To analyse the demographic and clinical characteristics of people attending physical rehabilitation centres run or supported by the International Committee of the Red Cross in countries and territories affected by conflict.Of 150 such rehabilitation centres worldwide, 38 use an electronic patient management system. We invited all 38 centres to participate. We extracted de-identified data from 1988 to 2018 and categorized them by sex, age, country or territory and reason for using rehabilitation services.Thirty-one of the 38 rehabilitation centres in 14 countries and territories participated. We included data for 287 274 individuals. Of people using rehabilitation services, 61.6% (176 949/287 274) were in Afghanistan, followed by 15.7% (44 959/287 274) in Cambodia. Seven places had over 9000 service users each . Overall, 72.6% (208 515/287 274) of service users were male. In eight countries, more than half of the users were of working age (18–59 years). Amputation was the most common reason for using rehabilitation services; 33.3% (95 574/287 274) of users were people with amputations, followed by 13.7% (39 446/287 274) with cerebral palsy. The male predominance was greater in the population aged 18–34 years  and in people with amputations  but was evident across all places, age groups and health conditions.The considerably lower attendance of females at the rehabilitation centres highlights the need to understand the factors that affect the accessibility and acceptability of rehabilitation for women and girls in conflict settings. The effects of conflict on population health include increased injury rates coupled with a collapse of health systems.–,While early rehabilitation has received more attention recently,The Physical Rehabilitation Programme of the International Committee of the Red Cross (ICRC) aims to bridge the gap between immediate humanitarian rehabilitation needs and long-term programming for people with disabilities in difficult environments.Convention on the Rights of Persons with Disabilities in 2006,Rehabilitation in all physical rehabilitation centres supported by the ICRC consists of assistive technology and physiotherapy. Over the past 30 years and notably after adoption of the United Nations ,Research on people using rehabilitation services in fragile countries is limited.Understanding the characteristics of people with disabilities who access physical rehabilitation centres is important to identify the main health conditions for which rehabilitation is sought and the affected populations with specific needs, so as to inform the development of rehabilitation systems in conflict settings. We aimed to examine existing data from patient management systems to determine the demographic characteristics and clinical presentations of people attending ICRC physical rehabilitation centres in different countries.This was a retrospective descriptive study of aggregated data from patient management systems for all people seeking rehabilitation services from 1988 to 2018 who were registered in participating physical rehabilitation centres. Data on people seeking services before the introduction of the patient management system had been manually transferred onto the system from the paper records. The timespan varied between physical rehabilitation centres depending on when the ICRC support began and when the patient management system was introduced .Physical rehabilitation centres partnered with the ICRC are advised, but not obliged to install the patient management system. At the time of data collection, 38 of 150 physical rehabilitation centres in 35 low-income and conflict-affected countries and territories had installed this system. The analysed data collection represents countries and territories, and physical rehabilitation centres that we consider were in the midrange of human and technological resource capacity to undertake electronic data collection. Outside this range were: (i) centres that had difficulty using software , and (ii) centres in countries and territories with more advanced health information systems than the patient management system. Some centres were not using the patient management system because of data protection policies and the perceived sensitivity of user files, despite guaranteed anonymity of the data.We wrote to the managers of all 38 physical rehabilitation centres using the patient management system explaining the purpose of the study in detail and inviting them to participate and provide us with de-identified data.The study population was newly registered users of rehabilitation services at the physical rehabilitation centres. On registration, demographic and clinical characteristics of the person seeking rehabilitation services are recorded as part of routine documentation.We retrieved data on the country or territory where the centre was located, and age and sex of the users and their main reason for attending the centre. The main reasons for attending the centre included a mix of symptoms (e.g. muscle weakness), causes (e.g. ageing), diseases , injuries (e.g. burns) or disorders .Data accuracy depended on the quality of self-reported information provided by the person attending the rehabilitation centre and the recorded observations of the staff of the centre who have varying levels of professional training. We considered variables such as sex and age as robust. However, given the lack of medical personnel and diagnostic tests, recording an accurate clinical diagnosis can be difficult.We cleaned, merged and aggregated data by sex and age, and organized into the variables of interest. We categorized people according to age as: young child (younger than 5 years); child (5–17 years); young adult (18–34 years); adult (35–59 years); and older adult (older than 59 years). We grouped the main reasons for attending the centre into: musculoskeletal ; neurological ; and paediatric  according to clinical group and age at registration.We used descriptive statistics for our primary analysis using Microsoft Excel, 2016 . We summarized data as counts and percentages.We received ethical exemption to conduct an analysis on de-identified data by the Commission Cantonale d’Ethique de la Recherche, Geneva, Switzerland (reference number: REQ-2019–00027). Data sharing agreements were approved by ICRC, Linköping University, Sweden and University College Dublin, Ireland.Of the 38 physical rehabilitation centres in low-income and conflict-affected countries and territories that had installed the patient management system, 31 from 14 countries and territories  participated in the study and provided data on 289 248 users. Seven centres could not participate because of challenges in data extraction during the study’s timeline, including remote physical rehabilitation centres without a permanent ICRC presence.Minor problems in the patient management system software resulted in invalid entries for 1974 users, which we excluded. The problems were: missing diagnosis (6 records), missing date of birth or age recorded as < 0 and > 99 (1793 records) and double entries (175 records). Thus, 287 274 unique user sets of data were included in the analysis.An important age cohort are people of working age (18 to 59 years); overall 51.5% (147 974/287 274) of the service users were in this age group and this was the case for most countries. However, in Gaza Strip, Togo and Democratic Republic of the Congo, the largest proportion of service users were younger than 5 years, 50.3% (4546/9029), 37.0% (423/1142) and 29.0% (750/2587), respectively. In Algeria, older adults constituted the greatest proportion of the service users .The sex distribution varied considerably across age groups in all countries and territories. However, in the young adult and adult age groups, a consistently greater proportion of men attended the rehabilitation centres compared with women in all countries and territories, except Togo where the proportions were similar.For children receiving rehabilitation, we found a smaller, but still important, difference in sex distribution in most countries and territories with more boys than girls attending the centres; only the Gaza Strip had equal sex distribution. The same trend was seen for older adults in most places; substantially more men than women accessed services, particularly in Ethiopia . Exceptions were the Democratic Republic of the Congo where 46.0% (105/228) in this age group were males and Togo where 42.0% were males (58/138).We categorized conditions for which more than 500 users sought rehabilitation services in each country by sex and age group (data repository).The data included in the study come from countries with ongoing protracted crisis, countries hosting populations from neighbouring conflicts and post-conflict countries. Protracted conflicts last years or decades and have highly changeable patterns, including changing intensity of fighting, shifting battle lines and high, fluctuating numbers of casualties. Restricted access to and availability and awareness of rehabilitation services during and after conflict explain the large number of new attendees at the rehabilitation centres with conflict-linked disability in the overall population, even in currently peaceful places such as Cambodia.A key finding of our study is the proportionally lower representation of females using rehabilitation services compared with males across all age groups. While we expected increased exposure to conflict-related conditions among men, a greater proportion of males than females also attended the centres for conditions not linked to conflict. Furthermore, even among people in the younger and older age groups attending the centres, who are usually not directly involved in violence, a greater proportion were males.–,––,To interpret these findings, we need to consider the main reason for attending the centre for males and females. About one third of the people using the rehabilitation services had undergone a limb amputation. This figure reflects the physical rehabilitation programme’s original specialization in fitting prosthetics for survivors of land mines who had lost a limb.–Another key finding was the substantial proportion of people of working age ; in males, about a third were 18–34 years. This finding demonstrates the importance of rehabilitation for people with disabilities so that they have the capacity to work where possible. The finding also highlights the adverse economic impact of armed conflict, where many people sustain injury and have long-standing disability. These people may become dependent on their families or communities. They may even require extra care within the family so that an additional person may have to cease paid employment and hence be unable to help sustain the family financially. Furthermore, in societies where men have a status as breadwinners of the family and where  capacity is considered closely associated with physical integrity, being disabled at a working age can affect male identity and have socioeconomic and psychological consequences.Our data show relatively few older adults with disability attended the rehabilitation centres, but this number is likely to change in the future. Longer life expectancy and greater numbers of people with multiple morbidity and age-related disabilities The large numbers of young children and children attending the rehabilitation centres  warrant discussion. This group constitutes the future workforce of a country and, apart from clubfoot, the main conditions for which these young people were attending require lifelong resource-intensive services, which is a considerable challenge in conflict settings.,Given the overall sex difference, we require greater understanding of the reasons for these differences in access, so that rehabilitation can be adapted to meet the needs of women and girls in the environments of the countries studied. The role of women in society is important and far-reaching: often women care for several generations of a family at the same time. For example, in conflict settings, women often keep social, education and health care systems running, stabilize families, homes and communities, or participate in social and physical reconstruction after the conflict has ended.Our study has some strengths and limitations. Providing rehabilitation services in low- and middle-income countries, particularly during protracted conflict, is difficult.ICRC support is as varied as the contexts in which the organization works, which the data collection reflects: both the data collection process and completeness varied between the physical rehabilitation centres. The number of users from whom data were collected ranged from 176 949 users in Afghanistan, where an ICRC programme has been operating for more than 30 years, to 207 users in an Algerian partner project, where the patient management system was installed just weeks before the beginning of our analysis. In some countries , the ICRC physical rehabilitation centres represent most functioning rehabilitation facilities. Their data may therefore reflect the national population of users of rehabilitation services and allow greater generalizability of the findings. In other countries , the data are less representative of population rehabilitation needs because other national and international organizations are also providing services. The ICRC closely collaborates with these organizations for referrals and to avoid duplication of services. Globally, the ICRC is the leading actor in conflict and post-conflict settings and resource-poor in terms of duration, size and scope of its operations. ICRC’s operations offer long-term support using a common approach that consists of four strategic objectives , which are adapted to the needs and circumstances in a specific context.The lack of reference data for population prevalence in low- and middle-income countries and conflict-affected countries for the health conditions examined in our study may confound interpretation of our findings relating to the underrepresentation of women. Our results relating sex distribution of service users are discussed relative to findings from studies in similar contexts.International statistical classification of diseases and related health problems or the International classification of functioning, disability and health (ICF).,The database was developed from observations in the field rather than through use of an existing classification system. This approach makes the patient management system less methodical than health information systems based on the Our study provides important insights on a highly vulnerable and under-researched group: people seeking rehabilitation services in fragile settings. In the absence of prevalence data, these initial findings may help guide future investigations estimating the burden of disability in conflict settings. Given the low representation of female users, our future research will build on these findings and explore gender aspects relating to access and provision of rehabilitation in conflict contexts. Research is also needed on rehabilitation outcomes in terms of functionality, reintegration and participation.


