In order to describe the role of introduced plants in Ecuador, and to test these three hypotheses, we asked if introduced plants are over-represented in the Ecuadorian pharmacopoeia, and if their use as medicine is best explained by the introduced plants’ greater availability, different therapeutic applications, or greater number of use categories. Drawing on 44,585 plant-use entries, and the checklist of >17,000 species found in Ecuador, we used multi-model inference to test if more introduced plants are used as medicines in Ecuador than expected by chance, and examine the support for each of the three hypotheses above. We find nuanced support for all hypotheses. More introduced plants are utilized than would be expected by chance, which can be explained by geographic distribution, their strong association with cultivation, diversification (except with regard to introduced diseases), and therapeutic versatility, but not versatility of use categories. Introduced plants make a disproportionately high contribution to plant medicine in Ecuador. The strong association of cultivation with introduced medicinal plant use highlights the importance of the maintenance of human-mediated environments such as homegardens and agroforests for the provisioning of healthcare services.Globally, a majority of people use plants as a primary source of healthcare and introduced plants are increasingly discussed as medicine. Protecting this resource for human health depends upon understanding which plants are used and how use patterns will change over time. The increasing use of introduced plants in local pharmacopoeia has been explained by their greater abundance or accessibility ( Understanding how people select plants for medicinal use has been a central question in ethnobotany . Early eZingiber officinale Roscoe), naturalized species  and commercially traded species . In some regions, the use of introduced species in traditional medicine is reported to be increasing  and from over 19,000 herbarium specimens [The Catalogue of Vascular Plants of Ecuador (Jørgensen and León-Yánez 1999), hereafter referred to as The Catalogue. Of the more than 17,000 recorded vascular plant species in Ecuador [We used a compilation of ethnobotanical data  contained in  Ecuador , hereaftpecimens . In addi Ecuador ,35, 5,17 Ecuador .the Encyclopedia that could not be matched with a species name in The Catalogue. A complete list of introduced medicinal plants analyzed in this study with cultivation status can be found in the supporting information  had been reassessed as synonymous with another species in our study, or had been reduced to a subspecies and, therefore, would no longer be included in our study. Out of 300 randomly selected native medicinal plants, none had been reassessed as synonymous with another species in our study, or had been reduced to a subspecies.In this paper, in order to provide the most comparable units for analysis, we included entries from our two sources at the species level, excluding subspecies and varieties. We also excluded species from analysis whose native or introduced status could not be determined. For analyses that included geographic distribution, we also excluded species in ormation . Cultivaes names  were updTo determine whether plant origin (introduced or native) helps to explain the selection of a plant for medicinal use in Ecuador, we created a 2×2 contingency table representing plant origin (introduced or native) and plant status as a medicinal or not. A Pearson’s Chi-squared test with Yate’s continuity correction was used to test the hypothesis of non-independence between plant origin and use as medicine.To understand the magnitude of potential differences in representation of introduced and native plants in the pharmacopoeia, we compared the proportion of introduced species used as medicine  to the tThe Catalogue [To test how well availability factors predict the use of introduced species as medicine, we estimated plant availability as the number of Ecuadorian governmental provinces in which the plant occurs, and by the plant’s cultivation status. The number of provinces of occurrence was used as a proxy for availability because it provides a measure of how widespread each plant is within the country. It was calculated from data in atalogue   was dependent on its availability (number of provinces of occurrence and cultivation status) and its origin (introduced or not). This error structure was selected given the binary data for the response variable. Plant origin was included into the model to explore its interaction with the number of provinces of occurrence. A significant interaction between plant origin and number of provinces of occurrence would suggest that the availability of introduced plants has particular significance for their use as medicinals. The continuous predictor (number of provinces of occurrence) was standardized to facilitate comparison with other predictors. Direct comparison of the number of plants in cultivation and number of provinces of occurrence were made between introduced and native plants for the flora overall, and for medicinal plants in particular, with Pearson’s Chi-squared test with Yate’s continuity correction and with a Kruskal-Wallis rank sum test.the Encyclopedia . We theied from  to see iSecond, we compared the number of species of native and introduced plants used to treat diseases introduced to the New World  and those already present in South America prior to Contact, using a 2×2 contingency table and a Chi-square test. This comparison indirectly tested if species may have been introduced to the pharmacopoeia to diversify options and fill a therapeutic vacancy. In order to designate plant species as treating Old or New World diseases, we categorized plant use records through newly created search criteria to provide information about the particular disease a plant treats. We included all diseases and syndromes (not symptoms) that could be identified as either New or Old World in origin . DiseaseThird, we calculated a medicinal redundancy score (the inverse of uniqueness) for each plant, which was the average number of additional plant species recorded as treating the same conditions that the plant treats. To calculate this, we used the same search criteria as mentioned above . A Wilcothe Encyclopedia. Differences between introduced and native plants were evaluated using a Kruskal-Wallis test for both comparisons. These, and all statistical analyses, were performed in R [To determine if introduced useful plants had a larger number of uses than native useful plants, we calculated the number of use categories for each plant , and the number of medicinal treatment categories  according to categories in med in R .2 = 203.48 df = 1, p < 0.0001; the Encyclopedia, while accounting for only 3.7%  of the documented plants in Ecuador [the Encyclopedia, seven were introduced  [We reject the null hypothesis that plant origin (introduced or native) is independent of its use for medicine  . IntroduThe best model for medicinal plant use included all predictors , and also the interaction between origin and number of provinces of occurrence, providing support for the availability hypothesis. A plant was more likely to be medicinal if it was introduced, if it was cultivated and if it occurred across a larger number of provinces. Occurrence over a larger number of provinces had a stronger influence on the chances of an introduced plant’s being medicinal compared to a native plant . Cultivation was the strongest predictor of medicinal use of a plant , followed by the number of provinces of occurrence , and plant origin .When cultivated plants were removed from this model, introduced status  and number of provinces of occurrence  were still significant predictors for a plant’s medicinal status. The interaction of plant origin and number of provinces of occurrence was not significant , meaning there was no detected difference in how availability by number of provinces influenced the probability of medicinal use for wild or naturalized introduced and native plants.2 = 6212, df = 1, p < 0.001). Introduced plants in the overall flora did not differ from native plants in the number of provinces of occurrence . Introduced medicinal plants were less widespread than native medicinals in the number of provinces of occurrence  and just less than 1% of native plants in Ecuador are cultivated . Introduced medicinal species made up 28% of species used to treat pre-Contact diseases and 16% of the species used to treat post-Contact diseases, or “Old World” diseases. Introduced species were less medically redundant than native plants , but they are unlikely to seriously affect the main results. Introduced plants were more likely to be used for medicine than would be predicted by chance. The majority of tested factors jointly help explain the over-representation of introduced plants in the pharmacopoeia, including greater availability at a province scale, stronger association with cultivation and greater usefulness based on diversification and versatility. For diversification, we find support based on use categories and redundancy, but not for treatment of introduced diseases. For versatility, we find support for therapeutic versatility, but not versatility of use categories.the Encyclopedia to emphasize collection in markets and homegardens. This may have increased the chance of identifying medicinal uses for introduced compared to native plants, as many cultivars and commercialized plants are introduced.The over-representation of introduced plants as medicine in our study could also result, in part, from a tendency of studies in the Catalogue. However, when cultivated species were removed from the analysis, there was no longer a significant difference between introduced and native plants with regard to the impact of number of provinces of occurrence on medicinal use. This suggests that the spread of introduced and cultivated species across provinces explains the above finding that the number of provinces of occurrence was more important in explaining medicinal use of introduced compared to native plants. However, given that many introduced weedy medicinal species are also cultivated, the disproportionate association of introduced species with widespread anthropogenic habitats could also explain their disproportionate use in medicine compared to native plants.We found consistent support for the availability hypothesis when considering the Ecuadorian pharmacopoeia as a whole. When analyzing patterns for introduced compared to native plants, we found that availability based on the number of provinces of occurrence was a stronger predictor of medicinal use for introduced plants. The stronger importance of geographic distribution for introduced plants was observed despite the fact that distribution could have been under-estimated for introduced plants in our data, as introduced plants are likely under-collected in studies used in the compilation of causing medicinal use. However, the strong association of cultivation with medicinal use highlights the importance of further