and bile acids after the trial is shown in Table The variation of bile acids profile as percent of total bile acids is shown in Figure As predictable, a significant correlation was observed between running time and sex, whereas no significant associations were found between running performance and variation of bile acids concentrations, expressed as the ratio between pre- and post-exercise serum values. The associations between running time and variation of bile acids concentrations after the run remained non-significant also after including sex as a covariate in the correlation analysisControversial information has been provided about the relationship between physical exercise and bile acids metabolism, mostly based on a limited number of cross-sectional studies. Sutherland et al carried out a small cross-sectional study including 14 male distance runners and 14 sedentary men . In agreTaken together, the results of our study demonstrate for the first time that exercise  acutely influences both the concentration and composition of bile acids in the blood of recreational athletes. Interestingly, middle-distance running was effective to acutely decrease the total concentration of serum bile acids, as well as the relative serum values of CA, DCA, CDCA, UDCA, GUDCA and HDCA, whereas the serum concentration of the remaining bile acids was mostly unaffected Table . The comThese findings may have important implications for GI cancer biology. It has been clearly established that bile acids play an essential role in carcinogenesis, as supported by reliable epidemiological and biological evidence –16. In pAs regards the biological link between bile acids and carcinogenesis, this association is supported by a variety of pro-carcinogenic effects that bile acids may exert, so including generation of reactive oxygen and nitrogen species, cell membrane perturbation, direct DNA damage, disruption of mitochondria, promotion of cell proliferation and mitotic events, reduced susceptibility to apoptosis, as well as activation of erbB2 and EGFR signaling cascades . TherefoIn conclusion, our results confirm reliable evidence that exercise, particularly aerobic or endurance exercise , may acutely decrease the concentration of total bile acids, especially that of the more mutagenic and carcinogenic compounds. We provide thus an additional and putative explanation to the favorable effects exerted by physical exercise for lowering the risk of many GI cancers in which bile acids my act as promoters and/or contributors . Unfortuhttp://www.dsnm.univr.it/?ent=iniziativa&id=5382, Last accessed, 12 February 2017). Specifically, 30 amateur runners  successfully performed a 21.1 km  run. All athletes were part of an amateur running team, regularly engaged in recreational running . The participants were asked to cease all exercise training and abstain from taking drugs or medications 48 hours before the event. No subject was regularly taking fibrates, bile acid sequestrants, niacin or statins. A control population was not included in this study since, as previously shown by Zheng et al, up to 2-4 hours fasting does not generate a significant variation of total bile acids values and bile acids composition in serum  and and23] aSince the values of all variables did not follow a normal distribution, as established by Kolmogorov–Smirnov test, results were shown as median and interquartile range (IQR). The statistical analysis was also based on non-parametric tests, entailing Wilcoxon test for paired samples, chi square test with Yates’ correction and Pearson’s correlation, using Analyse-it .All subjects enrolled in this study provided a written consent. Likewise, this study was approved by the local ethical committee  and was carried out in accordance with the Helsinki Declaration.


