Virtual and augmented reality (AR) have become popular modalities for training myoelectric prosthesis control with upper-limb amputees. While some systems have shown moderate success, it is unclear how well the complex motor skills learned in an AR simulation transfer to completing the same tasks in physical reality. Limb loading is a possible dimension of motor skill execution that is absent in current AR solutions that may help to increase skill transfer between the virtual and physical domains.LD; AR; AR and EG completed a 5-session prosthesis training protocol in AR while the CGLD performed simple muscle training. The EG attempted manipulations in AR while undergoing limb loading. The CGAR attempted the same manipulations without loading. All participants performed the same manipulations in physical reality while operating a real prosthesis pre- and post-training. The main outcome measure was the change in the number of manipulations completed during the physical reality assessments (i.e. completion rate). Secondary outcomes included movement kinematics and visuomotor behavior.We implemented an immersive AR environment where individuals could operate a myoelectric virtual prosthesis to accomplish a variety of object relocation manipulations. Intact limb participants were separated into three groups, the load control (CGAR and CGLD. This performance increase was accompanied by a shorter motor learning phase, the EG’s performance saturating in less sessions of AR training than the CGAR.The EG experienced a greater increase in completion rate post-training than both the CGThe results demonstrated that limb loading plays an important role in transferring complex motor skills learned in virtual spaces to their physical reality analogs. While participants who did not receive limb loading were able to receive some functional benefit from AR training, participants who received the loading experienced a greater positive change in motor performance with their performance saturating in fewer training sessions. The loss of a limb is debilitating, complicates various aspects of an individual’s daily life, and often results in decreased autonomy . AccordiRegardless of the myoelectric control method implemented, control of an upper-limb prosthesis can be a mentally and physically taxing task . ProstheHowever, this traditional timeline is not as effective as it could be. Previous work has shown that the time at which a prosthetic intervention is introduced post-surgery has a significant effect on long-term rehabilitation outcomes. Malone et al. defined a “golden period” of less than 30 days wherein beginning the prosthesis training process with an individual decreases the time to rehabilitation completion as well as increases the successful rehabilitation rate. Furthermore, early training intervention was shown to be critical in reducing the phantom pain incidence rate in the population studied . UnfortuTo circumvent limitations with traditional prosthesis training regimens, augmented reality (AR) has been leveraged as a rehabilitation technology. In AR systems, virtual objects are generated and combined with the real, physical environment of the user. AR boasts several advantages over related modalities , such as more accurate depth perception due to the incorporation of real world distance cues  and a reDespite AR prosthesis training having several advantages over traditional methods, the efficacy of AR training is still unclear. Although previous work has shown that some of the skills that are acquired performing virtual object manipulations are useful for physical prosthesis operation , the leaTherefore, an avenue to enhance the effectiveness of virtual environment-based rehabilitation is to increase the sensory fidelity of such systems. When operating in augmented reality, both tactile and proprioceptive senses are uncoupled from the virtual interactions displayed visually. Previous studies have shown that by providing haptic feedback, both user immersion and performance in rehabilitation regimens increase due to the provided sense of touch during virtual object interactions –38. FeedIn this work, we investigate the effect limb loading has on skill transfer between augmented and physical reality tasks used in LL rehabilitation. Participants underwent a 7-session longitudinal study wherein they trained the use of their prosthetic limb using traditional muscle training or the Prosthetic Hand Assessment Measure in AR (AR-PHAM) –43. UsinThe presented AR system allows a participant to operate a virtual upper-limb prosthesis to manipulate virtual objects through the AR-PHAM. The prosthesis extends from a bypass socket worn by the participant on their operating limb. Participants control the virtual prosthesis during rehabilitation tasks using the EMG signals collected from their operating limb. The system also logs task kinematic and electrophysiological data for offline analysis, including limb position, gaze behavior, and raw EMG Fig. .Fig. 1AnTo render the AR environment, the system uses the VIVE Pro Eye head-mounted display (HMD) . The HMD includes a pair of In the AR environment, participants operate a virtual prosthetic limb modelled after the Modular Prosthetic Limb (MPL) from the Johns Hopkins Applied Physics Laboratory . For theVirtual objects, such as the virtual prosthetic limb and AR-PHAM are anchored to locations in the physical environment using HTC VIVE trackers. These trackers combine infrared, optical LEDs with inertial measurement units to provide their 3D positions and orientations to the AR system. The AR system uses two of these kinematic trackers: one to anchor the virtual prosthesis to the operating limb and another to anchor the AR-PHAM to the participant’s physical environment. To anchor the virtual prosthesis, a tracker was affixed to a bypass socket attached to the user’s operating limb. To anchor the AR-PHAM, the other tracker was placed at a location on the floor with enough clearance in the physical world.Surface EMG data acquisition was accomplished using a wireless, eight-channel EMG band . Each electrode recorded bipolar surface EMG signals with a sampling rate of 200 Hz. Features were extracted from the EMG signal with a 250 ms sliding window with 50 ms of overlap. For each channel of EMG, the following time-domain features were extracted: mean absolute value, variance, waveform length, zero crossings, and slope sign change . These fKinematic data, such as positions and orientations from the HTC VIVE tracker, was filtered using a 6-Hz second-order Butterworth low-pass filter in both the forward and backward directions, resulting in fourth-order filtering with zero phase-distortion . Gaze daLD; AR; This study was conducted in accordance with a protocol approved by the Johns Hopkins University School of Medicine Institutional Review Board. Before being tested, each participant gave his or her written informed consent. The participants consisted of twelve individuals with intact limbs (IL). IL participants include 7 males and 5 females and range in age from 18 to 31 years old. All IL participants were right-hand dominant and naïve to pattern recognition myoelectric control. Participants were randomly assigned to either the load control group (CGParticipant prosthesis control proficiency was assessed before and after training using the Prosthetic Hand Assessment Measure (PHAM) .For the physical assessment, the user operated a prosthetic system including a bebionic3 prosthetic hand  and Motion Control Wrist Rotator . As mentioned previously, the prosthetic system implements 5 hand movement classes: RE, HO, HC, WP, and WS. An EMG band was placed circumferentially around the forearm of the participant’s dominant limb. The EMG band’s location and orientation were recorded to ensure a similar configuration between the pre- and post-test. Kinematic trackers were also mounted at joint locations on the operating limb: at the shoulder, the elbow, and the wrist. This prosthetic system was incorporated into the bypass socket to allow for end-effector consistency between all participants Fig. .Fig. 2ThThe physical testing protocol began with training the myoelectric pattern recognition classifier. While wearing the bypass socket, participants were presented with a series of visual cues, each prompting the activation of a specific hand movement class. Movement cues were presented for 5 s, of which EMG data was only collected for the last 3 s. For HO/HC, participants performed the anatomically correct hand movement, while for WP/WS, participants substituted wrist rotation with wrist flexion/extension for easier discriminability by the classifier. Furthermore, participants were instructed to activate each hand movement class with muscle contractions between 60 and 80% of their max voluntary amplitude. This was done to reduce the effect of muscle fatigue on classifier performance during prolonged assessments . ParticiEMG features were then extracted from the collected data and used to train the LDA classifier. Classifier validation was accomplished using a 67/33 train/test split. If the validation accuracy for each movement class was greater than or equal to 80%, the classifier was considered valid, and the participant proceeded to the next stage of validation. If not, the participant repeated the training data acquisition described previously until this threshold was achieved. Preliminary testing and previous results found 80% to be a reasonable threshold since training data was collected in multiple limb positions while the participant wore a bypass socket .In the next stage of validation, participants were allowed to practice operating the prosthetic system for a maximum of 5 min. If the participant was unable to elicit each hand movement class with reliability in a neutral limb posture (limb at side with elbow at 90°), they were given the opportunity to retrain the LDA classifier and restart the validation process. Once the participant felt comfortable controlling the prosthesis, they proceeded to attempt the PHAM.The PHAM consists of a series of object manipulations within a participant’s 3D reaching volume. Participants are tasked with transporting a cylinder from one start location on the PHAM’s frame to a prompted end location within a time limit. Each object transport requires 2 DoF, HO/HC and WP/WS. Tasks were considered unsuccessful if the participant dropped the cylinder during manipulation or if the participant was unable to complete the manipulation within the allotted time of 15 s. Participants were asked to complete a total of 4 tasks, 10 times each, prompted in a random order .Participants in the CGAt the beginning of each training session, participants were allowed to explore and become familiar with