investigation into the types of cultivation and the relationship of cultivation to availability for future theoretical development of the availability hypothesis. Questions associated with the development of the availability hypothesis are, for example: when are wild plants preferred despite availability of the same cultivated species?, how has global change influenced decisions to cultivate medicinal plants?, and when does cultivation increase or not the access to plants, and for whom?Of the three predictors of medicinal plant use tested in our model, cultivation was the strongest: a cultivated plant was nearly three-times as likely as a non-cultivated plant to be used medicinally. The strong association of medicinal use and cultivation is expected given that people cultivate useful plants to make them accessible, and newly accepted medicinal plants are often those that are already under cultivation in other regions. The latter may be the strongest factor influencing our data, given the discussion above, and given the association of introduced plants with cultural diffusion  and the The over-representation of introduced plant species as medicine in this study is consistent with results from  on weedyIn addition to geographic distance, availability in terms of local land tenure rights , sellingFinally, the northern Andes are a biodiversity hotspot considered a priority for biodiversity conservation . RegionaIntroduced plants made different treatment contributions than native plants by body system and treatment category Tables  and 3, lIn our study we found that introduced plants were less likely to treat post-Contact diseases than pre-Contact diseases Tables  and 5. SIn Ecuador, introduced medicinal plants had lower redundancy scores, indicating that they were more likely to treat conditions for which there were fewer treatment options . This suAloe spp. in Kenya, for example, determined that the most widespread species, Aloe secundiflora, was also the aloe species with the most recorded uses [Our results indicate that introduced medicinal plants do not vary from natives in the average number of use categories , but that they do treat a larger number of medical conditions. The greater versatility of introduced plant medicines, in terms of conditions treated, may be the result of direct selection by healers or communities for more versatile plants . It coulded uses .There are limitations to understanding plant use patterns by humans based on counting numbers of species, and using large, heterogeneous datasets. Even if fewer introduced species were utilized, the frequency with which each plant is utilized is important to consider, as is the efficacy of each plant ,25,56. TTo fully understand use patterns of plants for medicine by local and Indigenous Peoples, findings must be considered in the historic and contemporary cultural, political, economic and spiritual context of particular communities. For example, taboos, local stories, values and beliefs, and personal, family or community preferences and experiences could inform plant selection in ways that may or may not correspond to the values of efficacy, efficiency, and maximizing treatment options that are assumed in the hypotheses developed and tested here. Unfortunately, with urbanization, improvements in transportation, and changes in transmission of traditional knowledge, opportunities to acquire such local background knowledge are becoming rarer.availability hypothesis was supported in most cases. Plant medicinal use was positively associated with introduced status as well as availability in terms of cultivation and geographic distribution, with cultivation showing the strongest association with medicinal use. Geographic distribution increased the probability of medicinal use more quickly for introduced compared to native plants, suggesting accessibility is more important in determining medicinal use for introduced compared to native plants. In terms of the versatility hypothesis, introduced medicinal plants treated more diseases, but did not have more broad use categories than native medicinal plants. The potential for introduced plants to meet unmet medicinal needs (diversification hypothesis) was supported by the lower redundancy score for introduced compared to native medicinal plants, and by their different spectrum of body system and disease treatment, but not in the treatment of introduced diseases.Analysis of the two databases suggests that introduced plants are over-represented in the Ecuadorian pharmacopoeia. The disproportionate use of introduced plants in medicine was partially explained by all three tested hypotheses. The This study highlights the nuanced way in which multiple hypotheses contribute to explaining plant use patterns. This work also reinforces the importance of the maintenance of human-plant relationships across the spectrum of cultivation practices—in community gardens, homegardens, farms and agroforestry settings—as these are important anthropogenic habitats for the provisioning of cultural and medicinal services to local people, and their importance is likely to increase with global change. Further study could measure and directly compare the source and therapeutic contribution of particular introduced medicinal plants in local communities as well as the role of cultivation, commercialization and cultural beliefs in shaping use patterns.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S1 Text(PDF)Click here for additional data file.


Soft tissue sarcomas (STSs) remain a therapeutic challenge for pediatric and adolescent and young adult (AYA) patients. Still today, surgery, radiation therapy, and chemotherapy remain the mainstay of treatment. Obstacles in developing new treatment approaches to improve the outcome are: few patients to enroll in clinical trials, and the diversity of tumor biology between histologic subtypes. Pet dogs may offer an additional strategy to discover and test new therapeutic avenues. The number of dogs diagnosed with a STS each year in the United States is estimated to be around 27,000 to 95,000. In comparison, approximately 900 children less than 20 years old and 1,500 AYAs between 15 and 29 years old are diagnosed with a STS each year in the United States. The mainstay for treatment of STSs in dogs is also surgery, with radiation therapy and chemotherapy when necessary. Similar to what is seen in humans, grade and stage are prognostic in dogs. In one comparative study of the histology and immunohistochemistry of canine STSs, most tumors were diagnosed as the human equivalent of undifferentiated sarcoma, spindle cell sarcoma, or unclassified spindle cell sarcoma. But much work remains to be done to fully assess the validity of canine STSs as a model. Gene expression analysis has been done in a limited number of canine STSs. Tissue banking, development of cell lines, and the ability to mobilize large-scale clinical trials will become essential in veterinary medicine to benefit both dogs and humans. Soft tissue sarcomas (STSs) are a large and complex family of tumors with unifying features. The first obvious one is their tissue of origin. They arise from the tissues that emerge from the embryonic mesoderm and therefore are all mesenchymal. The WHO defines STSs as soft tissue tumors with malignant potential, that is, a propensity for locally destructive growth, risk of recurrence, and risk of distant metastasis , 2.Soft tissue sarcomas remain a therapeutic challenge for some pediatric and adolescent and young adult patients. Still today, surgery, radiation therapy, and chemotherapy remain the mainstay of treatment . For mosObstacles in testing new treatment approaches to improve the outcome are few patients to enroll in clinical trials, and the diversity of tumor biology between histologic subtypes . Pet dogWith that many more dogs diagnosed with a STS than children, pet dogs might represent a unique opportunity to advance our knowledge of STSs and discover new therapies. With the dog’s life span being substantially shorter, the ability to gather data and reach a conclusion regarding the efficacy of a treatment can be achieved in a significantly shorter time period.Currently, dogs too are treated with surgery, radiation therapy, and sometimes chemotherapy. The primary treatment modality in dogs is also surgery when feasible. Because of the invasive nature of many STSs, curative-intent surgeries are aggressive. Typically, a wide or radical excision is necessary for a complete excision . Wide exin vitro may not fully represent the tumor they originated from. The conditions in vitro are significantly different than the original conditions in vivo and undoubtedly a selection of cells occurred in vitro. In the dogs, the tumors being spontaneous, they possess the full heterogeneity of a natural tumor; (3) the dogs have an unmodified immune system. The state of the immune system is considered natural. The immune system may be able to interact with some of the treatments and affect response, for better or worse; (4) pet dogs share our environment and to some extent our lifestyles. The conditions in which pet dogs live in are not tightly regulated as they are for rodents and therefore not as artificial. This might have an impact on the response to a treatment; and (5) the size of a dog makes it such that the instruments and supplies used to diagnose and treat them are the same as they are in children and young adults. The size of a Chihuahua dog is similar to a baby  and the size of a Great Dane or Mastiff is the same as an adult (150–230 pounds). When performing imaging, surgery, radiation therapy, or chemotherapy, for example, in dogs, the same instruments and supplies are used as for humans. Therefore, the same limitations exist for dogs as for humans that are related to these instruments and supplies.But is the dog a good translational model? While some canine tumors have been described as a good translational model, with osteosarcoma being the classic example , substanFor dogs, STSs have conventionally been grouped together because of their similar biologic behavior and shared prognostic factors , 8, 19. While the convention has been to group all STSs together in dogs because of a shared biologic behavior and prognosis, there is evidence that the histologic type can have a prognostic significance. In dogs, neurofibrosarcomas, fibrosarcomas, and myxomas appear to have higher rates of local recurrence, whereas perivascular wall tumors have a lower rate of local recurrence , 23–25. Another unifying feature is that most STSs have peripheral compression of their cells, creating a pseudocapsule. The histologic evaluation of the pseudocapsule in human STSs has demonstrated varying integrity of this pseudocapsule with penetration by the tumor through the pseudocapsule increasing with tumor grade. The peripheral growth pattern of the tumor has been described as either pushing or infiltrative . The pusBut in some respects, our knowledge of STSs in dogs is limited compared to that in humans. Arguably, the most flagrant limitation and difference is the classification of STSs. In