Background: To inform global health policies and resources planning, this paper analyzes evolving trends in physical rehabilitation needs, using data on Years Lived with Disability (YLDs) from the Global Burden of Disease Study (GBD) 2017. Methods: Secondary analysis of how YLDs from conditions likely benefiting from physical rehabilitation have evolved from 1990 to 2017, for the world and across countries of varying income levels. Linear regression analyses were used. Results: A 66.2% growth was found in estimated YLD Counts germane to physical rehabilitation: a significant and linear growth of more than 5.1 billion YLDs per year . Low-income countries more than doubled (111.5% growth) their YLD Counts likely benefiting from physical rehabilitation since 1990. YLD Rates per 100,000 people and the percentage of YLDs likley benefiting from physical rehabilitation also grew significantly over time, across locations . Finally, only in high-income countries did Age-standardized YLD Rates significantly decrease . Conclusions: Physical rehabilitation needs have been growing significantly in absolute, per-capita and in percentage of total YLDs. This growth was found globally and across countries of varying income level. In absolute terms, growths were higher in lower income countries, wherein rehabilitation is under-resourced, thereby highlighting important unmet needs. Worldwide rehabilitation needs are growing in tandem with global population growth, population aging, and higher survival rates for people with severe health conditions and disability ,2,3. HowThe GBD study, which has incorporated data since 1990, is the most comprehensive global epidemiological study to date. It combines data from the best available sources , procFor the first time in the study’s history, the GBD 2017 reports data on injuries in terms of their nature or consequence , in addition to and apart from their cause  . This neOthers have used GBD study data to examine rehabilitation needs ,8. In thIn addition to the WHO’s analysis, a number of studies have used GBD data to examine particular conditions likely benefiting from physical rehabilitation, such as injuries  , musculoHow large are the estimated world’s YLDs  likely benefiting from physical rehabilitation in 2017?What is the percentage of the world’s YLDs likely benefiting from physical rehabilitation relative to total YLDs?Did any of these estimates change significantly over time ? If so, by how much? and, finally,Did any of those trends differ across countries of varying income levels?Using publicly available data from the GBD 2017, this paper aimed to provide a systematic global analysis of YLDs for the combined set of health conditions likely benefiting from physical rehabilitation, and specifically answer the following study questions:The answer to these questions would provide valuable benchmarks to inform global and local health and rehabilitation policies, research, and advocacy. Moreover, such findings could provide direction to funding priorities, as well as timely information for health system planning and strengthening activities, including for determining needs for physical rehabilitation services, as a means to allocate resources accordingly.http://ghdx.healthdata.org/gbd-results-tool).Systematic, secondary analysis of public-domain data from the GBD 2017, extracted from the freely-available web platform: the Global Health Data Exchange tool , “impairments”  and “injuries” , the authors selected those deemed likely to benefit from physical rehabilitation, as described below. Given that YLDs from “causes” are collective exhaustive, to avoid double counting, we do not cumulatively select YLDs from Injuries as a “cause”, but only YLDs from the nature of the injury. In addition, YLDs from “impairments” were limited to those not coming from “causes” we had already selected.We found no global standard to inform which health conditions potentially benefit from physical rehabilitation; thus, in determining which conditions to focus on as potentially benefitting from physical rehabilitation, we relied on the following: previous works using GBD data for rehabilitation ,8,19; paPhysical rehabilitation uses health-based approaches to optimize physical function and participation in persons with physical impairments  or symptoms  that are amenable to recovery, prevention, or management from physical rehabilitation services, facilities or providers . From this definition, we excluded rehabilitation of people with oral, mental health, substance abuse disorders, intellectual or sensory impairments per se, although partial overlap often occurs across different forms of rehabilitative interventions for those conditions. Of note, within the application of the working definition and exclusion criteria, ‘dubious’ selection decisions existed, e.g., health conditions for which it was not certain whether physical rehabilitation would be applicable or likely to provide benefits. For example, in Autism Spectrum Disorder, psychosocial disfunction and rehabilitative approaches are often dominant, but sensory-processing and motor impairments are prevalent and might benefit from physical rehabilitation as well ,33,34,35Indeed, toward informing these decisions, we searched PubMed primarily for aggregated evidence, preferably systematic reviews, on the effect of physical rehabilitation approaches  on each type of condition we identified as potentially “dubious” for inclusion. We