the AR environment for a maximum of 10 min. During each training session, participants were asked to accomplish a series of object relocation tasks on the AR-PHAM frame. Participants operated the virtual prosthetic limb via pattern recognition to manipulate cylinders from some initial configuration to some final configuration. Each pair of initial and final object configurations was characterized by 3 properties: (1) a positional change in elevation, (2) a positional crossing of the participant’s midline, and (3) a 90° change in object orientation. With this, each object manipulation task required 2 DoF (HO/HC and WS/WP) and proficient control in a large portion of the user’s reaching space. The tasks performed with the AR-PHAM are the same as those prompted during the physical assessment  is defined as when the object is within 2 cm of its target position and 15° of its target orientation and the participant sends a HO command to the prosthesis. All transition thresholds were determined experimentally using preliminary data.Each object manipulation task of the AR-PHAM was segmented into four phases to allow for more granular analysis of a participant’s task motor strategy. These phases are: ase Fig. . A task The main outcome measure reported is the change in the task completion rate for the physical PHAM. Experimental data from the AR-PHAM training period was also analyzed along two secondary dimensions: compensatory motion and visuomotor behavior. Evaluation along these secondary dimensions was used to assess the quality of the movements achieved during virtual object manipulation. Secondary analyses included data only from successfully completed tasks.y-component for x-component for Compensatory motion was quantified by computing the angular range of motion (RoM) for the glenohumeral and elbow joints. Of the upper-limb DoF, we computed the RoM for shoulder flexion and extension (mentclass2pt{minimVisuomotor behavior was quantified using the metrics defined by the Gaze and Movement Assessment (GaMA) , 52, 53.Statistical analysis was performed using Python 3.7 and MATLAB R2019b. The non-parametric Mann-Whitney test was used due to the limited sample size. For all metrics, the threshold for statistical significance was set at B) between the EMG feature distributions defining each possible movement classification  Fig. . ParticiAR experienced a significant increase of + 31.25% in the average task completion rate between sessions 1 and 5 .While training with the AR-PHAM, participants in the CGLD presented with a shoulder flexion range of AR, who completed pre-test manipulations with a shoulder flexion range of For both the pre-test and the post-test, participants in all groups presented with similar joint RoM. During the pre-test, the CGLD completed manipulations with a shoulder flexion range of AR completed the same set of manipulations with a shoulder flexion range of During the post-test, the CGAR. For the EG, the average joint RoM produced during successful manipulations over all AR training sessions was AR, the produced joint ranges were During AR training, for each upper-limb DoF of interest, the EG produced a greater average joint RoM when successfully completing an object manipulation when compared to the CGAR, the average percentage of time spent fixating on the prosthesis was 64.09 ± 23.85% of the total time spent attempting to transport a successfully grasped object. For the EG, the respective average percentage was 90.37 ± 13.32%. While these averages do not seem to meaningfully change throughout the course of the AR training, this trend in visuomotor behavior exists within all 5 training sessions with significant differences existing in training sessions 3 and 4  Fig. .Fig. 10PAR, which required nearly the entire training period to reach steady-state performance . One exulations . Althougulations .Our study was not without limitations. Most apparently, the longitudinal study was not conducted with a population of LL participants. While previous literature has shown that IL participants construct similar motor strategies as individuals with LL when using a bypass prosthesis, the results of this study can be strengthened with an extension of this work that explicitly includes the target population . AnotherAnother limitation of this work was the location of the prosthesis relative to the limb. In the AR environment, the virtual prosthesis was mounted as an extension of the user’s limb, as if the user was wearing a traditional socket interface. In contrast, the physical prosthesis system mounted the prosthesis parallel to the operating arm, offset by 4 cm. This is due to a limitation of the AR system’s rendering pipeline. Because the AR system renders the real-world environment using stereoscopic camera pass-through, it is not possible to render a virtual object (like the prosthesis) behind a real-world object (like the intact limb). Doing so would produce significant visual artifacts at the boundaries of the overlapping real and virtual objects due to insufficient resolution of the depth data measured from the HMD.It is unclear what effect this lack of offset may have had on a participant’s ability to embody the prosthesis. Page et al. claimed that prosthesis embodiment “depends on congruence , temporal and spatial synchrony , and ‘bodily resemblance’” . While nA limitation of the training framework proposed in this study is that proprioceptive information was provided by physically loading the participant’s operating limb. As stated previously, the residual limb of a prosthesis user may be hypersensitive to physical loading in the time right after the surgery, when a prosthesis training intervention may be the most valuable , 16. ThiThis study investigated the effect that limb loading has on complex motor skill transfer from virtual to physical upper-limb prosthesis control. Participants who underwent an AR prosthesis training regimen with their operating limb loaded produced a significantly greater post-training increase in functionality when compared to participants who underwent the same training without the limb loading. Secondary analyses show that both compensatory motion and hand fixation percentage are increased when performing manipulations with the operating limb loaded, irrespective of prosthesis control capacity. Overall, the increased sensory fidelity afforded by limb loading helped to increase the level of skill transfer from an augmented reality prosthesis control task to an analog in physical reality.


Physical and Rehabilitation Medicine (PRM) is the medical specialty of body functioning. Its aim is to diagnose, prevent and reduce disability resulting from the interaction between people and their environment , 2.The World Health Organization (WHO) Global Disability Action Plan 2014–2021 “Better health for all people with disabilities” is a significant step toward rehabilitation services. For a successful implementation of the WHO recommendations, PRM organizations and individual PRM specialists are urged to contribute to the improvement of PRM services worldwide .The International Classification of Functioning, Disability and Health (ICF) provides a widely accepted conceptual model and taxonomy of human functioning .PRM specialists guarantee the citizen's access to rehabilitation services as a human right –6.It is well-known that rehabilitation is essential to lower healthcare costs by decreasing the number of days spent in hospital, and that reducing disability improves quality of life. Varela et al. highlight the need for more scientific studies on the benefits of rehabilitation even in the preoperative phase, while we know that current studies confirm that early postoperative rehabilitation decreases pain and its consequences .In long-term disabilities, the rehabilitation process for patients with complex problems requires a carefully planned and integrated program by the PRM physician who provides advice on diagnosis, prognosis, treatment options and risks for the patient and family. The PRM physician must take his leadership role over the rehabilitation team, as well as assist in the development of treatment protocols; his holistic perspective on long-term rehabilitation management makes a unique contribution .High-quality rehabilitation care is a constituent element of healthcare systems worldwide. The implementation of these standards needs to be validated worldwide with particular attention to low- and middle-income countries. The standardization of staff training at both undergraduate and postgraduate levels is a key element in ensuring the highest standard of rehabilitation care. International bodies, such as the UEMS Board for PRM or the International Society for PRM, have already delivered normative documents setting standards in postgraduate PRM training.They highlight the need to develop competency-based education, training physicians with the proper skills and knowledge required to meet the healthcare needs of people with disabilities, as a powerful mechanism to align education and training with health system priorities.This is of particular value for countries with limited resources, where the knowledge and skills of rehabilitation physicians need to reflect not only the health profile of the population, but also the strengths and weaknesses of the health system.As life expectancy increases, disability rates caused by the diseases listed above increase , 10.The World Disability Report published by WHO in 2011 also states that the prevalence of severe and moderate disability is higher in Africa than in many other regions of the world especially in younger (<60 years) population groups , 13.A number of publications report a prevalence of disability in the general population ranging from 1.7% in Mali  to 17.1%Disability prevalence in Cameroon was recently estimated in a survey of a sample of 1,617 adults aged 18+ using the Washington Group tools, which capture self-reported activity limitations in functional domains described in the ICF . There aA study in a health district in Cameroon showed that many disabilities, such as orthopedic problems (mainly fractures), infectious diseases and neurological disabilities , were due to traffic accidents and inappropriate medical interventions . In MaliA large number of studies explored the effect of disability on health, education, social participation and livelihoods of people with disabilities.Adults with disabilities were more likely to experience serious health problems and report limited access to healthcare and rehabilitation services .A literature review published in 2018 on five West African countries defined important policy and program implications as follows:(1) Application of standardized tools for monitoring the implementation of