humans, STSs are separated into over 50 different subtypes by histological and molecular classifications , 31–33. Another difference between the classification of canine and human STSs is the diagnosis of undifferentiated sarcoma. Whereas the diagnosis of undifferentiated sarcoma has been in use in veterinary medicine for a while , 35, thiThe features that will likely be very helpful to correlate canine and human tumors are genetic aberrations. Included in the latest publication on the WHO classification of human tumors of soft tissues are molecular genetic and cytogenetic characterizations. The inclusion of these features has been credited for allowing “more reproducible diagnosis, a more meaningful classification scheme, and provides new insights regarding pathogenesis” . The latCOL1A1-PDGFB gene fusion found in human dermatofibrosarcoma protuberans was found in a dermatofibrosarcoma protuberans-like canine tumor, with the equivalent fusion found being COL3A1-PDGFB in the dog Develop large-scale tissue banking and establishment of canine tumor cell lines: at what is arguably the largest tumor tissue bank from a single site, the Flint Animal Cancer Center at Colorado State University had STS samples from 219 dogs as of September 2017. Of these, 157 samples were available in RNA snap, 139 were preserved in RNA later, and 139 had at least 1 fresh frozen tumor sample available. The Canine Comparative Oncology and Genomics Consortium (CCOGC) is another resource for collecting and preserving canine biospecimens. The CCOGC has been able to provide canine STS samples for studies and will undoubtedly continue to play a key role in collecting and preserving tumor samples.(B)Perform large scale molecular genetic and cytogenetic analyses of the different canine histologic types and of different grades for each.(C)Improve the classification of STSs in dogs, which will have to include genetic and cytogenetic data to better parallel the human classification and allow comparisons and pairing with human tumors.(D)Determine the prognostic significance of this improved classification in dogs.To find out if the dog is a relevant translational model for STSs, important steps are required to achieve this goal:Arguably, the single most important bottleneck in achieving these goals thus far has been the limited funding. Financing these studies may turn out to be an investment in the longer run. If and when the dog has been deemed a relevant model, the pediatric and veterinary medical communities will collaborate closely to enable designing and conducting large scale clinical trials in dogs. The Comparative Oncology Trials Consortium (COTC) would likely play a major role. The COTC is an active network of 22 academic comparative oncology centers, which are managed by the NIH-NCI-Center for Cancer Research’s Comparative Oncology Program. Its mission is to design and execute clinical trials in dogs with cancer to assess novel therapies, with the goal to generate data to help development of their future use in human cancer patients.Investigating STSs in dogs to a greater and deeper level than has currently been done to ascertain if the dog is a relevant translational model will undoubtedly benefit the dog as we will gain a better understanding of these tumors. Should the dog turn out to be a good to excellent translational model, then testing new therapies in dogs will become justified and children and AYAs are likely to benefit from this approach. And in testing new therapies, our pet dogs will also benefit from these clinical trials, not to mention their human owners. With approximately 44% of all households in the United States having a dog , this wiThe author confirms being the sole contributor of this work and approved it for publication.The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To evaluate new mouth rinse containing sea salt, xylitol, and lysozyme on biofilm formation and gingival health in a group of young adults.  The subjects were divided into two groups of 15 subjects each: control (A) and experimental group (B). The Turesky modification of Quigley-Hein plaque index was used to evaluate plaque scores while the presence or absence of gingival bleeding was used to determine gingival health. Measurements were done at baseline and at the end of the one-month trial period by one blinded examiner on six representative teeth. Group (A) maintained standardized oral health practices for the duration of the experiment. In addition, group (B) rinsed with a tablespoon of the provided sea salt mouth rinse for 30 seconds once in the morning and at night. After the 30-day trial period, subjects in both groups were reassessed as per baseline. Results. There were no statistically significant differences in the overall reduction from baseline in the mean plaque and gingivitis scores on all surfaces or on individual surfaces.  Within the limitations of the study, rinsing with sea salt for thirty days did not affect the gingival and plaque scores in a group of young adults. Chronic gingivitis is a common inflammatory condition affecting a large population of the world and could lead to the development of periodontitis and eventual loss of teeth , 2. As cThere is, therefore, a need for newer, cost effective, and tissue friendly rinses that can be used long term as an adjunct to standard oral hygiene methods. Salt water rinses have been traditionally recommended for use postoperatively, mainly after extractions, for periodontal and other oral infections, and for patients with alveolar osteitis –13.The alleged beneficial effects of salt water rinses include promoting uncomplicated healing by inducing vasodilation and facilitating phagocytes to the site of injury, lowering the bacterial load by slightly alkalizing saliva, and acting as an astringent and as a bacteriostatic agent , 11. DesA sample of 30 participants, aged 20–26 years of age, were randomly selected (obtained from random.org) from among first and second year students currently enrolled at the College of Dentistry, University of Saskatchewan, Saskatoon, Canada. The inclusion criteria were as follows: being dentate, medically healthy, no orthodontic bands, and an anticipated ability to attend the two scheduled visits. Exclusion criteria included: a significant medical condition , pregnancy, and a recent history of, or ongoing, antibiotic therapy. All potential subjects were screened prior to the exam and selected as per the inclusion/exclusion criteria. The study was conducted in full accordance with ethical principles and with the approval of the University of Saskatchewan, Biomedical Research Ethics Board. Participants signed an informed consent form and were free to withdraw from the trial at any time. The experiment was designed as a randomized, single-blind study in which the subjects were randomly divided into two groups of 15 with group A being the control and group B the test.t-test. The level of significance was set at α  = 0.05.The clinical examinations were conducted at the Dental clinic, College of Dentistry, University of Saskatchewan by one of the investigators (ET) who remained blind throughout the study period. This examiner was trained and calibrated to ensure the accuracy of the recordings. The calibration was done on five subjects not involved in the study. The Turesky-Gilmore-Glickman modification of Quigley-Hein plaque index  was usedThe effects of rinsing the mouth with sea salt twice a day for a period of thirty days on plaque biofilm and bleeding on gentle probing the sulcus are shown in Tables Despite the lengthy practice of using saline solutions to manage selected oral conditions such as alveolar osteitis, acute mucosal lesions, and after minor oral surgical procedures, there are very little published clinical data attesting to its efficacy within the oral cavity. The present study involved the use of a mouth rinse consisting of sea salt, the antimicrobial enzyme lysozyme, and xylitol, a polyalcohol commonly used as a nonsugar sweetener, to determine its effect on plaque biofilm and gingivitis in a group of dental students.The few clinical studies investigating the effect of rinsing with sea salt have been mostly carried out in the Philippines and India , 18. MicThe current study, however, did not demonstrate any statistically significant difference in plaque scores or gingivitis scores (bleeding on gentle probing the sulcus) between those who rinsed for thirty days with a solution containing sea salt, lysozyme enzyme, and xylitol with those who did not, in a group of dental students attending the College of Dentistry, Saskatoon, Canada. Dental students were utilized as subjects as they were present on site and were able to attend all scheduled examinations. It was also presumed that the students would be more compliant to following instructions specially pertaining to rinsing twice a day with the provided sea salt rinse than the population at large. However, dental students, in general, incline to have better oral hygiene and are supposedly better motivated than the general population, and consequently any changes in gingival bleeding and plaque inhibition before and after therapy may be assumed to have been slight and hence could have influenced the results. In order to minimize this limitation, the sample was randomly drawn from 1st and 2nd year students who tend to have a poorer oral hygiene than their senior counterparts .Limitations of the present study also included the comparatively small sample size, the relatively short trial period, and possibly compliance issues within the test subjects who were provided bottles of the sea salt rinses to take home and were, therefore, unsupervised. Although written and verbal directions were provided, it is likely that some individuals may not have used the rinse as per instructions. In addition, the relatively short follow-up period of thirty days and the rinsing time of thirty seconds may have been not enough to produce a meaningful result and could be considered a limitation. This study was designed as a preliminary study to estimate the parameters for test and control measurements (plaque and gingivitis). Hence, it consisted of a convenience sample. Further, the time restraints (the study was conducted during the school term) and the cost involved to conduct the study using a larger population for an extend period of time also limited the sample size and the duration of the study. According to Connelly , extant Based on the current results, it appears that rinsing with a solution containing sea salt, xylitol, and lysozyme for thirty seconds, twice a day for a period of thirty days, has no significant benefit over brushing and flossing alone, on a sample of 30 dental students. However, considering some of the limitations of this pilot study and based on empirical information and traditional use of salt water rinses, further clinical studies must be attempted involving a larger sample size, subjects from the diverse population, and a longer trial period before any decisions could be made concerning its role as a therapeutic agent in the management of chronic gingivitis.