Aim of Work. We tried to evaluate the potential role of FFAs in CSF in the diagnosis and the prognosis of ICU patients with AIS while comparing the results to traditional neurological scoring systems. Patients and Methods. Our study included 80 patients who were admitted to ICU with acute ischemic stroke (AIS) within 24 hours of the onset of cerebral infarction. CSF samples were obtained at admission. The FFA levels were measured using the sensitive enzyme-based colorimetric method. The NIHSS, GCS, and mRS were evaluated at admission and at 30 days. Univariate and multivariate analysis were used to evaluate the stroke outcome according to FFA levels in CSF.  Brain ischemia initiated significant increase in FFAs in animal studies. Accumulation of FFA can lead to liberation of inflammatory byproducts that contribute to neuronal death. Increased risk of systemic thromboembolism was seen in animal models after FFA infusion possibly through activation of factor XII by stearic acids. The clinical studies that examined the relation between stroke in humans and CSF biomarkers are infrequent. µl, sensitivity of 62.9%, and specificity of 72.2%. There was a significant correlation between FFA in CSF and the mRS >2 at 30 days. The ROC curve showed a cutoff value of 0.27 nmol/µl, specificity of 69.2%, and sensitivity of 59.7%. There was a significant correlation between FFA in CSF and the NIHSS ≥ 16 at 30 days. The ROC curve showed a cutoff value of 0.27 nmol/µl, specificity of 72.2%, and sensitivity of 62.9%. Our study subdivided patients according to infarction volume and compared the 2 subgroups with FFA in CSF. We found a significant difference between 2 subgroups. FFA levels showed a positive correlation with infarction volume ≥145 ml. The ROC curve showed a cutoff value of 0.25 nmol/µl, sensitivity of 76.9%, and specificity of 71.4%. Our study showed that FFA in CSF was a significant predictor of all-cause mortality . The ROC curve showed a cutoff value of 0.27, specificity of 72.2%, and sensitivity of 62.9%. There was a positive correlation between FFA in CSF and neurological causes of mortality . The ROC curve showed a cutoff value of 0.37 nmol/µl, specificity of 76.1%, and sensitivity of 61.5%.  Worsening of the GCS (<7) at 30 days showed a significant correlation with FFA in CSF. The ROC curve showed a cutoff value of 0.27 nmol/ FFA in CSF may serve as an independent prognostic biomarker for assessing the prognosis of acute ischemic stroke and the clinical outcome. It might be a useful biomarker for early detection of high-risk patients for poor outcome and hence more aggressive treatment. Acute ischemic stroke (AIS) is diagnosed by clinical examination after exclusion of mass lesion or intracranial hemorrhage by CT or MRI. Treatment of intracranial complications, reperfusion strategies, monitoring of biological and vital parameters, and optimization of homeostasis are some indications for patients with AIS to be admitted to intensive care unit (ICU) .Brain ischemia initiated significant rises in FFAs in animal studies .Accumulation of FFA can lead to uncoupling of oxidative phosphorylation and liberation of inflammatory by-products including reactive oxygen species that contribute to neuronal death .Increased risk of systemic thromboembolism was seen in animal models after FFA infusion. A possible mechanism is activation of factor XII by stearic acids .Brain biomarkers might help in the diagnosis and management of AIS .With the presence of blood-brain barrier, the ideal biomarker for brain injury should be brain specific, appears very early, and the peak level reveals the severity and suggests the neurological outcome .The clinical studies that examined the relation between the stroke in humans and CSF biomarkers are infrequent.We tried to evaluate the potential role of FFAs in CSF in the diagnosis and the prognosis of ICU patients with AIS while comparing the results to traditional neurological scoring systems.Our study included 80 patients with acute ischemic stroke (AIS) (group 1) who were admitted to ICU within 24 hours of the onset of cerebral infarction and whose lesion was confined according to neurological examination and computed tomography (CT) or magnetic resonance imaging (MRI) in comparison to 28 age- and sex-matched healthy subjects served as the control (group 2).The study was conducted in critical care unit at Shebin El Kom Teaching Hospital in the period between October 2016 and May 2017.Age less than 18 yearsStrokes that are due to nonvascular cause  or was an extension of a previous strokeTransient ischemic attack (TIA), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH)Patients treated with a recombinant tissue plasminogen activator(i)History taking and clinical examination including general and neurological examinations.(ii)Routine laboratory investigations.(iii)a × b × c) where a is the maximal longitudinal diameter, b is the maximal transverse diameter perpendicular to a, and c is the number of 10 mm slices containing infarction, and lesions were classified according to their sizes as follows:Small to medium, when size is less than 145 mlLarge, when size is equal to or more than 145 ml , 9Brain imaging, either CT or MRI brain. The infarct size was estimated according to the rules used by Sims et al.  (size = (iv)The Glasgow Coma Scale (GCS) at admission and 30 days .(v)Stroke severity being assessed by the National Institutes of Health Stroke Scale (NIHSS) score at admission and 30 days .Included patients were subjected to the following:Patients were classified according to stroke severity; more than 20 is considered severe stroke .In-hospital or 30-day mortalityThe modified Rankin Scale was used to assess functional disability and was evaluated at admission and at one month from stroke onset Patients were prospectively followed up for the following outcomes:Good outcome (score 0 to 2)Dependent or dead (score 3 to 6) The patients were divided according to the modified Rankin Scale score into the following categories:CSF samples were obtained within 24 hours from admission under complete aseptic conditions. The FFA levels were measured using the sensitive enzyme-based colorimetric method.χ2) test was performed. The exact test was used instead when the expected frequency is less than 5 [P values less than 0.05 were considered as statistically significant.Data were coded and entered using the statistical package SPSS  version 24. Data were summarized using mean, standard deviation, median, minimum and maximum in quantitative data, and using frequency (count) and relative frequency (percentage) for categorical data. Comparisons between quantitative variables were done using the nonparametric Mann–Whitney test. For comparison of serial measurements within each patient the nonparametric Friedman test and Wilcoxon signed rank test were used . For coms than 5 . Correlas than 5 . The ROCThere was a highly significant difference between the patients group and the control group concerning FFA concentration in CSF .The GCS at 30 days shows a significant correlation with FFA in CSF .There was a significant correlation between FFA in CSF and the mRS >2 at 30 days .There was a significant correlation between FFA in CSF and the NIHSS ≥ 16 at 30 days .Our study subdivided (group 1) patients according to infarction volume and compared the 2 subgroups with FFA in CSF. We found significant difference between 2 subgroups .P value 0.007)  patients  .P value 0.037)  .µl in the patients group and 0.22 + 0.04 nmol/µl in the control group, which reflects significant elevation of FFA levels in CSF in patients with AIS compared to healthy controls (P < 0.001).Our study results revealed that the mean value of FFA levels in CSF at admission was 0.34 + 0.24 nmol/P < 0.0001).These findings were consistent with Sun et al.  who statP value 0.037). These results suggested that FFA in CSF might be a helpful predictor of outcome in AIS.Our study reported a significant linear correlation between FFA in CSF and the mRS >2 at 30 days .Likewise, Pilitsis et al.  reportedP value 0.049).In our study, we found a statistically significant linear correlation between FFA in CSF and the NIHSS ≥ 16 at 30 days after the onset of stroke . These results suggested that FFA in CSF could be a respectable prognostic predictor of severity in AIS.Moreover, we found a statistically significant linear correlation between FFA in CSF and the GCS < 7 at 30 days from stroke onset .Also, Niu et al.  studied µl vs. 0.24 + 0.6 nmol/µl) (P=0.007), with a cutoff value of 0.27, specificity of 72.2%, and sensitivity of 62.9%.In our study, we found a statistically significant correlation between FFA levels and all-cause mortality. In patients who died, FFA levels were 1.5 folds greater compared to patients who survived  after adjusting for other confounders such as age, previous stroke, HTN, and the NIHSS, with a sensitivity of 93.44% and specificity of 61.11%. These results indicated that FFA in CSF might be a useful predictor of mortality.Also with multivariate analysis, there was an increased risk of death associated with FFA levels ≥0.27 nmol/In association with our results, Wei et al.  and DuanOur results additionally showed a significant correlation between FFA levels in CSF and neurological causes of mortality with a statistically significant difference between survivors and nonsurvivors due to neurological insult as a cause of death.This supports the suggestion that the local increase of FFA in CSF is related to neurological insult, and hence its impact on mortality.P value 0.001).Large volume infarction conveys increased risk of worsening of neurologic status, incapacity, stroke severity, and even death. Our results showed a significant correlation between FFA and infarction volume ≥145 ml .On the other hand, our results showed no correlation between FFA levels in CSF and patients with AF . This supports the prognostic role of FFA in CSF and the evidence that persistent elevation after stroke episode brings risk of stroke repetition.We also reported higher FFA levels in patients with AIS who had previous stroke  and blood lipids. Unfortunately, in our study, we could not exclude definitely these conditions.Nakano et al.  detectedIn our study, we assessed FFA in CSF only at admission, so the follow-up data regarding the peak level and duration of elevation are missing.We tested FFA only in CSF without plasma samples, and this was performed after the stroke event, which might not accurately represent prestroke status and the relation between CSF and plasma levels.It has been shown that normalization of plasma FFA levels with acipimox, a nicotinic analog, normalized insulin resistance in obese, nondiabetic subjects and improved insulin resistance in obese patients with T2DM. Nicotinic acid or long-acting nicotinic acid analogs effectively lower plasma FFA levels. Unfortunately, their use is associated with a rebound of plasma FFA to very high levels, which makes this class of drugs unsuitable for the long-term control of plasma FFA.β-oxidation, and oxidative phosphorylation [Thiazolidinediones (TZD) lower plasma FFA levels for long-term and without rebound. They do this primarily by stimulating fat oxidation through a coordinated induction of genes in the adipose tissue related to FFA uptake, binding, rylation . Howeverrylation .γ and fibrates through activation of PPAR-α), their use in combination produces greater decreases in plasma FFA levels as well as greater improvements in insulin sensitivity than the use of either drug alone [Fibrates, another class of lipid-lowering drugs also lower plasma FFA levels modestly and without rebound primarily by stimulating fat oxidation in the liver . As bothug alone .κB pathway and thus may reduce the incidence of atherosclerotic vascular problems.Lowering of plasma FFA, in addition to improving insulin sensitivity, may also prevent activation of the proinflammatory and proatherogenic NFThe use of such medications or others needs further studies to weigh their efficacy especially in patients with AIS and their role either as prophylactic or therapeutic.FFAs level in CSF can provide important therapeutic applications:Contraindications for lumbar puncture include candidates for thrombolysis and severe brain injury with increased intracranial tension (ICP). Those patients were excluded from our study. Hypothetically, if CSF samples were taken from such patients, their results could affect our results in a way or another.Our study population was relatively small in size (only 80 patients), while larger sample size population might be needed for better analysis of statistics and data validation in a long-term prospective cohort study.Also, we measured all-cause mortality; however, categorization of death is sometimes unreliable in clinical practice.Despite the special training needed to apply the NIHSS, still there is a remarkable interobserver variability . Also, iHence, the addition of FFA in CSF to the traditional clinical scores might have better prognostic accuracy.FFA in CSF may serve as an independent prognostic biomarker for assessing the prognosis of acute ischemic stroke and its clinical outcome. It might be a useful valid surrogate biomarker for early detection of high-risk patients for poor outcome and hence more aggressive treatment.