programs and policies at national level;(2) Improving stakeholder coordination mechanisms at the country level;(3) Supporting countries in using unified approaches to measuring disability and social exclusion;(4) Strengthening the rigor of the evaluations of the effectiveness of disability-specific interventions;(5) Disaggregation of routine data from development programs by disability .A disability research team established the need to define strategies to improve the activities of daily living of people with disabilities in Cameroon .A descriptive cross-sectional study pointed out that disabled people, and children in particular, are still marginalized, vulnerable and with little chance of recovery. Therefore, there is a clear need to improve the quality and availability of rehabilitative care with programmatic interventions that improve the accessibility to rehabilitation services for people with disabilities, provide them with the necessary safeguards, ensure implementation of existing laws, and neutralize any barrier to their social participation .Regarding disability associated with human immunodeficiency virus (HIV) infection, a 2019 study shows that antiretroviral therapy improves impaired immune function. It is reported in the literature that physical (aerobic/endurance) exercises also seem to induce beneficial effects .In another 2019 study, Ibeneme et al. argue that while aerobic exercise does not improve levels of inflammatory biomarkers (IL-6 and IL-1β), it does significantly improve cardiopulmonary function in HIV-infected patients .The importance of rehabilitation medicine is also evident from a 2019 literature review on HIV-infected children with impairments and disabilities. Unfortunately, we know that pediatric health systems in Sub-Saharan Africa are not integrated with rehabilitation in chronic diseases such as HIV while integration to pediatric Rehabilitation in a holistic approach would be important. This scoping review proposes a synthesis of existing evidence on rehabilitation intervention strategies for disability-related barriers in children living in Sub-Saharan Africa .The incidence of diabetes mellitus (DM) in Africa is not only a health problem but also imposes a significant economic burden. Diabetic peripheral neuropathy is a common microvascular complication of DM that increases the potential for morbidity and disability due to ulceration and amputation. Based on the study analysis, the highest prevalence of diabetic peripheral neuropathy in patients with DM was reported in West Africa at 49.4%. The need for a rehabilitation medicine approach also has its importance here .Despite concerns about underreporting of cerebral palsy (CP) in many African communities, the prevalence estimates reported here were generally higher than the estimated 2–2.5 of 1,000 in most studies conducted in the United States or Europe . It is lThere is a paucity of studies in Africa, South-East Asia and the Eastern Mediterranean region on pulmonary diseases, with increasing prevalence of chronic obstructive pulmonary disease, both globally and regionally .In the same way patients with idiopathic pulmonary fibrosis (IPF) generally experience poor quality of life. A study reports that these patients are poorly referred to palliative care even in developed countries, while in developing countries no data are available on the use of palliative care or the burden of health care management. Therefore, more awareness and research on the palliative care needs of patients with IPF is recommended, particularly in resource-limited settings such as South Africa .About the burden of stroke in Africa, the results of a review suggest that is high and still rising. The incidence of stroke in Africa is becoming a public health challenge; unfortunately scarcity of data has limited research and consequently also the response to the exact public health burden.In 2019, a total of 1.89 million stroke survivors were estimated among people aged 15 years or older in Africa. There is a need for extensive research on both stroke and other vascular risk factors to institute appropriate policy, and effective preventive and management measures .Regarding the rheumatologic diseases, a systematic review identified the paucity of latest prevalence data on arthritis in Africa .After this excursus of the most important diseases that afflict the African continent, this systematic review of the empirical literature, from 2016, emphasizes the importance of exploring the sustainability of health interventions in Sub-Saharan Africa.From the analysis of these studies, we can define the importance of rehabilitation and the need for more studies in this area .For the application of proper rehabilitation in the field of PRM, a study emphasizes the need to understand the current learning styles of physiotherapy students and if necessary also change the teaching styles in order to provide high quality education. Currently, physiotherapy students have specific learning styles of active participation supported by practical internship activities and theoretical concepts. Further research would be fundamental to define and standardize learning styles in physiotherapy courses .The results of a study published in 2009 offer the first global portrait of the dynamics of demand and supply of human resources for rehabilitation: the lowest supply of rehabilitation health professionals was found among low- and middle-income countries, many located in Sub-Saharan Africa, where the burden of cause-related diseases requiring rehabilitation professional skills tends to be greatest. Worldwide, people with disabilities have many unmet health and rehabilitation needs but continue to face significant barriers in accessing mainstream health services, and consequently have poorer health outcomes. Currently, a double burden is found in low- and middle-income countries. Unfortunately, human resources for rehabilitation are often a neglected component of health services .In light of what has been examined so far, we discuss the current situation of disability and PRM in the Cameroon healthcare system and their possible perspectives.Healthcare system promotes equity in people. In addition, WHO reported that people with disabilities are also entitled to attain the best possible quality of care without discrimination. In the same vein, Cameroon has signed and ratified numerous national and international conventions on disability with the aim to attain a number of privileges for disabled persons, which have been recently characterized by Foti et al. . It is iRehabilitation aims to optimize functional ability, enhance quality of life and reduce disability in people with impaired health conditions through interventions. According to the WHO, countries with the lowest levels of health (and education) fail to sustain real growth and development , 36. AreThe current Cameroon medical system woefully underprepares clinicians to efficiently prescribe exercise-based rehabilitation. In addition, the majority of fellowships offer no training in exercise prescriptions. In Cameroon, the PRM curricula are not available in the existing medical schools. However, general physiotherapy and/or rehabilitation, speech therapy, occupational therapy, orthoprosthesis and psychomotricity programs are offered by some universities and institutions in Cameroon as elective teaching modules. Therefore, PRM as a medical specialty is not well-known.Curriculum is an initial step for the development of any field and guide health research. In Cameroon, research in the field of rehabilitation also suffers. Thus, we propose some following points for a call to action to implement and disseminate this impactful discipline in Cameroon:(1) Develop a 4-year higher specialty training program in PRM;(2) Gain recognition of the new specialty in Cameroon by the Ministry of Higher Education;(3) Establish a system such as training and research in rehabilitation to ensure continuity competence of physicians practicing PRM in Cameroon, according to recommendations and standards provided by international PRM boards: “To acquire the wide field of competence needed, specialists in Physical and Rehabilitation Medicine have to undergo a well-organized and appropriately structured training of adequate duration. In fact they are required to develop not only medical knowledge, but also competence in patient care, specific procedural skills, and attitudes toward interpersonal relationship and communication, profound understanding of the main principles of medical ethics and public health, ability to apply policies of care and prevention for disabled people, capacity to master strategies for reintegration of disabled people into society, apply principles of quality assurance and promote a practice-based continuous professional development” , 38.We can confirm that high-quality rehabilitation care is essential within health systems, especially for low- and middle-income countries. The importance of adapting staff training both at university and post-graduate level is a fundamental element to ensure the highest standard of rehabilitation care.The review carried out on the literature relating to the main diseases that cause disabilities in Africa with particular regard to Cameroon highlighted shortcomings in the health systems both at a social and welfare level; for this reason, the aim is to define training courses and strategies that can guarantee the best level training to provide better intervention systems for professionals in PRM. This is why the international bodies of PRM highlight the need to develop training that allows education to be aligned with the priorities of the health system.As regards Cameroon, a fundamental aspect would be to recognize the specialization in PRM by the Ministry of Higher Education, developing a 3 or 4-year educational program and improving scientific research in this field.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.Publication of article was funded by Chair of Physical Medicine and Rehabilitation, Clinical Sciences and Translational Medicine Department, Tor Vergata University, Rome, Italy.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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The β3-adrenergic receptor (β3-AR) has long been viewed as a potential therapeutic target for dealing with obesity. Although the lipolytic and thermogenic role of β3-AR in brown/beige adipocytes is well defined, the β3-AR’s adipogenic role in white adipocytes remains unclear at present. In this study, we investigated the expression and function of β3-AR in 3T3-L1 murine white preadipocytes. Knockdown of β3-AR led to less lipid accumulation and triglyceride (TG) content as well as less expression and phosphorylation levels of CCAAT/enhancer-binding protein-α (C/EBP-α) and peroxisome proliferator-activated receptor-γ (PPAR-γ) during 3T3-L1 preadipocyte differentiation. These findings reveal that the β3-AR inhibitor or antagonist could be a promising candidate for potential preventive and therapeutics against obesity.