Peng Yu Sai, “Fish Gill of Mobulid Ray”) from devil and manta rays  poses a significant threat to these marine fishes because of their extremely low productivity. The demand for these gill plates has driven an international trade supplied by largely unmonitored and unregulated catches from target and incidental fisheries around the world. Scientific research, conservation campaigns, and legal protections for devil rays have lagged behind those for manta rays despite similar threats across all mobulids.International trade for luxury products, medicines, and tonics poses a threat to both terrestrial and marine wildlife. The demand for and consumption of gill plates , we examined how threats and protective measures overlap with species distribution. We then used a species conservation planning approach to develop the Global Devil and Manta Ray Conservation Strategy, specifying a vision, goals, objectives, and actions to advance the knowledge and protection of both devil and manta rays.Our literature review revealed that there had been nearly 2.5-times more “manta”-titled publications, than “mobula” or “devil ray”-titled publications over the past 4.5 years (January 2012–June 2016). The majority of these recent publications were reports on occurrence of mobulid species. These publications contributed to updated Area of Occupancy and Extent of Occurrence maps which showed expanded distributions for most mobulid species and overlap between the two genera. While several international protections have recently expanded to include all mobulids, there remains a greater number of national, state, and territory-level protections for manta rays compared to devil rays. We hypothesize that there are fewer scientific publications and regulatory protections for devil rays due primarily to perceptions of charisma that favour manta rays. We suggest that the well-established species conservation framework used here offers an objective solution to close this gap. To advance the goals of the conservation strategy we highlight opportunities for parity in protection and suggest solutions to help reduce target and bycatch fisheries. Manis spp.) and the Black Rhino (Diceros bicornis) and also a number of marine organisms such as sharks and rays (subclass Elasmobranchii) and seahorses (genus Hippocampus). China is a leading importer and exporter of many species due to a high demand for luxury products, medicines, and tonics derived from wildlife  and two species of manta ray (genus Manta) currently make up the subfamily Mobulinae , attains a maximum disc width  of five metres , can reach up to seven metres disc width , in large mobulid species are among the lowest of all elasmobranchs (manta raya in Mexican fisheries).The life history and ecological traits of mobulids make them highly sensitive to overexploitation. Nine species of devil ray  would create additional pressure on devil rays, combined with the inherent vulnerability of the entire subfamily, led us to prioritize the development of the Global Devil and Manta Ray Conservation Strategy. A workshop was convened in Durban, South Africa from 9 to 12 June 2014 to develop a Global Devil and Manta Ray Conservation Strategy. In addition to the workshop attendees, inputs from a wider network of devil and manta ray experts informed the Strategy. This paper summarizes of the current state of devil and manta ray scientific research, conservation, and protection , and highlights discrepancies between the two genera. We also introduce the global conservation strategy, a living document aimed at guiding future research, policy, and outreach.During both the workshop and the development of this document, a significant dichotomy emerged with respect to the understanding of and concern for devil and manta rays. To illustrate this, we first summarize the trends in scientific research on devil and manta rays by updating (a) the systematic literature analysis of In order to examine trends in devil and manta ray scientific research, we extracted scientific papers from the ISI Web of Science Core Collection and Google Scholar on 30 May 2016. Our specific aim was to update the systematic literature search conducted up to the year 2011 by Eleven geographic distribution maps of Extent of Occurrence (EOO) and Area of Occupancy (AOO) were generated prior to the workshop and refined during and following the workshop based on current species distribution knowledge. The EOO is defined as “the area contained within the shortest continuous imaginary boundary which can be drawn to encompass all the known, inferred or projected sites of present occurrence of a taxon” . The AOODevil ray and manta ray AOO distribution maps were grouped by genus in order to map and compare: (a) locations of known fishing pressure through target and incidental fisheries from , and (b)The IUCN SSG Global Devil and Manta Ray conservation strategy workshop was attended by 18 experts who held knowledge from nine of the 19 Major Fishing Areas as recognized by the Food and Agriculture Organization of the United Nations FAO; . FourteeThrough a series of workshop subgroup discussions and plenary sessions, participants at the strategy workshop developed a vision, goals, objectives, and