Augmented Reality (AR) provides an alternative to the traditional forms of interaction between humans and machines, and facilitates the access to certain technologies to groups of people with special needs like children. For instance, in pediatric healthcare, it is important to help children to feel comfortable during medical procedures and tests that may be performed on them. To tackle such an issue with the help of AR-based solutions, this article presents the design, implementation and evaluation of a novel open-source collaborative framework that enables to develop teaching, training, and monitoring pediatric healthcare applications. Specifically, such a framework allows for building collaborative applications and shared experiences for AR devices, providing functionalities for connecting with other AR devices and enabling real-time visualization and simultaneous interaction with virtual objects. Since all the communications involved in AR interactions are handled by AR devices, the proposed collaborative framework is able to operate autonomously through a Local Area Network (LAN), thus requiring no cloud or external servers. In order to demonstrate the potential of the proposed framework, a practical use case application is presented. Such an application has been designed to motivate pediatric patients and to encourage them to increase their physical activity through AR games. The presented games do not require any previous configuration, as they use ARCore automatic surface detection technology. Moreover, the AR mobile gaming framework allows multiple players to engage in the same AR experience, so children can interact and collaborate among them sharing the same AR content. In addition, the proposed AR system provides a remote web application that is able to collect and to visualize data on patient use, aiming to provide healthcare professionals with qualified data about the mobility and mood of their patients through an intuitive and user-friendly web tool. Finally, to determine the performance of the proposed AR system, this article presents its evaluation in terms of latency and processing time. The results show that both times are low enough to provide a good user experience. Augmented Reality (AR) has been drawing more and more interest in the last years both for industrial and entertainment purposes ,2. ThereSpecifically, the term AR refers to a technology that provides an environment in which virtual objects are combined with reality, thus integrating computer-generated objects in the real world . TherefoThis article presents a novel collaborative framework that is able to synchronize shared experiences where multiple AR devices detect each other and interact through a Local Area Network (LAN) without depending on a remote server. Thus, the framework allows for deploying shared AR applications anywhere, even without an Internet connection, as long as the devices are connected to the same local network.In addition, this article proposes a practical use case where an AR mobile application is presented, describing the design and development of an innovative architecture for AR gaming experiences. Such an application is focused on helping pediatric patients and includes the necessary tools and accessories to monitor its use and the physical condition of the patients according to their application usage patterns. Since the proposed type of application should facilitate and motivate the physical activity of pediatric patients, the use of AR is essential, because it provides the ability to use the real world environment as a playground. In this way, it is possible to create three-dimensional activities that foster player physical activity in order to interact with the game. Moreover, the AR mobile gaming framework described in this article allows multiple players to engage in the same AR experience, so children can interact and collaborate among them sharing the same AR content, which is placed at the same positions.Furthermore, the proposed system includes a web data crowdsourcing platform for doctors and medical staff that is able to manage pediatric patient profiles and that facilitates the visualization of the data collected by the mobile application. Such a web tool also allows for configuring the different parameters of the AR system so as to restrict access or to enable the specific activities that each children can perform with the mobile application. Thus, the developed system provides a very useful tool for developing AR experiences focused on patients with long pediatric stays at the hospitals.It provides a detailed description on how to develop a novel open-source collaborative AR framework aimed at implementing teaching, training and monitoring pediatric healthcare applications.It details how to make use of the developed AR framework so as to implement from scratch a practical pediatric healthcare application. Such an application does not need any previous configuration from the user and includes the possibility of creating shared AR experiences between different mobile devices. In addition, the developed system enables the collection and visualization of custom usage data, which can be remotely monitored and analyzed.The performance of the framework is evaluated in terms of latency and processing time in order to demonstrate that it provides a good user experience. In addition, it is worth noting that the presented framework is open-source (under GPL-3.0 license), so it can be downloaded from GitHub  and thenSpecifically, this article includes three main contributions:The rest of this paper is structured as follows. AR and MR are currently considered two of the most promising technologies for providing interfaces to visualize and explore information  and theyIn the literature there are some recent preliminary works of collaborative AR/MR applications. The most promising developments use expensive smart glasses like Microsoft HoloLens . For exaThere are other recent works devoted to providing mobile collaborative AR experiences. For example, Zhang et al.  proposedThe concept of collaboration can be also understood as a way of enabling the interaction between Internet of Things (IoT) and AR/MR devices . For insA number of articles endorse the use of technologies like AR or Virtual Reality (VR) as a mean through which the quality of life of pediatric patients can be improved. For example, Gómez et al.  proposed“Me van a hacer un transplante” (“I’m going to have a transplant”) whose main objective is to inform and reassure pediatric patients before operations in order to reduce their fear and uncertainty. In the case of “Nixi for children” [“Me van a hacer un transplante” [Different commercial applications are available for easing pediatric stays. For instance, there are projects such as “Nixi for children” or hildren” , the aimsplante” , it is aThere are other applications that were devised with the idea of facilitating the communication between children and health-care personnel through different games and activities. For example, “Dupi’s magic room”  is a pro“En calma en el quirófano” [“REM volver a casa” [Regarding patient stress management, there are a few applications aimed at reducing pre-operative or post-operative anxiety, although they are mostly focused on adult patients. An example is irófano”  , remote servers, or sophisticated expensive AR/MR devices.Regarding pediatric healthcare use cases, all the solutions cited in Among the analyzed applications, only a few target children and there is only one solution that makes use of AR. Regarding this aspect, “EntamAR” uses a platform which needs an ad hoc solution for each game and location where the game is to be played. This fact involves the need for carrying out a previous process in which the room has to be scanned and the game has to be re-assembled using the mentioned AR platform.Therefore, after analyzing the previously mentioned alternatives, it was concluded that there is a lack of autonomy of the AR systems when it comes to provide a complete User Experience (UX). Moreover, none of the analyzed alternatives offer a mechanism for monitoring patients in order to visualize their state or evolution.Due to the previous issues, the framework presented in this article is focused on enabling the development of AR applications that motivate the mobility of hospital patients and that needs no previous configuration from the user. In addition, the open-source framework provides a novel feature that has not been found in the state of the art: it allows pediatric patients to share the same AR experience in real time, so they can collaborate among them when playing the games. Furthermore, the developed system enables the collection and visualization of patient usage data. Such data can be really useful for doctors, who will have a dynamic and indirect way for collecting data on the mobility and mood of their patients.The next subsections describe the internal components of the developed framework. Specifically, it is first detailed the communications architecture used by the AR applications that make use of the collaborative framework and, next, the design and implementation of the framework are described thoroughly.The backend hosts a remote database and manages the requests made from web and mobile applications through a Representational State Transfer (REST) Application Programming Interface (API). In this article it is assumed that a mobile application  is in charge of gathering and managing the data collected from the users and is responsible for storing such data on a local database on each device. Moreover, the mobile application is responsible for sending usage data to the backend server.As far as data storage is concerned, only the minimum necessary information is stored in the mobile device local database in order to guarantee the proper functioning of the application. For instance, in a pediatric healthcare application, the remote database would store all the essential personal information on the patients: height, the difficulty level of the games, year of birth and the dates when the users were created and modified.All the AR mobile devices within the same LAN connect with each other without requiring to connect to the Internet. Such a communication is handled by the framework, which is able to keep track of the status of each user and propagate the events that occur in each of the application instances.The devised system has to support AR visualization and interaction.It has to allow two or more players to place 3D objects in a way that they are synchronized regarding materials or animations performed on the objects.If new objects are incorporated into the scene, they have to appear on all of the connected mobile devices at the appropriate positions.The system has to provide scoreboards and a method to keep them synchronized at all times.The system should allow an easy method to create, host and join games, keeping in mind that the application that would use the proposed framework could be used by children.The system has to provide a way to store usage data from users and gather them in a centralized location, so it can be easily accessed and analyzed.During the design of the proposed collaborative framework, the following requirements were considered:Considering the previous requirements, the proposed framework was designed to provide a set of tools to develop AR games for pediatric healthcare that is composed by the following components, which are described in the next subsections: the AR subsystem, the backend server, the communications subsystem and the visualization subsystem.Augmented Reality and game engine. It must be first noted that there are actually two main types of AR: marker-based and markerless AR . In addiMobile Platform. For the selection of the mobile platform, the