Copper-based friction material (CFM) and paper-based friction material (PFM) are the two most commonly used clutch friction materials. The friction and wear characteristics of these two kinds of friction materials under dry conditions were investigated by the pin-on-disc test over a broad range of applied loads, rotating speeds and ambient temperatures. Before experiments, the running-in test was conducted to stabilize the coefficient of friction (COF) and wear amount of the test samples. After experiments, the metallographic micrographs of the tested samples were presented to investigate the wear mechanisms. Experimental results showed that both the COF and wear depth of the CFM are much greater than these of PFM. The COF of CFM decreases with the increase of applied load, and changes slightly with the variation of rotating speed, whereas it increases first and then decreases with the increase of ambient temperature. However, the COF of PFM decreases dramatically with the increase of the rotating speed and ambient temperature, while it remains stable at first and then decreases slowly as the applied load increases. Additionally, under such three working conditions, the wear depth of CFM changes linearly, while the wear depth of PFM varies greatly. This study can be used as a guide for selecting friction materials for clutches with different applications. Friction materials play a significant role in the clutch system ,2. The fThe CFM manufactured by powder metallurgy has been widely applied to heavily-loaded wet clutches because of their excellent mechanical, thermal and tribological properties. A simplified experiment was developed to predict the friction performance of CFM wet clutches by the pin-on-disc test . Zhao etPFM is basically composed of fibrous reinforcements, binders, friction modifiers and fillers, etc. The fibers play a vital role in maintaining strength, thermal stability, and the friction performance of PFM. At present, various kinds of fibers—for example, carbon fiber, Kevlar fiber, ceramic fiber, and cellulose fiber—are gradually emerging to act as reinforcements in PFM ,13,14,15It is reported that the main failure modes appearing in clutches are friction material degradation and the deformation of separate plate ,25. As tHerein, the friction and wear characteristics of the CFM and PFM are investigated and compared experimentally. The influence of the working conditions  on the variations of COFs and wear depths of friction materials is presented. The wear mechanisms of CFM and PFM are also explored. Finally, the conclusions provide guidance for selecting suitable friction materials for clutches with different applications.The experimental equipment, Universal Material Tester (UMT-5)  simplified model of the working chamber in UMT-5 is presented in 2 (5 wt%), graphite (6 wt%) and some other additive materials; while PFM mainly includes cellulose fiber (50 wt%), nitrile modified phenolic resin (25 wt%), BaSO4 (10 wt%) and kaolin (10 wt%), and some other additive materials. The thermophysical properties of the pin and disc are listed in The test samples are shown in As shown in N is the total number of samples of the instantaneous COF.The representative test signals are demonstrated in After the running-in experiments, the friction material will have better bearing characteristics, more stable COF, lower wear rate and energy loss, so as to obtain longer service life. Since the specific procedures and methods for running-in test have been described in our previous studies , only thAs shown in As illustrated in As illustrated in As shown in The characteristics of the worn surface after the test can reveal the wear mechanisms. Since the friction properties of friction materials are directly related to the temperature, the metallographic figures of CFM and PFM are presented under various ambient temperature conditions as shown in As shown in Both the COF and wear depth of the CFM are much greater than these of PFM under the dry condition. The failure of CFM is caused by the variation of wear mechanism. With the gradual deterioration of the working condition, CFM will successively experience the abrasive wear, furrow wear, adhesive wear and peeling wear. Moreover, the failure of PFM is related to the wear of fibers and the softening and decomposition of resin, which will produce a much smoother surface.As to CFM, the applied load can result in a linear decrease in COF, whereas the rotating speed can only cause a slight fluctuation in COF. Additionally, the ambient temperature can lead to a parabolic decrease in COF. The temperature range of 100–175 °C is most suitable for CFM, where the COF is high enough and the wear is slight.As for PFM, with the increase of applied load, the COF remains stable at first, and then decreases slowly. The rotating speed and COF are inversely proportional. With the increase of ambient temperature, although the COF between 175–325 °C is relatively stable, the overall variation trend of COF is significantly decreased.Under such three working conditions, the wear depth of CFM changes linearly. However, the wear depth of PFM varies greatly: The wear depth decreases inversely with the increase of applied pressure; with the increase of rotating speed, it decreases at first, and then increases slightly, and finally remains stable; it changes in cosine form as the ambient temperature increases.In order to evaluate and compare the friction and wear characteristics of the CFM and PFM during the clutch engagement process in the dry condition, the pin-on-disc tests are conducted with applied load, rotating speed and ambient temperature taken into account. The main conclusions are as follows:


Right ventricular (RV) function has proven to be a prognostic factor in heart failure with reduced and preserved ejection fraction and in pulmonary hypertension. RV function is also a cornerstone in the management of novel clinical issues, such as mechanical circulatory support devices or grown-up congenital heart disease patients. Despite the notable amount of circumferentially oriented myofibers in the subepicardial layer of the RV myocardium, the non-longitudinal motion directions are often neglected in the everyday assessment of RV function by echocardiography. However, the complex RV contraction pattern incorporates different motion components along three anatomically relevant axes: longitudinal shortening with traction of the tricuspid annulus towards the apex, radial motion of free wall often referred as the “bellows effect”, and anteroposterior shortening of the chamber by stretching the free wall over the septum. Advanced echocardiographic techniques, such as speckle-tracking and 3D echocardiography allow an in-depth characterization of RV mechanical pattern, providing better understanding of RV systolic and diastolic function. In our current review, we summarize the existing knowledge regarding RV mechanical adaptation to pressure- and/or volume-overloaded states and also other physiologic or pathologic conditions. Compared to the left ventricle (LV), whose anatomy and function has been the subject of intensive research, right ventricular (RV) morphology and mechanics were traditionally less studied in contemporary science. In the past few decades, novel diagnostic techniques and important epidemiology studies have brought RV function back into the scientific spotlight. RV function has proven to be a prognostic factor in heart failure with reduced and preserved ejection fraction and in pulmonary hypertension. RV function is also a cornerstone in the management of novel clinical issues, such as mechanical circulatory support devices or grown-up congenital heart disease patients. In our current review, we summarize the existing knowledge regarding RV mechanics in different overload conditions and emphasize the role of non-longitudinal contraction of the chamber and its evaluation.The myocardium is a complex three-dimensional network of myofibers in a multiple helical arrangement with important functional consequences. A contraction of these bundles deforms the ventricle and generates ejection, whereas the relaxation aids diastole; moreover, knowing the myofiber orientation helps to understand the pattern of RV contraction in the three-dimensional space. On the epicardial surface, circumferentially oriented myofibers are present; these myofibers are components of the myofiber tracts that are shared with the LV, encompass the subpulmonary infundibulum and advance more or less parallel with the atrioventricular groove. At the apex, this layer spirals into the deep  layer of the RV. However, this subendocardial fiber orientation is rather longitudinal Fig. . In physMechanistically, the RV shows a distinctive, peristaltic-like contraction pattern: the activation starts from the inlet portion and ends at the infundibulum . During Accordingly, three main mechanisms contribute to RV pump function: (1) shortening of the longitudinal axis with traction of the tricuspid annulus towards the apex; (2) inward  movement of the RV free wall, which is often referred as the “bellows effect”; and (3) bulging of the interventricular septum into the RV during the left ventricular contraction and stretching of the free wall over the septum (causing shortening in the anteroposterior direction).Normative data are still lacking regarding the relative contribution of the longitudinal, radial, and anteroposterior components of RV wall motion to global ejection. Under physiological conditions, the longitudinal shortening was suggested to account for the majority of RV pump function ; howeverTwo-dimensional echocardiography is barely capable of thoroughly characterizing RV morphology and function. Still, RV function assessment is often based exclusively on tricuspid annular plane systolic excursion (TAPSE), which refers only to the longitudinal shortening of the chamber. The estimation of RV volumes based on 2D geometrical assumptions (as regarding the LV) are not used routinely; instead, fractional