further gave priority to locating and selecting systematic reviews from Cochrane Database of Systematic Reviews, whenever available . As an example, we found that the quantity, quality and strength of the evidence base for cardiac rehabilitation varies across various cardiac conditions ,40,41,42Finally, among the set of conditions in YLDs, i.e., the aggregative measure of the GBD study that focuses exclusively in non-fatal impacts of health conditions. YLDs are the years lived with any short-term or long-term health loss weighted for severity by the disability weights. Concretely, YLDs are computed by combining the estimated prevalence of a health condition with the estimated number of years people typically live with those sequelae, up to the population life expectancy threshold. Importantly, the prevalence of sequelae from each condition is classified by severity levels , each one having a respective disability weight [Among the measures available in the webtool, we only extract data for y weight ,6,80,81.y weight ,6,81.number (YLD counts), rate , and percentage . For age, we extracted YLDs both for all ages and age-standardized rates. With those specifications, we obtained YLDs likely benefiting from physical rehabilitation under the following forms, used as measures for the analysis:YLD Counts: Nominal amount of YLDs;YLD Rates: YLDs per 100,000 people, i.e., adjusted for population size only;Age-standardized YLD Rates: YLD values adjusted for both population size and ageing;Percentage of YLDs Benefiting from Physical Rehabilitation: The proportion of YLDs from conditions likely benefiting from physical rehabilitation among total YLDs, provided in percent values.For our metrics, we extracted YLD data for prevalent world) and for high, upper middle, lower middle, and low-income countries, according to the World Bank Income Levels. We also extracted YLDs for all the years from 1990 to 2017, and for each selected health condition  the YLDs data for all the selected health conditions—within each of the “years”, “locations”, and “metrics”. Percent changes from 1990 to 2017 were also computed for the combined values.r2 values of pilot regression models, then we determined which regression model type  best fit the plotted data, and recorded the respective r2 values. Given differences in r2 values <0.02 between the models, we retained the linear regression option. Linear regression analyses, using the analysis of variance (ANOVA)—which account for the data on every year between 1990 and 2017, then were used to test for statistical significance, notably of a non-zero yearly change, considering the full time-period between 1990 and 2017, inclusively. We used the linear regression analytical approach even for the data that fitted an exponential or logarithmic-type of regression. In those cases, we tested the models using either the actual YLD values or a ‘log-transformed’ version of these. As there was no difference in the statistical significance for any case, we retained linear regression analyses using the actual YLD values. This facilitated the interpretation of the results since the coefficient and their confidence intervals refer to the estimated annual change in YLD values, i.e., the slope of the linear regression line. The significance level for the analysis was set at p = 0.05.For inferential statistics, first we plotted the entire time series of the combined values for each location, within each YLD metric. Using visualization and r2 0.99). While countries from all income levels had significant and linear growths, low-income countries more than doubled (111.5% growth) their YLD Counts, likely benefiting from physical rehabilitation for the 28-year period.r2 = 0.5)) and was only significant at a 95% confidence level (p = 0.02). Of note, upper middle-income countries had a yearly growth of 42.6 YLDs per 100,000 people , significantly higher than any of the comparators, i.e., no overlap among the 99% CIs.r2 = 0.46), the former had a logarithmic decrease . Overall, in this metric, we observed the smallest magnitude of changes: a maximum of 2.7% change from 1990 to 2017.On Age-standardized YLD Rates, which adjusted YLDs for population size and ageing, p < 0.01; minimum r2 = 0.87). However, while high-income countries had the highest percent value in 2017 (48.6%), low and middle-income countries (LMICs) grew significantly on an order of up to seven times: 0.200 (99% CIs 0.185–0.215) versus 0.030 (99 CIs 0.024–0.037). In a final metric, Finally, First, YLD Rates for low-income countries grew over time in a linear shape, not logarithmic. Second, the percentage of YLDs Benefiting from Physical Rehabilitation did not significantly change for high-income countries for the subgroup of conditions, while it did in the main analysis. Lastly, in the subgroup of conditions, Age-standardized YLD Rates decreased significantly worlwide but increased significantly in low-income countries.This paper is, to our knowledge, the first systematic, secondary analysis of global physical rehabilitation needs, based on publicly-available data from the most comprehensive source of global epidemiological data to date, i.e., the GBD 2017. In addition to an over 66% global increase in YLD Counts from 1990 to 2017 , we found a 17% increase in YLD Rates, i.e., per size of the population. Therefore, the growth of YLDs from all conditions likely benefiting from physical rehabilitation have outpaced that of the population. The