considered alternatives were the two most used platforms at the moment (Android and iOS), as well as the use of a hybrid mobile development framework. After considering the compatibility with the libraries provided by ARCore and with the used game engine, it was decided to develop the application for Android, since, as it was previously mentioned, it is currently the most popular mobile operating system, it has a wider support and a growing number of ARCore-compatible devices. However, other platforms might be taken into consideration in future work.Local database. The local data storage system is located on each mobile device and stores all the data collected by the application. For each patient, information is collected about his/her daily mood survey results, as well as the playing time and his/her step count . In addition, the patient profile settings are stored on the local database. All the mentioned data and settings can be also visualized and modified from the web application. In the case of Android, local storage can be implemented through the shared preferences, the internal/external storage system or by using a local database . Due to The AR subsystem is divided into the following sub-components:The backend server was designed as a web server that follows the Model View Controller (MVC) pattern. Such a software architecture pattern separates the data presentation layer from the management logic of the user interactions. The server is therefore in charge of managing the business logic and the data access layer, including all the infrastructure that supports the provision of the provided services.The backend server provides a REST API through which various endpoints can be accessed.Server software. Different technologies (frameworks and programming languages) can be used for implementing the backend server, like Java , C# , JavaScript  or Python . Among the available solutions, Django was selected due to its learning curve, available documentation, libraries and extensions ), community support, security and scalability.Remote database. It can be implemented by using cloud storage ) , Azure  or GooglDifferent technologies can be used for developing the Visualization Subsystem, like Angular , React , Vue 5353, BootsThe development of shared AR experiences requires the use of a system that facilitates the communications among AR devices. For the proposed system, the mentioned system has to be compatible with Unity and should provide an easy way to implement the requirements of the AR games: to spawn virtual objects at a specific spot, to detect which user has first performed certain action and to keep the scoreboards synchronized.The first alternative to develop the framework may consist in using the tools provided by Unity. In this case, it would be necessary to use the UNet network library , which pAnother alternative provided by Unity is Multiplay , a game The other two best known options are Mirror  and PhotConsidering the previous analysis, it was decided to use Mirror as the baseline for the implementation of the collaborative framework. This is due to its similarity with the deprecated UNet and the large number of users and documentation they offer. In addition, the fact that Mirror is a free software project means that the code can be accessed at all times, and can even be easily modified or extended if necessary.One of the priorities that is always present in a hospital environment is to improve the quality of life of patients. For instance, one of the consequences of hospitalization is an increase in patient stress levels, including children, who usually experience increases in their stress levels, which derive into aggressive behaviors, isolation and difficulties when recovering from medical procedures . MinimizDuring periods of hospitalization, play activities are often used in the form of therapeutic play or play therapy, thus providing an improvement in their physical and emotional well-being, while also reducing patient recovery time. Games can help to reduce the intensity of the negative feelings that occur during children’s hospitalizations, thus being appropriate, for example, in pre-operative period preparations and invasive procedures . TherefoTo show the technical capabilities and the performance of the proposed AR framework, a demonstrative experience was created. In such an application, part of the games were adapted so that they can be used both by children with complete or restricted mobility. It is important to note that the application is intended to test the developed system from a technical point of view and demonstrate its technical capabilities. No empirical scientific tests with children were made. Any applications made with this framework will have to be assessed taking into account medical considerations and tests will have to be carried out. In our future work we will tackle these issues as soon as the COVID-19 pandemic allows for carrying out the experiments in safe scenarios. For example, one possibility would be to perform the evaluation as follows. First, the testing group would be split into two subgroups: one that would use the application daily and another that would not. The idea would be to conduct periodic surveys during their hospital stay asking for changes on, for instance, children’s behavior, pain level or mood improvement, among others. The final stage of the experiment would consist in comparing the results of the two groups and verify the effectiveness of the proposed application. Another useful experiment would require to conduct surveys before and after children undergo medical tests, thus evaluating and comparing the results to verify if the mobile application is also effective in such scenarios. At the same time, throughout this evaluation process, the usability of the application would also be examined, looking at how children use the application and including questions in the surveys about such a topic.AR should be included in the mobile application in order to encourage children to perform daily physical activity. Since AR can integrate the virtual elements of the game into a real scenario, it is possible to provide new augmented experiences and to increase player engagement and motivation.Children are the target of the AR application, so the User Interface (UI) needs to be as simple as possible and the mobile device should be comfortable and easy to use. For these reasons, the use of mobile devices such as mobile phones or tablets are a better option than smart glasses or HMD devices. In addition, HMD devices like Microsoft HoloLens smart glasses are much more expensive, they are designed for adult-size heads, they are quite heavy (579 g) and have a steep learning curve.The mobile AR application should be designed to host games aimed at children between 6 and 14 years old. This decision implies that the UX design needs to be adapted to the mentioned age range. As a consequence, the AR application has to implement simple interfaces, large buttons and actions that require a minimum number of steps.In order to be able to run the application on different mobile devices, its computational resource requirements need to be limited, thus emphasizing its performance rather than visual details. For such a reason, cartoon low-poly aesthetics are appropriate, since they help to reduce computational complexity.The mobile AR application needs to collect the children’s usage data so that they can be later visualized and managed through a web platform as well as through the developed mobile application. Such data should be displayed by using simple charts, where playing time, steps and daily surveys can be shown in an attractive way.It is important to consider that the games to be designed are intended to encourage patients to engage them in moderate physical activity inside a hospital within a restricted area. For example, as it will be described later in The proposed games should also be multi-player games and ideally foster the cooperation of the pediatric patient with other people  in order to solve a problem. For instance, the game described in The requirements for playing the game should be minimized. Therefore, the use of external components  or previous scenario-recognition phases should not be necessary so as to avoid scanning the environment and thus removing the need for creating and personalizing the games for each hospital room. As a consequence, the developed solution should be flexible enough to be used during the most common situations and should be adapted to the abilities and the most common limitations of a pediatric patient.Considering the system objectives mentioned in Following the requirements previously indicated in In case the user logs in by scanning a barcode but does not grant the data storage permission, the application will not collect or store information about the patient. In contrast, when the user logs in by scanning a barcode and accepts the necessary storage permissions, it is checked whether the daily survey is required . When the user completes the survey or in the case that it is not necessary to do so, the user menu is shown, which enables accessing the AR games and viewing the user statistics stored in the local database of the device.The data collected by the mobile application are stored so that they can be viewed by the medical staff and patient families in a quick and efficient way. The data collection process consists of two steps: first, the mobile application collects and stores data in its local database; then, if an Internet connection is available, the data are sent to a server, where they are stored permanently.The devised application design also considers other usability aspects in order to adapt the controls and interfaces to the different constraints of the mobile application users. For instance, the interface is as simple as possible, with a limited amount of different screens, so users do not need to navigate through multiple screens to get to the different parts of the application. In addition, the amount of shown text has been minimized and icons have been incorporated, so that children can easily understand how to use the application.Regarding the four games described later in Finally, attention should be paid to the fact that environmental conditions affect ARCore performance when detecting and tracking surfaces . For thiIn the proposed use case, the backend is used to save the data collected from the mobile devices, providing an information access point to the healthcare personnel and to patient’s family. This means that healthcare professionals do not have to collect manually the local usage data from each device. In addition, having a central database allows the information to be synchronized among different devices. Furthermore, the backend database can be used to back up local data, allowing for installing and uninstalling the application without losing patient data.Three GET requests were designed: one for obtaining user profile information; another for determining whether the patient has already filled his/her daily survey; and a last request, devised for the website, which provides the summary of all the patient data so that they can be easily displayed on charts. In addition, the REST API defines three POST requests that are used to send information to the server regarding new users, games and surveys.The web frontend is the interface through which remote users and the backend server communicate. Since the backend server was designed by using the MVC pattern, the frontend corresponds to the view part of the pattern.To implement the frontend, a website was devised to visualize and manage patient data remotely. Specifically, the website was designed to provide easy navigation and access to each patient’s data in a clear and simple way. To access each patient’s data, the remote viewer only has to enter the barcode number of the monitored patient. The website also provides a menu to modify the patient settings and restrictions of the games.Home page. It provides a welcome page with a video showing all the games and a summary on the features of the mobile and web applications. In addition, a button is provided through which the remote user can access the patient search page. A screenshot of the home page is shown in Search page. It is used to look for a patient profile by inserting his/her barcode number. User data edition page. In this page the patient’s personal information can be edited. A screenshot of the edition page can be seen on Patient data page. It can be accessed from the search