Science advice based on physiology is supporting harvest decisions for sockeye salmon by providing a mechanistic understanding for in river mortality. This success is a function of political will, clarity in management objectives, and science management integration. Uncertainty in results and institutional caution are major challenges for using science advice. Oncorhynchus nerka) and the increased understanding and quality of scientific advice that emerges. We submit that success in increasing the quality of scientific advice is a function of political motivation linked to funding, legal clarity in management objectives, collaborative structures in government and academia, personal relationships, access to interdisciplinary experts and scientific peer acceptance. The major challenges with advancing scientific advice include uncertainty in results, lack of integration with management needs and institutional caution in adopting new research. We hope that conservation physiologists can learn from our experiences of providing scientific advice to management to increase the potential for this growing field of research to have a positive influence on resource management.The inability of physiologists to effect change in fisheries management has been the source of frustration for many decades. Close collaboration between fisheries managers and researchers has afforded our interdisciplinary team an unusual opportunity to evaluate the emerging impact that physiology can have in providing relevant and credible scientific advice to assist in management decisions. We categorize the quality of scientific advice given to management into five levels based on the type of scientific activity and resulting advice . We argue that, ideally, both managers and researchers have concomitant but separate responsibilities for increasing the level of scientific advice provided. The responsibility of managers involves clear communication of management objectives to researchers, including exact descriptions of knowledge needs and researchable problems. The role of the researcher is to provide scientific advice based on the current state of scientific information and the level of integration with management. The examples of scientific advice discussed herein relate to physiological research on the impact of high discharge and water temperature, pathogens, sex and fisheries interactions on in-river migration success of adult Fraser River sockeye salmon ( The recent expansion of knowledge in the field of conservation physiology see  has led Much has been written about how different scientific disciplines create knowledge . In the Less familiar to researchers is the parallel, stepwise progression that fisheries managers commonly use ‘to learn’ about their environment in order to make informed decisions and develop policies Fig. . For manResearchers and managers are embedded in very different institutional environments, with different mandates, pressures and reward systems. Social science research has shown that scientists are most influenced by their community of peers. Career rewards in the form of research funding, promotions, reputation and influence are based on the system of peer review; a system that encourages scientists to speak predominantly amongst themselves and to communicate in ways that are most useful to peers rather than potential outside users of their knowledge and findings. Managers, on the contrary, are judged on their successful handling of real-world problems that involve a wide range of other actors, including politicians, bureaucrats, conservation groups, indigenous groups holding special rights and other users of the resources. In this complex institutional environment, managers draw on multiple forms of social and ecological knowledge, including personal and collective experience, professional judgement, intuition and direct observation, as well as scientific models and data  fisheries. This iconic salmon species is arguably the most culturally important and well-studied Pacific salmon in Canada  on in-river mortality of Fraser River sockeye salmon. The aim is to characterize the five levels of scientific advice and to showcase the recent emergence of physiology in connection with the quality of scientific advice. This recap identifies the conditions in the management and science realms that we associate with success in providing scientific advice at higher levels.In the second part of this paper, we discuss the current scientific advice given to management based on the physiological research into the role of pathogens, sex and fisheries interactions in understanding in-river mortality. The purpose of the second section is to showcase both the breadth of success in using conservation physiology and the current challenges for advancing the utility of this information for management. Our goal is to provide other conservation physiologists with an understanding of the steps that are likely to be involved in gaining management uptake of their research, based on our successes and challenges using the rich history of biological and physiological research conducted on Fraser River sockeye salmon. We recognize that local geopolitical, sociocultural and institutional norms will influence the extent to which the specifics described here apply, but we submit that the lessons learned and general approach described herein should be of broad relevance to those working in different jurisdictions on different species and issues.This section focuses on the historical progression of scientific advice related to water temperature and discharge that has been provided to management in response to high in-river mortalities of Fraser River sockeye salmon. For each level of scientific advice, we describe the type of scientific activity that has occurred and the resulting scientific advice that has been provided to managers through time. We also discuss the scientific and management activities that facilitate a higher level of scientific advice. These examples help to characterize our idealized model of scientific advice Fig. .The earliest written records of run failure associated with Fraser River sockeye salmon date back to catch records from the Hudson Bay Company in the 1800s . AlthougEstimates of these discrepancies over the past 20 years have a cumulative total net loss of 18 million fish. In comparison, 80 million fish were harvested and 70 million escaped to spawn during the same time period . These in-river losses represent substantial foregone opportunities for First Nation communities to access salmon for food, social and ceremonial purposes, limitations for angler participation, millions of dollars in lost revenue to the salmon fishing industry, reductions in spawners for other ecosystem values, and loss of future recruitment. Therefore, in-river mortality associated with adverse migration conditions provides a clear problem, for which researchers can provide scientific advice on likely factors and mechanisms contributing to mortality and, thus, speak to the efficacy of potential mitigation measures. We will describe some of the research and information given at different levels of scientific advice over the years in relationship to in-river mortality.The first level of scientific advice, and lowest level of veracity, in response to a management problem involves the simple generation of ideas based on the researcher's current knowledge base. This brainstorming is done without any direct empirical testing, before providing their best ‘notions’ to management, and is therefore subject to the potential cognitive frailties associated with any expert opinions . We are The next level of scientific advice requires researchers to formulate a testable hypothesis regarding their ideas and start fundamental  research. The scientific advice at Level 2 is based on the scientific ‘observations’ derived from this basic research. In our example, observations of delays and downstream mortalities in the Fraser Canyon were meticulously recorded by field experts during the major rock slides from 1911 to 1914 . It was Prior to the 1960s, there is almost no explicit mention of thermal impacts in relationship to adverse migration conditions for sockeye salmon  even thoThe third level of scientific advice is founded on the research results from more scientifically rigorous studies. This requires the researcher to work on generating biologically based descriptive models related to understanding the problem as identified by management and to present these model outputs (i.e. ‘descriptions’) to managers as scientific advice. In the case of the impacts of environmental conditions on in-river migration mortality, the continued challenge for researchers was to seek robust, scientific explanations for these in-river losses. In the 1960s, it became clear that high water temperatures, in addition to high discharge, during in-river migration were linked to natural mortality. It was the researchers within the agencies responsible for managing the fisheries who started a lot of the work on water temperature impacts on sockeye salmon physiology, examining the connections to disease , swimminThe involvement of our group with the research on Fraser River sockeye salmon migration problems in the 1990s was initially focused on high discharge and not thermal physiology. The aim was to describe swimming performance  and, ultToday, the direct and indirect physiological impacts of high water temperature comprise a large portion of the Level 3 scientific advice given to managers regarding the factors that impact in-river survival of Fraser River sockeye salmon. This research on thermal physiology has developed from historic pattern recognition of increasing high mortality events associated with high migration temperatures  to a focThe fourth level of scientific advice presents predictions of different outcomes to aid management in decision-making. This means moving from descriptive models focused on an improved biological understanding to predictive models, complete with an estimate of uncertainty , in Article VI, Annex IV, Chapter 4 (10), to prevent overfishing by both countries. The treaty states that spawning escapement goals are a clear management objective of the agreement, and there is a clear mechanism to incorporate scientific advice into the process, as stated in Article VI, Annex IV, Chapter 4 (13b): ‘incorporate … management adjustments [harvest changes] that deal with environmental conditions  during in-river migration that could significantly impact the Fraser River Panel's ability to achieve spawning escapement objectives’ . This leThe descriptive models used in generating Level 3 scientific advice are about understanding biological relationships between adverse migration conditions and in-river mortality. The model selection criteria typically rely on biological realism , model fit and model sensitivity. The main target audience for descriptive models is other researchers (i.e. for primary publication), whereas the predictive models, such as those described herein, are built for applied management purposes. As such, the developers of predictive models that forecast events for managers have to consider some key additional features in model selection, including model predictive power (e.g. bias and precision), forecasting constraints for predictor variables (e.g. water temperature and discharge forecasting) and management constraints (e.g. lead time to adjust fish harvest). The last of these features reflects the fact that predictive models are built to predict the outcome of different management responses within a realistic set of conditions. In the case of Fraser River sockeye salmon, in-season harvest adjustment models that use water temperature as a predictor variable must rely on forecasted temperatures . This isCommunication’ section below). To get to this point, scientists and managers worked together to create a management prescription to outline how scientific advice on the impacts of water temperature and discharge on sockeye salmon mortality (in the form of model predictions) can be used in harvest planning. For Fraser River sockeye salmon, this involved adjusting harvest plans pre-season, using long-range forecasts of summer water temperatures and discharges in in-river loss models  annual stock assessment spawning ground enumeration studies, assuming a 50:50 ratio for salmon starting the spawning migration; however, annual information on variation in sex ratios of adults returning to the lower river are limited . The ratOur next example uses capture-and-release mortality research to show a more direct connection between the researchers and managers in moving advice from Level 3 to our current attempts to provide Level 5 scientific advice. During the past 10 years, we have focused a large portion of our efforts on understanding the fate of Pacific salmon released after capture, using physiology to elucidate the mechanisms behind lethal and sub-lethal responses , b. MajoPredictions of capture-and-release mortality associated with different fishing gear and at different temperatures have been generated based on field telemetry and holding studies that couple survival and physiology. For example, this work has shown that long-term mortality rates for beach-seined and angled sockeye salmon range from 20 to 30% during average summer water temperatures of 18°C . HoweverThe time line for managers and researchers to develop a management prescription and start applying new scientific advice at Level 5 will vary. The new research behind the post-release mortality rates for sockeye salmon  basis for how different factors impact fishing-related mortality, as well as a review of the mortality rates themselves. In other words, the official scientific advice will be based in large part on the ability of physiologists to explain why certain factors, such as injury, air exposure, handling time, capture time and revival methods, are important in generating estimates of fishing-related mortality (reviewed by Scientific advice is not being given in a vacuum; meaning that this information will disseminate beyond the initial management audience, and therefore, it is important to be cognisant of the interpretation and use of this information by different groups. A communication plan is likely to be essential for success at the fifth level, but ideally it should be initiated the first time that managers and researches begin to exchange information and be the responsibility of both managers and researchers. The first priority for communicating research results is to satisfy management requirements, but researchers cannot be naïve to how other groups, such as the media, environmental groups, scientific community and fishing groups, can accidently misinterpret or deliberately spin the results. Misrepresentations can potentially derail the ability of managers to use physiological research, as exemplified earlier with the focus on upper lethal thermal limits , becauseThe reasons for the success of our work include political motivation, funding, accountability, legal clarity, institutional environment, personal relationships and peer acceptance. For example, fisheries management recognized the potential problem of temperature-based in-river loss after a series of high-profile reviews in the early 1990s  and agaiThe major challenges to providing scientific advice beyond Level 3, the simple descriptions of nature, are rooted in the different demands of science and management. Scientists are rewarded based in large part on developing novel scientific explanations for how the world works . TherefoThe temperature- and discharge-based mortality models are an exception in that we have performed retrospective evaluations of model performance at the behest of management (