area change (FAC) is calculated. Although this technique is a 2D approach and partially incorporates radial motion direction, FAC describes RV function in a single cut of a very complex 3D structure. Speckle-tracking echocardiography emerged as a valuable tool for a more quantitative, semi-automated approach. Global longitudinal strain is showing an established diagnostic and prognostic value regarding LV pathologies , and proAs a recent advancement, 3D echocardiography may overcome these shortcomings. Several software solutions are available to reconstruct the endocardial surface of the RV for a better appreciation of its geometry and to allow the measurement of volumes and subsequent ejection fraction. In addition, novel postprocessing solutions have become available for a deeper analysis of shape and function. Beyond 3D speckle tracking, curvature analysis and the separate quantification of the different motion components  are promising in terms of obtaining a deeper understanding of RV physiology and pathophysiology , 11.In conditions accompanied by pressure overload, the challenge for the RV is to remain coupled to the increased afterload. The major mechanisms include adaptive myocardial hypertrophy, which leads to increased wall thickness and reduced wall stress, and alterations of muscle properties, such as myocardial fiber orientation and also RV shape . The relRV-LV interactions should not be neglected in pulmonary hypertension. There is a parallel interaction via the leftward bowing of the interventricular septum and an in-series interaction as the RV fails to supply an adequate LV preload. Another interesting aspect of ventricular interdependence is functional linkage via common myofibers. In experimental models of pulmonary artery banding, the addition of a mild aortic band increases the contractility of the pressure-stressed RV, and this change is probably attributable to the Anrep effect and the continuity of myofibers . Better Although pressure overload induces prominent changes in RV structure and function, RV remodeling seems to be highly reversible, and the recovery of RV function could be observed after appropriate treatment. Patients with pulmonary hypertension showed markedly improved RV function and decreased RV wall thickness after lung transplantation, even with severe preoperative RV dysfunction . The degWhen RV preload increases, wall stress is maintained by dilation of the chamber, along with preserved end-systolic volumes in the early stages; these observations suggest increased contractile function through the Frank-Starling law, which effectively compensates for altered hemodynamic conditions. Clinical experience includes an accompanying increase in RV longitudinal shortening. The significant elevation of RV preload may be also tolerable with maintained global function in acute and chronic settings, and these observations led to the conclusion that RV volume overload is a benign condition that lacks hemodynamically detrimental consequences. However, there is growing evidence from tricuspid and pulmonary regurgitation patients that strongly emphasizes the negative effects of RV volume overload –21.In the clinical setting, the main etiologic factors of RV volume overload are tricuspid regurgitation (TR), pulmonary valve regurgitation, and left-to-right shunts. The latter two entities are almost exclusively associated with congenital heart diseases; for such diseases, in addition to the presence of RV volume overload, other complex structural and functional aspects must be taken into consideration and will be discussed later. Approximately 80% of TR is functional, and the nature of the primary disease also significantly affects pathophysiology and presentation . The majCongenital heart diseases (CHD) represent a wide range of cardiac malformations, in which RV characteristics are also the cornerstones of disease presentation and progression. Depending on the nature of the abnormality, the RV may be exposed to severe pressure and/or volume overload. In certain types of defects, the myofiber architecture also differs from the physiological architecture , and thiIn isolated atrial septal defect (ASD) patients, increased preload results in the dilation of the RV, along with maintained/increased contractility in compensated state . Global In intracardiac shunts, the main driver of RV geometric and functional remodeling is the altered loading conditions of the ventricle, whereas in complex malformations of the heart, such as tetralogy of Fallot (ToF), the RV myoarchitecture is primarily affected. In contrast with healthy individuals, in ToF patients, a prominent middle layer with circumferentially oriented myofibers is also found, similar to the LV architecture. Consequently, we may hypothesize a relative dominance of radial RV function. In the current era of ToF management, total surgical repair is performed in the first years of life. Still, pulmonary regurgitation as a consequence of the repair procedure is a common finding. This volume overload of the RV may be tolerated for the long term; however, current data support the finding that the restoration of valve function must be performed to preserve RV function . In the Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy that predominantly affects the RV. While the genetic background of AC is established, other factors, such as the volume load of the RV, may precipitate the disease and accelerate progression . VentricIn heart failure with preserved ejection fraction (HFpEF), it has been shown that more than 50% of total deaths are attributable to right heart failure . In the In heart failure with reduced ejection fraction (HFrEF), right heart failure develops because of gradual increases in afterload due to pulmonary hypertension and because of tricuspid regurgitation accompanied by volume overload. Due to the given pericardial space, the enlargement of one ventricle will affect its counterpart. Moreover, in the presence of overload conditions, misalignment of interventricular interactions and normal cardiac cycle events can lead to mechanical dyssynchrony. Geometrically, this change often means that in the early stages, the bulging of the septum will be more prominent, and the space for RV volume will drop. This effect may imply a heavier dependence on longitudinal shortening of the free wall, as seen in other conditions in which a heavily distorted RV geometry is present . RV failChanges in RV mechanical pattern in conduction abnormalities and during RV pacing also attract scientific interest. Pacing from the RV results in a contraction pattern that is similar to a left bundle branch block . This efThe assessment of RV function by echocardiography is also key in the selection of candidate patients for ventricular assist device implantation. The presence of RV dysfunction is unequivocally associated with worse outcomes. Carluccio et al. investigated and followed up 200 patients with HFrEF but normal TAPSE . RV freeLeft-sided valvular diseases subsequently affect the right heart through the varying burden of pressure- and/or volume overload. However, RV function is commonly found to be significantly altered following cardiac surgeries, such as coronary artery bypass grafting (CABG), surgical valve repair, or heart transplantation , 42. TheThe evaluation of RV function following orthotropic heart transplantation deserves special attention because RV failure is still one of the major determinants of cardiac complications and mortality during the early postoperative period . The altIn conclusion, the decline in RV longitudinal function after cardiac surgery does not necessarily indicate a reduction in global RV systolic function. Therefore, reporting of RV parameters that also incorporate radial function is highly recommended .Regular exercise training is associated with significant changes in cardiac dimensions and function, which are also referred to as athlete’s heart . TraditiAlthough very few prospective follow-up studies were performed in the field, current data suggest that the volumetric adaptation of the RV to exercise is more pronounced than that of the LV and that the eccentric type of hypertrophy is expected at all levels of training . RestingIn our review, we have provided a brief summary of the existing literature regarding the mechanical adaptation of the RV to different overload conditions. The RV, which is often referred to as the “forgotten chamber”, has emerged as an important factor and prognosticator for several cardiovascular conditions. The avoidance of RV failure is now a major and explicit goal, for instance, in pulmonary hypertension, HFpEF, and CHD patients.Echocardiography is the first-line modality for assessing and monitoring RV morphology and function. However, 2D approaches fail to provide a good estimation of the non-longitudinal contraction of the chamber. Notably, the subepicardial layer of the RV myocardium consists of circumferentially oriented myofibers, which play a significant role in the complex contraction pattern. Nevertheless, further prospective studies are needed to assess the clinical value of in-depth characterization of RV mechanics. While pressure overload seems to affect the RV in a uniform way, the mechanical characterization of a volume-overloaded RV is more complex. Beyond contractility, the preload and afterload determine RV function, and the effect of pericardial constraint should not be neglected. Surgical procedures induce an instant shift in the functional pattern.To provide a clinical recommendation on the assessment of RV function, it is important to emphasize that the sole evaluation of longitudinal shortening does not grant sufficient information concerning the majority of RV-related pathological conditions Table . If applUsing advanced imaging modalities, the knowledge gap in our understanding of the adaptation of RV shape and function appears to be narrowing. As for the LV, segmental and subsequent motion pattern analyses are the next steps in RV research activity.