actions  aimed atThe group used Specific, Measurable, Achievable, Relevant/Realistic, and Time-Bound (SMART) criteria as a guide for setting objectives and actions. In some cases, workshop participants prioritized countries or regions based on known threats . Following the workshop, experts revised the goals, objectives, and actions outlined in the strategy, and collaborated on the development of this paper to provide context for the strategy.Mobula spp. from 1980 to 2011, whereas our study identified 21 novel peer-reviewed studies focused on Mobula spp. over the past four years (2012–2016).Since the literature review conducted by For devil rays (21 studies), the research theme  is confirmed to be present throughout the Red Sea and Gulf of Aden, whereas previously it was only reported in the upper Red Sea. Generally, there have been range extensions across the central Atlantic with new sightings of the Bentfin Devil Ray Mobula thurstoni  in West Africa, ranging across the isolated Atlantic islands of the Canaries, Azores, and Ascension. Furthermore, there were significant new records in the Indo-west Pacific nations of the Philippines, Vanuatu (for the Bentfin Devil Ray), Fiji and Palau (for the Chilean Devil Ray).Novel reports on occurrence of mobulid species updated species-specific Area of Occupancy and Extent of Occurrence maps for the eleven species of devil and manta ray . CompareMobula japanica , Chilean Devil Ray, and Bentfin Devil Ray. Three species are found only in the Atlantic Ocean and Mediterranean Sea. The Atlantic Devil Ray Mobula hypostoma  is found only in the western Atlantic and has an apparently disjunct distribution in the Caribbean and northern Gulf of Mexico and also in the South Atlantic continuous along the coastlines of Southern Brazil, Uruguay, and Northern Argentina. The eastern Atlantic counterpart is the Lesser Guinean Devil Ray Mobula rochebrunei  that was described from Guinea and is thought to be present in Mauritania, Senegal, Guinea-Bissau, and Angola. Finally, the largest species—the Giant Devil Ray—is apparently only found in the Mediterranean Sea. There are three smaller (approximately 1 m disc width) Indo-Pacific species: two found only in the Indian Ocean and western Pacific Ocean, the Pygmy Devil Ray Mobula eregoodootenkee  and the Shortfin Devil Ray Mobula kuhlii , and one species found only in the eastern Pacific, the Smoothtail Devil Ray Mobula munkiana Notarbartolo di Sciara, 1987. The larger of the two manta ray species, the Giant Manta Ray, has a near circumglobal distribution in tropical and subtropical waters and is most similar to those of the three largest devil ray species, whereas the Reef Manta Ray Manta alfredi  has an Indo-West Pacific distribution.The devil rays fall within three broad classes of geographical distribution. The three largest-bodied species—at least 1.8 m disc width—have near circumglobal tropical and subtropical geographic ranges: the Spinetail Devil Ray Species-specific differences in international, national, and state/territory protection occur across the 11 mobulid species. The Giant Manta Ray has the largest number of international, national, and state/territory protection of any mobulid species, followed by the Reef Manta Ray . SpeciesWhen grouped by genus, protections for devil rays under two key international agreements are now equal to those for manta rays , yet natWorkshop participants agreed on an overall vision for the status of devil and manta rays, and three goals aimed at achieving this vision, as well as a series of sixteen objectives and associated actions to support the goals  examine how this apparent charisma gap between devil and manta rays arose, (2) track the recent path of manta ray protection to see where this protection can be extended to include the devil rays, (3) consider how responsible trade and demand reduction can curtail targeted fishing, and (4) and examine how incidental fishing mortality can be minimized.Tourism and related economic sectors have partially fuelled the conservation activities surrounding manta rays. Translating this success to devil rays, however, may be challenging because of biological differences that make devil rays harder for tourists to easily and reliably access. Both species of manta ray reach a large body size, form predictable aggregations, and are accessible to divers . Some spMustelus canis), which can be landed with their fins removed according to an exceptionally lenient fin-to-carcass ratio . In many places around the world, shark finning has been banned largely based on concerns over cruelty, yet few regulations prohibit the removal of wings from live skates. We caution that variation in public awareness, and care for a biased subset of chondrichthyans and other marine organisms, will lead to problematic asymmetries in scientific knowledge, conservation campaigns, and protective regulations , obligating the 122 Parties to strictly protect the species and collaborate toward regional conservation. In 2013, the two manta ray species were listed under CITES Appendix II, the world’s oldest and largest multilateral environmental agreement with the legal mechanisms in place to hold Parties accountable to