page after registering a patient in the database. As it can be observed in Specifically, the web application offers the following pages that users can navigate through:In order to validate the proposed mobile AR framework, the use cases described in the next subsections were tested, verifying the authentication and initialization of the system, and each of the developed games, as well as the web application.Within the mobile application, there are two available options: the user can access with or without scanning the barcode. In order to use the application and store the patient’s usage data, the patient must first log in. The way to log into the application is by scanning the barcode of the hospital identification bracelets, as it can be seen in Once the barcode is scanned, it is checked whether the patient is registered in the system. If the patient is not registered, such a registration is then performed by asking for permission to collect and store his/her data. Then, the login process continues by checking whether the patient must take his/her daily survey and, then, the main menu is displayed. During this process, if an Internet connection is available, requests will also be made to the server to check if there are any data about the user on the backend server.The daily survey is shown during the login process once a day for each registered patient. As it is shown on If a user does not want to register or send his/her usage data, he/she would choose the login without barcode option, in which it is only possible to access the application and start a gaming session.Within the Unity project there is a main scene where the rest of the scenes are loaded. This scene has an object to which a parameter is passed with the scene number that has to be loaded next.ARCore is used to detect horizontal surfaces, which is necessary for the correct positioning of 3D objects on real scenarios. During this process, raycasting is performed from the camera in the direction of the user to check for collisions with the surfaces detected by ARCore. The collision point is where the virtual objects will be placed.The system of user interfaces, that includes the buttons and the interactions with the user through scripts that can be adapted to each specific scene, is the same for all scenes. Users can show/hide the main menu and restart the game. In addition, in the “Map explorer” and “WakaMole” games, users are able to scale and rotate the map in order to see it from a more comfortable point of view without having to move excessively. As it was previously mentioned, such a functionality is aimed at easing the interactions of patients whose reduced mobility prevents them from solving a challenge because they are not able to visualize the map from all the required perspectives.Moreover, the developed mobile application enhances its UX through haptic feedback, which is used to reinforce the response of the system to user interactions. Thus, when the user makes a mistake, a short vibration is emitted, while when the game is completed a repetition of vibrations is emitted as a ‘celebration’. In addition, it is also considered appropriate to add a particle system that simulates confetti to indicate that an objective was achieved and to reinforce the positive feeling of the user.Another aspect that is considered important is to adapt the size and position of the map scaling and rotation sliders when rotating the mobile device. In this way the shape of the sliders is not distorted, since Unity’s way of managing the interfaces is by ratios and distances to anchors. In the case of the screen rotation, it is an event that is collected by the Android application and then sent through a message system that a script receives in Unity.The first of the activities devised for pediatric patients was the game “Marco polo”, which does not involve AR, but which enables testing the rest of the components of the developed system. Specifically, the game requires a minimum of two people: one would hide the mobile device and would click on a button, while the rest of the players will try to find the mobile device by being guided by the sound it plays.In Once the level is selected, the game can begin. A timer has also been added to keep track of the time from when the device is hidden to when it is found.The main objective of this game is for the patient to walk and do a minimum of physical activity. The game consists of walking through a room or corridor, aiming the camera of the device towards the floor to detect the surfaces, where animals will appear. When the animals are displayed, the patient will have to "collect" them by clicking on the 3D objects. When an animal is registered, its silhouette will light up on a panel located on the lower left side of the screen, making the user aware of the animals still to be found and showing how many of them have already been collected.Once a surface is detected, an internal counter is triggered which, after a random time within a range, will cause an animal to appear on the surface that the user is targeting. The instantiated animal (3D model) will be randomly chosen from a list of animals that is passed to the scene controller for this purpose. After the user clicks on the animal, the counter will be activated again, restarting this cycle, which will stop when all the animals on the list are displayed.This game challenges two patients to solve a map in a collaborative way. For this purpose, users can play two roles: the explorer, who has to guide a character through the map, and the assistant, who has the clues to discover the steps the explorer has to follow to solve the puzzle.For this game there are two different maps available: Savannah and North Pole, which are shown on This activity uses the ARCore surface detection tool in order to place the map on a surface at the beginning of the game. In each map, the position of the characters and obstacles is predefined, changing in each execution small details that will be used to indicate the order of the resolution of the challenge. The correct order for the solution of each map can be found in the posts that can be accessed by the other player from their device. Thus, completing the game is a task that needs to be achieved with the collaboration between the two patients.In addition, a timer has been included to count the time it takes the players to solve the challenge. This is meant to encourage the patients to keep playing and moving on a daily basis.This game was designed thinking about children who cannot move or have very little mobility, as they can play without the need for walking around a map. The game is for two patients that play against each other, trying to ’capture’ as many animals as possible. The animals appear periodically at random points on the map, and have a time limit after which they disappear. The player who first clicks on an animal gets a point. The game ends when one of the players reaches a previously agreed score, since there is no time limitation.To perform the previously described process, the users need to be connected to the same game. For such a purpose, one of the players starts a new game, and the other one joins the game introducing a game code as it is illustrated in After the matchmaking process is completed, the new scene containing the game is loaded. If only one of the players clicks on the animal, there will be no conflicts, since there is enough time for the message to be sent from the client to the server . The problem arises when both players click on the same animal almost simultaneously, as both event messages would reach the server and a point would be added to each player. In order to solve this problem, the message flow has been implemented in such a way that the client sends its own identifier to the server, and when the server notifies the clients that the animal has been clicked on, it also sends such an identifier. This allows each client to check if the received identifier matches its own before giving the order to add a point to its scoreboard. When one of the scoreboards is incremented, it is automatically updated in all clients, as they remain synchronized at all times. An example of the such scoreboards can be observed at the bottom of the screenshot on the right of The developed collaborative AR game described in Device 1 (tablet): Samsung Galaxy Tab S4 with 4 GB of RAM, 64 GB of internal memory and a Qualcomm Snapdragon 835 processor .Device 2 (smartphone): OnePlus 6T with 8 GB of RAM, 128 GB of internal memory and a Snapdragon 845 processor .To evaluate the performance of the developed system, four sets of tests were carried out by using two different mobile devices. Such devices acted first as clients and then as hosts of the game in two different scenarios: through a local network  and through the Internet, when the two users were in remote locations. The used devices have the following specifications:First, at one point during the game, a client sends a message to transmit a game event.Then, the server receives the message over the network.Next, the server waits until the next frame processing slot is ready.The received message is parsed and processed by the server, which sends a response to the client.The client receives the message from the server over the network.The client waits until the next frame processing slot is ready.The message is parsed and processed by the client.Each set of tests consisted in playing the game for 10 min. During such a time, the latency and the processing time data of every packet were collected and stored in a local file. It should be noted that the mentioned data were obtained in a way that they represent accurately the latency/time that the application will experience in a real environment. In addition, it is worth noting that, due to the single-thread nature of Unity, the measured times include the waiting times that the application requires during its execution in order to manage the processing slots of the used frames. Specifically, the following are the main steps included in the estimation of the latency:Although the previous steps estimate times that are slightly higher than the existing network latencies , they provide more realistic and accurate estimations on the times that a user of the game will experience in real life.Both Since, for each scenario, network latency is essentially the same (with slight oscillations due to traffic load), the observed latency differences are related to their processing time, which is the time required by the application to process a package and render the interface changes. This paper presented the design, implementation and evaluation of an open-source collaborative framework to develop teaching, training, and monitoring pediatric healthcare applications. The framework enables functionalities for connecting with other AR devices and for enabling real-time visualization and simultaneous interaction with virtual objects.In order to show and asses the technical capabilities and the performance of the proposed open-source collaborative framework, an AR application was developed in order to demonstrate its potential for future researchers and developers of pediatric healthcare applications. Such an AR application actually consists of two applications: a mobile gaming application and a web application aimed at monitoring the progress of pediatric patients in terms of mood and performed activities. The collected data are shown in a user-friendly way through charts, so their representation is intuitive and easy to understand.The developed AR system was evaluated by using two different mobile devices  with different hardware capabilities. The conducted performance tests measured the latency and the processing time of every packet during real games. The obtained results show that average latency is always below 200 ms for every tested device, which results in a smooth gaming experience. However, it was also observed that the selected AR device impacts user experience substantially. In addition, it was concluded that wireless communications should be carefully examined in AR environments where network latency is critical. Nonetheless, considering the previous observations, it can be stated that the proposed open-source AR collaborative framework can help future researchers to develop the next generation of AR collaborative pediatric healthcare applications. As future work, the authors plan to conduct a thorough evaluation of the mobile app with pediatric patients as soon as the current COVID-19 pandemic situation allows it.