Wearable sensing and information and communication technologies are key enablers driving the transformation of health care delivery toward a new model of connected health (CH) care. The advances in wearable technologies in the last decade are evidenced in a plethora of original articles, patent documentation, and focused systematic reviews. Although technological innovations continuously respond to emerging challenges and technology availability further supports the evolution of CH solutions, the widespread adoption of wearables remains hindered.This study aimed to scope the scientific literature in the field of pervasive wearable health monitoring in the time interval from January 2010 to February 2019 with respect to four important pillars: technology, safety and security, prescriptive insight, and user-related concerns. The purpose of this study was multifold: identification of (1) trends and milestones that have driven research in wearable technology in the last decade, (2) concerns and barriers from technology and user perspective, and (3) trends in the research literature addressing these issues.This study followed the scoping review methodology to identify and process the available literature. As the scope surpasses the possibilities of manual search, we relied on the natural language processing tool kit to ensure an efficient and exhaustive search of the literature corpus in three large digital libraries: Institute of Electrical and Electronics Engineers, PubMed, and Springer. The search was based on the keywords and properties to be found in articles using the search engines of the digital libraries.The annual number of publications in all segments of research on wearable technology shows an increasing trend from 2010 to February 2019. The technology-related topics dominated in the number of contributions, followed by research on information delivery, safety, and security, whereas user-related concerns were the topic least addressed. The literature corpus evidences milestones in sensor technology (miniaturization and placement), communication architectures and fifth generation (5G) cellular network technology, data analytics, and evolution of cloud and edge computing architectures. The research lag in battery technology makes energy efficiency a relevant consideration in the design of both sensors and network architectures with computational offloading. The most addressed user-related concerns were (technology) acceptance and privacy, whereas research gaps indicate that more efforts should be invested into formalizing clear use cases with timely and valuable feedback and prescriptive recommendations.This study confirms that applications of wearable technology in the CH domain are becoming mature and established as a scientific domain. The current research should bring progress to sustainable delivery of valuable recommendations, enforcement of privacy by design, energy-efficient pervasive sensing, seamless monitoring, and low-latency 5G communications. To complement technology achievements, future work involving all stakeholders providing research evidence on improved care pathways and cost-effectiveness of the CH model is needed. As the worldwide population grows and the access to health care is increasingly being demanded, real-time monitoring of various physiological signals has driven the research and development of diverse wearable and implantable systems. Connected health (CH) describes the new paradigm of a technology-enabled model of health and lifestyle management . It is iWearables, as well as hearables (in-ear devices) and nearables (neighboring devices that interact with wearables) integrated into the wider concept of Internet of Things (IoT), are being considered the most likely technologies to transform future health care and lifestyles ,3. This The importance gained by wearables among consumer devices can be tracked by their increasing share in consumer electronics shows promoting self-care and health management. According to the International Data Corporation, 172.2 million wearable units were shipped in 2018 , and thiThe first body area networks (BANs) and wearable units comprised a number of sensors with a processing unit and wireless nodes assembled on printed circuit boards ,7. The dHowever, the user feedback reviews report that initial user enthusiasm on wearables is often lost because of unclear use cases (unclear end user need), price, and associated complexities in device pairing with a smartphone . The traThe role that sensing, and information and communication technologies have gained as essentials in digital health has been summarized and elaborated in numerous research articles on sensors, data analytics, and secure and reliable communication platforms for CH solutions ,10-16. TThe transformation of the wearable landscape in the last decade is thus evidenced in a plethora of original articles and patent documentation and summarized and compared in numerous focused systematic reviews -16,19-21With the more general, high-level perspective on the research on wearable technology, user-related concerns and challenges experienced over broad application area, this scoping review aimed at overlooking research trends unconstrained to a particular user group, health condition, or lifestyle scenario and including both mHealth and smart living environments. The extensive search scope is supported by automated search procedures relying on natural language processing (NLP) algorithms. The trends over the last decade were analyzed using a set of identified articles from 3 large digital libraries.Many studies elaborating on the use of sensors and wearables in assisted living environments, CH, and wellness and fitness apps were published in the last decade -16,19-22This study aimed to identify and scope the scientific literature related to wearables in health monitoring, as measured by trends in the research evidence available in 3 large digital libraries: Institute of Electrical and Electronics Engineers (IEEE), PubMed, and Springer. The study scoped the field from several perspectives aiming to capture key drivers and major constraints in the deployment of wearable technology for health. The enabling technology relies on advances in sensing, processing, communications, and data protection. Conversely, multiple user perspectives imply privacy, utility, complexity, price, relevance, reliability, and significance of delivered feedback.The objective of this study was to scope the research on wearable technology for health with regard to the following research questions:What are the most significant research trends and milestones on wearables seen as an enabling technology and as a key driver facilitating CH solutions?What are the most critical identified barriers and concerns from the technology and user perspectives and what trends are reflected in the research literature relating to these issues?As an added value, this review can help identify the topics that need more detailed research in terms of elaboration of the obstacles and potential breakthroughs. The list of relevant articles resulting from this study can be filtered with respect to different fields  to identify articles of interest for a systematic review in a specific subfield. The details in the list facilitate fast manual screening and selection of the subset of articles for further qualitative analysis. This type of preliminary search in planning a systematic review provides valuable answers on the feasibility , relevance , and amount of time needed  to conduct a systematic review.This study adopted a scoping review methodology to identify and process the literature on wearables published from January 2010 to February 2019. Using a scoping technique, we aimed to examine the research evidence in the broad field of wearables, analyzing technology trends, including the resolved and emerging issues. The lack of a qualitative analysis of identified papers, the broad topic range, and the number of studies involved defined our approach as a scoping review and differentiated it from a systematic review ,31. The All emerging review types share their basis in scientific methodology, that is, they rely on formal and explicit methods for search and assessment of published studies and synthesizing of research evidence in conclusions on a well-defined research question . One of Identification of a research question;Identification of relevant studies;Study selection;Charting the data; andCollating, summarizing, and reporting the results.The identification of relevant studies and study selection stages in the scoping review methodology corresponds to the PRISMA workflow phases: study collection, scanning, and eligibility evaluation. To ensure transparency, we have enclosed the workflow chart to illustrate the number of identified, scanned, and included articles in this scoping review .The scope of this study was substantial and the collected research evidence on wearables surpassed the potentials of a manual search. Relying on the advances in NLP algorithms, the NLP tool kit  was usedIn the following sections, we clarify the usage of the NLP tool kit for study identification, selection , and charting the data. It is worth noting that no quality assessment of the selected articles has been conducted, as this review has a scoping character. Instead, in the final step, we collated, summarized, and reported the results by aggregating the included studies to address the objectives of this review.This stage concerns the development of a plan comprising decisions on which digital libraries will be queried, relevant time span, suitable keywords, and properties that should be satisfied. This scoping review has employed the NLP tool kit  enablingThe NLP tool kit input parameters are a collection of keywords that are used to identify potentially relevant articles and a set of properties that should be satisfied by the identified articles. The input is further expanded by proposing synonyms to the search keywords and properties. Synonyms can be provided by the user or proposed by the tool kit and fine-tuned if needed.Keywords are search terms or phrases that are used to query a digital library . Eventual duplicates in the results are removed in a later phase. Properties are words or phrases that are being searched in the title, abstract or keywords section of the articles identified with the keywords. Examples of such properties employed in this study are “monitoring,” “recommendation,” and “detection.” Property groups are thematically, semantically, or otherwise grouped properties for a more comprehensive presentation of results. For example, the property group for the set of properties given in the example above can be “information delivery.” Start year indicates the starting year of publishing (inclusive) for the papers to be included in the study. End year is the last year of publishing (inclusive) to be considered in the study. This review encompasses studies published from January 2010 to February 2019. Minimum of the relevant properties is a number denoting the minimum number of properties that an article has to contain to be considered as relevant. In this study, this value was set to 3, providing a right balance between falsely identifying relevant papers and potentially missing a relevant paper.When researches perform a scoping review according to the above-mentioned methodology, the actual tasks they perform involve searching digital libraries with different search phrases, often involving complex Boolean conditions. The NLP tool kit counterpart to these phrases are the keywords described above. By screening the title and abstract, a reviewer determines whether the article is indeed relevant for the study. In the NLP tool kit, this process is automated using the properties and their synonyms to define what we are looking for in an article. Articles that contain more properties are considered as more relevant. Undoubtedly, a human reader might better understand the context and better assess the relevance of an article. However, the NLP tool kit is mimicking these tasks, but in an automated and more thorough way, providing incredible efficiency of the scoping review process. For more information about the actual implementation, we refer the reader to the study by Zdravevski