trade restrictions. The 183 Parties are thus required to issue permits to export manta rays (or manta ray products) only after demonstrating that they are sourced from legal and sustainable fishing operations . In 2014Trade regulation can lead to both positive and negative outcomes. Trade may cease, or continue at sustainable levels as a result of regulation; or trade may continue illegally, or continue without full regulatory compliance. Trade regulation, therefore, should be promoted and implemented with careful consideration of socio-economic drivers. Sometimes governments find it simpler to ban, rather than regulate, trade . RegulatOne approach to preventing negative conservation outcomes from trade regulation involves attempting to understand relevant socio-economic drivers and associated stakeholder behaviour. Investigations into the mobulid gill plate trade found it to be centered in Guangzhou, China, and involve only a handful of large suppliers (Another important consideration of regulating mobulid ray exploitation is the effect on livelihoods and food security of fishing communities. Human populations in many tropical coastal communities are growing rapidly, have low income, and rely heavily on fish for protein and income . MobulidIncidental catch in both large and small-scale fisheries is a key challenge to the conservation of mobulids, given mortality during capture, evidence for low rates of post-release survival , and incThe IATTC’s 2015 prohibition on the retention, transshipment, storage, landing, and sale of all devil and manta rays in large-scale, Eastern Tropical Pacific tuna fisheries is a significant step toward mobulid protection, but compliance has yet to be evaluated, and exceptions made for small-scale fisheries compromise the conservation goals that drove the original proposal (Action 5.13; While the IATTC mobulid measure can be seen as progress for some purse seine fisheries, more attention to the incidental catch of mobulids in data-poor trawl fisheries, particularly midwater trawls, is needed. A study on the pelagic megafauna taken incidentally in large-scale European trawl fleets targeting sardinella, sardine, and horsemackerel off the Northwest Africa shelf found that approximately one mobulid is taken for every hour of trawling . More reResearch and regulations for both devil and manta rays have recently increased substantially, due in large part to these species’ high sensitivity to over-exploitation. Manta rays, however, have been a greater focus for scientific investment and protection, owing to the added factors of perceived charisma and importance to the dive tourism industry. To bridge this charisma gap and encourage equal protection for all mobulids, as warranted by similar life history and threats, we present a global conservation strategy that draws on components from well-established and successful species conservation frameworks. We are hopeful that sustained interest and collaborative implementation initiatives from the full range of stakeholders will improve the outlook for these remarkable fishes.


Vaccination is a complex ecosystem with several components that interact with one another and with the environment. Today’s vaccine ecosystem is defined by the pursuit of polio eradication, the drive to get as many of the new vaccines to as many people as possible and the research and development against immunologically challenging diseases. Despite these successes, vaccine ecosystem is facing keys issues with regard to supply/distribution and cost/profitability asymmetry that risk slowing its global growth.The conference “Vaccination ecosystem health check: achieving impact today and sustainability for tomorrow” held in Annecy-France  took stock of the health of today’s vaccination ecosystem and its ability to reliably and sustainably supply high-quality vaccines while investing in tomorrow’s needed innovation.Small and decreasing numbers of suppliers/manufacturing facilities; paucity of research-driven companies; regulatory pressures; market uncertainties; political prioritization; anti-vaccine movements/complacency; and technological and programmatic issues were acknowledged as the major challenges that could weaken today’s vaccination ecosystem. The expert panel discussed also drivers and barriers to a sustainable vaccination ecosystem; the metrics of a vaccination ecosystem; and what should be added, removed, increased, or reduced to maintain the health of the vaccination ecosystem.The online version of this article (doi:10.1186/s12919-016-0069-y) contains supplementary material, which is available to authorized users. Vaccination comprises a complex ecosystem similar to natural ecosystems; it can be represented as an organism-community of international organizations, vaccine manufacturers, donor agencies, foundations, nongovernmental organisms, etc. that interact with one another and with the environment. As a consequence, modifications or variations in one of its components can affect the ecosystem balance.National immunization programs together with Gavi, the Vaccine Alliance (Gavi), international aid, philanthropic donors, tiered pricing by large research and development (R&D) vaccine manufacturers, and