Glucose concentration in the blood stream is a critical vital parameter and an effective monitoring of this quantity is crucial for diabetes treatment and intensive care management. Effective bio-sensing technology and advanced signal processing are therefore of unquestioned importance for blood glucose monitoring. Nevertheless, collecting measurements only represents part of the process as another critical task involves delivering the collected measures to the treating specialists and caregivers. These include the clinical staff, the patient’s significant other, his/her family members, and many other actors helping with the patient treatment that may be located far away from him/her. In all of these cases, a remote monitoring system, in charge of delivering the relevant information to the right player, becomes an important part of the sensing architecture. In this paper, we review how the remote monitoring architectures have evolved over time, paralleling the progress in the Information and Communication Technologies, and describe our experiences with the design of telemedicine systems for blood glucose monitoring in three medical applications. The paper ends summarizing the lessons learned through the experiences of the authors and discussing the challenges arising from a large-scale integration of sensors and actuators. Tight monitoring of blood glucose levels is of capital importance for keeping this key physiological parameter under control, and is needed in a number of medical applications encompassing the treatment of diabetes and the management of intensive care therapy, which are briefly described in the following.Dexcom G5 CGM sensor as a substitute for glucometers based on fingerstick tests [Diabetes is a family of chronic diseases affecting an ever increasing number of patients. According to the World Health Organization, the worldwide prevalence of diabetes was 422 million adults in 2014, increasing from 108 million in 1980  is causeAvoiding hyper- and hypo-glycemia is very important also in critically ill patients, such as those admitted in intensive care units. In these cases, the need arises to adopt a suitable algorithm for the regulation of glucose infusion based on CGM to improve glycemia control and prevent large BGL oscillations as well as hypo- or hyper-glycemia episodes. For example, failure to achieve a proper glucose control in preterm newborns is associated with an impaired neurological development only observed during the second year of life , while iEffective sensing technology and advanced signal processing techniques are certainly of capital importance to attain an effective blood glucose monitoring. Nevertheless, collecting measurements only represents part of the process, since other essential tasks are delivering these measures and/or any related alerts to the several actors involved in the blood-glucose management process. Those actors include the clinical staff responsible for planning and administering the therapy, the parents of pediatric patients or the significant others of adult ones. Despite being located far from the monitored patient, these people need to be kept up to date with his/her conditions in order to undertake the most appropriate actions. A remote monitoring system, by taking care of the delivery of any relevant information to the right players, becomes an important part of the sensing architecture.In this paper, we emphasize the advantages of remote monitoring, illustrating the technological components required to implement it. We start recalling the evolution that occurred within the Information and Communication Technology (ICT) architectures for acquiring data from patients and sending them remotely for perusal or analysis. Although we provide examples mainly concerning glucose monitoring or diabetes management, the applicability is rather general as they may be effectively exploited in different clinical contexts as well. We also illustrate some projects carried on by the authors where glucose sensors and insulin pumps have been integrated into a remote monitoring architecture operating in real time. Differences will be highlighted among systems addressing various patient populations, such as adults, children and newborns. The paper ends with a discussion on the lessons learned by the authors and the current trends for deploying remote monitoring solutions on a large scale.Even though remote monitoring has not entered the routine clinical practice yet, during the past few decades, several projects have been developed in different clinical contexts exploiting it for research purposes. During this time period, the dramatic progress occurred in ICT has deeply affected the way in which remote monitoring is accomplished. In the following section, we review the evolution of the main architectures that have been used over the years to collect data from patients, with particular emphasis on glucose and diabetes monitoring context.The first prototypical systems attempting a systematic collection of data from diabetes patients started to appear in the late 1990s . The limThe strict separation between the PU and MU was dictated by the discontinued nature of the connection and the need to render each component independent from the other one. This separation also allowed additional services to be easily integrated into each component since both stored patient data locally. As a matter of fact, it soon became clear that, for remote monitoring systems to be effective, besides just offering plain data collection, they had to show a proactive behavior processing those data at the knowledge level ,17,18. TThe strong distinction between PU and MU faded during the first decade of the new century, as telemedicine services began to be deployed over stable network connections, eventually accessed through mobile devices such as smartphones  that werThe switch to the SOA paralleled the PDAs gradual demise. In fact, since PDAs were mainly connectionless devices, they could not stand the widespread availability of network connections. However, despite smartphones were hailed as the successors of the PDAs, during the first decade of the current century, they had very poor computational power and limited display capabilities that made an immediate replacement of PDAs almost impossible. Thus, it was not unusual to observe some blending of SOA with older architectures depending on the devices used .Diabeo system [2DMM project [Roche Acculink system. Despite the latter was a closed system using a proprietary modem technology, it simplified the remote transfer of patient data fully preserving the SOA paradigm in that project. Incidentally, we may note that glucose sensors lag far behind current ICT standards usually found in other appliances, and, in most cases, they are not compliant with those standards at all. As a matter of fact, across the first decade of the century, glucometers even lacked basic Universal Serial Bus (USB) or wireless capabilities and their interfacing occurred just through serial connections or dedicated infrared transceivers hooked up to the PC serial port. Eventually, by the end of the first decade, some projects began to use smartphones for encapsulating specific services on the patient’s side, such as alerts and reminders [LifePhone project [The early versions of the o system , for exa project  represeneminders , therefo project .Body Gateway shown in Bluetooth with the Network Hub, usually a smartphone, which is the key for enabling network connectivity and enacting the remote monitoring that is the subject of this paper. A BAN architecture may be instantiated with minimal work to support several scenarios exploiting different devices in various medical contexts [Rather interestingly, the improvements in ICT caused once more a paradigm shift concerning data collection and upload. The need to acquire signals using multiple sensors attached to the body, and possibly operate on it through different actuator devices led to a new architectural schema known as Body Area Network (BAN) . BANs arcontexts ,30.AndroidTM smartphones is suitable for running even complex algorithms. Moreover, smartphones may also be effectively used as functional input devices thanks to their valuable displays besides still acting as Network Hubs for the telemedicine services. Thus, they are being increasingly used as prototyping devices with enhanced graphic capabilities that are available at a cost much lower than the one required for designing a custom new board from scratch. When a smartphone is used according to this paradigm, besides acting as a Network Hub, it also plays the role of a Body Gateway, with both components coalescing into a single device. However, when this solution is implemented, all the body connected devices must be capable of communicating using Bluetooth technology, since this is the only short range wireless technology supported by smartphones. An interesting example is given by the Diabetes Assistant (DiAs) [AndroidTM smartphone used for implementing an Artificial Pancreas. The DiAs will be better described in Incidentally, we observe that the computational power of modern t (DiAs) ,32, whicRoche Diabetes Care GmbH  was the first company to sell a complete remote monitoring system with their Acculink. This was essentially a proprietary modem that allowed patients to regularly send data from their Accu-Chek glucometers to their doctor’s office even without owning a PC. Roche also provided the application to be installed on a server at the clinic for receiving and storing the patient’s data, therefore ensuring a better follow-up by doctors among scheduled visits [The architectures for remote monitoring have evolved over the years, as described in d visits .DiaSend , which started its business in 2006 offering integration capabilities for all the major glucometers on the market in addition to many insulin pumps. The patient may use either his PC or his smartphone to download data from the devices and upload them onto a remote server managed by DiaSend so that they become easily accessible to the clinical staff. The company claims that almost 2000 clinics worldwide have already made arrangements with them and nearly 350,000 patients are regularly using it.Currently, almost any manufacturer supports downloading data from their glucometers. However, this still happens through different proprietary protocols that prevent the actual integration of data into a single application. Moreover, manufacturing companies are not interested in running remote monitoring services by themselves. Those problems were recognized by ®iBGSTAR produced by Sanofi , which is essentially a glucometer implemented as a hardware plugin for the smartphone. It is a very small piece of hardware that fits the iPhone or iPod docking connector and allows for measuring BGL using test strips. The hardware has a very small display that comes in handy just to preserve its usability as a standalone tool. However, the ®iBGSTAR is best used in combination with the Diabetes Manager app, also from Sanofi. This app allows for importing BGL readings into the smartphone where they may be complemented with additional information manually provided by the patient concerning meals, insulin delivery, physical activity, drugs taken or notes. The application gives then a complete overview of the patient’s state since it allows searching for specific events and produces charts and statistic diagrams.Smartphones have been also increasingly exploited by manufacturers to simplify the acquisition of BGL measurements and import their values into the digital ecosystem. An interesting example is provided by Dexcom Inc.  with their G5 Mobile CGM System. This system encompasses two different smartphone applications, the Mobile/Share