et al .Upon provision of the defined input categories, the literature search was started using only the specified keywords to query the selected digital libraries. The NLP tool kit indexed the following digital libraries : IEEE Xplore, Springer, and PubMed. It is worth noting that the NLP tool kit has used search engines of the corresponding publishers and retrieved the search results. Depending on the digital library in each search, the number of retrieved articles was constrained. In the PubMed library, all articles matching the given search criteria were retrieved for further analysis. The IEEE’s search engine limits the number of articles in each search to 2000, all of which were retrieved. For Springer, the search for each keyword separately is limited to 1000 articles or 50 pages with results, whichever comes first, sorted by relevance determined by Springer.After articles had been identified based on the specified keywords and retrieved from the publishers, the study selection (screening and eligibility assessment) procedures followed.Upon merging the results from multiple independent keyword-based searches, some articles could be present multiple times because they could be identified by different keywords or in multiple libraries. Therefore, the collected articles were screened, and duplicates were removed using their digital object identifier (DOI). In addition, the screening process discarded articles that were not published in the required time span  or for which the title or abstract could not be analyzed because of parsing errors, unavailability, or other reasons.The selection of studies from the remaining subset of articles relied on the advanced functionalities enabled by NLP tools. The NLP tool kit automates analysis of a title and abstract for each study, significantly reducing the number of articles for manual screening. The automated eligibility analysis involved the following processing: tokenization of sentences ,35 and EThe processed articles were selected  if they contained at least 3 of the predefined properties in its title or abstract . To help in the eligibility analysis, the selected articles were sorted by the number of identified property groups, number of identified properties, number of citations (if available), and year of publication, all in descending order. For the relevant articles, the tool kit automatically generated a bibliographic file (as defined by BibTeX reference management software) for simplified citations.The information flow diagram illustrating the numbers of identified, screened, processed, and removed studies in the automated NLP procedure is presented in the Results section  to ensurThe listing of the relevant identified articles extracted from IEEE, PubMed, and Springer is available in To replicate the results manually, the keywords in To answer the research questions, we defined indicators to be extracted from the selected studies. The trends in the past decade were analyzed relying on a broad scope of literature. The processed and retained relevant articles were aggregated by several criteria:Source  and relevance selection criteria;Publication year;Digital library and publication year;Search keyword and digital library;Search keyword and year;Property group and year;Property and year, generating separate charts for each property group; andNumber of countries, number of distinct affiliations and authors, aiming to simplify the identification of collaboration patterns .These aggregated metrics are available in the form of comma-separated values files and charts. The plotting of the aggregate results was integrated and streamlined using the Matplotlib library  and NetwA similar graph for the countries of affiliations was generated. The top 50 countries by the number of collaborations were considered for this graph. Countries and an edge between them are shown if the number of bilateral or multilateral collaborations was in the top 10% (above 90th percentile) within those 50 countries.Using charted data and extracted evidence, we were able to analyze the trends in data and provide qualitative analysis for each thematic segment (as defined by the property groups). The results were reported with regard to the raised research questions. The meaning of these findings was related to the study purpose, and the potential impact on the future research direction was discussed.Using the NLP tool kit and searching 3 digital libraries: PubMed, IEEE, and Springer, we identified 21,288 studies with potential relevance . DuplicaThe distribution of the number of collected and relevant articles per year is presented in Combining the information on the digital library (source) and publication year of the identified relevant articles, the obtained distribution reveals that IEEE, being a more technology-oriented library, has an increasing trend in the number of relevant articles from 2010, peaking in 2017 . PubMed The authors’ affiliations were used to identify wearables’ research community clusters and eventual hubs at the research forefront. Multiple country associations were discovered, but for the sake of presentation clarity, the graph in The selected keywords used to map the literature corpus on wearables with respect to the set research questions appear in the relevant articles with different distributions. monitoring as the essential function of a wearable system tightly connected with the key technology: sensing .Microcontroller-based systems can as well be included within different textile fabric for health applications . Some prLow-power microelectronics, biocompatible materials, micro- and nano-fabrication, advances in data transmission, and management of sensor drift have driven the development of implantable biosensors . Recent The new generation of implantable sensing solutions for tissue and organ monitoring is enabled by advances in epidermal electronics based on soft lithography and thin-film sensors ,54. For in-ear placement of such a device requires a flexible and comfortable fit and provides stable position regardless of the subject’s gross movements. The viscoelastic foam used as a substrate additionally ensures artefacts absorption, as the ear channel is affected by small movements, when speaking, swallowing, or chewing. The solution proposed by Goverdovsky et al [Hearables are one of the latest wearable devices aiming to integrate sensing of multiple physiological signals into a single device . The in-ky et al  offers cImplantable pacemakers, pressure sensors, cochlear implants, drug infusion pumps, and stimulators are all examples of implantable devices delivering therapy or providing physiological monitoring . The majIngestible sensors for image and data recording in gastrointestinal endoscopy have already proven their benefits in early detection of gastrointestinal cancers . IngestiBesides tracking basic physiological parameters  sensing functions in wearable medical devices have also moved off the body toward contactless or seamless ambient embedded physiological sensing in, for example, keyboards, joysticks, steering wheels, bicycle handles, doors , mattresOne of the limitations for a widespread adherence to wearable electronic products concerns the power supply needs ,9,63. AcEnergy harvesting technologies have been explored as an alternative energy source to recharge power batteries or super capacitors. The ongoing research in this domain has investigated technologies to explore motion ,65, therComplementary efforts are being invested in the integration of power-efficient technologies and design techniques in wearable systems. Among those are energy-efficient and low-power wireless communication, voltage scaling, low-leakage and low-voltage complementary metal oxide semiconductors , and powThe medical data are low in volume, but with strict requirements in terms of latency, link reliability, and security . WearablBANs enable wireless communication in and around a human body in 3 different tiers: intra-BAN, inter-BAN, and the beyond-BAN. Intra-BAN communications refer to communications between on-body sensors, within the surrounding body area, enabling wireless data transmission to a personal server. According to the application and design parameters, the intranetwork can be wired or wireless, or even use the human body as a communication medium. Wired networks, as a second type of communication infrastructure for BAN applications, provide high-speed, reliable, and low-power solutions .The international IEEE 802.15.6 standard enables delivering of low power, short range  reliable wireless communications, with data rates from 75.9 kbps to 15.6 Mbps, making use of industrial, scientific, and medical bands, as well as frequency bands approved by national medical and regulatory authorities .The inter-BAN communications include communicating data from personal devices such as smartphones to the access points, either in an infrastructure-based manner or in an ad hoc manner. Wireless BANs can interact with other existing wireless technologies such as ZigBee, wireless local area networks (WLAN), Bluetooth, wireless personal area network, video surveillance systems, and cellular networks .protocols, cloud-based systems, and fog systems as research topics in the wearable CH domain. The major challenges in BAN are associated with media (path loss because of the body absorption), physical layer (minimization of power consumption with uncompromised reliability and interference), medium-access control layer , security, and transmission  [Finally, the beyond-BAN tier connects the access points to the internet and other networks. Beyond-BAN architectures can be implemented in cloud or fog network infrastructures  implyingmission) .Limited spectra and the need for higher data rates drive the communication community toward the new generation of cellular networks such as 5G ,63. The The design of wearable antennas, with safety concerns, device-centric architectures, and smart device communication are some of the changes 5G will require. The development of 5G brought the promises supporting the wearables market, such as radio-frequency sensor charging , reductiThe 5G architectures proposed to serve wearables include microbase stations for blanket coverage, whereas local coverage and data throughput should be ensured with small base stations and remote radio headers (RRHs) . RRHs caThe large volume and heterogeneous data types collected using wearable technology have grown beyond the abilities of commonly used data processing techniques . The necHigh-performance computing permits efficient processing of large data volumes through a map-reduce framework . AdvanceThe research in the user-associated information delivery is primarily concerned with recommendations, provision of feedback, and real-time user insight . CurrentTo gain wider consumer preference, the information generated by wearables has to be fitted into specific contexts, offering the needed insight and recommendation on actions that should be taken. The second generation of wearable systems, which aims to enable context sensing, needs to integrate many different types of context information, such as sensor information, user profiles and preferences, activity patterns, medical history, and spatial information (location and environment conditions). If not strictly depending on medical condition, the timing, content, and frequency of prompting have to be adjusted to user preferences . As a baThe transformation of wearables from measurement devices into resources of reliable real-time information, history mining, and smart and personalized decisions would qualify them for health and performance monitoring solutions.Wearables will reshape individuals and society, promoting self-care and health management, moving care outside hospitals, affecting enterprises, and revolutionizing health care ,82,83. Twearables fatigue attitude, which is noticeable in a significant percentage of wearables being discarded within the first 6 months of use [Another big hurdle for deploying wearable systems in the real-world concerns technology acceptance ,85. Evens of use .Our findings are aligned with the outcomes of the user feedback reviews on wearable technologies ,83, as tPreserving privacy and confidentiality is a priority to be considered in design