the availability of generic vaccines have significantly decreased vaccine access gaps between high- and low-income countries by improving vaccination of the world’s poorest children. However, this success should not prevent continuous examination of whether we are fully optimizing the huge untapped potential of today’s vaccines without damaging the benefit that future vaccination innovation can bring.Today’s vaccine ecosystem is defined by the pursuit of polio eradication, the drive to get as many of the new vaccines to as many people as possible and the R&D pursuit of vaccines against immunologically challenging diseases such as HIV, Malaria, TB, Dengue, RSV, HSV, Chlamydia and others. This era is also characterized by the emergence of major private donors and government subsidies. These donors and their agencies aim to extend global access to all vaccines through «push and pull» innovation in vaccines and vaccines systems. To achieve this they implement “market-shaping” aimed at incentivizing increased volumes, lower prices and new producers of high volume, low-cost versions of existing vaccines.To take stock of the health of today’s vaccination ecosystem and its ability to reliably and sustainably supply high-quality vaccines while investing in tomorrow’s needed innovation, Fondation Mérieux organized a conference entitled “Vaccination ecosystem health check: achieving impact today and sustainability for tomorrow” on January 19–21, 2015, in Annecy, France. Participants included representatives from international organizations  and industry.To elicit more consideration of the vaccine ecosystem, a breakout session was held for participants in small working groups to discuss how to keep the vaccination ecosystem healthy.This report summarizes selected issues discussed by participants, including the key findings and recommendations for future approaches to addressing this issue.The vaccine ecosystem involves a large number of actors  with mutual interactions Fig.  1]. Vac. Vac1]. The Gavi Alliance mainly ensures access to immunization in poor countries. Currently, Gavi supports routine vaccination programs , vaccination campaigns , stockpile for outbreak responses  and malaria vaccine pilot, supply and procurement strategy. UNICEF works in partnership with governments, global partners, and a large number of suppliers. The continuous changes in both supply and demand creates a dynamic market that requires continuous monitoring and management. Indeed, the annual vaccine procurement has increased significantly since 2000 due to the introduction of new vaccines. In 2014, UNICEF procured 2.70 billion doses of more than 40 vaccines for 100 countries at a value of $1.474 billion. Currently, the largest contributions come from industrialized countries, but emerging markets’ participation is increasing over time.The participants attempted to analyze the health of vaccine eco-system in terms of coverage, demand, supply, and R&D.The establishment of the World Health Organization Expanded Program on Immunization (WHO-EPI) more than 40 years ago, adequate program design and implementation and international cooperation have led not only to increased vaccine coverage rates around the world, but also to reduced disease burden –4, and tAn important unaddressed challenge is to vaccinate the 20% of the world’s children born each year that do not receive even the most basic vaccinations. In 2011, the Global Vaccine Action Plan (GVAP) for the Decade of Vaccines (DoV) was created with the ambitions to close the equity gap in vaccine delivery and to unleash vaccines’ vast future potential. The new global vaccines and immunization framework provides space for all stakeholders to improve delivery, demand, and research. GVAP mid-point targets were 1) Diphtheria-Pertussis-Tetanus (DTP3) coverage >90% in all countries and >80% in every district by 2015, 2) polio transmission stopped by 2014, 3) maternal and neonatal tetanus eliminated by 2015, 4) measles eliminated in four regions by the end of 2015, 5) rubella eliminated in two regions by the end of 2015, and 6) introduction of one or more underutilized vaccines in low- or middle-income countries by 2015. An independent assessment performed by the Strategic Advisory Group of Experts on Immunization (SAGE) in 2014 expressed concerns about low implementation of GVAP as all targets except the last one were off track.The vaccine industry is entering a period of uncertainty that threatens the new vaccine pipeline. Additional needs for basic science research; continuously rising manufacturing standards and regulatory requirements; the scientific challenge of developing vaccines for unmet needs ; and increased cost, time, and risk of vaccine research and development driven by late-stage (phase 3) trials are among major contributing factors that limit the number of vaccines that a company is willing or able to develop to meet public health needs. One important result of this situation is that major companies are only interested in blockbusters. Therefore, main vaccine manufacturers do not consider many infections with somewhat restricted market size such as Lyme, cryptosporidium, and West Nile a top priority. Furthermore, the