App and the Follow App. The former is installed on the patient smartphone and displays real-time glucose data and trends directly. Using this app, the patient may designate up to five people as followers, thereby including caregivers, clinical staff, family members or significant others. Once those people have installed the Follow App on their smartphones, they will all receive in real time the CGM readings and will be notified about critical situations occurring to the patient in order to possibly undertake actions.A different remote monitoring paradigm is being adopted by Nightscout Project [CGM in the Cloud and eventually turned into The Nightscout Foundation [Nightscout is able to interface and acquire data from sensors manufactured by Dexcom , Medtronic  and Abbott (FreeStyle Libre).The need for a monitoring platform that overcomes the inherent limitations of proprietary protocols is probably best witnessed by the  Project , which wundation  in 2014.During the past several years, the authors have been involved in the development of several telemedicine systems. These systems have been used in important clinical trials for remotely overseeing blood-glucose control. In this section, we summarize our experiences focusing on three projects, each one having different features and, in particular, different recipients of the information generated by the blood-glucose measurement devices.Since 2007, our group has been active in the design and testing of a closed-loop strategy for the treatment of T1D in adult patients, the so-called Artificial Pancreas (AP). The AP  is a minAP@home project, an initiative funded by the European Union within the 7th Framework Programme aimed at designing and implementing the AP [Since 2010, we have been part of the g the AP . During g the AP . The stug the AP , and eveg the AP . This fig the AP ,43. Thesg the AP , was fung the AP , the brig the AP . Howeverg the AP . Out of g the AP . Also inThroughout all of these trials, the main users of the telemedicine system were the members of the clinical team and the bioengineers overseeing the study. The effectiveness of the remote monitoring system was assessed after each trial, resulting in a close collaboration among clinicians and bioengineers, with the goal of improving it. Over time, summary panels were added to allow a prompt recognition of the situation by the staff; visual and audible alarms were implemented to immediately draw user attention whenever required; and the detailed patient chart was improved tracking additional events such as exercises, stress tests, notes, etc. Eventually, an additional component was developed sending summary messages or alarms to the staff phones, which were used as pagers. This was particularly useful during longer trials scheduled near the end of the project, when the supervision by the staff around the clock was no longer affordable.AP@home project, the main users of the telemedicine system remained the members of the study team, we took the opportunity to investigate the patient perception of the usefulness of that tool. For this purpose, we administered ad hoc questionnaires about the assistance time required in case of complications, the quality of patient–physician communication, the reduction of control visits in terms of number and costs, the perceived serenity and safety, and the amount of money that patients would be willing to pay for the system. In nearly 80% of the answers, patients highlighted positive feelings towards the service. However, after comparing questionnaires administered during the hotel trials with those occurring at home, it emerged that, in the latter case, patients were more uncertain about the usefulness of the system. The increment in the percentage of answers expressing uncertainty, increasing from 3% at the hotel to 17% at home, could be due to the need of being more tightly monitored perceived by the patients when they are at home.Although, for the AP@home project development, paralleling the improvements on the AP, to reach the level of functionality and reliability required for the main trial at home. A detailed description of that evolution and the performance of each hardware configuration adopted is provided in [AP@home is reported in DiAs [Body Gateway and Network Hub.The hardware used for remote monitoring was upgraded several times during the vided in . The fin in DiAs  as the cDiAs is a smartphone-based AP platform capable of running the control algorithm. To ensure the operation of the smartphone as a medical device, the Linux kernel of its operating system  was modified to remove any application not related to the study; prevent the installation of external applications from the store; forbid its use for issuing voice calls or surfing the web; and include self-checks concerning system integrity. The smartphone adopted for the study was a Nexus 5 by LG Electronics  offering state-of-the-art Bluetooth wireless connectivity that was used for directly interacting with the peripherals: the CGM sensor and the insulin pump. Thus, according to this configuration, the smartphone acted as Body Gateway.The Roche Accu-Chek Spirit Combo by Roche Diagnostics GmbH , that natively offered the possibility of being wirelessly controlled using Bluetooth. However, the CGM of choice was the Dexcom G4 Platinum by Dexcom, Inc. , which only provided a USB port and lacked Bluetooth connectivity. To overcome this problem, a USB to Bluetooth Low Energy converter  of the University Hospital in Padova. Since preterm newborns are fragile patients, heel pricks for taking blood samples may not be as frequent as required, and the probability that hypo- or hyper-glycemia episodes will go undetected is much higher than in adults. To overcome the problem, the NICU started investigating the effectiveness of using CGM sensors to support the best practices for calculating glucose infusion rates based on the literature [Neokid is therefore to enforce remote monitoring of blood glucose values on those patients and automate the computation of the infusion rates, suggesting in real time the most appropriate values to the NICU staff. Moreover, all the neonates at the NICU are monitored and their data are displayed on a central monitoring station alerting the staff whenever an alteration of any vital parameter is noticed. This is crucial in an eventful setting, such as the NICU, where centralized monitoring facilitates the simultaneous analysis of multiple parameters and is essential for properly driving clinical decisions. Unfortunately, there is still no commercial equipment available addressing the acquisition of CGM data and making them available on the ward control panel. Before Neokid, CGM was accomplished through separate glucometers lying on cradle drawers and their readings could only be acquired when some member of the staff visited each cradle. Thus, Neokid also helps in integrating CGM data for all patients on a single PC display, tracking any clinical alteration or maneuver. Besides the plain acquisition of CGM values, Neokid also allows for annotating events such as rest, intraventricular hemorrage, acidosis, pneumothorax or pain and to correlate their occurrences with CGM values during data analysis.The last project developed by the authors early in 2016 and still under way is terature  and compNeokid project, the chosen CGM device is still the Dexcom G4 Platinum with Share. Thanks to the release by Dexcom, Inc. of the protocol for communicating via Bluetooth Low Energy with the receiver, the authors developed a telemonitoring application running on a smartphone. This application replicates in real time the information sent by the Dexcom G4 Platinum with Share and relays these data to the remote monitoring server using a 3G/UMTS/WiFi connection. The server includes a web application, similar to those already discussed in the previous sections, which makes data available to nurses and doctors on a PC located in the ward room of the NICU. An additional component has also been developed to accomplish the calculations of the glucose infusion rates adopting an algorithm published in the literature [For the terature .Neokid system is shown in The functionality of the main components developed for the Neokid project is an interesting example of the advantages that may be achieved when software design issues enforce modularity and reusability. First, we were able to reuse the whole web application already implemented for the AP@home project with very limited changes. Moreover, even though the web application was mainly meant to be accessed in the ward, thanks to its generic availability on the Internet, doctors could make use of it also from their offices, and sometimes even from home. Finally, knowledge of the protocol for interacting with the CGM devices is essential, and, when it is disclosed by the manufacturers, custom applications may be successfully implemented in very short time periods.The In this paper, we reviewed the evolution of the architectures adopted for the remote monitoring of glucose and diabetes data over the past few decades. We also illustrated our experiences in developing some telemedicine systems that were used for overseeing the operation of AP devices in adults or adolescents and for centralizing the management of blood glucose infusion rates in preterm newborns treated at the NICU. Based on those experiences, we observed that the integration of portable medical devices into remote monitoring architectures poses several issues. The first one is related with the design and development of new medical devices. We know that this process is inherently very long, mainly due to the several regulatory steps required to ensure its safe use on patients. Since, on the contrary, the evolution of ICT technologies occurs at a much faster rate, a possible solution for being successful with this integration is to take into account some sort of backward compatibility. This should be accomplished with the twofold purpose of interfacing with devices still based on old technologies and standards but quickly moving to more recent ones as soon as the devices are updated. We followed this approach exactly in our projects concerning the remote monitoring of AP devices, frequently updating the architecture over a limited time period to support its interfacing with devices using each time updated technology standards, as described in A second issue is that, differently from the ICT market, a plug-and-play approach for medical devices faces several further challenges, especially for what concerns the safety of the final system and the liability in case of errors. While, in the past, the connection among medical devices mainly occurred through wires and just required a basic serial protocol, the adoption of wireless connectivity opened up new security issues that had to be properly addressed. Security and encryption protocols are already available and regularly used in a transparent way in modern ICT applications. However, they require extensive memory and computational capabilities that are still unsuitable for resource limited devices such as CGM sensors and insulin pumps . MitigatAnother issue is related to the importance of taking care of the final users of a system. Once the prototype has been completed and safety issues have been addressed and verified, developers should deeply consider suggestions coming from the actual users in order to make their system more targeted to its final context of use . This beAs for the methodological standpoint, the large amount of data generated by the automatic feed of a multitude of sensors, such as those envisioned by the Internet of Things , is expeIn summary, we observe that the rapid development of a large variety of affordable portable medical devices, like insulin pumps and CGM sensors, and the ubiquitous availability of networking resources, are enabling new paradigms of care in which remote monitoring becomes a key feature for enforcing safety during outpatient studies . The tec