specifications. Communications should be encrypted and secured, and the involved parties should ensure confidentiality. This is particularly important in the case of wireless data communications that are easier to intercept . PersonaDifferent user concerns, such as quality of experience, security, privacy, technology acceptance, and human-centered design, are relevant research topics in the wearable CH domain and can be used to identify future challenges and research trends. Although some of them  might be decreased as the end user pool gains digital competence and technology matures with time, some of them  will probably evolve and mix with other, more societal research topics such as environmental impact, circular economy, and digitalization of society. These can raise a new set of concerns related to the socioeconomic impact of wearable technologies in combination with IoT and 5G technologies used for health care and lifestyle.It is worth mentioning that another spectrum of concerns and barriers relates to the stakeholders involved in the provision and management of health care. Health professionals need scientific evidence on the reliability of collected data, the performance of analytical models mapping the collected data to disease progression, and eventually positive patient outcome in using wearable-based CH solutions . ReshapiSafety and security are primary considerations for medical devices, tightly coupled with reliability at all system levels. Our findings confirm the increasing importance and research efforts related to these major user concerns . If the Along the life cycle of a wearable device, efficient mechanisms are required to detect and diagnose deviations occurring in the captured data. Correct differentiation of errors due to system-related faults from those due to a change in health status is a necessity. Increased level of false alarms  would prevent user reliance, reduce user alertness, and hamper user adherence to the provided feedback.Both features, safety and security, are technology conditioned and should be ensured by the system design. Wearable medical devices are required to comply with IEC 62366-1:2015 standards  that regThe CH paradigm involves more connectivity and communications into health care and medical devices. Any device connected to the internet is prone to be targeted for malicious purposes, putting it at a constant threat of damage, theft, and financial cost.The number of detected data breaches in health care organizations has increased significantly in the last several years . The reaAfter the General Data Protection Regulation was put in place on May 25, 2018, the requirements for data protection and privacy assurance have been raised and unified across Europe. The health care and monitoring systems have to adhere to the privacy by design principle, which requires the incorporation of privacy protection in systems design and not as an afterthought add-on solution.This study considered only 3 digital libraries, and some relevant articles from nonindexed publishers were not considered. However, keeping in mind the size of the considered digital libraries, we believe that the obtained results are indicative for the purpose of the study.All digital libraries that were used in this work have different internal search engines with different rules for the maximum number of papers that can be retrieved and different formatting of search results. The papers obtained for this study are the results of the same search query sent to those different search engines. However, keeping in mind the number of papers that were analyzed within this scoping review, we believe that specificities of the publishers’ search engines have limited impact and have not influenced the findings of this work.In the future, the NLP tool kit needs to be extended to process more digital libraries. In addition, there is an apparent need of a Web app that will make it available to a wider audience. Until then, readers are encouraged to contact the authors if they are interested in using the tool kit.Wearable medical solutions, integrated into the wider concept of IoT, provide for pervasive data acquisition from a body and beyond, and rely on powerful data analytics, smart networking, and machine-to-machine communications to facilitate patient-centric, personalized, and holistic care. Although technological innovations and availability support the emergence of CH solutions, the widespread adoption of wearables is still hindered by numerous concerns related to reliability, security, and cost-effectiveness.This scoping review maps the scientific literature related to wearable technology in health care starting from January 2010 to February 2019, identifying the research trends related to enabling technology, and the trends in addressing the concerns from both user and technology perspectives. The NLP tool kit supported search procedures applied over 3 large digital libraries, IEEE, PubMed, and Springer, which provided for a representative subset of 2406 articles on wearable technologies for medical applications.On the basis of the investigated sample, the main findings reflect key drivers in the field, some research gaps and relevant topics that would benefit from more systematic qualitative knowledge synthesis:User concerns were the least addressed topic, whereas the enabling technology research was the main focus in the literature within the observed time period;Major breakthroughs were made in sensor technology, data analytics, communications, and computing architectures (edge and cloud);Research on battery technology and efficient solutions for energy harvesting has lagged, implying energy efficiency as one of the major constraints in designing wearable solutions for pervasive monitoring;Research on communication technologies focuses on 5G featuring low-latency, massive connectivity, and high capacity to mitigate the current challenges with respect to real-time feedback, energy, and computing constraints;The research related to the user-associated information delivery was mainly focused on monitoring and measurement information and much less on the provision of feedback recommendation and prescriptive insight; andThe most addressed concerns from the user perspective were technology acceptance and issues related to safety and security, implying privacy and reliability as the most central topics.This study confirms that applications of the wearable technology in the CH domain are becoming mature and established as a scientific domain. However, further research and development are required to improve their reliability, comfortability, and dependability levels. The research focus shifts from sensors and data analytics toward the sustainable delivery of valuable recommendations, reliable, energy-efficient, and low-latency communications and computation offloading. Sensor data integration goes beyond body-level integration to include context sensing, location and environment metrics, medical history, pattern of activities, and user preferences. This is essential for making wearables a robust patients’ representation interface and reliable node of the IoT infrastructure that makes CH a reality.There is a further need to explore and provide the literature evidence supporting the positive experiences, improved patient outcomes, and cost-effectiveness of CH solutions. Practical adoption in the field still demands design and validation of new care pathways, optimization of interventional strategies, and a sound business model.


Vitamin C, also known as ascorbic acid, is an essential micronutrient in the human body. Vitamin C is a co-factor for at least 15 enzymes involved in the biosynthesis of collagen and L-carnitine, Hypoxia-Inducible Factor (HIF) degradation, peptide amidation, tyrosine metabolism, and the conversion of dopamine to norepinephrine (Institute of Medicine (US) Panel on Dietary Antioxidants Related Compounds, Vissers and Das highlights the fact that vitamin C has been used for many years by cancer patients in an unregulated environment, either as a dietary supplement or in pharmacological doses administered by infusion. Daily vitamin C supplementation can likely reduce the incidence of gastric, esophageal, oral, pharyngeal and cervical cancer, and vitamin C-rich fruits may help prevent colon cancer and lung cancer . Alterations in GSH metabolism is further associated with increased glutathionylation of GAPDH, altered glucose metabolism, and high ROS levels and GSH oxidation. We believe the scope of this research topic provides the reader with insights into the multiple molecular mechanisms responsible for the anti-cancer properties of vitamin C.Whether vitamin C has anti-cancer properties or not has been debated for decades  has been used for decades as a complementary, alternative, and adjuvant medicine in clinic, and has been shown to significantly prolong the survival of patients  in Montreal, Canada, their work demonstrated that vitamin C did not seem to hold promise with regard to prostate cancer prevention.In the present research topic, Pires et al. analyzed the combination of high concentrations of vitamin C with reduced concentrations of drugs conventionally used in CRC patients and found that pharmacological vitamin C increased the efficacy of Iri and Oxa against CRC.A combination of nutrition, nutraceuticals, and drugs is the preferred therapeutic approach to fight against cancer. Colorectal cancer (CRC) is classified a fatal type of cancer, and conventional first and second line chemotherapeutic regimens for CRC are based on a combination of drugs including fluoropyrimidine, oxaliplatin (Oxa), and irinotecan (Iri). Helicobacter pylori are closely related to stomach diseases and gastric cancer. A large number of clinical reports have shown that ascorbate deficiency is associated with gastritis. In patients with H. pylori-infected gastritis, H. pylori, first discovered by Robin Warren and Barry Marshall, is one of the most common bacterial infections in gastritis, with H. pylori infection exceeding 50%. Gastritis and peptic ulcers are also caused by infectious pathogens that eventually develop into chronic gastritis, mucosa-associated lymphoma, and even gastric adenocarcinoma. In this research topic, Mei and Tu summarizes the relationship between vitamin C and H. pylori infection, and outlines potential strategies to prevent H.pylori infection that are based on emerging advances in our understanding of ascorbic acid physiology and pharmacology.Another important part of this research topic is to discuss vitamin C in the treatment of infectious diseases. It is well-known that Gram-negative bacteria Wang et al. summarize the effects of vitamin C on five skin diseases  and emphasize the clinical application of vitamin C as an adjuvant for drugs or physical therapy for other skin diseases.The final chapter in this research topic brings together a number of related dermatological studies which have shown that vitamin C can effectively promote the formation of the skin barrier via collagen synthesis, establishing a natural antioxidant barrier in the dermis, and regulating skin cell growth, differentiation, and signal transduction. Severe vitamin C deficiency leads to atopic dermatitis (AD) and porphyria (PCT). Vitamin C can be an effective drug for treating skin diseases, but the appropriate doses require further study. In this research topic, Together, this research topic gives insight into the multiple and complex roles of vitamin C, and in particular its involvement in cancer and infectious diseases. It provides guidance for therapeutic approaches and future research on the clinical use of high-dose intravenous vitamin C. Through research we need to better understand the mechanisms of vitamin C action, the optimal administration route, the appropriate dose and administration frequency. From such work we will gain insights into the clinical value of vitamin C, its role at a physiological and biochemical level, and expand the value of vitamin C in the treatment of cancer and infectious diseases. We look forward to new applied and useful data in this growing area.JW, FW, and CC planned and edited this special topic. JW and FW wrote this editorial. JW and CC revised this editorial.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.