The synergy between biological and bioengineering advances is critical to developing novel and impactful translational therapies. However, there currently are few opportunities for regenerative scientists to be exposed to the methodologies commonly employed in the clinic by rehabilitation professionals, and most rehabilitation scientists and clinicians are not exposed to the many advances of regenerative medicine. This disconnect has impeded the pace of progress in the field. The Eighth Annual International Symposium on Regenerative Rehabilitation brought together basic scientists, engineers, and rehabilitation clinicians to present scientifically rigorous and cutting-edge research and clinical management, focusing on new and innovative approaches that combine discoveries in tissue engineering, medical devices, and cellular therapies with rehabilitative protocols. However, there currently are few opportunities for regenerative scientists to be exposed to the methodologies commonly employed in the clinic by rehabilitation professionals. Conversely, most rehabilitation scientists and clinicians are not exposed to the many advances of regenerative medicine. This disconnect has impeded the pace of progress in the field. To this end, the International Consortium for Regenerative Rehabilitation—comprised of 16 institutions—aims to increase interdisciplinary interaction. Thus, as technologies are developed and our understanding of regenerative biology progresses, advances may be efficiently translated to the clinic2.Regenerative Rehabilitation seeks to optimize patient outcomes through an integration of two fields: regenerative medicine and rehabilitation science. The former focuses on tissue repair or replacement due to loss from injury, disease, or age. This is achieved primarily through the enhancement of endogenous stem cell function or the transplantation of exogenous stem cells. The latter focuses on the use of mechanical and other stimuli to promote functional recovery. This synergy between biological and bioengineering advances is critical to developing novel and impactful translational therapiesTo address this need, the annual international symposium is designed to propel the translation of regenerative technologies into functionally relevant treatment interventions that have the potential to transform rehabilitative healthcare. The Eighth Annual International Symposium on Regenerative Rehabilitation brought together basic scientists, engineers, and rehabilitation clinicians in order to create a fertile ground for discussion, interaction, and networking across disciplines. The symposium took place on 24–26 October 2019, in Charlottesville, Virginia, and was co-hosted by the University of Virginia and the Uniformed Services University of the Health Sciences.Scientific: to promote the clinical translation of scientific discoveries in the field of regenerative medicine by communicating and disseminating research findings that demonstrate the synergistic relationship between regenerative medicine and rehabilitation; (2) Programmatic: to provide multiple forums in which scientists, rehabilitation clinicians, and trainees may interact, exchange ideas, and identify novel research directions relating to the field of Regenerative Rehabilitation; (3) Mentorship and training: to introduce the concept of Regenerative Rehabilitation to promising graduate students, medical residents, clinical fellows, post-doctoral research fellows, and other junior investigators and clinicians, inspiring and supporting them to embrace and incorporate innovative technologies in their nascent clinical practices and research programs.The symposium held sessions to address three principle objectives: (1) The scientific sessions brought together world-renowned researchers and clinicians to present on scientifically rigorous and cutting-edge research and clinical management. Topics focused on new and innovative approaches that combine discoveries in tissue engineering, medical devices, and cellular therapies with rehabilitative protocols.5. His work has pioneered the use of material-alone, cell-alone, and material+cell approaches to address tissue defects of varying size as well as across all four levels of tissue complexity 6. Dr. Atala highlighted two important lessons learned through his research. First, is the value of a methodical approach. The genesis of each line of investigation is thorough cell biology and materials sciences studies, then transitioning to small, medium, and large animal studies. Only after which does it reach human patients for testing and long-term follow-up. Second, is the necessity of a multidisciplinary team—including cell and molecular biologists, material scientists, biochemists, and physicians—where team science has helped propel this technology from the bench to the bedside. Dr. Atala also discussed work in the cell therapy area, such as the use of skeletal muscle for shoulder cuff injuries, and concluded by sharing his future directions in stem cell therapy, specifically the use of amniotic fluid and placental stem cells7. He emphasized their clinical utility with respect to ease of collection, shared properties with embryonic and adult stem cells, lack of tumor potential and rejection concerns, and storage capabilities.Drs. A. Bobby Chhabra and Fred Epstein from the University of Virginia opened the meeting by emphasizing the importance of interdisciplinary collaborations in research. Opportunities like this symposium do not just highlight existing teamwork but foster new engagement and relationships that are critical to translational success. Picking up on this theme, Dr. Anthony Atala (Wake Forest Institute for Regenerative Medicine) shared his journey through a three-decade long research career in tissue and organ engineering, including the successful implantations of tissue engineered kidneys, bladders, and sexual organs8. Indeed, the new vascular network formation is very sensitive to biomechanical conditions, but the regulatory role of matrix deformations and remodeling during tissue regeneration in vivo needs to be evaluated. He showed how functional loading has a potent time-dependent effect on both mineralization and vascular growth in vivo, with early loading being detrimental whereas delayed loading enhanced outcomes9. Additionally, in a controlled, in vitro model, Dr. Guldberg and his group have demonstrated that allowing the vascular network to develop for 5 days before adding compression plus shear optimized outcomes. Dr. Guldberg’s Regenerative Rehabilitation approach to large bone defect repair nicely demonstrated the clinical relevance of timing and method of stimulation in designing rehabilitation protocols.Plenary speaker Dr. Robert Guldberg (University of Oregon) provided an insightful talk on the preclinical and in vivo models his lab uses to assess vascular and bone growth under different load conditions, with both acute and delayed treatment models. His group has pioneered the integration of implantable wireless sensors to monitor the mechanical environment within the regenerative niche10. As an extension of this pioneering work, Dr. Engler kicked off the session with an engaging presentation on leveraging biomaterials to better approximate extracellular matrix properties to induce cardiomyocyte phenotypes. This disease-in-a-dish approach allows for induction of pathological cardiomyocytes responses to study, identify, and subsequently interrogate signaling pathways, which may ultimately inform clinical interventions. These interesting results suggest that any culture system should require specific dynamic materials that change as the niche does in vivo. Dr. Fabrisia Ambrosio (University of Pittsburgh) then shared her work on extracellular vesicles and the protein Klotho. Understanding how circulating factors affect the mitochondrial function of muscle stem cells provides insight into how muscle loses its ability to heal with increasing age, which could present an interventional target to restore one’s molecular profile to a more “youthful” stage.This session focused on the role of mechanical stimulation for enhancing stem cell function. In 2006, Dr. Adam Engler  and colleagues first demonstrated that stem cells are highly mechanosensitive and that biophysical characteristics of the extrinsic microenvironment is a potent driver of stem cell lineage specification11. The results demonstrated that, although gene therapy alone can improve endurance, muscles in the mdx mouse model treated with gene therapy and combined with exercise are capable of adapting to training and achieving significant gains. Consequently, this Regenerative Rehabilitation therapeutic approach has great clinical potential for development of effective drug and physical therapy treatments of DMD.Dr. Robert Grange (Virginia Tech) talked about the pathogenic mechanisms and treatments for Duchenne muscular dystrophy (DMD), with a focus on rescuing dystrophic muscle so patients can better perform and enjoy activities of daily living. His Regenerative Rehabilitation approach was to use gene therapy in combination with endurance exercise in a rodent model—the mdx mouse—to significantly improve the time-to-fatigue during the final treadmill run at the end of the training period. Dr. Grange has previously shown that mdx muscles can functionally adapt to chronic exercise, but exercise alone is not enough to completely overcome the maladaptive response of dystrophic muscle3T), an NIH-funded resource network established in 2015. The mission of AR3T is to support the expansion of scientific knowledge, expertise, and methodologies across the fields of regenerative medicine, biophysics and rehabilitation. To fully realize this goal, AR3T promotes education, training, research support, and funding opportunities (www.ar3t.pitt.edu). Dr. Rando reiterated AR3T’s support of the Symposium and described the broad range of opportunities that are available through AR3T to help researchers develop and succeed with innovative lines of Regenerative Rehabilitation research. The opportunities include short-term sabbaticals to AR3T sites, consultations with subject matter experts, pilot funding, technology development grants, paired mentoring experiences, and access to diverse educational courses.Co-director Dr. Thomas Rando (Stanford University) shared an overview of the Alliance