β3-adrenergic receptor (β3-AR) is expressed predominantly in mature white and brown/beige adipocytes. Although the lipolytic and thermogenic role of β3-AR in brown/beige adipocytes is well defined, the adipogenic role of β3-AR in white adipocytes remains unclear at present. In this study, we investigated the expression and function of β3-AR in differentiating 3T3-L1 cells, murine white preadipocytes. Of note, the expression of β3-AR at the protein and mRNA levels was highly induced in a time-dependent manner during 3T3-L1 preadipocyte differentiation. Interestingly, the results of the pharmacological inhibition study demonstrated the roles of p38 MAPK and PKC in the induction of β3-AR expression in differentiating 3T3-L1 cells. Knockdown of β3-AR led to less lipid accumulation and triglyceride (TG) content during 3T3-L1 preadipocyte differentiation with no cytotoxicity. Furthermore, knockdown of β3-AR resulted in a decrease in not only expression levels of CCAAT/enhancer-binding protein-α (C/EBP-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), fatty acid synthase (FASN), perilipin A, and leptin but also phosphorylation levels of signal transducer and activator of transcription-5 (STAT-5) during 3T3-L1 preadipocyte differentiation. In summary, these results demonstrate firstly that β3-AR expression is highly up-regulated in p38 MAPK and PKC-dependent manners, and the up-regulated β3-AR plays a crucial role in lipid accumulation in differentiating 3T3-L1 cells, which is mediated through control of expression and phosphorylation levels of C/EBP-α, PPAR-γ, STAT-5, FASN, and perilipin A. Obesity is defined as abnormal fat accumulation in the human body. Obesity has now become a global pandemic, based on the fact that it is highly associated with the development of many human chronic diseases such as type 2 diabetes, hypertension, and cancer ,2. ObesiPreadipocyte differentiation also called adipogenesis, is a multistep process that occurs in the form of cellular, morphological, and biochemical changes . The proRNA sequencing is a technique for identifying differentially expressed RNAs in cells or tissues by high-throughput sequencing . In ordeControl shRNA plasmid (Cat. No. sc-108060) and β3-AR shRNA plasmid (Cat. No. sc-39869) were purchased from Santa Cruz Biotechnology . PD98059, SB203580 (Cat. No. BML-E1294) was purchased from Enzo . SP600125 (Cat. No. 420119) was from Calbiochem . LY294002 (Cat. No. ST-420) and GF109203X (Cat. No. EI-246) were purchased from Biomol . 3-isobutyl-1-methylxanthine (IBMX), dexamethasone, and insulin were bought from Sigma . Primary antibodies specific for anti-β3-AR, anti-C/EBP-α, and anti-PPAR-γ, anti-actin, anti-phospho (p)-STAT-3 (Y705), anti-STAT-3, anti-phospho (p)-STAT-5 (Y694), and anti-STAT-5 were purchased from Santa Cruz Biotechnology . Anti-perilipin A antibody was purchased from BioVision . The anti-FASN antibody was purchased from BD Bioscience . Super Signal™ West Pico PLUS Enhanced chemiluminescence (ECL) (Cat. No. 34080) was purchased from Thermo Scientific . All Plasticware, including 6-well, 24-well plates, 60 mm, and 100 mm cell culture dishes, were obtained from SPL Life Sciences .2. 3T3-L1 preadipocytes were grown up to the contact inhibition stage and remained in the post-confluent stage for 2 days (D0). Differentiation was induced by changing the medium to DMEM supplemented with 10% FBS  plus a cocktail of hormones (MDI) that include 0.5 mM IBMX (M) (Sigma), 0.5 µM dexamethasone (D) (Sigma), and 5 µg/mL insulin (I) (Sigma) for 2 days (D2). Cells were switched to DMEM supplemented with 10% FBS and 5 µg/mL insulin for additional 3 days (D5). Cells were then fed every other day with DMEM supplemented with 10% FBS for further 3 days (D8).3T3-L1 preadipocytes  were cultured in Dulbecco’s Modified Eagle’s Medium  supplemented with 10% heat-inactivated fetal calf serum  and 1% penicillin/streptomycin  at 37 °C in a humidified atmosphere of 5% CO3T3-L1 preadipocytes seeded into 6-well plates. After overnight incubation, cells were transfected with control or β3-AR shRNA using LipofectamineTM 2000  for 6 h. The culture medium from the transfected cells was removed and refreshed with DMEM containing 10% FCS, followed by incubation for 48 h. Differentiation of the control or β3-AR shRNA-transfected 3T3-L1 cells was induced as per the above-mentioned differentiation conditions.On D8 of differentiation, control or β3-AR stably knock-down 3T3-L1 cells were washed with phosphate-buffered saline (PBS) and fixed with 10% formaldehyde for 2 h at room temperature (RT). Next, cells were washed with 60% isopropanol and dried at RT. Cells were then stained with Oil Red O working solution  for 1 h at RT and washed with deionized water. Stained LDs in control or β3-AR knock-down 3T3-L1 cells were visualized under the light microscope .Control or β3-AR shRNA-transfected 3T3-L1 preadipocytes were seeded in a 24-well plate and grown under the above-mentioned differentiation. On D8 of differentiation, cell counts were performed by staining control or β3-AR knock-down 3T3-L1 cells with 0.4% trypan blue dye. The cell count analysis was performed in triplicates. Data are mean ± standard error (SE) of three independent experiments.On D8 of differentiation, intracellular TG content in control or β3-AR shRNA-transfected 3T3-L1 cells were quantified using AdipoRed assay reagent kit  according to the manufacturer’s protocol. Fluorescence intensity was quantified with excitation and emission at 485 and 572 nm, respectively, using Victor3 .g for 20 min at 4 °C. The supernatant was saved, and its protein concentration was determined using bicinchoninic acid (BCA) protein assay kit .At the designated time points, 3T3-L1 cells were lysed in RIPA buffer (Sigma) supplemented with a proteinase inhibitor cocktail (1×). The cell lysates were centrifuged at 12,074× w/v) skim milk in TBST for 1 h at room temperature. Membranes were incubated with specific antibodies at 4 °C. Later, membranes were rinsed with TBST buffer and further incubated with anti-goat IgG or anti-mouse IgG, or anti-rabbit IgG coupled with horseradish peroxidase for 2 h at RT. Next, membranes were rinsed three times with TBST and developed with enhanced chemiluminescence (ECL) reagents. Actin expression levels were used as an equal protein loading control.Proteins (50 µg) were loaded and run in 10% of SDS-polyacrylamide gel electrophoresis (SDS-PAGE). After separation of proteins, transferred onto polyvinylidene difluoride membrane  and then blocked with 5% . Three micrograms of total RNA were reverse transcribed using a ran-dom hexadeoxynucleotide primer and reverse transcriptase. Single-stranded cDNA was amplified by PCR with the following primers: β3-AR sense 5′-CCAGTCCCTGCCTATGTTTGT-3′; anti-sense 5′-GATGGTCCAAGATGGTGCTT-3′; C/EBP-α sense 5′-TTACAACAGGCCAGGTTTCC-3′; anti-sense 5′-GGCTGGCGACATACAGTACA-3′; PPAR-γ sense 5′-AGGCCGAGAAGGAGAAGCTGTTG-3′; anti-sense 5′-TGGCCACCTCTTTGCTCTGCTC-3′; FASN sense 5′-TTGCTGGCACTACAGAATGC-3′; anti-sense 5′-AACAGCCTCAGAGCGACAAT-3′; perilipin A sense 5′-C ACTCTCTGGCCATGTGGA-3′; anti-sense 5′-AGAGGCTGCCAGGTTGTG-3′; leptin sense 5′-GACACCAAAACCCTCAT-3′; anti-sense 5′-CAGTGTCTGGTCCATCT-3′; 18S rRNA sense 5′-CCATCCAATCGGTAGTAGCG-3′; anti-sense 5′-GTAACCCGTTGAACCCCATT-3′. SYBR Green PCR Master Mix  was then analyzed with the LightCyclerâ96 Machine . All reactions were performed in triplicate for each sample. Quantitation was performed by the comparative Ct (2e Ct) method. The Ct value for each sample was normalized by the value for 18S rRNA.t-test and one-way ANOVA to analyze the statistical difference between two or more groups. p < 0.05 was considered statistically significant.Numerical data are expressed as the mean ± S.D. for at least three independent experiments. We employed Student’s The experimental protocol for the differentiation of 3T3-L1 preadipocytes into adipocytes is depicted in We next sought to explore which signaling factor(s) or mechanism(s) are responsible for the induction of β3-AR mRNA expression in 3T3-L1 preadipocytes as well as during 3T3-L1 preadipocyte differentiation. Of interest, as shown in Using β3-AR shRNA transfection, we next sought to directly explore the role of β3-AR in 3T3-L1 preadipocyte differentiation. As shown in To elucidate the molecular mechanisms underlying the β3-AR-mediated lipid-reducing effect, we next examined the effects of β3-AR knockdown on expression and/or activity (phosphorylation) of adipogenic transcription factors  during the differentiation of 3T3-L1 preadipocytes into adipocytes. As shown in Next, we determined whether β3-AR knockdown alters expression levels of FASN, an enzyme responsible for fatty acid synthesis , perilipβ3-AR is regarded as a potential anti-obesity target, given that it is expressed predominantly in white and brown adipocytes cells and its selective agonists have lipid-lowering effects by inducing lipolysis and thermogenesis. However, the expression regulation and adipogenic role of β3-AR in white adipocytes remain unclear. Here, we reported that β3-AR expression is highly elevated in differentiating 3T3-L1 preadipocytes in p38 MAPK and PKC-dependent manners. The knockdown of β3-AR resulted in a significant reduction of lipid accumulation as well as a reduction in the TG content in differentiating 3T3-L1 preadipocytes, mediated through modulation of the expression and phosphorylation levels of C/EBP-α, PPAR-γ, STAT-5, FASN, and perilipin A.As of now, how β3-AR expression is regulated during white preadipocyte differentiation remains unclear. Previous studies have shown the expression of β3-AR in white adipocyte tissue (WAT), but the signals were higher in infant brown adipocyte tissue . As bothIt has been well documented that the constitutive activation of β3-AR induces the appearance of brown/beige adipocytes in different adipose tissue depots via adipogenesis . HoweverAdipocyte differentiation also involves lipogenesis and LDs stabilization ,30. FASNWe demonstrate that β3-AR expression is highly up-regulated in p38 MAPK and PKC-dependent manners. The up-regulated β3-AR plays a crucial role in lipid accumulation or storage in differentiating 3T3-L1 cells, mediated through modulation of expression and phosphorylation levels of C/EBP-α, PPAR-γ, STAT-5, FASN, and perilipin A. The present findings suggest that inhibitors of β3-AR expression or β3-AR antagonist(s) may be used as potential preventive and therapeutics against obesity.