Ovarian superovulation and increased follicle-stimulating hormone concentration for infertility treatment may be the risk factors of developed granulosa-cell tumor. The aim of this report is to introduce a case of granulosa-cell tumor which was discovered after ovarian stimulation.A 31-yr-old woman with clinical presentation of massive abdominal distention was referred to the gynecology and oncology department of an academic hospital, Mashhad University of Medical Sciences in Aug 2017. She had the history of secondary infertility and was undergoing In Vitro Fertilization protocol and ovarian stimulation, but, the cycle was canceled. The patient suffered from gradual abdominal distention one month after the end of IVF procedure despite pregnancy failure. 2-3 months after management of the ovarian hyperstimulation syndrome, investigation revealed large ovarian mass and increased tumor marker inhibin. Exploratory laparotomy was performed and revealed stage III ovarian cancer. The final pathology report indicated juvenile granulosa cell tumor. So, optimal surgical staging and cytoreductive surgery without fertility preserving were perfumed. Chemotherapy was recommended due to the advanced stage of ovarian cancer. Unfortunately, she experienced metastatic diseases in pelvic and abdomen in less than six months; and currently is receiving the second and third line chemotherapy.Persistent ovarian enlargement or ascites during or after infertility treatment should be carefully considered and managed. The important side-effects of ovulation induction for infertility treatment included stimulation and multiple pregnancies; moreover, the possibility of increased mitotic activity of granulosa cells in the ovary must be notified . GranuloAccordingly, clomiphene citrate and human menopausal gonadotropins have been used since the early 1960s; it was expected that special ovarian tumors must be found in the coming decades than previously, but it really has not happened , 5. In oThe aim of this report is to report a case regarding the possible relation between anulosa-cell tumor and ovarian stimulation.A 31 yr-old woman with complaints of massive abdominal distention and respiratory distress was referred to the gynecology and oncology department of an academic hospital, Mashhad University of Medical Sciences in Aug 2017. In past medical history, she mentioned a secondary infertility for four yrs and had one child aged eight yrs. The patient was candidate for In Vitro Fertilization (IVF) protocol due to tubal factors. In the first cycle of ovarian stimulation, metformin and Gonal-f 75 IU for six days were prescribed  and thenDespite the failure of IVF, she was under the outpatient care and supportive treatment with possible diagnosis of hyperstimulation syndrome. Therefore, antagonist GnRH was prescribed for two days. At the next delayed month visit, because of persistent symptoms with the probability of hyperthyroidism, she received gonadotropin hormone agonist (Decapeptyl). She was re-evaluated due to unresponsive to treatment within this period. Trans-abdominal and transvaginal ultrasonography were performed that showed multiple multiloculated cystic masses with predominantly solid components in both adnexa. The results of cross-sectional CT-scan and magnetic resonance imaging suggested the ovarian neoplasm. Also, massive peritoneal and pleural effusion was detected . In thisExploratory laparotomy was performed that showed massive ascites fluid and multi solid cystic masses in both ovaries extended up to the Xiphoid. Complete resection of the tumor was done. Pathology report of frozen section was unable to confirm the malignancy. But, permanent histology indicated the tumor cells with round-to-ovoid nuclei and eosinophilic or vacuolated cytoplasm or microfollicular and trabecular. Moreover, Call-Exner bodies were observed in most areas which were compatible with juvenile granulosa cell tumors. A positive immunohistochemical staining for inhibin was the key point of this diagnostic feature . So, surgical staging surgery and optimal cytoreductive surgery without fertility preserving were done. At this stage, although pelvic and abdominal cavity appeared normal without any residual disease in the first surgery, one month later in the second surgery, we unpredictably encountered malignant tumor even in the omentum (stage IIIc of disease); so complete cytoreductive surgery was again performed. Then, three cycles of adjuvant chemotherapy with bleomycin, etoposide, and cisplatin (BEP) were prescribed. Unfortunately, she experienced metastatic diseases in pelvic and abdomen in less than six months, and currently is receiving the second line chemotherapy. Now the patient is under follow-up.An informed consent was obtained from the patient for publication of this case report and accompanying images.It is not clear that granulosa-cell tumor discovered during ovarian stimulation was a pre-existing tumor or incidentally caused by ovarian stimulation. Also, like as our case, it is unknown that tumor progression is due to drug effects or the natural phenomena of tumor led to cancer. Ovarian stimulation due to excess gonadotropins and its effects on the growth of ovarian surface may cause the carcinogenic effect. Since the gonadotropin receptors of both normal ovarian tissue and ovarian cancer are similar and also the tumor had a rapid progression, it is possible that superovulation affects the tumor growth . This phenomenon is one of the hypotheses of ovarian cancer in the early menopausal age, especially in the age group of 50-59 yr. Moreover, increased secretion of gonadotropins and development of cancer have been confirmed in animals . DespiteSubsequently, exploratory laparotomy must be considered after radiological investigation and evaluation of tumor marker. After confirming the diagnosis of malignancy by frozen section, appropriate surgical staging and optimal cytoreductive surgery should be performed , 14. In A relation between of granulosa-cell tumor and ovarian stimulation may have ruled out. In some studies reported that the possibility of overstimulation contributed to the development of tumor. Although we cannot prove a causal link between growth of ovarian tumor and ovarian stimulation Because our patient was not undergoing ovarian stimulation and ovarian tumors were identified during follow-up.However, due to the potential additional risk associated with several reproductive factors influencing ovarian cancer risk, with regard to the different treatment schedules, the types and effects of certain drugs should be attended. Ideally, we emphasize on the strategies to improve the fertility rates without any risk of malignancy. In the current case, no relationship was found between ovarian stimulation and iatrogenic granulosa-cell tumor, but it is recommended that proper evaluation of patients before in vitro fertilization and careful monitoring of the ovaries during stimulation be considered as the standard of care in the infertility centers. In addition, if possible, post procedure surveillance and any suspected symptoms be assessed and long follow-up of these patients is suggested. In fact, the possibility of any relationship between fertility drugs and risk of ovarian cancer is an important question that requires further evaluation through large studies with sufficient follow-up time. Moreover, in the absence of pregnancy, any persistent and progressing enlargement of the ovary needs to be consulted with gynecologist oncologist at the first step and then, applying tumor markers and imaging modalities at the second step. Persistent ovarian enlargement or ascites during or after infertility treatment should be carefully considered and managed.There is no conflict of interest in this regard.


Given the association between a range of neurological disorders and changes in the gut microbiota, interest in the gut microbiota has recently increased. In particular, the significant involvement of the autoimmune processes in the development of epilepsy, one of the most serious and widespread neurological diseases, has led to a suggested link with the gut microbiome. Because the constitution of the gut microbiome can be influenced by diet, dietary therapy has been shown to have a positive impact on a wide range of conditions via alteration of the gut microbiota. An example of one such diet is the ketogenic diet (KD), which promotes a diet that contains high levels of fat, adequate levels of protein, and low levels of carbohydrate. Due to the near-total elimination of carbohydrates from the individual's food in this ultra-high-fat diet, ketone bodies become an important source of energy. Although the ketogenic diet has proven successful in the treatment of refractory epilepsy and other illnesses, the underlying mechanisms of its neuroprotective effects have yet to be fully elucidated. Nevertheless, recent studies strongly indicate a role for the gut microbiota in the effective treatment of epilepsy with the ketogenic diet. The latest advances regarding the links between the ketogenic diet, gut microbiota, and epilepsy are reviewed in this article, with a particular focus on the role of the gut microbiota in the treatment outcome. The diverse population of microbes in the gastrointestinal tract, including archaea, bacteria, fungi, protozoa, and viruses, is generally referred to as the gut microbiota . InvestiEpilepsy is among the most serious and widespread neurological disorders and represents a major liability for the healthcare system . MoreoveSignificant involvement of autoimmune processes in the development of epilepsy has been noted in a growing body of research –12. BecaA number of studies on epilepsy and microbiota have recently been published, and many have demonstrated the significant impact of diet on the composition of the gut microbiota and on the subsequent health of the individual , 18. TheThe gut microbiota is a multifaceted ecological population that contains trillions of microorganisms that inhabit the animal digestive tract and exhibits a range of dynamic interactions with the host's immune system and assists in maintaining the metabolic dynamic equilibrium –25. RathEpilepsy is a widespread serious and chronic neurological disorder that can severely delay development, reduce brain function, and lead to a significant mortality rate , 38. AppThe involvement of the gut microbiota in the pathogenicity of autoimmune conditions has been clearly demonstrated . The gutβ [Based on the crosstalk between autoimmunity, the onset of epilepsy, and microbiota, it is feasible that the constitution of the gut microbiota population could influence both the individual's susceptibility to epilepsy and the subsequent progression of the disease , 56. Expβ , 58, andβ . Hence, β .Although investigations into the link between epilepsy and the intestinal microbiota remain in their infancy , Table 1Lactobacillus and Bifidobacteria were noted in individuals with fewer seizures (a maximum of four seizures in 1 year). Meanwhile, the drug-sensitive patients displayed gut microbiome populations comparable to those of the control group. These results indicate the possible involvement of dysbiosis in the development of drug-resistant epilepsy; hence, a novel approach to the treatment of drug-resistant epilepsy might involve restoration of a healthy gut microbial population [For instance, the 16s ribosomal DNA obtained from faecal samples was subjected to high-throughput sequencing to examine the microbiome compositions of 49 drug-sensitive epilepsy patients, 42 drug-resistant epilepsy patients, and a control group of 65 healthy individuals . The gutpulation .Another recent study examined whether rats can be made susceptible to epilepsy by induced dysbiosis resulting from chronic restraint stress . ProgresAlthough the clinical application of microbiota in the treatment of brain diseases has not been widely investigated, one strategy with positive potential is restoration of the gut microbiota via faecal microbiota transplantation (FMT) . This apIn another contemporary study, the effects of antibiotics upon the frequency of seizures were investigated in six interesting drug-resistant epilepsy cases . Short-tγ-aminobutyric acid, and CD-14 were evaluated along with quality of life (QOLIE-10) and the number of seizures before and after the treatment [A group of 45 drug-resistant epileptic patients were given a 4-month course of probiotics in a prospective study in which the levels of interleukin 6, reatment . Intentireatment . These rω-3 fatty acids can reduce chronic inflammation and prevent weight gain [Numerous studies have shown that the composition of the diet is a key factor in determining the composition of the gut microbiome in various conditions of health and at various stages of life . Indeed,ght gain .th century, and its application in the treatment of epilepsy was inspired by age-old observations regarding the positive effects of fasting [The ketogenic diet (KD) restricts the caloric intake to 10% to 25% and consists of more than 90% fat, almost no sugar, and just sufficient amounts of vitamins, minerals, and proteins . Despite fasting . The the fasting . To incr fasting . The ant fasting , 83–87.  