key factor influencing per-capita growth has been the global population ageing, which is why the world’s Age-Standardized YLD Rates for all conditions potentially benefitting from physical rehabilitation did not significantly change over the studied time-period. Aging of the population is likely to continue to be a worldwide phenomena for the next several decades . GlobalGrowth in need for physical rehabilitation was particularly prominent in LMICs. For instance, in low-income countries, the YLD Counts more than doubled since 1990, likely due to population growth from high fertility rates as YLD Rates grew at a much less pronounced rate. In fact, increases in YLD Counts were inversely proportional to the countries’ income levels, such that the greatest increase in needs for physical rehabilitation was found in countries with lower income levels and the least rehabilitation infrastructure. Indeed, rehabilitation resources in many LMICs remain quite limited ,83,84. TNonetheless, we note that, in low-income countries, we also observed a logarithmic growth in YLD Rates, flattening around the year 2000  have been, altogether, key for the continued growth in the percentage of YLDs Benefiting from Physical Rehabilitation. The higher the percent value, the higher the expected impact of physical rehabilitation, i.e., in terms of being able to reduce a higher share of the global burden of non-fatal health conditions.The paper’s limitations are the following: First, the YLD measure is, at best, a proxy indicator of need for physical rehabilitation. For instance, functional data at the population level, e.g., from the Model Disability Survey, and/or other disability statistics, whenever available, might be used in alternative or complement to provide a more comprehensive picture of populations’ physical rehabilitation needs ,110,111.Second, there is no global standard of conditions that potentially benefit from physical rehabilitation which we could use for the selection of specific health conditions to include in our main analyses. To inform that selection, we relied on previous research on physical rehabilitation, a working definition of physical rehabilitation, and tailored searches on PubMed. Nonetheless, tailored searches conducted on PubMed, to identify and help select of health conditions likely benefiting from physical rehabilitation, do not equate to a systematic review itself. For conditions which were particularly uncertain with regards to potential benefits from physical rehabilitation, we employed explicit, a priori evidence-informed reasoning about the potential trade-offs for over- vs. under-estimation of physical rehabilitation needs.Third, while a separate analysis for a subgroup of health conditions historically associated with physical rehabilitation need is present, it does not equate to minimum requirements in terms of a physical rehabilitation need.Fourth, once we partly relied on published evidence to ground selection decisions and our trade-off reasoning, any under-research on the rehabilitation of conditions less common in high-income countries  might have biased that reasoning. It is unknown whether the such putative under-research contributes under-estimate the magnitude of physical rehabilitation needs, especially in lower income countries.Fifth, we used inferential statistics with YLD estimates, rather than direct data collection with metrics to quantify the nature and degree of physical disability. Moreover, the uncertainty intervals of the underlying YLD estimates could not be computed for our ‘combined’ values , although they exist in the public domain for each included condition in isolation .Sixth, the quantity and accuracy of the data used to compute the GBD estimates is typically lower in lower income countries, which can include a less accurate detection or registry of data for many health conditions, especially non-communicable diseases or injuries. That can partly justify why the LMICs have much lower values for example in the Age-Standardized YLD Rates, across the time-series, when compared to high-income countries. Therefore, it is possible that the true magnitude of physical rehabilitation needs in LMICs remain partly obscure in these results. In addition, the quantity and accuracy of the underlying data in 2017 is likely superior to what it was back in 1990. This means a lower precision for the GBD estimates for the earlier years. However, lower preciseness does not imply systematic error  toward over- or under-estimation of YLDs for the earlier times. To reduce potential bias, at each new cycle, the GBD study uses the more complete and updated data, measurement and classification systems, and estimation methods to re-calculate the entire time-series, not just the estimates for the more recent years .Seventh, the presence of auto-correlation in the time series was not ruled out, i.e., we did not assess whether error terms were significantly correlated over time. Nonetheless, many of the simple linear regression models had nearly perfect fits with the underlying time series data, meaning that the magnitude of each of those errors was negligible. In addition, we used only simple linear regression analyses which did not account for what had changed over time apart from population growth and ageing. The latter ones here were inherently accounted for when we performed analyses using “Age-standardized YLD Rates” instead of simple YLD counts.Finally, we focused on