pressure to keep vaccine prices low, both in developed and developing countries, threatens to move manufacturing capability out of North America and Europe to reduce costs.Today’s vaccine ecosystem is facing keys issues with regard to supply/distribution and cost/profitability asymmetry that risk slowing the global health of vaccine ecosystem. Indeed, a disconnect exists between the WHO global vaccine action plan (GVAP) and market shaping This could be due to overdependence on “price reduction” metrics and underdeveloped metrics for future innovation and supply security. Furthermore, cost/profitability asymmetries could provoke market exit and market failure when reinvestment is required. Several years of yellow fever vaccine shortage illustrates this situation well , 6. New Possible solutions discussed during the conference for sustaining a healthy vaccination ecosystem are summarized in the following paragraphs.High-quality data are crucial to empower immunization program management, to increase vaccine uptake and to reach those children who are never vaccinated. Regular data review, data triangulation with other available sources, periodic data quality assessment, and training of health care workers are examples of methods that could considerably improve data quality. Household surveys to measure immunization coverage are also needed to validate administrative data and provide additional information on missed opportunities and timely vaccination. Using traditional methods such as home-based vaccination records and new technologies such as modern Information, Communication and Technology (ICT) tools can also considerably improve data quality and thus contribute to improvement in coverage.Another issue that can influence global vaccine coverage concerns the sustainability of financial support for Gavi–eligible graduating countries. Price-freezing for a period of five years is a possible solution, currently under evaluation, for these countries to sustain their expanded immunization programs without facing huge economic impact.Weak immunization supply chain systems are another bottleneck to achieving immunization goals. Fortunately, key supply chain challenges have been diagnosed and their importance acknowledged. New technologies to reduce storage volume, expand the reach of cold chain to areas without reliable energy sources using solar equipment or long-lasting vaccine containers, provide new vaccine delivery models, allow combined vaccines and better schedules (number or timing of doses) are some technical solutions that exist and/or are in development and that could address vaccine supply challenges.As described previously, the existing disconnects between demand and supplies are due to the limited number of manufacturers and buyers and the increasing demand in terms of vaccine products. Gavi adopted a supply and procurement strategic goal to shape the vaccine market by balancing supply and demand, ensuring security of supply, minimizing the cost of vaccines, and fostering development of appropriate and quality vaccines. So far, Gavi increased the number of vaccine suppliers from five in 2001 to 15 in 2014, including manufacturers from emerging markets. Other procurement strategies could further improve vaccine supply, including negotiation such as selective contracting/exclusive dealing and auctions.Possible solutions for sustaining vaccine research and development and innovation are 1) incentives for industry to invest in new vaccines and improve old vaccines, 2) agreement between Food and drug administration/European medicine agency (FDA/EMA) to limit numbers needed for efficacy trials , 3) increased interaction between high- and low-income countries to facilitate technology transfer, and 4) set-up of an international vaccine development fund that would support biotech escalating from lab to proof of concept and vaccine manufacturers developing vaccines for tropical and neglected diseases. Policies that make innovation and distribution reasonably profitable could also address these issues. Such policies include providing government supports for development and production, reducing uncertainty by establishing clear property rights, taxing negative spillovers, and subsidizing positive spillovers. Innovation must be profitable, but regulation to lower prices can slow innovation and diffusion by reducing return on investment. A price that is affordable to governments and donors and reasonably covers manufacturer’s minimum requirement could thus enhance vaccine R&D. Price discrimination, i.e., different prices for the same product in different settings , could also allow profitability to be maintained, thus generating more innovation. In low-income countries, differential patent rights, compulsory licenses, prizes, and advance market commitments to recommend a vaccine once licensed could also address supply and innovation.Conditional licensure of vaccines as part of a system that would incorporate a requirement for rapid cycle and other real-time evaluations following introduction is another potential solution. Indeed, the cost and time of large routine safety trials prior to vaccine licensure are constantly increasing and could have a negative