fasting , 88–90.Although the positive effects of the KD in reducing epileptic seizures are well proven, the precise mechanism by which this occurs has yet to be fully elucidated. Nevertheless, the recent literature indicates some advances in this topic , 91, 92,Few studies have dealt with the involvement of the gut microbiota in the treatment of epilepsy with the KD , 95. Exaet al. after a study in which two mouse models of refractory epilepsy were used to demonstrate mediation of the protective effect by the gut microbiota [Parabacteroides and Akkermansia muciniphila increased, during the KD diet; hence, these specific changes may play a part in the protection from seizure activity observed. Furthermore, these changes were linked to increased bulk and glutamate levels of gamma-aminobutyric acid (GABA) in the hippocampus.Remarkable findings relating to the microbiota- and ketogenic diet-dependent protection from seizures were reported by Olson crobiota . The susPrevotella, Bifidobacterium, and Bacteroides. The microbiota in epileptic infants was found to differ from that of healthy controls and was also shown to change significantly, with increases in beneficial bacteria and decreases in pathogenic bacteria, in response to the KD [Following on from this, Hampton suggested that the antiseizure effects of the KD could be attributed to gut microbes. This study was the first to demonstrate the direct involvement of the microbiota in providing the antiseizure effects of the KD in mice . This sto the KD . Hence, Alistipes, Clostridiales, Lachnospiraceae, Ruminococcaceae, and Rikenellaceae relative to those who responded to treatment [In a separate investigation, the faecal microbiota profiles of children with resistant epilepsy revealed decreased diversity, with decreased levels of Firmicutes and increased levels of Bacteroidetes after 6 months of KD treatment . The subreatment . This sureatment .How does the gut bacteria influence the onset of epilepsyIs it possible to use the composition of the gut microbiota as a marker to monitor the effectiveness of treatment, as has been done in mouse modelsCan the bacterial composition be modified as a therapeutic approachThe above-mentioned study was critiqued by E. Spinelli and R. Blackford, who raised the following questions:These commenters also point to the need for a large-scale multicentre investigation to build upon the above observations and to better demonstrate whether a possible microbe-based treatment is a rational choice in paediatric refractory epilepsy .Bacteroidetes, Bifidobacterium spp., Clostridium cluster XIV, Clostridium perfringens, Desulfovibrio spp., Enterobacteriaceae, Faecalibacterium prausnitzii, Firmicutes, and Lactobacillus spp. were quantified by reverse-transcription polymerase chain reaction (RT-PCR). The faecal microbial profiles demonstrated statistically significant enhancement in the levels of Desulfovibrio spp., a group of bacteria believed to contribute to aggravated inflammation of the gut mucosa resulting from ingestion of animal fats [In another recent study, six individuals with GLUT1 deficiency syndrome were asked to collect faecal samples before and after 3 months of KD treatment to compare the microbiota compositions . Bacteromal fats .In view of the above research, a future prospective investigation on alterations in the gut microbiota of epileptic children subjected to KD treatment is warranted. In addition, it may be logical to propose an empirical test of the potential for prebiotics or probiotics to reestablish the optimum ecological balance of the intestinal microbiota in individuals whose faecal samples indicate dysbiosis .Bifidobacteria, Dialister, and Eubacterium rectale along with an increase in the relative abundance of Escherichia coli [Bifidobacteria and E. coli contributed significantly to the functional changes [A study in 12 children with drug-resistant epilepsy was recently published online . Faecal hia coli . Alterat changes . The stuThe KD incorporates a range of mechanisms that lead to decreased neuronal excitability, including alteration of the gut microbiota . FurtherRecent studies have demonstrated a close link between epilepsy and the gut microbiome. Moreover, the mechanism behind the antiseizure effects of the KD in epileptic patients may be contributed by the gut microbiota. There is therefore much potential in optimising the KD to promote specific microbes as a neuroprotective treatment for drug-resistant epilepsy. Nevertheless, numerous questions must still be fully addressed, including the specific mechanism by which the gut microbiota influences the onset of epilepsy and the possible clinical applications of findings relating to the function of gut microbiota in the KD treatment of epilepsy. Moreover, these questions can only be answered with the establishment of large multicentre research efforts. The KD has potential benefits not only in epilepsy but also in numerous other disorders linked to changes in GABA, including Alzheimer's disease, anxiety, autism, Parkinson's disease, and schizophrenia. Hence, a broad spectrum of grave health issues could be positively affected by the development of a neuroprotective therapy involving microbes.


Therefore, the repurposing of existing drugs for these conditions is believed to be an efficient and dynamic approach that can substantially reduce the investments spent on drug development. Currently, there is emerging evidence that suggests the potential effect of a beta-lactam antibiotic, ceftriaxone (CEF), to alleviate the symptoms of different experimentally-induced neurological disorders: Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, epileptic-seizure, brain ischemia, traumatic brain injuries, and neuropathic pain. CEF also affects the markers of oxidative status and neuroinflammation, glutamatergic systems as well as various aggregated toxic proteins involved in the pathogenesis of different neurological disorders. Moreover, it was found that CEF administration to drug dependent animal models improved the withdrawal symptoms upon drug discontinuation. Thus, this review aimed to describe the effects of CEF against multiple models of neurological illnesses, drug dependency, and withdrawal. It also emphasizes the possible mechanisms of neuroprotective actions of CEF with respective neurological maladies.To date, there is no cure or disease-modifying agents available for most well-known neurological disorders. Current therapy is typically focused on relieving symptoms and supportive care in improving the quality of life of affected patients. Furthermore, the traditional  During the period of 1990–2015, the overall mortality from neurological illnesses was increased by 37%  related disorders is an attractive, efficient, and dynamic drug development approach that can substantially reduce the investment spent during drug development in terms of both time and money  is a third generation cephalosporin, under the group of β-lactam antibiotics, and is the most frequently used drug for local (skin and soft tissue infections) as well as systemic community and hospital-acquired infections , Ace2 (a gene that encodes enzymes play a part in Aβ metabolism), and the expression of gene of β-actin. Furthermore, CEF amplified the gene expression of Mme and Ide (genes that encode enzymes involved in Aβ degradation) as well as the expression of EPO gene   is one of the most prevalent forms of dementia  have also been reported . In a neVarious studies reported the protective role of CEF against different models of brain ischemia . CEF preCEF also showed protective activity on animal models of stroke . CEF str−) levels in PFC, NAc, and associated brain regions  by increasing glutamate uptake. Even though the mechanism is not clear, stimulation of GLT-1 by CEF is one of the suggested mechanisms in preventing the development of tolerance to cannabinoids  and amitriptyline (5 mg/kg) significantly attenuated morphine-induced dependence compared to the administration of CEF or amitriptyline alone. This enhanced effect could be due to the additive or synergistic effect of CEF and amitriptyline on morphine-induced drug dependence  was thought to be attributed mainly to biochemical alterations of the monoamines and their receptors  produced an important role in the progression of epileptic-seizures because they gradually disrupt the intracellular calcium homeostasis, which leads to neuronal loss  in the brain can induce neuronal damage and excitotoxicity that contributes to the pathogenesis of various neurological disorders including epilepsy, ALS, cerebral ischemia, parkinsonism, and AD (Massie et al., Several studies have revealed that the mechanism of action behind the beneficial effect of CEF in neurodegenerative diseases like PD (Leung et al., The upregulation of GLT-1 expression is associated with the significant attenuation of the neuronal damage caused by brain ischemia, and the overexpression of GLT-1 in the ischemic cortex is associated with a reduction of the size of the lesion and improves behavioral and cognitive recovery (Harvey et al., −, xCT, and GLT-1 are reduced in the NAc following substance of abuse (Massie et al., Abnormal regulation of glutamatergic neurotransmission, due to an excessive amount of Glu in brain reward circuitry, has been involved in both initiation and expression of addiction to the drug of abuse related behavior (Kalivas et al., Long-lasting neuroinflammation and oxidative stress are the other pathological processes involved in brain aging and neurodegeneration (Lee et al., In addition to neuroinflammation, oxidative stress, and mitochondrial dysfunction have also been involved in the development and progression of a wide range of neurodegenerative and mental disorders Tobe, . There wBDNF is a neurotrophic factor which plays a crucial role in neuronal survival, neurogenesis, and plasticity. It has also been reported that abnormal BDNF expression is involved in several neurological illnesses. There are few studies that report CEF caused upregulation and restoration of reduced BDNF levels in certain animal models (Lee et al., Besides, CEF might exert its neuroprotective actions through other mechanisms such as by affecting Aβ and tau protein