Background Most of the Brazilian population relies on public healthcare and stroke is a major cause of disability in this country of continental dimensions. There is limited information about access to rehabilitation after stroke in Brazil.Objective To provide comprehensive information about Access to Rehabilitation After discharge from public hospitals in Brazil (AReA study), up to 6 months after stroke.Methods The present study intends to collect information from 17 public health centers in 16 Brazilian cities in the 5 macroregions of the country. Each center will include 36 participants (n = 612). The inclusion criteria are: age ≥ 18 years old; ischemic or hemorrhagic stroke, from 6 months to 1 year prior to the interview; admission to a public hospital in the acute phase after stroke; any neurological impairment poststroke; patient or caregiver able to provide informed consent and answer the survey. Patients can only be recruited in public neurology or internal medicine outpatient clinics. Outcomes will be assessed by a standard questionnaire about rehabilitation referrals, the rehabilitation program  and instructions received. In addition, patients will be asked about preferences for locations of rehabilitation .Trial Status The study is ongoing. Recruitment started on January 31st, 2020 and is planned to continue until June 2022.Conclusion The AReA study will fill a gap in knowledge about access to stroke rehabilitation in the public health system in different Brazilian regions. According to the World Health Organization (WHO), rehabilitation is a set of interventions designed to optimize functioning and reduce disability in individuals with health conditions in interaction with their environment. It is a core health service for individuals throughout their life course, across the continuum of care for a range of acute and chronic health conditions, among them, poststroke patients.Current guidelines recommended that subjects with stroke should be assessed by a multidisciplinary team within 24 to 48 hours after admission and referred to a rehabilitation program immediately after discharge.Despite many gaps in knowledge, there is some evidence that rehabilitation is insufficient for patients with stroke in different parts of the world.For instance, while a Canadian studyEven in developed countries, the rehabilitation process often does not follow evidence-based practices and is not conducted by a multidisciplinary team.Some barriers to rehabilitation are shared by low- or middle-income and high-income countries. Referral delays (50%) and difficulties in transportation/distance to healthcare facilities (39%) were reported by 239 responders to surveys in Peru and in the United States of America as the main obstacles for rehabilitation.In addition, patients with mild or severe impairments tend to be less frequently referred to rehabilitation services.In Brazil, stroke is a leading cause of death and disability.For instance, in a university hospital in São Paulo, the largest Brazilian city, 70% of 665 patients followed-up for 4 years after a first-ever stroke did not receive any type of rehabilitation after discharge. These patients had low socioeconomic and educational levels, in addition to high severity of neurological impairments.Identifying barriers to access the rehabilitation interventions is crucial to improve the health system integration and the resources required to deliver them safely and effectively. Such information would contribute to strengthening health systems in rehabilitation, guiding health policies, planning, and budgeting.Considering the limited available evidence about access to rehabilitation after stroke in Brazil, SCD-BAN invited neurologists and rehabilitation professionals from five different Brazilian regions to participate in a comprehensive observational study – AReA (Access to post-stroke REhabilitation After stroke in Brazil). The main objective of the present study is to provide quantitative information about access to rehabilitation after discharge from public hospitals, up to 6 months after stroke. Secondary objectives are to assess predictors of access to rehabilitation, and the association between rehabilitation and functional outcomes.In the present multicenter study, we aim to include 612 patients between 6 months and 1 year after ischemic or hemorrhagic stroke.The final study protocol and written informed consent were approved by the Albert Einstein Hospital Ethics Committee  and by Ethics Committees of each participating center. Written informed consent must be obtained either from the patient or his/her family member through the SurveyMonkey platform. Progress reports are submitted to the coordinating center Ethics Committee, every 6 months.The inclusion criteria are: age ≥ 18 years old; ischemic or hemorrhagic stroke, from 6 months to 1 year prior to the interview; admission to a public hospital in the acute phase after stroke; any neurological impairment poststroke; patient or caregiver able to provide informed consent and answer the survey. Patients with other neurological conditions such as Parkinson or Alzheimer disease are excluded. Patients can only be recruited in public neurology or internal medicine outpatient clinics, not in rehabilitation facilities or clinics, in order to avoid bias.st, 2020 and is planned to continue until June 2022. The first case of COVID-19 was diagnosed in Brazil in February 2020The participants are invited to participate after regular outpatient visits in 17 centers distributed in 11 states across Brazil . RecruiThe following data are collected: gender, age, educational level, time from stroke, type (ischemic or hemorrhagic), lesion location, number of strokes, performance of computed tomography (CT) or magnetic resonance imaging (MRI) for diagnosis, National Institutes of Health Stroke Scale (NIHSS)The primary outcome is the percentage of patients who had access to any physical therapy session after hospital discharge within the first 6 months after stroke onset.The secondary outcomes are: referral to physical therapy after hospital discharge, regardless of actual access; the percentages of patients who had access to each of the following professionals after discharge: occupational therapist, speech therapist, neurologist, psychologist, physiatrist and nutritionist; the percentage of patients who received health instructions until 6 months after stroke; preferences of patients and families regarding the rehabilitation process .Outcomes will be assessed by a standard questionnaire .The first part is related to rehabilitation referrals that the participant received within the first 6 months after hospital discharge and the rehabilitation program . The second part is related to instructions received  and the preference of the participant .http://nihss-portuguese.trainingcampus.net) and the modified Rankin Scale (mRS -https://forms.gle/KqChiJvRNsfGe5oU6) scores.Prior to recruitment, all researchers involved in data collection are required to receive online certification in assessment of the NIH stroke scale .Training in ethical principles and clinical research is also required. Some courses in English or Portuguese are suggested  from each center receives a training link to the questionnaire registered on the SurveyMonkey platform. He or she practices the interviews with the researchers involved in data collection. Then, the PI receives the link for the questionnaire and a Microsoft Excel, version 2210, 64 bits,  template to register the data.The questionnaire can be answered by the patient/participant or, if impossible due to language barriers, by a proxy. The interview lasts ∼ 20 minutes.The local PI is responsible for supervising data collection, storage, and transfer to the coordinating center. Conforto A. B. and ROC oversee the study. Every month, local PIs receive a newsletter with information about the progress of the project, deadlines, and instructions. Data are anonymously stored on the SurveyMonkey platform.The present study was approved by the Human Research Ethics Committee of Albert Einstein Hospital (CAAE: 19110619.7.1001.0071), the coordinating center, and by local ethics committees from participating centers. All participants or proxies must provide informed consent through the SurveyMonkey platform. Progress reports are submitted to the coordinating center Ethics Committee every 6 months.Sample size was not formally calculated in the present observational, exploratory study. We plan to include 612 participants representative of patients from the five main Brazilian regions.Descriptive statistical analysis will be performed for all outcomes in each center and in the total sample.Chi-squared tests will be performed to compare the following variables according to access or lack of access to each professional involved in rehabilitation care: age, gender, area (North/Northeastern/Western states of Brazil versus South/Southeastern states), NIHSS and timing of data collection .Three multivariate logistic regression models will be performed to identify independent predictors of access to rehabilitation in the overall sample. The dependent variables will include access to any type of professional involved in rehabilitation; access to physical, occupational, and speech therapy; access to all professionals . The independent variables will include region, age, gender, and type of stroke.Percentages of access to physical therapists and access to other professionals across each region will be compared with chi-squared tests.In addition, an exploratory logistic regression analysis of the association between the amount of time spent in all rehabilitation sessions  and mRS scores (≥ 2 or < 2) will be performed. Age, gender, and NIHSS score will be included as covariates.P-values ≤ 0.05 will be considered statistically significant. The program that will be performed the statistical test will be JASP statistics, version 0.14.3 Eric-Jan Wagenmakers (room G 0.29) Department of Psychological Methods University of Amsterdam Nieuwe Achtergracht 129B Amsterdam, The Netherlands.One of the national priorities in the fight against stroke in Brazil, a Latin-American country of continental dimensions is to structure rehabilitation services and home care.Physical rehabilitation is a key intervention after stroke in low- and lower-middle income countries, improving outcomes such as functional ability, walking capacity, and balance.In the present study, access to physical therapy was chosen as the main outcome because of a perception that, in clinical practice, this is the most widely available rehabilitation intervention in Brazil. We hypothesize that occupational therapy, speech therapy, physiatry consults or psychological support are less often offered by the SUS. This study will address this hypothesis and allow comparisons between different Brazilian regions.The questionnaire in the AreA study addresses some particular issues: upper limb rehabilitation, because more than half of stroke survivors continue to have upper limb disability for months to yearsth, 2020The first case of SARS-CoV2 infection was identified in Brazil on February 26Until now, telerehabilitation is not widely available in Brazil. No evidence-based systems are available in the SUS. Internet use in the country is one of the greatest in the world but access is limited in remote areas.In summary, AReA will provide a snapshot of rehabilitation services in Brazil and most of the data will be collected during the COVID-19 pandemic. The results of the present study will be key to develop public health strategies and to guide efforts to provide novel rehabilitation options in a challenging context, to change the game against disability from stroke.