evolving trends for overall needs for physical rehabilitation and then in a narrow, conservative subgroup of conditions benefeting from physical rehabilitation, and did not perform sub-group analyses across specific groups of conditions  as these have been performed by other groups that have used GBD data.This systematic secondary analysis of the GBD 2017 provides global data on current physical rehabilitation needs, and on how those needs evolved since 1990, including across countries of varying income level.Physical rehabilitation needs have been growing significantly over time across locations, not only in absolute terms, but also per-capita and in percentage of the total amount of total YLDs. This means that not only has physical rehabilitation been growing, but also that physical rehabilitation is now capable of averting a higher portion of the global burden of disability. The highest absolute growth of physical rehabilitation needs was observed in countries of lower income level, which typically have deprived rehabilitation infrastructure. Finally, only in high-income countries did a significant reduction in age-standardized needs per capita occur, which can be related to the wider implementation of physical rehabilitation services in these countries.The use of the comprehensive, up-to-date GBD estimates for the needs-side of the rehabilitation resources-planning equation, albeit imperfect, is a readily available means to help health planners to meet the physical rehabilitation needs of the global population. These needs were found to be high and increasing, including per-capita, across countries of varying income level.


Spinal cord injuries result in devastating impairments that can produce severe functional limitations. However, few documented studies have investigated the levels of function and factors that influence functional ability at discharge from in-patient rehabilitation facilities in Gauteng following such injuries. This necessitated further investigation.Fifty participants were recruited for this cross-sectional, observational study. Participants were recruited from one private and one government spinal rehabilitation unit in Gauteng. A custom-developed questionnaire was used to establish the physical and demographic characteristics of the sample, whilst existing classification scales and measures were used to establish the degree of a lesion and a patient’s associated functional ability. Data were analysed using descriptive statistics. Multiple regression analysis was performed to determine factors that influenced the level of functional ability.Patients achieved an average functional independence score of 64.6 (± 27.6) at discharge according to the Spinal Cord Independence Measure III. Longer stays at rehabilitation facilities were associated with higher scores, whereas scores decreased with increasing patient age. Pressure sores and spasticity affected scores negatively. The type of funding also influenced patients’ scores, with government funding being associated with the best outcome. Both the degree and the level at which the injury occurred could be considered predictive measures that influenced functional independence scores.Most participants were not functionally independent at discharge. Factors such as patient age, length of rehabilitation, presence of pressure sores or spasticity, degree of motor ability and location of the injury should be considered in tailoring rehabilitation therapy. Spinal cord injury (SCI) refers to a physical injury to the spinal cord that disrupts normal spinal cord function  were approached for possible inclusion in the study. The sample size was calculated based on the most common factors that may affect the functional outcome of persons with SCIs. The following factors were identified from literature:age at onset of injurylevel of injurytime to admission after the injurypresence of a pressure sorepresence of a urinary tract infection.For every factor that is considered to have a possibility of influencing the results of the study, at least ten participants are required Nunnaly . TherefoTo be considered for participation, individuals had to have either a traumatic or a non-traumatic SCI resulting in paraplegia, as defined by the American Spinal Cord Injury Association (ASIA) classifications A and B, and had to be older than 18 years (for consent purposes). Individuals with impairments not related to the SCI, unstable vital signs and pre-existing physical and cognitive problems were excluded from participation.A three-part questionnaire was developed to establish the physical and demographic characteristics of the participant at discharge from an in-patient rehabilitation unit. The first section focused on demographic details and was filed separately and coded to ensure the participant’s anonymity. The second section related to possible demographic and physical factors that could influence the function of each participant, such as date of injury, date of discharge from the acute hospital, date of admission to and discharge from the rehabilitation facility, respectively, neurological injury level, age at onset of injury, gender, and set bladder and bowel routines. The third section was used to determine whether participants experienced any secondary complications since their injury, including those experienced during their hospital stay , reasons for early or delayed discharge, and type of health care funding . To ensure content