metabolism and clearance in an AD model, prevent polymerization of α-synuclein in DLB (Ho et al., Generally, it appears that the shared mechanism of actions of CEF in the range of various neurologic disorders is through the upregulation of GLT-1 expression and the reduction of proinflammatory mediators and oxidative stress. However, this requires further investigation in order to verify the suggested and possible other newer neuroprotective mechanisms of CEF for each neurological ailment.This review revealed that the beta-lactam antibiotic, CEF might have neuroprotective actions, which can affect a wide array of neurological disorders including AD, PD, HD, stroke, brain ischemia, seizure, and drug/alcohol dependency and withdrawal. It is particularly interesting as CEF affects the wider pathological states of CNS disorders including glutamatergic system, oxidative stress, neuroinflammation, apoptotic index, and various toxic protein aggregations. Since most of the studies conducted so far are preclinical studies, clinical studies such as randomized clinical trials and further mechanistic studies are required to assure its neuroprotective actions in real clinical scenarios.EY developed the research concept and took initiatives of the work by drafting the manuscript while KT and HH provided greater contributions toward collecting, extracting, and organizing relevant data and also revising the review paper and agreed to be accountable for all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The crosstalk between gut microbiota (GM) and the immune system is intense and complex. When dysbiosis occurs, the resulting pro-inflammatory environment can lead to bacterial translocation, systemic immune activation, tissue damage, and cancerogenesis. GM composition seems to impact both the therapeutic activity and the side effects of anticancer treatment; in particular, robust evidence has shown that the GM modulates the response to immunotherapy in patients affected by metastatic melanoma. Despite accumulating knowledge supporting the role of GM composition in lymphomagenesis, unexplored areas still remain. No studies have been designed to investigate GM alteration in patients diagnosed with lymphoproliferative disorders and treated with chemo-free therapies, and the potential association between GM, therapy outcome, and immune-related adverse events has never been analyzed. Additional studies should be considered to create opportunities for a more tailored approach in this set of patients. In this review, we describe the possible role of the GM during chemo-free treatment of lymphoid malignancies. The use of small molecules and immune-targeted therapies has had significant impact on the prognosis of some cancers. Data have shown that gut microbiota composition may play a significant role in determining the efficacy and safety of such therapies. So far, the relationship between microbiota and hematologic malignancies is not well understood.The aim of this review was to describe the possible role of the gut microbiota (GM) and microbial translocation profiling during chemo-free treatment of lymphoid malignancies. A web-based search of MEDLINE (PubMed) was performed from 2009 until March 2018 in order to identify pertinent articles. We structured our term search using the following keywords: “gut microbiota; chemo free treatment; lymphoid malignancies”. This review first describes the characteristic of the gut microbiota and its relationship with both the immune system and inflammation and microbial translocation. Then, we report what is known about the interplay between microbiota cancer, hematologic disorders, and lymphoid malignancies.The human microbiota is composed of numerous micro-organisms including eukaryotes, archaea, bacteria, and viruses, which colonize the whole human body: skin surface, airways, and genital and gastrointestinal systems . It cons13–1014 bacterial cells [Bacteroidetes phyla and Gram-positive Firmicutes phyla, with small proportions of Actinobacteria, Proteobacteria, and Verrucomicrobia [The majority of microbes harbored in the gut (GM) are bacteria, at around 10microbia . For thiBacteroides and Parabacteroides and is able to derive energy from carbohydrates and proteins (Western diet); Enterotype 2 is rich in Prevotella and Desulfovibrio and their hydrolases are specialized in the degradation of plant fibers; and Enterotype 3, the most frequent, is rich in Ruminococcus as well as co-occurring Akkermansia [Resilience measures the extent to which, and how permanently, any kind of stress may perturb GM composition ,6. To beermansia ,8. GM can influence physiological human homeostasis: it has metabolic functions, provides protection against pathogens, and modulates the immune response. GM modifications associated with disease are being increasingly frequently studied. Dysbiosis includes any condition that disrupts the stable composition of that GM. It can be caused by infection and by environmental factors such as antibiotics consumption or dietary changes ,12. SeveThe GM has multiple functions and the relationship with the host is regulated by a complex network of interactions. The GM is involved in energy harvest and storage and plays a role in generating nutrients from substrates indigestible by the host, such as starch and soluble dietary fiber. These products act as energy substrates for the host and, unfortunately, as effectors of immune responses and tumorigenesis ,14.The crosstalk between GM and the immune system is intense and complex. The gastrointestinal (GI) tract is one of the body niches where the external environment meets the internal one. The GI tract is composed of enterocytes covered by mucous, immunoglobulins A, and glycocalyx, which separates the luminal environment from the lymphoid tissue. To reach the lymphoid tissue, antigens pass through the cells (transcellular movement mediated by pumps and channels) or through paracellular compartments (tight junctions). The intestinal barrier then acts as a physical barrier and its integrity is crucial for maintaining the balance between health and disease . The intBacteroides fragilis in suppressing the production of IL-17 and in protecting against potential inflammatory reactions initiated by bacterial antigens.Even in healthy intestine, commensal bacteria influence immune homeostasis. Pattern recognition receptors, like toll-like receptors (TLRs), present on the enterocytes recognize pathogen associated molecular patterns (PAMPs) of commensal bacteria, promoting the initiation of the inflammatory response ,17 by thClostridiales species, for example, suppress immune response by promoting Tregs polarization and IL-10 production [Enterococcus hirae increase the level of Th17 and then stimulate the immune response [Several studies and animal models have demonstrated that GM composition leads to a proper maturation of the immune system and the production of haemopoietic cells . Clostrioduction ,22. Enteresponse ,23. Streptococcus pneumoniae and Staphylococcus aureus by bone-marrow derived neutrophils in a nucleotide-binding oligomerization domain-containing protein 1 (NOD1), an intracellular pattern-recognition receptor. [While there is accumulating evidence on the role of GM in gut local immunity, more data are needed to confirm the relationship between the GM and systemic immunity and inflammation. For example, Ichinohe et al. ,25 showeeceptor. ,26. Microbial translocation (MT) is defined as the non-physiological passage of the GI bacteria from the gut lumen to the local mesenteric lymph nodes . In physMT has been extensively studied in animal models and the endpoint used to quantify MT is the number of organisms cultured in the regional lymph nodes . In receThe relationship between GM and MT is important because translocating bacteria and microbial components may aggravate a pre-existing inflammatory status. To the best of our knowledge, there are no studies on the links between modifications of GM composition, MT, and inflammatory status. Considering the above, the interest in the potential crosslink between dysbiosis and disease, in particular with cancer, is not surprising. Several epidemiological studies demonstrated the association between intra-abdominal infections, the use of antibiotics, the consequent dysbiosis, and an increased incidence of colorectal cancer. Carcinogen-induced models of tumorigenesis highlighted the oncogenic effects of some bacterial metabolites and ROS species . OncogenBifidobacteriumlongum, Collinsella aerofaciens, and Enterococcus faecium were more abundant in the stool samples (collected before the start of therapy) of chemo-free therapy responders, thus supporting the anti-tumor effects of the Bifidobacterium species. In another set of metastatic melanoma patients receiving anti-PD1 therapy, Wargo et al. [Ruminococcaceae, whereas non-responders showed a higher percentage of Bacteroidales.We now focus on the potential role of the GM in the response to chemo-free treatments. Chemo-free cancer therapy is a novel therapeutic approach that aims to control the malignancy by taking advantage of the immune system’s physiological activity. Chemo-free agents include cytokines, checkpoint inhibitors, agonists of co-stimulatory receptors, T cells manipulators, oncolytic viruses, vaccines, and therapies directed at other cell types . Currento et al. ,36 foundMany other studies were designed with different patients to better characterize GM composition and its contribution in chemo-free therapies efficacy and toxicity . The resIn their review, Gopalakrishnan et al.  summarizGM seems to have an impact on the products of the hematopoietic systems. Although the underlying mechanisms are unclear, the pool of the bone marrow myeloid cells is strongly correlated with GM composition . Balmer Helicobacter pylori [Considering the close interplay between the immune system and the GM, the lymphoid tissue is involved in the oncogenic process. One example of this is mucosal-associated lymphoid tissue (MALT) lymphoma, which is strongly associated with the presence of certain bacteria, such as r pylori   per gram of human feces) [As discussed above, beyond bacterial species, almost 1500 virotypes colonize the gut lumen (10n feces) . This asn feces) . For thin feces) .Given what was described above, we hypothesize that the immunostimulatory and antitumor effects of BCRi in patients with lymphoid malignancies could be influenced by distinct gut microbiota compositions. Therefore, the study of the gut microbiota in these patients might be important for recognizing different enterotypes able to distinguish among patients who have and have not achieved a clinical response and those at greater risk to experience immune-related adverse events (irAEs).Thanks to the progress in the fields of biotechnology, genetics, and genomics, clinicians can use the analysis of big data as an additional tool to choose the best decision-making algorithm; this is called precision medicine ,55. Specific gut microbiota states are reportedly associated with autoimmune disorders and, although the relationship between microbes and host immune responses suggests an association of the GM composition with lymphoma and blood cancer, mechanistic understanding of how the microbiota directly or indirectly impacts hematopoiesis is limited.No studies have evaluated the relationship between GM and therapy outcome in patients with lymphoproliferative disorders treated with chemo-free therapies. Evidence on the relationship between GM and MT in this set of patients is lacking.Further studies should be considered to open up the possibility for more tailored approaches, in terms of precision medicine, that consider the systemic impact of GM.