Long non-coding RNAs musculoaponeurotic fibrosarcoma oncogene family, protein G antisense 1 (lnc-MAFG-AS1) regulates hepatocellular carcinoma (HCC) progression and treatment resistance in multiple ways, while its engagement in HCC clinical management remains obscure. The current study aims to explore the relationship of lnc-MAFG-AS1 with tumor features, liver function indexes, tumor markers, and prognosis in HCC patients.One hundred and fifty-two surgical HCC patients who underwent tumor resection were retrospectively analyzed. Their tumor and adjacent tissues were acquired and then proposed to reverse transcription-quantitative polymerase chain reaction to detect lnc-MAFG-AS1 expression.p < 0.001], with a high area under the curve  to distinguish them via receiver operating characteristic curve analysis. Tumor lnc-MAFG-AS1 was linked with multifocal nodules (p < 0.001), increased Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.018), and elevated China Liver Cancer (CNLC) stage (p = 0.008), which also correlated with an abnormal alpha-fetoprotein (AFP) level (p = 0.004), However, lnc-MAFG-AS1 was not linked with other disease conditions, tumor properties, liver function indexes, or tumor markers . In addition, patients with a high expression of lnc-MAFG-AS1 exhibited worse overall survival than those with a low expression of lnc-MAFG-AS1 [median (95% CI): 34.0 (24.5–43.5) vs. 48.0 (41.5–54.5) months] (p = 0.011), which was further validated by univariate Cox’s analysis  and multivariate Cox’s analysis .Lnc-MAFG-AS1 expression was increased in HCC tumor tissue than in adjacent tissue [median (interquartile range): 2.730 (1.685–4.198) vs. 0.990 (0.703–1.468), Lnc-MAFG-AS1 relates to multifocal nodules, increased BCLC stage, elevated CNLC stage, and abnormal AFP level and predicts pejorative prognosis in HCC patients. Hepatocellular carcinoma (HCC) ranks as one of the most prevalent and deadly cancers with 906,000 new cases and 830,000 deaths per year globally . SeveralLong non-coding RNAs musculoaponeurotic fibrosarcoma oncogene family, protein G antisense 1 (lnc-MAFG-AS1), which belongs to non-coding RNAs that lack protein-coding ability with a length of more than 200 bp, has been recently discovered to be an oncogene in several cancers –12. For Therefore, the current study aims to investigate the relationship of lnc-MAFG-AS1 with tumor features, liver function indexes, tumor markers, and prognosis in surgical HCC patients.This study retrospectively analyzed 152 surgical HCC patients treated by surgical resection from the period January 2016 to December 2019. The screening of patients was based on the following criteria: (1) those who had a pathological diagnosis of primary HCC, (2) those primarily treated by surgical resection, (3) those who had retrievable tumor and adjacent tissues that were fresh-frozen in liquid nitrogen, and (4) those whose preoperative clinical data, laboratory test data, as well as survival data were accessible and available. The following patients were omitted: (1) those who had tumor or adjacent tissue specimens were not eligible for RNA isolation due to improper preservation, (2) those who had a history of other cancers, and (3) those who had failed to follow-up within 3 months after surgery. Ethical approval was acquired from the Ethics Committee. Written informed consent was required from either the patients or their families.All patients’ tumor and adjacent tissues (stored in liquid nitrogen) were acquired from the hospital specimen library. All samples were cryopreserved and feasible for reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay. In addition, patients’ clinical data, including basic information, tumor features, liver function indexes, and tumor markers, were also abstracted from their medical records. The CNLC stage of the patients was retrospectively assessed according to the documented tumor features . Moreove−ΔΔCt method. RT-qPCR was performed in triplicate. The primers were constructed according to the previous study  and GraphPad Prism 7.01  were used for analysis and graphing, respectively.A comparison of lnc-MAFG-AS1 expression was done by using the Wilcoxon matched-pairs signed rank test or the Wilcoxon rank-sum test. The accuracy of lnc-MAFG-AS1 in identifying the different tissues was analyzed using the receiver operator characteristic curve. When evaluating the correlation between lnc-MAFG-AS1 and OS, the patients were classified into lnc-MAFG-AS1 high and low groups on the basis of the median expression of lnc-MAFG-AS1 in the total tumor tissue. The Kaplan–Meier curve for OS was analyzed using the log-rank test. Prognostic factor analysis was performed using univariable and multivariable Cox’s proportional hazard regression. A Analyzed HCC patients showed an age of 57.3 ± 8.9 years; among them, 86.8% were males, and 13.2% were females . The BCLp < 0.001] (Lnc-MAFG-AS1 was higher in HCC tumor tissue than in adjacent tissue  . Besides< 0.001] .p < 0.001), increased BCLC stage (p = 0.018), and elevated CNLC stage (p = 0.008) (p = 0.004)  . From th= 0.004) . Howeverp = 0.011) (During a median follow-up of 30 months (range: 5–60 months) in this study, unfortunately 71 (46.7%) patients died. It was then observed that patients with a high expression of lnc-MAFG-AS1 exhibited worse OS than those with a low expression of lnc-MAFG-AS1 [median (95% CI): 34.0 (24.5–43.5) vs. 48.0 (41.5–54.5) months] (= 0.011) . In detap = 0.013] (p = 0.040)  correlated with unfavorable OS  . Subsequ= 0.040) .p = 0.118) (p = 0.010)   but was = 0.010) .Many lncRNAs have been discovered to be ontogenetic, such as lncRNA NEAT1, lncRNA GAS5, and lncRNA MALAT1 –24. Within vitro and in vivo by interacting with NM IIA subunits   , 13, 14.In addition, the present study also discovered that lnc-MAFG-AS1 expression was related to multifocal nodules, increased BCLC stage, elevated CNLC stage, and abnormal AFP level in HCC patients. The possible explanations are listed: First, lnc-MAFG-AS1 promotes HCC migration and invasion in multiple ways, such as miR-6852, miR-3196-mediated OTX1, MYH9, MYL12B, and MYL6, to facilitate the development of multifocal nodules , 14. SecIt was also uncovered that lnc-MAFG-AS1 related to unfavorable OS in HCC patients, which was validated by using K–M curve analysis, univariate Cox’s analysis, and multivariate Cox’s analysis. The possible explanations are: First, lnc-MAFG-AS1 relates to multifocal nodules, increased BCLC stage, elevated CNLC stage, and abnormal AFP level in HCC patients, which are indirectly related to deteriorative prognosis. Second, lnc-MAFG-AS1 regulates the drug resistance of HCC, which then affects the preoperative and postoperative treatment response, or the response to therapy after relapse, to directly relate to HCC prognosis .Several limitations could be mentioned in the study. First, because the enrolled HCC patients were mostly not local patients, the treatment they received during the follow-up period and a detailed DFS information could not be obtained, leading to a lack of proper analysis. Second, only resectable HCC patients were included in this study. Therefore, the related findings might not be suitable for unresectable HCC patients.In conclusion, lnc-MAFG-AS1 relates to multifocal nodules, increased BCLC stage, elevated CNLC stage, and abnormal AFP level and predicts pejorative prognosis in HCC patients. These findings may help prognostic risk stratification of HCC, while further validations are needed.


Whilst the majority of the literature suggests that balloon kyphoplasty (BKP) can relieve pain associated with vertebral compression fractures (VCFs), evidence of high-viscosity cement (HVC) vertebroplasty (VP) or low viscosity cement (LVC) BKP for the treatment of VCFs at the levels of high and mid-thoracic vertebrae remains limited. The purpose of this study was to identify the different outcomes between HVC VP and LVC BKP used to repair high (T4–6) and mid (T7–9)-thoracic VCFs. A total of 114 patients with painful collapsed single-level vertebrae at high to mid-thoracic level who had undergone HVC VP or LVC BKP at a single tertiary medical center was reviewed retrospectively. All patients were divided into the HVC VP group (n = 72) and the LVC BKP group (n = 42). Clinical outcomes including demographic data and visual analogue scale (VAS) were compared. Radiographic data were collected preoperatively, postoperatively, and at final follow-up. More volume (ml) of cement injection was seen in the LVC BKP group . The operation time (minutes) of the HVC VP group was significantly less than that of the LVC BKP group . Leakage rate of cement was also fewer in the HVC VP group . Compared with preoperative data, the VAS was improved after surgery in both groups. The LVC BKP group corrected more middle vertebral body height and local kyphosis angle than the HVC VP group. The outcomes of LVC BKP were not superior to that of HVC VP. HVC VP might be a good alternative to LVC BKP in the treatment of osteoporotic VCFs in high to mid-thoracic spine. Vertebral compression fractures (VCFs) account for one-fourth of all osteoporotic-related fractures1. VCFs can lead to severe back pain, loss of mobility, spinal deformities, and even neural compromise with neurologic deficits3. The thoracolumbar junction (T12-L2) accounts for 60–75% of VCFs secondary to osteoporosis, and 30% are involved in the L3–L5 region4.Osteoporosis in the elderly population remains a major public health challenge. Any sudden force of axial compression, distraction, and/or rotation on brittle bone could lead to osteoporotic fractures. By 2025, 3 million osteoporotic fractures and $25 billion in related health care costs will occur in the USA6. These percutaneous cement augmentation procedures can be divided into the following: simple vertebroplasty (VP), balloon kyphoplasty (BKP), and vertebral stenting9. All these three methods require polymethylmethacrylate (PMMA) to stabilize the fracture and alleviate pain. Most complications from the above procedures are related to the leakage of PMMA cement beyond the fractured vertebral body. While most cases of cement leakage are asymptomatic, they can potentially result in infection, nerve tissue injury, pulmonary emboli, and even death10. Burton et al. believed that cement viscosity and injection volume are critical factors for controlling cement leakage11. Subsequently, various materials and novel bone cements have been developed and introduced in the market to prevent this condition. Some authors even suggested that cement leakage could be eliminated completely when the viscosity of the material was increased to a consistency that is comparable to dough12.Although conservative treatment including bed rest, analgesics, and bracing can manage most patients with VCFs, debilitating pain and substantial functional limitations often continue to greatly impact their quality of life. Percutaneous cement augmentation for VCFs have acquired popularity in spine surgeons because of their dramatic pain relief and improvement towards life quality for patients14. The site of injury where treatment occurred in most cases of these studies were at the thoracolumbar junction. The management of high (T4–T6) to mid- (T7–T9) thoracic VCFs has been largely unexplored. To the best of our knowledge, the current studies focusing on the outcomes of HVC VP compared with LVC BKP for high to mid-thoracic VCFs are limited. Thus, the goal of this study was to investigate and compare clinical outcomes using HVC VP and LVC BKP in the treatment of the high to mid-thoracic VCFs.Direct comparisons between high viscosity cement (HVC) VP and low viscosity cement (LVC) BKP have been reported in the literature sporadicallyThis retrospective study commenced after permission from Chang Gung Memorial Foundation Institutional Review Board (IRB) (number: 202101883B0) was granted. All methods in this study were performed in accordance to relative guidelines and regulations. The written informed consent was waived by Chang Gung Memorial Foundation IRB as this study only involved review of radiographs and medical charts, and did not disclose personal patient information. From January 2015 to December 2020, consecutive series of patients who underwent cement augmentation for spinal lesions at a single tertiary medical center were reviewed. We included patients with single level osteoporotic VCF at levels T4-T9, who received treatment with HVC VP or LVC BKP. Diagnosis was made from plain films, and additionally confirmed with either computed tomography (CT) or magnetic resonance imaging (MRI). Exclusion criteria included patients with high-energy mechanism trauma injury, infection, primary or metastatic malignancy, and those who previously received in situ vertebral-level open reduction and internal fixation.15We recorded patient demographics, comorbidities, the vertebral level of the compression fracture, time of procedure (operation time did not include cement coagulation time), hospital length of stay, complications, and clinical outcome results. Clinical outcomes were evaluated by a pain scale determined by the visual analogue scale (VAS), a continuous scale from 0 to 10, with 0 indicating no discomfort/pain and 10 indicating extreme pain. Patients were asked to rate their pain after a verbal explanation of the scale. The pain scale was