validity of the questionnaire, therapists with experience in the field of SCI rehabilitation and research were consulted to develop and determine whether the questions were appropriate for the aim of the study.The ASIA classification scale of neurological impairment was used to describe the level and completeness of the lesion. Very good levels of inter- and intrarater agreement have been established in all components of the ASIA neurological examination when assessing patients with acute to chronic SCIs  was used to determine the level of functional ability post SCI. This is an efficient measure for the functional assessment of individuals with SCI and the concurrent validity of the scale is supported by the high correlation with the functional independence measure, although the SCIM has been found to be more responsive to change in function of persons with SCI .P < 0.1). However, data were not distributed normally; therefore, the data were transformed to achieve normality before analysis. After the univariate analysis was performed, a stepwise regression was performed. Variance inflation factors (VIFs) were checked for possible co-linearity. None of the VIFs were close to 10 and only factors with VIFs above 10 would warrant further investigation for co-linearity; therefore, there was no effect of co-linearity in the results.Data were analysed using descriptive statistics for age, gender, classification of funder, time to rehabilitation admission, LOS, ASIA motor score, all post SCI complications, and SCIM III score. A univariate analysis was conducted on all items using STATA 10 statistical software to determine any significant factors that affected the functional ability of SCI patients at discharge. This was followed by a multiple regression analysis on only those factors with a moderate significance (n = 40) than female participants . Most of the participants in this study sample qualified for workers’ compensation, which means that they had an injury on duty , followed by those who used medical aid , received government-funded treatment  and those who paid privately for their rehabilitation .A total of 50 patients participated in this study. Average age, LOS, time to rehabilitation admission and ASIA motor scores are shown in n = 38), sustained at a low spinal level , and followed either a set bladder management programme  or a bowel management programme .Participants’ general physical characteristics are shown in n = 21) experienced back pain, whereas 12% (n = 6) experienced shoulder pain. About a third of the participants  developed a pressure sore during their acute hospitalisation , whereas 26% (n = 13) developed a pressure sore during their stay at the rehabilitation facility.Post SCI complications experienced by participants are shown in The results of the multiple regression analysis of the factors that influenced functional ability of individuals post SCI are presented in P = 0.01).Relative to participants whose SCI rehabilitation was government funded, individuals whose therapy was funded by workers’ compensation (owing to being injured on duty) scored 4.8% lower on the SCIM III score sheet, followed by participants who used medical aid or private insurance (8.1% lower SCIM scores) and participants who paid out of their pockets for rehabilitation (10.8% lower SCIM scores). Participants with low-level injuries had a 6.6% higher SCIM score relative to those with high-level injuries  and participants who paid out of their pockets for rehabilitation (10.8%). Similar trends could not be found reported in literature, but from the authors’ clinical experience, individuals whose rehabilitation expenses are covered by government tend to have a relatively longer hospital stay than those who use medical aid or private insurance. Should a health care funder not supply adequate funds for full rehabilitation in a private rehabilitation facility, individuals using medical aid may be discharged prematurely. Owing to medical aids increasingly curbing expenses, patients are not eligible for prolonged stays in rehabilitation units . However, there is often a shortage of government-funded SCI rehabilitation beds (Hardcastle Although this study identified factors that may influence the functional ability of individuals at discharge from rehabilitation, it did not focus on the functional ability of the participants on admission into rehabilitation, psychosocial factors, the type and duration of daily therapy sessions or the level and intensity of spasticity. However, despite these limitations, the findings of the study provide useful insights for clinical practice.The majority of the participants in this study were discharged from in-patient rehabilitation facilities before they could reach functional independence. It may therefore be necessary to emphasise the importance of outpatient rehabilitation after discharge or consider increasing the LOS to help them reach optimal functional independence. Factors such as an advanced age, short rehabilitation stays, the presence of pressure sores or spasticity, low ASIA motor scores and high-level SCIs may warrant close monitoring for functional outcomes and more attention during in-patient rehabilitation. When working towards functional recovery of an individual with a SCI, therapists should do regular ASIA testing to monitor changes in an individual’s neurological level of injury and take into account the functional implications of the level of the lesion.