Recently, with the development of artificial intelligence technologies and the popularity of mobile devices, walking detection and step counting have gained much attention since they play an important role in the fields of equipment positioning, saving energy, behavior recognition, etc. In this paper, a novel algorithm is proposed to simultaneously detect walking motion and count steps through unconstrained smartphones in the sense that the smartphone placement is not only arbitrary but also alterable. On account of the periodicity of the walking motion and sensitivity of gyroscopes, the proposed algorithm extracts the frequency domain features from three-dimensional (3D) angular velocities of a smartphone through FFT (fast Fourier transform) and identifies whether its holder is walking or not irrespective of its placement. Furthermore, the corresponding step frequency is recursively updated to evaluate the step count in real time. Extensive experiments are conducted by involving eight subjects and different walking scenarios in a realistic environment. It is shown that the proposed method achieves the precision of  With the rapid development of MEMS  techniques and wireless communications, the smartphone as a research platform is attracting more and more attention in both academia and industries due to its merits in the following aspects: easy to carry, ubiquitous operations, rich sensing abilities, etc. Moreover, with the ample motion sensors  embedded in commercial off-the-shelf (COTS) smartphones, there have emerged an abundant of motion related applications, including tracking and positioning, activity recognition, health monitoring, augmented reality systems, and so on.Nowadays, the tracking and positioning service based on GPS  has become a killer application on smartphones, but is usually out of service in indoor environments on account of the blockage of GPS signals. As such, a variety of alternative technologies ,2,3,4,5 Therefore, various walking detection and step counting methods have been developed based on one or both of the following two physical phenomena: the moment when the same heel of a pedestrian strikes the ground once during each gait cycle results in a sudden rise in accelerations ,20,21,22Among existing studies, most of them adopt accelerometers that are cheap and equipped in almost every COTS smartphone, and the others adopt gyroscopes that are relatively expensive and were not equipped in low-end smartphones a few years ago. Gyroscopes and accelerometers measure the first-order and second-order features, respectively, indicating that gyroscopes are able to capture more precise motion information than accelerometers. Moreover, since walking motion results in cyclic signals as mentioned above, the frequency domain features are intuitively more suitable than time domain features as far as walking detection is concerned.This paper deals with walking detection and step counting in a practical scenario in which the placement of a smartphone can be arbitrary and also alterable during walking, and proposes a novel algorithm by employing a gyroscope and extracting frequency domain features of the three-dimensional (3D) angular velocities returned by the gyroscope. To be specific, fast Fourier transform (FFT) is adopted to quickly derive the spectrum of the Euclidean norm of 3D angular velocities; a thorough experimental analysis illustrates distinct characteristics in the spectrum irrespective of the smartphone placement, motivating us to design a thresholding technique to decide whether walking is being performed. On these grounds, walking frequency can also be estimated given the spectrum result, so that the steps can be indirectly counted by multiplying the walking frequency and its duration. Finally, extensive experiments are carried out by inviting eight subjects in different realistic scenarios, and a comparison is made by involving both existing well-known algorithms as well as popular commercial products. It is shown that the walking detection accuracy of the proposed algorithm can be as high as The contributions of this paper can be summarized as follows. First, we take advantage of gyroscopes and frequency domain features of walking motion to identify walking and count steps. Second, the experimental spectrum analysis reveals that the frequency domain features produced by unconstrained smartphones display similar characteristics, resulting that the proposed method is robust to different smartphone placement. Third, walking frequency is estimated and smoothed by using the spectrum information obtained by FFT, which simplifies the implementation of counting steps compared to other approaches like peak detection, autocorrelation, etc. Finally, extensive experiments are conducted by evaluating not only the well-known counterparts but also several popular commercial products.In general, the existing studies can be categorized into time domain approaches, frequency domain approaches and feature clustering approaches, which will be briefly reviewed in what follows.The time domain approaches include thresholding ,18, peakThe thresholding approach counts steps by judging whether sensory data satisfy some predefined thresholds that differ according to various devices held by different users at different positions. In , the autThe peak detection approach estimates steps based on the number of peaks given a sequence of sensory data, and does not rely on predefined thresholds, but suffers from interference peaks due to environmental noises and occasional disturbance. In , authorsSimilarly, the zero-crossing counting approach counts steps by detecting the number of zero points in sensory data, which is susceptible to disturbing sensory data and usually needs to filter and smooth original sensory data in advance. In , raw gyrThe autocorrelation approach detects cyclic periods directly in the time domain through evaluating autocorrelation , and is The frequency domain approaches focus on the frequency content of successive windows of measurements based on short-term Fourier transform (STFT) , FFT 3131, and cloyed in  too smooThe feature clustering approaches employ machine learning algorithms, e.g., Hidden Markov models (HMMs) ,38,39, KA fair and extensive comparison has been made among various techniques in a practical environment in , and shoTo sum up, even though great efforts have been invested, it is still challenging to detect and count steps with unconstrained smartphones in an accurate and efficient manner. In this paper, we adopt the gyroscope that is becoming more and more popular in COTS smartphones and the efficient FFT method to implement a novel and practical method for simultaneous walking detection and step counting. Due to the advantages of the gyroscope and frequency domain approach, the proposed method relieves the restriction of most existing studies that assume the usage of smartphones in a constrained manner.The proposed algorithm firstly decides whether walking is performed based on the Fourier spectrum obtained by FFT because the frequency domain features are relatively stable no matter where a smartphone is placed and incur slight changes with regards to different users walking in various situations.Differently from most of the existing algorithms that rely on accelerations, the proposed algorithm utilizes angular velocities measured by the gyroscope embedded in COTS smartphones, due to the following aspects: (1) the gyroscope is more sensitive and more accurate than the accelerometer; (2) accelerations suffer from jitters and local minima, whereas angular velocities are smooth and in a good cyclicity regardless of the smartphone placement; and (3) angular velocities normally oscillate around zero during walking, as shown in Additionally, on the basis of spectrum information, the walking frequency can be instantly estimated with respect to every user in different situations, such that the steps can be adaptively counted by multiplying the walking frequency and walking duration. Since it is unnecessary to detect and count specific peaks or zero-crossing points that are severely polluted by noises, relatively accurate step counts are expected.The flow diagram of the proposed algorithm is illustrated in The walking detection part relies on sliding time window, selecting the sensitive axis and spectrum analysis, which will be elaborated in what follows.In order to continuously detect walking activities, the algorithm is designed on the basis of a sliding time window. As suggested in , the typMoreover, according to the Shannon Sampling Theory, it is sufficient that the sampling frequency is more than two times the maximum walking frequency. As such, by trading off the energy consumption and minimal sampling frequency, the sampling frequency is set to be 20 Hz.Since the base-2 FFT algorithm is adopted, the number of instances in each time window is the power of 2, so that it is reasonable to let the time window include 64 instances, with the result that the corresponding duration at the sampling frequency of 20 Hz is Supposing that a smartphone holder is asked to perform an identical activity repeatedly, it is true that the 3D data derived by the gyroscope of the smartphone in the device reference frame demonstrate different characteristics according to the position and attitude of the smartphone, as shown in a with i within the current time window, and N is the size of the time window and equals 64.The measurements of the gyroscope incur constant bias, thermo-mechanical white noise, flicker noise or bias stability, temperature effects, and calibration errors . In general, the measurement noises appear to be quite obvious when the measurements are relatively small, and, on the contrary, can be ignored when the measurements are huge. Therefore, it is advisable to select the axis whose data has the maximum magnitude. Moreover, regarding the walking activity, no matter where the smartphone is placed, certain cyclic features are always involved in all the 3D data. Inspired by the above analysis, we come up with the following simple method based on the absolute values of the 3D angular velocities to select the sensitive axis in the proposed algorithm, namelyBased on the above steps, we can determine the sensitive axis of angular velocities, and the corresponding data are fed into the process in this step.n-th point after transformation, denoted FFT is applied to transform the time domain angular velocities into the following frequency domain dataIn order to investigate the influences of different activities, the spectrums of the angular velocities with respect to six usual activities are plotted in As can be seen from Additionally, the spectrums of the angular velocities produced by switching among different smartphone placement  are plotted in Inspired by the observation, we propose identifying walking activities by comparing the amplitudes of different frequencies. Specifically, the average amplitude within the typical walking frequency range   5) are st), namelyc denotes the step count.As mentioned perviously, the proposed method count the steps by multiplying the walking frequency , which are vulnerable to noises, with the result that both the computational overheads and step counting accuracy are improved. To do so, the step counting part is composed of three steps, i.e., increasing the walking duration, estimating the walking frequency and counting steps, as illustrated in In the first step, as long as the walking activity is identified in the current time window, the walking duration is increased by summing A is the amplitude, f denotes the frequency, and e are constant coefficients with In the second step, the walking frequency is estimated on the basis of the spectrums obtained in the walking detection part. In general, during the walk of a smartphone holder, the walking frequency should correspond to the maximum amplitude in the resulting spectrum. However, since the frequencies in the practical spectrums are quantized, directly assigning the frequency with the largest amplitude to the walking frequency is definitely inaccurate and unacceptable. Therefore, the curve fitting technique is adopted to regress the most possible value of the walking frequency. Specifically, the following polynomial fitting function is establishedn varying from 2 to 6. After that, the frequency falling in this range and maximizing the amplitude A is returned as the estimate of the walking frequency.Since the walking frequency is generally between d to fit . As a red to fit  with thei-th time window, i-th time window, and Additionally, the weighted moving average filter is applied to smooth the estimate, namelyi-th time window can be determined using the walking duration t and the walking frequency In the third step, the accumulated step count after the rding to .In this section, extensive experiments are conducted and a thorough performance analysis is reported by comparing the proposed method with both existing well-known methods and commercial products.In the experiments, an app see a is deveIn the first scenario, every subject is asked to complete a sequence of different activities listed in In the second scenario, every subject is asked to perform different walking activities listed in Two well-known walking detection methods belonging to the time domain approaches and frequency domain approaches, respectively, i.e., thresholding based on the standard deviation of accelerations   and recall (denoted R) are evaluated as below:In order to have a clear knowledge about the performance of the walking detection methods, both precision  from walking activities, which cannot be done by the other two methods; in addition, the proposed method denies the other two non-walking activities with symbols B and C as walking, but its copy using acceleration cannot. However, the results are consistent with the overall results in A to be the step counting accuracy as follows:Define The accuracies of different step counting methods and products in the second scenario are listed in By taking into account of walking activities, it can be observed that the accuracies span a wide range between In summary, the experiments have verified that the proposed method is able to deliver superior performance in both walking detection and step counting under various complicated situations compared to the existing well-known methods and popular commercial products.In this paper, we proposed a novel walking detection and step counting method for users with unconstrained smartphones. Differently from most existing studies, the proposed method adopted the gyroscope data and extracted critical walking features in the frequency domain. Moreover, an indirect step counting method was reported by multiplying the walking frequency and the walking duration to mitigate the negative influences of random noises in the time domain. Finally, a thorough experimental analysis was presented by taking into account various complicated but real situations, and showed that the proposed method is able to achieve superior and stable performance in comparison with both existing well-known methods and popular commercial products. This work will not only benefit many existing relevant applications, but also accelerate the emergence of more applications relying on accurate walking detection and step counting. Regarding future works, we would like to apply the proposed method in smartphone oriented localization and navigation.The proposed method is applying for a patent and now has been handed over to the agency.