for Regenerative Rehabilitation Research & Training , Dr. Sunil Gandhi , and Dr. Gunes Uzer (Boise State University) were selected to present on their ARDr. Gandhi discussed his progress in the development of a method for live imaging of somatosensory fibers in cervical spinal cord that can help to determine whether effective human neural stem cell engraftment enhances robotic-assisted therapy after spinal cord injury, thus improving recovery. Dr. Uzer showed a 3D printable, repeatable, adaptable and easy-to-use model of bone marrow that will be useful for studying cell responses in specific mechanical environments.The Department of Defense (DoD) has increasingly relied on the role of Regenerative Rehabilitation to advance the translation of cutting-edge regenerative technologies for the functional recovery of severely wounded soldiers and civilians. This is evidenced by recent funding opportunities such as the RESTORE effort that calls for Regenerative Rehabilitation research and the AFIRM effort to advance regenerative medicine. Along these lines, Colonel Sarah Goldman  illustrated how war has motivated medical advances and she discussed applicable DoD medical research funding opportunities, including opportunities within the Congressionally Directed Medical Research Programs and other DoD Medical Research efforts.12.The plenary speaker of this session was Dr. Robert Mauck (University of Pennsylvania), sharing his translational mechanobiology work. He focused on how to motivate cell migration towards a wound site and how to use mechano-activation to our advantage for improved factor delivery to promote formation and repair of musculoskeletal tissue13. More specifically, demonstrating the importance of a Regenerative Rehabilitation approach, he showed that regeneration of neurons in the cord following SCI was significantly increased with a combination of exercise and cell graft.Dr. John Houle (Drexel University College of Medicine) shared his research on the duality of exercise after spinal cord injury (SCI), which can promote neural plasticity but also block aberrant neuroplasticityDr. David Weiss (University of Virginia) brought a valuable orthopedic surgeon’s perspective to the session. He discussed the challenges in trauma surgery when dealing with volumetric muscle loss (VML), how to evaluate the injury, and the long path ahead to regenerating muscle for massive loss injuries. He described UVA’s collaborative approach for studying VML, which includes working with the Biomedical Engineering Department to quantify the location and magnitude of VML and with the Kinesiology Department to perform functional testing.14. He also shared the multiscale biomechanical approaches currently being used to understand and ideally develop new rehabilitative approaches and therapeutics to reverse it . Drs. Joanne Borg-Stein  and Kenneth Mautner (Emory University) both shared their esteemed insights into bone marrow aspirate and adipose-derived stem cells. There are clinical logistics to consider with respect to the patient and provider, and certain rehabilitation protocols can be used to optimize the precision of regenerative medicine. Gaps in clinical practice using regenerative medicine approaches include identifying the best cell source, correct dose, best route of delivery, and optimal timing and type of rehabilitation. This led to an excellent panel discussion led by Dr. Borg-Stein, Dr. Mautner, Dr. Nelson Hager , and Dr. Quanjun Cui (University of Virginia). Topics included the clinical rationale behind using bone marrow versus adipose, the role of age in deciding treatment approach, what factors may play a role in responding to treatment, and the need to establish standards for stem cell therapeutics. This session’s clinical focus brought home the importance of collaborating in the translational process so that research data can be used to inform rehabilitation protocols to be used in combination with regenerative medicine therapies.This session began with plenary speaker Dr. George Christ (University of Virginia), who focused on volumetric muscle loss and the profound functional deficit that can be disproportionate to the volume lost15. Importantly, he challenged attendees to consider how neural technologies could be combined with regenerative medicine approaches in the brain and spinal cord to enhance stem cell differentiation and the formation of new connections that will result in improved healing.This session provided examples of translational research in the field. Dr. Michael Boninger (University of Pittsburgh) discussed the application of assistive technologies to increase function and participation in individuals with neurological disabilities. This is a very crucial topic that is reported to be of relevant impact in different aspects of neurological patient lives, such as in health, psychological and social status, education, and motor or cognitive learning16. The idea of the AxoMax technology is to use a biodegradable polymer tube containing a drug delivery system to promote the growth of peripheral nerves over large gaps (>3 cm), overcoming the current clinical limitations in nerve repair. One future direction is to add electrical stimulation and exercise to maximize outcomes.Dr. Kacey Marra (University of Pittsburgh) shared her authentic, humorous, and valuable perspective on what the translational research timeline looked like for her AxoMax technology, detailing the 20-year buildup from idea to human clinical trials to forming a companyDr. Silvia Blemker (University of Virginia) shared her collaborative research on 3D muscle modeling, which provides insight into the form, function, and biology of muscle. This work has wide-reaching applications for studying atrophy, injury, and dystrophy, as well as to inform the design and testing of tissue engineering technologies for muscle repair.17. Understanding these altered movement strategies will better inform the design of regenerative and rehabilitation approaches to prevent the development of chronic movement compensations.Dr. Shawn Russell (University of Virginia) spoke on the functional assessment of biomechanics, where the kinematics and kinetics of animal locomotion can be powerful tools for quantifying functional change after volumetric muscle lossOver the past 8 years, the symposium series has evolved to meet the needs of such a disparate audience. While a strength of the symposium is in bringing so many different students, researchers, and clinicians together in one place, there was also a need to program in targeted learning opportunities to meet specific needs.A Clinical Special Interest Group (SIG), formed in response to the growing number of rehabilitation clinicians, provides an opportunity to meet and share experiences related to the treatment of regenerative medicine therapies in the clinic. The Clinical SIG breakfast discussion, led by Drs. Carmen Terzic (Mayo Clinic Rochester) and Quanjun Cui, allowed attendees to share ideas and strategies for clinical approaches following regenerative medicine therapies to optimize outcomes.Held for the first time at the symposium, a breakfast discussion led by the University of Pittsburgh’s Dr. Fabrisia Ambrosio and Mrs. Paula Davis centered on diversity and inclusion. Attendees shared multiple perspectives and thoughts on supporting diversity in the student body and at the faculty level. Recommendations that resulted from the breakfast included that we should all obtain training on diversity and implicit bias, as each one of us can be an ally, and to support diversity across the STEM pipeline.Post-symposium workshops were “Clinical Study Design for Regenerative Rehabilitation” led by Dr. Marcas Bamman (University of Alabama), and “Rehabilitation Strategies in Preclinical Models” led by Dr. Linda Noble-Haeusslein . The goal of Dr. Bamman’s workshop was to address challenges and current opportunities specific to clinical trials in medical rehabilitation. These included trial design, issues in recruitment and retention, funding opportunities, and mobile technology integration into rehabilitation trials. An introduction to clinical trial resources for investigators was given, specifically the REACT Center and the Medical Rehabilitation Research Resource (MR3) Network Coordinating Center. The goals of Dr. Noble-Haeusslein’s workshop were to overview preclinical research design using a rodent model and to cover methods of rehabilitation and outcome measurements. Together, these will help optimize basic regenerative rehabilitation research for more successful translations of basic research to the clinic.A pre-symposium workshop was led by Dr. Rosemarie Hunziker—a former program director of the National Institute of Biomedical Imaging and Bioengineering—on how to maximize success in NIH grant writing. Geared towards trainees, early investigators, and those who may not be familiar with NIH funding, Dr. Hunziker provided an in-depth and entertaining crash course on the tips, tricks, and common challenges of the NIH.A poster session provided an excellent networking opportunity between senior researchers, clinician scientists, and students. A vast spectrum of topics was presented, including implantable sensors, biomaterials, molecular and cellular responses to biophysical signals, and mechanical stimulation in cellular therapeutics and tissue engineering.3T was selected for renewal and received its notice of award July 2020. Due to COVID-19, the AR3T Executive Leadership recently made the difficult decision to postpone the 2020 symposium to 4–6 November 2021 at the University of Texas, Austin. However, a number of virtual options are being planned in the interim that will tap into the pioneering aptitude of our community to deliver world-class education and spotlight Regenerative Rehabilitation innovation.This symposium featured world-renowned researchers and clinicians, focusing on the emerging field of Regenerative Rehabilitation; it succeeded in creating a platform for bridging several areas of expertise in a setting that fosters discussion, interaction, cross-discipline pollination and networking. Drs. Paul George (Stanford University) and Shailly Jariwala  shared a success story of how networking at last year’s Symposium led to their collaborative project, submitted to the Department of Defense, using nerve conduits combined with electrical and chemical stimulation for the treatment of peripheral nerve injury. This session invited attendees to think of innovative approaches and collaborations to continue moving the field of Regenerative Rehabilitation forward. Looking ahead, the P2C grant supporting AR