Objective: the objective of this review is to analyze the advances in the field of rehabilitation through virtual reality, while taking into account non-immersive systems, as evidence have them shown to be highly accepted by older people, due to the lowest “cibersikness” symptomatology. Data sources: a systematic review of the literature was conducted in June 2019. The data were collected from Cochrane, Embase, Scopus, and PubMed databases, analyzing manuscripts and articles of the last 10 years. Study selection: we only included randomized controlled trials written in English aimed to study the use of the virtual reality in rehabilitation. We selected 10 studies, which were characterized by clinical heterogeneity. Data extraction: quality evaluation was performed based on the Physioterapy Evidence Database (PEDro) scale, suggested for evidence based review of stroke rehabilitation. Of 10 studies considered, eight were randomized controlled trials and the PEDro score ranged from four to a maximum of nine. Data synthesis: VR  creates artificial environments with the possibility of a patient interaction. This kind of experience leads to the development of cognitive and motor abilities, which usually positively affect the emotional state of the patient, increasing collaboration and compliance. Some recent studies have suggested that rehabilitation treatment interventions might be useful and effective in treating motor and cognitive symptoms in different neurological disorders, including traumatic brain injury, multiple sclerosis, and progressive supranuclear palsy. Conclusions: as it is shown by the numerous studies in the field, the application of VR has a positive impact on the rehabilitation of the most predominant geriatric syndromes. The level of realism of the virtual stimuli seems to have a crucial role in the training of cognitive abilities. Future research needs to improve study design by including larger samples, longitudinal designs, long term follow-ups, and different outcome measures, including functional and quality of life indexes, to better evaluate the clinical impact of this promising technology in healthy old subjects and in neurological patients. Virtual reality (VR) is a trending, widely accessible, contemporary technology of increasing utility to biomedical and health applications . VR is tVR ranges from non-immersive to fully immersive, depending on the degree to which the user is isolated from the physical surroundings when interacting with the virtual environment. Non-immersive virtual reality allows for interacting with the environment through mouse or joystick; immersive virtual reality, instead, uses tools that are connected to the human body in order to perform the same motor task ,4. Non-iThe use of VR technology in rehabilitation derives from research in computational neuroscience involving motor learning mechanisms . VR provVR provides alternative rehabilitation programs with new and effective therapeutic tools that can improve the functional abilities in a wide variety of rehabilitation patients in a neurological setting, offering several features, such as goal-oriented tasks and repetition. The use of VR environments for virtual augmented exercise has recently been proposed as having the potential to increase exercise behavior in older adults  and it aMoreover, VR training has been mostly described for the upper limb ,15, but To our knowledge, systematic reviews or meta-analyses have been undertaken to review the utility of VR technologies in a single arm of rehabilitation , focusing on a specific pathology  ,7,9.Despite the growing evidence of the positive effects of VR in rehabilitation of functional and cognitive abilities, some systems still raised concerns regarding their acceptability with complex clinical populations, as, for example, the older people. In particular, during trials with immersive systems, few adverse events have been described by participants, including headache and dizziness . FinallyThe objective of this review is to analyze the advances in the field of rehabilitation through VR, while taking non-immersive systems into account, as evidence have shown to be highly accepted by older people, due to the lowest “cibersikness” symptomatology . For thiThe methodology of this systematic review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, as the main aim of this work is mapping all the available literature in the rehabilitation with non-immersive virtual reality. A systematic review of the literature was conducted in June 2019. The data were collected from Cochrane, Embase, Scopus, PubMed, and Science Direct databases, analyzing manuscripts and articles of the last 10 years (from June 2009 to June 2019), in order to obtain the latest evidence in the field.Based on consultation with the multidisciplinary team, non-immersive VR studies and applications related to rehabilitation intervention were searched while using the following search terms, and the combination thereof: non-immersive, virtual reality, virtual game, rehabilitation, motor impairment, and cognitive impairment.After the preliminary search, 26 articles resulted from PubMed, 19 from Scopus, 283 from Science Direct, 10 from Embase, and 11 from Cochrane.The findings were analyzed and screened by four experts of the team, a bioengineer, a clinical neuropsychologist, a statistician, and a neurologist. In particular, three review