Apnea of prematurity (AOP) is one of the most common diagnoses in preterm infants. Severe and recurrent apneas are associated with cerebral injury and adverse neurodevelopmental outcome. Despite pharmacotherapy and respiratory support to prevent apneas, a proportion of infants continue to have apneas and often need tactile stimulation, mask, and bag ventilation and/or extra oxygen. The duration of the apnea and the concomitant hypoxia and bradycardia depends on the response time of the nurse. We systematically reviewed the literature with the aim of providing an overview of what is known about the effect of manual and mechanical tactile stimulation on AOP. Tactile stimulation, manual or mechanical, has been shown to shorten the duration of apnea, hypoxia, and or bradycardia or even prevent an apnea. Automated stimulation, using closed-loop pulsating or vibrating systems, has been shown to be effective in terminating apneas, but data are scarce. Several studies used continuous mechanical stimulation, with pulsating, vibrating, or oscillating stimuli, to prevent apneas, but the reported effect varied. More studies are needed to confirm whether automated stimulation using a closed loop is more effective than manual stimulation, how and where the automated stimulation should be performed and the potential side effects. Almost all infants born at <28 weeks gestational age (GA) or with a birth weight of <1,000 g are diagnosed with apnea of prematurity (AOP) –5. StudiThe etiology is related to the immaturity of respiratory control and poor myelination of the brainstem , 7 but t2) values  values . Also, a) values .Mechanical stimulation might improve the common used and effective tactile stimulation technique by enabling a direct response, as this will shorten the apnea hence reducing hypoxia and bradycardia. In addition, combining mechanical stimulation with the detection of imminent apnea could lead to preventive stimulation methods. The effect of mechanical tactile stimulation on apnea has been studied but has not led to implementation in the NICU or a commercially available device yet.We systematically reviewed the literature with the aim of providing an overview of what is known about the effects of manual and mechanical tactile stimulation on the termination and prevention of apnea in preterm infants.To identify convenient studies the online databases MEDLINE, PubMed, and Scopus were searched for English articles from 1970 to 2017, using the search strategy as described in Table All clinical trials reporting the effects of tactile stimuli on apnea in premature infants or animals were included in this review. Studies using devices that are believed to affect the breathing patterns by other forms of stimulation that involved a tactile component, like oscillating waterbeds, were included. Clinical trials examining the effect of stimulation of multiple senses on apnea were excluded. The same applied to articles comparing only the effects of tactile stimulation with stimulation of another sense. Abstracts or other forms of articles that are not primary research studies were also excluded. Two authors (Sophie J. E. Cramer and Arjan B. te Pas) reviewed the records for inclusion and exclusion criteria, and disagreements were resolved by consensus.Study characteristics from the included studies were identified using a data extraction form. The following data were extracted: author, year, study objects, study design, detection signals, stimulation mode, stimulation characteristics, duration, and main results.The search strategy led to 448 articles. Five additional articles were selected from the references of the studies that met the inclusion criteria. After elimination of the duplicates, a selection of 21 articles was made based on title and abstract. Another 6 articles were excluded following full-text assessment, resulting in a selection of 15 articles for this review . This difference was present during the whole experiment although stimulation was only administered 5 out of every 15 min. All four studies using a vibratory stimulus reported a significant decrease in apneic spells or breathing pauses  to the respiratory center remain unclear. It is postulated that tactile stimulation affects respiratory control by activating the brainstem reticular formation causing arousal . Ioffe eFurthermore, the effect of mechanical stimulation on the respiratory center is dependent on nerves that are targeted. The skin contains multiple sensory receptors, which are all most sensitive to a specific frequency range . The senIn 1975, Kattwinkel et al.  showed tin utero environment by activation of the somatic proprioceptors or the cutaneous receptors in the skin. In the first study, Korner et al. (Oscillating air- or water mattresses were used most often to stimulate the infants and are believed to mimic the r et al.  showed ar et al. . Howeverr et al.  has failr et al.  and a for et al. . The inar et al.  even repIn response to the oscillation beds, Jirapaet  aimed toSvenningsen et al.  conducteMore recent studies have investigated the effect of vibration as the sole stimulus, which resulted in a significant reduction of apnea or interbreath intervals and a significant reduction in intermitted hypoxia in all cases. Two of the three studies also reported a positive effect on the amount and duration or the intensity of bradycardia.Kesavan et al.  stated tvia somatic or visceral mechanoreceptors in the thorax region. The fact that these receptors can influence the respiratory rhythm is supported by studies that used electrical stimulation to activate the intercostal afferents (Smith et al.  and Blocfferents , 58. Howfferents . The strfferents . Furtherfferents . The lasfferents , althougfferents .It is possible that continuous mechanical stimulation, as is used in all included studies, could negatively influence the sleeping cycles of the infant by causing arousal or increasing the amount of active sleep. However, Bloch-Salisbury et al.  showed tIn this systematic review only English articles were considered. Relevant articles found in three databases and additional interesting references were included. By using this methodology it cannot be ruled out that relevant articles are missed. Furthermore the decision to include all modes of stimulation led to a high variety of, i.e., study designs, goals, definitions, measuring methods, and results. These big differences made it very difficult to compare the results.In most of the studies, tactile stimulation had a positive effect on the amount of apnea or was able to successfully terminate the apnea, but many important questions remain unanswered. The main issue would be finding out how to stimulate the most optimal pathway to the respiratory center. This means that more research should be performed on the effect of different frequencies, amplitudes, and locations of stimulation on all types of apnea but also to the influence of sleep state, hypoxia, and other environmental effects as well as possible adverse effects such as arousal and habituation.Closed-loop systems should be used in studies that investigate the effect of stimulation on the termination of apnea with the aim to prove the added value of a direct response. Although continuous stimulation of infants might prevent apnea without causing harm, it may be more beneficial to only stimulate the infant when needed . This reIn conclusion, it is clear that somatic afferents can influence respiratory center activity. Although manual tactile stimulation is the most common intervention for interruption of apnea, the effectiveness of different techniques were not studied. Mechanical stimulation is believed to improve the current treatment by reducing the risk of cross-contamination and enabling a direct response, but data are scarce. Studies demonstrated that it is possible to terminate apnea with a closed-loop mechanical pulsating or vibrating system and that mechanical vibratory stimulation of 250 Hz is equally effective as manual stimulation in terminating apnea.Several studies investigated the effect of tactile stimulation on the prevention of apnea. However, there were large variations between the studies in terms of study design, stimulation characteristics and measured outcomes. Although an oscillating mattress was used in six studies, this form of stimulation did not lead to a consistent effect in reducing apnea. Continuous pulsating significantly reduced central and mixed apnea but was only studied once. Different forms of vibrating stimuli were shown to significantly reduce apnea, hypoxia, and bradycardia.To select the most effective way of stimulation to treat or prevent apnea, more knowledge is required about the neuronal pathways to the brains that are activated by mechanical tactile stimulation, the effect on all types of apnea and the corresponding adverse effects. More studies are needed to confirm whether automated stimulation using a closed loop is more effective than manual stimulation, how and where the automated stimulation should be performed and the potential side effects.SC performed the literature search, selected the studies, and wrote the first draft of the manuscript. AP contributed to selecting the studies and writing an editing the manuscript. All the authors contributed to the final draft of the manuscript by critically reviewing previous manuscripts.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.