recorded preoperatively and 6 months after surgery at the follow-up visit. As there is no universally accepted cut-off point, we used Boonstra et al.’s study as reference in determining a VAS score greater and equal to 3 as cut-off for moderate-to-severe pain16. Figure Radiographs of the studied cases were blindly reviewed by an observer who did not attend the surgeries. Radiographic parameters included the preoperative, postoperative, and 6-month follow-up anterior vertebral height (AVH), middle vertebral height (MVH), posterior vertebral height (PVH), local kyphotic angle (KA), and Cobb angle (CA). These parameters were measured manually on plain radiographs in lateral and sagittal planes and were calculated using a formula that had been described by Hsu et al., iMedicom, Korea) were as follows. Patients were placed in a prone position under antiseptic conditions with administration of a dose of prophylactic intravenous antibiotics. During the procedure, all patients were awake under intravenous fentanyl and local lidocaine anesthesia. Under fluoroscopy, a puncture needle was placed percutaneously into the fractured vertebrae through a unilateral or bilateral transpedicular approach. In general, all patients received a unilateral approach. If it was evident that the cement did not project cross the midline on fluroscopy, was then a bilateral approach utilized. The HVC VP procedure was similar to the LVC BKP procedure except for balloon insertion and inflation. The volume of injected cement was dependent on the bone defect and the individual patient's condition. Figure The surgical procedures for all patients treated with HVC VP  or LVC BKP  for the analysis of continuous variables. The cut-off for statistical significance was p < 0.05.This study was performed after obtaining Institutional Review Board (IRB) approval of Chang Gung Medical Foundation. IRB No. 202101883B0.A total of 114 patients with painful collapsed single-level vertebrae at high to mid-thoracic level who underwent vertebral body augmentation were enrolled. According to their surgical procedures, 72 patients were treated with HVC VP versus 42 with LVC BKP. In the HVC VP group, there were 57 women and 15 men (mean age: 74.61 ± 13.41 years). In the LVC BKP group, there were 38 women and 4 men (mean age: 77.57 ± 7.14 yeas). Other demographic data including body mass index, comorbidities, and osteoporosis T-score were similar between the two groups. A falls accident was the cause for 44.4% of the compression fractures in the HVC VP group and 61.9% in the LVC BKP group; the other patients appeared to have sustained vertebral compression fractures for no apparent reason. Evaluation of preoperative MRI data showed no significant differences between the groups for the presence of a vacuum cleft and endplate fractures of the vertebral body. The average hospital length of stay was 3.35 ± 1.41 days and 3.48 ± 2.22 days in the HVC VP and LVC BKP groups, respectively. The average last follow-up time was 1 year.The volume of cement injected was significantly higher in the LVC BKP group (4.40 ml ± 1.71 ml) than in the HVC VP group (3.66 ml ± 1.36 ml) (p < 0.001). However, the HVC VP group was associated with fewer cases of cement leakage . There were no neurologic deficits or symptomatic emboli in these patients. The operation time for the HVC VP group (33.34 ± 6.02 min) was significantly less than that for the LVC BKP group (39.05 ± 10.11 min) (p = 0.011). The operation time did not include cement coagulation time. During the 6 month follow-up period, there was no difference between the groups for the incidence of adjacent fractures following cement augmentation . Pain relief following surgery was highly desired by patients. Both groups showed considerable improvement in the follow-up VAS scores . There were no significant differences in the preoperative and postoperative VAS scores between the two groups. Table Both groups showed increased AVH, MVH, PVH, corrected KA, and CA after the cement augmentation procedure. Before surgery, both groups had similar AVH, MVH, PVH, KA, and CA data. After surgery, the LVC BKP group obtained significantly greater height (mm) in postoperative AVH and MVH , but there was no significant difference for PVH between the two groups after surgery. The LVC BKP group had a significantly more corrected MVH than the HVC VP group . At final follow up, both groups again showed similar AVH, MVH, and PVH. Recurrent vertebral height loss following cement augmentation was encountered in both groups, but there was no significant difference between the groups . The values of local angles and vertebral body–associated parameters are summarized in Table 10. Zhao et al. performed a meta-analysis study which demonstrated patients treated with BKP was more effective than VP according to superior scores for long term VAS and Oswestry Disability Index, improved KA and mean vertebral body height, and significantly reduced risk of cement leakage17. However, some studies did not support that BKP is superior to VP for pain relief and functional improvement19. In this current study, VAS outcomes reflecting pain relief after vertebral body augmentation at high to mid-thoracic vertebrae was similar for  HVC VP and LVC BKP.VP and BKP are common interventions for the treatment of osteoporotic VCFs. The difference between VP and BKP is that BKP adds a procedure of balloon inflation in the collapsed vertebrae. Both interventions use bone cement to stabilize the fracture. Clinical studies of different cement augmentation procedures have been encouraging. Several studies have suggested both VP and BKP improve quality of life, pain relief, functionality, and restores vertebral body height20. By contrast, the incidence of VCFs at high (T4–T6) and mid- (T7–T9) thoracic vertebrae is lower and associated research is limited. The thoracic spine is part of the thoracic cage, which serves to protect vital organs and provide rigid support to bear and disperse substantial axial loading forces. Patients with a compression fracture over the high to mid-thoracic vertebrae can suffer high to mid-back pain, which can be exacerbated with respiration and may radiate to the anterior chest. Anatomically, the thoracic vertebrae is characterized by small pedicles with the diameter becoming narrower as the thoracic level gets higher. Therefore, nervous tissue would likely be intolerable when cement leakage into the thoracic canal occurs. To minimise the risk of cement leakage, Liu et al. recommended that LVC BKP is preferred over LVC VP for osteoporotic VCFs of mid-thoracic vertebrae21. Another key factor to reduce the incidence of cement leakage is viscosity of the cement in VP. Alhashash et al. demonstrated that HVC VP had a relatively low risk of cement leakage for patients with VCFs22. However, they focused mostly on lower thoracic and lumbar spine levels. Based on our study, the cement leakage rate is lower with HVC VP in relation to LVC BKP  after cement augmentation for high to mid-thoracic vertebrae. A meta-analysis study by Chen et al. also confirmed that HVC VP holds the lowest rate for cement leakage after cement augmentation when compared to LVC BKP and LVC VP23.The most frequent area involved in VCFs is the thoracolumbar junction (T12-L2), followed by the lower lumbar area (L3–L5)24. Similar results are also observed in BKP with Chen et al. demonstrating decreased volume of cement injection could also reduce the incidence of cement leakage25. Although most leaks were clinically asymptomatic, they carry the risk of pulmonary embolism and neurologic compression which are considered major complications in cement augmentation procedures. In this study, cement volume of injection was significantly lower in the HVC VP group . Moreover, HCV VP alleviates the need for bone cavity creation within the injured vertebra, thus significantly reducing the procedure time , Thus, we believe HVC VP is more reliable than LVC BKP when applied to high to mid-thoracic vertebrae.Cement injection volume has been reported as one of the risk factors for cement leakage in percutaneous VP and BKP. Zhu et al. recommended that < 3.5 mL of bone cement per vertebrae should be injected to minimize the risk of volume-associated cement leakage26. The results showed all these procedures would increase stress on the endplates of the adjacent segments, especially the superior levels during flexion. Another finite element study revealed that when cement filling volume reached 30–40.5% of the volume of a vertebral body, this also increases the stress tolerated by the adjacent segments. However, when the injected cement volume exceeded the defined range, stress distributions on fractured and adjacent vertebral bodies not only increased but led to development of adjacent vertebral fractures27. Clinically, the incidence of adjacent fractures have been reported to range from 5.5 to 52% after VP and BKP29. In our study, the incidence of adjacent fractures following HVC VP and LVC BKP was 8.3% and 9.1%, respectively. We believed the incidence of adjacent fractures at high to mid-thoracic vertebral levels would be far less than that at the thoracolumbar junction because a smaller vertebral body size has consequently less cement injection and additional protection is encouraged by the thoracic cage.The biomechanics of the fractured segment are altered following cement augmentation. The reconstructed vertebrae is more rigid than its adjacent segments. It acts as an upright pillar that reduces the inward physiologic bulging of the endplates of the augmented vertebrae. Liao et al. made a finite element model of osteoporotic VCFs with cement augmentation with VP, BKP, and vertebral stentsIn this study, all radiographic results including AVH, MVH, PVH, local kyphotic angle, and Cobb angle showed significant postoperative improvement in both groups. The HVC VP group showed comparable radiographic outcomes to those of the LVC BKP group in terms of kyphotic reduction, but with less vertebral body height restoration (determined by postoperative AVH and MVH). It is believed that the effect of balloon inflation on the injured vertebrae and more cement injected in the LVC BKP group resulted in these radiographic advantages immediately after surgery. However, more severe re-collapsed vertebrae were also shown in the LVC BKP group, which resulted in final follow-up radiographic parameters that had no statistical difference between two groups. These changes in radiographic data did not influence clinical outcomes.31. Dr. Georgy was the first author to describe his experiences in using HVC VP and BKP for osteoporotic VCFs, and his data showed HVC VP had a significantly lower rate of cement leakage30. Data from Wang et al. revealed injected volume was higher with BKP but cement leakage rate was lower in HVC VP14. Sun et al. and Lin et al. all demonstrated similar clinical results for VAS and Oswestry Disability Index (ODI) scores with either HVC VP or BKP, and restoration of height for the middle vertebrae appeared superior in the BKP group31. The biggest difference between our study and the above four reference papers was that our study included cases that involved only the high to mid-thoracic spine, but the thoracolumbar junction stood the majority of cases in the reference articles. Nevertheless, our data drew similar results to that of the above references.In the past two decades, the majority of the literature published discuss the differences LVC VP and LVC BKP for spinal compression fractures. However, studies that compare HVC VP and LVC BKP is very scarce. After a search in PubMed, we found only four clinical research studies published discussing the use of HVC VP versus LVC BKP in the treatment of osteoporotic VCFsIndeed, there are limitations to our study. First, the nature of a retrospective study might include inherent bias. Moreover, clinical outcomes for daily function such as ODI or 36-Item Short Form Survery (SF-36) would provide additional beneficial clinical functional information but could not be evaluated due to unavailability of data in a retrospective study. Second, the procedures were performed by different surgeons at our center, and we were unable to account for technique variation. Third, although the results were clear and comparable between the groups, a longer follow-up period is necessary to assess whether HVC can alleviate BKP-related risks in the treatment of osteoporotic VCFs in high to mid-thoracic vertebrae. Fourthly, the medical insurance policy in Taiwan does not subsidize the use of CT or MRI for evaluating bone cement leakage or adjacent fractures respectively, therefore the diagnosis using plain film inherently has a high false negative incidence and data may therefore be restricted.In this study, both HVC VP and LVC BKP groups were safe and effectively achieved pain relief for patients with high to mid-thoracic osteoporotic VCFs. The mean operation time of HVC VP was significantly shorter than that of LVC BKP, but vertebral body height and local kyphosis angle could be corrected better postoperatively by LVC BKP. In addition, HVC VP demonstrated a lower bone cement leakage rate and incidence of adjacent segment fracture compared to LVC BKP. Thus, HVC VP might be a good alternative to LVC BKP in the treatment of osteoporotic VCFs in high to mid-thoracic spine.