impact on the vaccine development pipeline without concomitant and dramatic increase in our ability to assess safety. The examples of Rotateq and Rotarix show that despite very large phase 3 clinical trials, increased risk of intussusception only became apparent and statistically significant in the post licensure period Table .Table 1RSimilarly, post-introduction data on pneumococcal conjugated vaccines (PCV) show that the vaccine had higher impact on the reduction of invasive pneumococcal diseases, otitis media, and all causes of pneumonia than what was reported in phase III clinical trials Table .Table 2CConditional licensure will lower the financial barriers to development of new vaccines and consequently allow a broader portfolio of vaccines to be developed.In recent years, a compelling line of inquiry has established the economic benefits of health, at both individual and aggregate levels. Most economic evaluations of vaccines focus on a narrow set of vaccination-mediated benefits  and fail to account for the role of vaccination as a driver of wealth and its known impact on health, leading to potentially sizable undervaluation of the true economic value of vaccines. A broader perspective in economic analysis considers other benefit categories including 1) outcome-related productivity gains, 2) behavior-related productivity gains, 3) community externalities , and 4) utilitarian value of health gains. Cost-effectiveness and benefit-cost analyses are tools to assess the value of vaccination. The latter is more appropriate for economic analysis because it looks at a range of health and non-health related outcomes that are expressed in terms of a dollar value. The example of Hib vaccine in children provided evidence of a benefit-cost ratio above 1 . AnotherConceptualizing the full benefits of vaccination allows better recognition of the value of vaccination as a driver of both wealth and health. Monetizing the impact of vaccination provides policymakers with sufficient information to make well-informed decisions about including other new vaccines in national immunization programs.Breakout sessions following the overall presentations on the current status of today’s vaccination ecosystem allowed participants to discuss main topics that deserved more in-depth attention.Different factors were identified as drivers or barriers that could influence the sustainability of the vaccine ecosystem in terms of vaccine coverage, supply and demand as well as R&D , today’s vaccination ecosystem faces several challenges that could weaken it. These include small and decreasing numbers of suppliers/manufacturing facilities; paucity of research-driven companies; regulatory pressures; market uncertainties ; political prioritization ; anti-vaccine movements/complacency; and technological and programmatic issues .However, the panel identified several potential solutions. Guaranteed return on investment for donors, governments, and global stakeholders; presence of multiple effective suppliers to reduce monopolies and secure supply; financing for research and development; political prioritization by raising awareness about needs; empowerment of developing country manufacturers ; and balance of public-private perspectives for global public goods and distinction of the roles of each sector could positively affect the vaccination ecosystem.In parallel, the current low-price-focused market shaping could lead to critical asymmetry between cost and profitability for Gavi–dedicated vaccines. This phenomenon is apparent in the supply shortage for most Gavi vaccines, exit of R&D producers from production to heritage vaccines, increased concentration of most vaccine production by fewer producers, increased number of vaccines with just one or two suppliers, and static or falling levels of vaccine producers and R&D activity. Challenging vaccine prices is complex. The need exists to collect more accurate data to assess the full benefits of vaccines because we cannot challenge the cost without considering the whole benefits. Piggyback analysis, i.e., economic evaluation embedded in clinical trials, would be a good way to quantify economic values of vaccines in terms of productivity, for example. However, this would need expensive long-term follow-up.To summarize, the concept of an ecosystem is a useful way of thinking about vaccines. A healthy ecosystem should be able to maintain its organization and function over time in the face of external stress. The supply issue is a central aspect that requires much more work. Research and development also face challenges. Prioritizing a list of vaccine-preventable diseases to target and matching it with R&D activities could optimize the latter, especially if a global development fund is in place. Mechanisms such as regulatory reforms and technical innovation to improve access to markets and shorten disruption periods could also contribute to the sustainability of the vaccination ecosystem. Our goal should be to investigate how we can best work together to ensure the sustainability of increasing global vaccination without damaging global vaccine production and/or R&D. A shared responsibility is needed to keep the vaccination ecosystem healthy.