The prognostic value of androgen receptor splice variant 7 (AR-V7) for the treatment response of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we aimed to synthesize relevant studies that assessed the prognostic value of AR-V7 status for the treatment response of mCRPC patients treated with androgen receptor signalling inhibitors (ARSis) and chemotherapy.AR-V7 and prostate cancer to identify relevant studies published before 25 September 2019. The main outcomes were prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS). Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale.We searched the PubMed, Embase, and MEDLINE databases by using the keywords P < 0.001), shorter PFS  and shorter OS  than AR-V7-negative patients. Although AR-V7-positive patients treated with chemotherapy also had a lower PSA response rate  and shorter OS than AR-V7-negative patients , there was no significant difference in PFS  between these groups. Furthermore, AR-V7-positive patients receiving ARSis had a shorter median OS than those receiving chemotherapy ; There was no significant difference among AR-V7-negative patients .A total of 1,545 patients from 21 studies were included. For the mCRPC patients treated with ARSis, AR-V7-positive patients had a lower PSA response rate (OR 6.01, 95% CI 2.88–12.51; AR-V7 is a potential biomarker of treatment resistance in mCRPC patients. AR-V7-positive mCRPC patients had poorer treatment outcomes than AR-V7-nagetive patients when treated with ARSis. AR-V7-positive patients have better outcomes when treated with taxane than ARSis. Furthermore, the ability of AR-V7 status to predict treatment outcomes varies from different detection methods. The detection of AR-V7 before treatment is important for the selection of treatment modalities for mCRPC patients. Prostate cancer is one of the most common cancers among male patients in the world . Most paAR-Vs, which lack the C-terminal ligand-binding domain but retain the transactivating N-terminal domain, are constitutively activated as transcription factors and activate the target genes without any ligand , 10. In Therefore, we conducted this meta-analysis and summarized the available data from clinical studies to assess the prognostic value of AR-V7 in the treatment outcomes of mCRPC. The primary aim of our meta-analysis was to compare the prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) of mCRPC patients with different AR-V7 statuses treated with ARSis or taxanes. We also performed subgroup analysis according to the detection methods for AR-V7 status.This work was executed in accordance with the Preferred Reporting Items for Systemic Reviews and Meta-analysis (PRISMA) guidelines . It was We conducted a systematic literature search by searching the PubMed, Embase, and MEDLINE databases. Studies that assessed the association between AR-V7 status and treatment outcomes of patients with mCRPC and that were published between January 1974 and September 2019 retrieved. The complete retrieval strategy was: (((((AR-V7) OR AR3) OR androgen receptor splicing variants 7) OR androgen receptor 3)) AND ((((prostate cancer) OR prostate tumor) OR prostate neoplasm) OR prostate carcinoma). In addition, the reference lists of the included studies and related reviews and reports were screened.The inclusion criteria were as follows. (1) Studies reported the association between AR-V7 status at baseline and time-to-events outcomes for mCRPC patients treated with ARSis or chemotherapy, including PSA response, clinical and/or radiographic PFS or OS. (2) Odds ratios (ORs) or hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were reported directly or could be calculated. (3) The clinical studies were performed with adults and were published in English. The exclusion criteria were as follows. (1) The study was a review, case report, comment, editorial, or meta-analysis. (2) The study only contained an AR-V7-positive or an AR-V7-negative cohort but not boths. (3) The Study only reported the Kaplan-Meier survival curve without available HRs and 95% CI. If there were multiple reports published as sequential studies from the same cohort, the most recent follow-up report was included.According to the inclusion and exclusion criteria, the initial selection of studies was based on the titles and abstracts of all studies. Then we assessed the full texts of the potential studies. All studies were independently screened by two investigators (JW and YZ). A third researcher (CW) was consulted to resolve disagreements.Data extraction was conducted by two reviewers (XG and PY) independently. Basic information and patient characteristics were extracted from all included studies. To analyze the potential predictive value of AR-V7, PSA response rates and the HRs (95% CIs) of PFS and OS in patients with different AR-V7 statuses and different treatment regimens were collected. The Newcastle-Ottawa Quality Assessment Scale (NOS) was applied to assess the quality of the eligible studies by two trained investigators (JG and RL). Discrepancies were resolved by discussion with a third reviewer (ZL).According to the classification criteria reported in the included articles, patients were divided into two groups, AR-V7 positive and negative. ORs with 95% CIs were used to analyze the correlation between AR-V7 status and PSA response. HRs with 95% CIs were used to estimate the association between AR-V7 status and PFS and OS. We also performed a subgroup analysis based on the methods for the detection of AR-V7.P < 0.05 was considered statistically significant. Considering the relatively conservative results, we used random effect models for this meta-analysis. The heterogeneity was evaluated by the 2I statistic. Publication bias was detected by Begg’s funnel plot and Egger’s regression test if the number of included studies was more than ten. Publication bias was considered to be significant if Begg’s funnel plot was asymmetric or if P < 0.10 for Egger’s test. For a meta-analysis with more than ten studies, sensitivity analysis was applied to verify the stability of the results.The meta-analysis was performed by using Stata software . The flow diagram of the search and screening process is shown in P < 0.001; 2I = 50.5%; P = 0.011). Subgroup analysis revealed that in the studies that used reverse transcription-polymerase chain reaction (RT-PCR) , immunofluorescent staining (IFS) , droplet-digital PCR (dd-PCR) , or immunohistochemistry (IHC)  for the detection of AR-V7, there were statistically significant differences in PSA response rates between AR-V7-positive and AR-V7-negative patients , while the PSA response rate of AR-V7-negative patients was 45.7% . There was significant heterogeneity among these studies . Subgroup analysis revealed that in the studies that used RT-PCR , IFS , and dd-PCR  for the detection of AR-V7, AR-V7-positive patients had significantly shorter PFS than AR-V7-negative patients . Subgroup analysis revealed that in the studies that used RT-PCR , IFS , and dd-PCR  for the detection of AR-V7, AR-V7-positive patients had significantly shorter OS than AR-V7-negative patients . The differences were also nonsignificant in the subgroup analysis based on AR-V7 detection methods (Seven studies reported the association between AR-V7 status and PSA response in mCRPC patients treated with chemotherapy. The PSA response rate of AR-V7-positive patients was 28.2% (95% CI 22.0–35.3%), while the PSA response rate of AR-V7-negative patients was 44.1% . Subgroup analysis revealed that in the studies that used IFS, there was a statistically significant difference in OS between AR-V7-positive and AR-V7-negative patients .Three studies compared the OS of mCRPC patients treated with chemotherapy or ARSis. For AR-V7-positive patients, those receiving ARSis had shorter OS than those receiving chemotherapy . In addition, no obvious asymmetry was found in Begg’s funnel plot for the studies that examined PFS and OS , which might be due to the limited sample sizes of the studies that used nested PCR or RISH. Takeuchi et al.  or RNA i et al.  reportedi et al.  conductei et al. , severali et al. , 24. In i et al. . TherefoHowever, the prognostic value of AR-V7 in the treatment of mCRPC with taxane has yet to be elucidated . In our The advantages and disadvantages of AR-V7 detection methods were discussed before . Among AConsidering the heterogeneity among the included studies, we also analyzed the possible risk of bias and the potential limitations of the studies. First, only observational studies were included in our meta-analysis and some clinical characteristics such as visceral disease and pain status were not considered. Second, the differences in patients’ baseline characteristics may influence the pooled results. The Gleason score was only reported in 13 studies and the proportion of Gleason scores greater than 8 points was also inconsistent in the included studies , 37–39. In summary, AR-V7 is a potential biomarker of treatment resistance in mCRPC patients and AR-V7-positive mCRPC patients had shorter OS than AR-V7-negative patients when treated with ARSi or taxane. AR-V7-positive mCRPC patients showed poorer outcomes including PSA response, PFS, and OS than AR-V7-negative patients when receiving ARSis. AR-V7-positive patients had better outcomes when treated with taxane than ARSis. The detection methods for AR-V7 may influence the prognostic value of AR-V7 status on the treatment outcome. The detection of AR-V7 before treatment for mCRPC patients is important for the selection of treatment regimens.All datasets presented in this study are included in the article/Conceptualization: SW and XL. Methodology: YZ. Investigation: XG and PY. Data curation: JG and RL. Formal analysis: JW, CW, and ZL. Writing, review and editing of the manuscript: JW, YZ, TW, and XL. Study supervision: JL and XL. All authors contributed to the article and approved the submitted version.This work was supported by Innovation Foundation of Huazhong University of Science and Technology  and National Natural Science Foundation of China .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.