Abderrazak Hajjioui talks to Tatum Anderson about the need to prioritize multidisciplinary rehabilitation education, practice and research. Q: When did rehabilitation become the prime focus of your career?A: During my medical school training and subsequent internships. I noticed that Moroccan practitioners tended to be more interested in patients’ diseases than in the patients themselves or in the quality of life they were going to have once they had been “treated” or “cured”. It really struck me when I was working in the neurology department of the Ibn Sina University hospital in Rabat; we would receive stroke patients, make a diagnosis, give them medication and then send them back home. This despite many of the patients being barely able to move or walk or take care of themselves. Witnessing those outcomes, and the complaints of the patients and their families, steered me towards a greater interest in rehabilitation. Q: You were one of the first Moroccan doctors to specialize in rehabilitation. What kind of challenges did you face?A: The most obvious was the lack of specialists in the domain to teach me and my junior colleagues. I spent my first year of residency in Morocco and then spent several years in France, where I was able to pursue my specialization at the University of Versailles Saint-Quentin and René Descartes University in Paris. Once qualified, there was an opportunity for me to lead the hospital’s rehabilitation programme in Fez, a responsibility I was happy to take on.Q: Have others in Morocco followed in your path?A: Not as many as I would have expected. Unfortunately, rehabilitation is not a priority in Morocco. This is expressed in many ways, but notably in education. For example, until recently we didn’t have a course or programme on rehabilitation in the national undergraduate medical curriculum. Lacking exposure to rehabilitation, very few graduating doctors opt for it as a career choice in their residencies.Q: What are the main obstacles to developing the field of rehabilitation in Morocco?A: As in many low- and middle-income countries, lack of resources is a factor, but so is the distribution of those resources – the decisions taken about where resources should go. We are willing to spend money on emergency surgery, and acute medicine, but not on rehabilitation. We send patients home from acute medicine or emergency departments without rehabilitation, and they suffer as a result, often dying from complications.“The priority is always given to acute care.”Q: Can you say more about that?A: Research my team and I did on the outcomes and quality of life of people with spinal cord injury and with brain injury – the most common acute conditions in Morocco – revealed that roughly half of the patients die of complications in the first year after the acute phase, and those are the patients who have received some limited rehabilitation support. It is just not acceptable that we send stroke patients home after a short hospital stay with a prescription for physiotherapy at city-based ambulatory rehabilitation centres that generally lack capacity and rehabilitation infrastructure. Sometimes they get a wheelchair, sometimes they don’t. And the situation is not going to get any better as the demand for rehabilitation continues to increase.Q: What is driving that increase in Morocco?A: As in many countries, the ongoing epidemiological transition towards increased prevalence of noncommunicable diseases, driven in part by increasing obesity and sedentary lifestyles, is driving increased demand. So too is population ageing, driven by increased life expectancy – and increased years lived with disability – and declining fertility. According to the WHO/IHME Rehabilitation Needs Estimator  that provides global-, regional- and country-level data visualizations of the estimated need for rehabilitation globally) in 2019, 11 million people out of a population of 37 million in Morocco experienced conditions that could benefit from rehabilitation.Q: What can be done to meet the demand for rehabilitation services?A: First, we need to change the vision and perceptions of decision-makers with regard to rehabilitation. Working in collaboration with the Ministry of Health, my colleagues and I are advocating to improve the awareness of rehabilitation, as part of universal health coverage, highlighting rehabilitation’s importance to health and well-being. Of course, the medical profession perceptions of rehabilitation must also change. I am talking about my fellow professionals. For example, at my hospital we have funds allocated for capacity development and could develop rehabilitation departments. But the priority is always given to acute care. So, we need to do more to raise awareness among doctors and decision-makers.Q: You are a clinician and an educator. What, if anything, needs to change in the way rehabilitation is taught in universities?A: First it needs to be made a core part of educational curricula. I have worked with a network of medical schools to develop a module of 10 hours on rehabilitation and disabilities. The module was introduced into the national curriculum in 2015. I am also now working with the National School of Public Health to incorporate a module on rehabilitation into a course on health facilities management for future policy-makers. In addition, I launched two university diplomas: one concerning cardiovascular and pulmonary rehabilitation, chronic disease and ageing, and the other concerning the neuro-rehabilitation of adults. Rehabilitation education should also encourage multidisciplinary approaches. As part of our university diplomas, we invite rehabilitation teams comprised of doctors, physiotherapists, speech therapists, occupational therapists, orthotists and prosthetists and nurses to take the same course on how to manage, for example, stroke survivors from the acute phase to their reintegration into the community. This collaboration is essential to develop shared language and approaches and to build our teams. It’s important to remember that education is not limited to university or medical school. One of the biggest challenges we face is how to provide training for the different kinds of rehabilitation professionals once they graduate.Q: Is that because of a lack of specialists or a lack of rehabilitation centres in which to train?A: Both. For example, there are no post-acute inpatient rehabilitation centres in the public health system. Rehabilitation should begin as early as possible after surgery and is best delivered through a versatile, multidisciplinary inpatient and outpatient approach. Unfortunately, in Morocco, as in many lower-income countries, rehabilitation services are only delivered as ambulatory and thus they are not accessible to the patients who are most disabled. In the public health system, there are about 24 000 beds for acute care, with an occupancy rate of less than 65%, but zero beds for rehabilitation patients. The same is true of more specialized rehabilitation capacity. I know many physiotherapists who want to get specialized training in neurological rehabilitation, for example, but we don’t have any neurological rehabilitation departments to send them to. This lack of capacity and lack of opportunities discourages graduates from specializing in rehabilitation and is one of the reasons why so few medical graduates are recruited to train and work in rehabilitation.“We send stroke patients home after a short hospital stay.”Q: To what extent is the brain drain a problem?A: It is a big problem here, especially with France being so close and so many of our graduates speaking French as a second language. As I mentioned, I pursued my studies in France and could have stayed there. I chose to come back. Many do not. So, yes, the migration of young graduates and the best rehabilitation professionals to the most developed countries is a big problem, as is the unequal distribution between the different cities and regions of the Kingdom of Morocco.Q: How important is developing local research capacity to strengthen rehabilitation?A: Research is of crucial importance and an area of great concern. We need researchers to publish data about rehabilitation and health issues in the Moroccan context to establish the evidence base needed to guide public health policy. We also need rehabilitation research that answers the questions being raised by health policy-makers regarding the needs of the population. Unfortunately, despite efforts made in recent years, research in rehabilitation in Morocco is still limited by several barriers. These include the absence of a research community, lack of funding, insufficient experience of researchers, and barriers to access such as high publication fees. We also have a problem of quality which is in part a reflection of conditions in the field. How can we produce a good paper about stroke rehabilitation when we don’t have a stroke rehabilitation department? It is a chicken and egg situation: research drives capacity development which drives better research. Of course, this problem is not limited to the Moroccan health system. We need to train, strengthen and encourage researchers working across low- and middle-income countries worldwide. It’s worth remembering that an estimated 80% of people with disabilities live in these countries. It is for this reason that I am also committed to regional capacity development and am working with WHO and many nongovernmental organizations to advance that agenda.Q: What are your hopes for the future?A: I would like to see rehabilitation services, both specialized and general, established at different levels of the health system in Morocco. I would also like to see rehabilitation embraced as a core component of SDG 3 . Rehabilitation not only reduces the burden of disability – it enables people living with disability to fully participate in the life and work of their communities and society as a whole. As such, it is clearly vital to the realization of global health and well-being and beyond that the overarching goal of sustainable development.