authors independently reviewed titles and abstracts that were retrieved from the search in order to determine whether they met the predefined inclusion criteria. A fourth review author (a statistician) moderate any disagreement. The full text articles were subsequently analyzed.The first screening was based on the analysis of the title and of the abstract, as well as deduplication of the findings. Another researcher confirmed the accuracy of the papers selection and screened for any possible omission. After the first step, 11 articles resulted from PubMed, two from Scopus, and 0 from Science Direct, Embase, and Cochrane.Studies conducted on adult patients aged ≥65 yearsStudies devoted to use a non-immersive virtual reality in rehabilitationStudies including upper limb rehabilitation, lower limb rehabilitation, or cognitive rehabilitationRandomized clinical trials, with control group that received conventional rehabilitation therapyBefore-after comparison of a single groupReview articlesWe included RCTs and reviews written in English that aimed to study the use of non-immersive virtual reality in rehabilitation. Thus, we selected studies meeting the following criteria:Conference proceedingsStudies for which the full text was not foundStudies written in languages other than EnglishTechnical papersQualitative studiesOn the contrary, we excluded studies that met the following criteria:All case-report studies and case-control studies were excluded for a lack of sustainability of results, as well as works concerning the development of new technologies.After the screening based on the inclusion/exclusion criteria, conducted on the full text articles, the studies were selected as follows: 0 from Scopus, 10 from PubMed, and no one from Cochrane, Science Direct and Embase, and one from other sources. The countries of the selected studies are: Spain (2), France (2), Italy (2), Israel (1), United State of America (1), Canada (2), and Brazil (1). The fact that the studies have been performed in different countries shows that the topic is of general interest. A total of 10 papers were included. Studies are both reviews ,23 and cQuality evaluation was performed based on the PEDro scale and on the Cochrane’s Risk of Bias (RoB) tool, suggested for evidence based review of rehabilitation while using non-immersive virtual reality ,33. The All of the studies were focused on older people with a mean age of 65.2 (±9.4) years for the experimental group and 69.2 (±9.4) years in the control group. The number of participants that were involved in all the studies is 1008 ranged from 6 to 376.To our knowledge, of the older people involved in the trials, 586 were males and 392 females.n = 593), followed by older people at high risk of falls, with more than two falls in six months (n = 182), patients with amyotrophic lateral sclerosis (n = 30), AD (n = 24), or PD (n = 24).The majority of the patients suffered from stroke  within one-year post-stroke. It is a before-after study and all the subjects performed training with a treadmill equipped with a VR system. All the participants made significant improvements in their ability to walk, increasing the over ground walking speed and the Berg Balance Scale (BBS) scores.The study of Walker et al.  reportedThe study of Turolla et al.  involvesThe study of Allain et al.  involvesIn a study of Saposnik et al. , 141 posThe objective of Mirelman et al.  was to vThe study of Segura-Ortì et al.  involvesIn the study of Trevizan et al. , the perPelosin et al.  analyzedA review of the evidence on VR efficacy in patients affected by a neurological disease is mandatory due to the rapid development of VR programs in the last years and the increasing literature on VR application in neurological conditions, in order to enable clinicians to have an up-to-date understanding of the potential clinical beneficial effects of these techniques.Therefore, the aim of this paper was to systematically evaluate the evidence of the effectiveness of VR compared to conventional therapies. It must be stressed that few studies summarize the current best evidence on the effectiveness, user compliance, feasibility, and safety of VR interventions for rehabilitation treatment in neurological disorders.VR creates artificial environments with the possibility of a patient interaction. This kind of experience leads to the development of cognitive and motor abilities, which usually positively affect the emotional state of the patient, increasing collaboration and compliance.Moreover, the VR rehabilitative treatment might be personalized according to the specific abilities and needs of the subject.Parkinson disease is one of the most common age-related brain disorders with both dopamine-related motor symptoms and nonmotor symptoms due to other neurotransmitter circuits involvement, such as the cholinergic, noradrenergic, and serotonergic pathways.The cognitive decline is among the most common and relevant nonmotor symptoms in PD and it affects different cognitive domains, in particular attentional, visuospatial and executive domains, and also memory. VR in the cognitive PD treatment could be useful in improving, in particular, the visuospatial and executive abilities, which represent the most compromised aspects of cognitive decline in PD patients .Moreover, falls are frequent in ageing and PD patients, due to an impairment in the cholinergic-mediated gait pathway. A rehabilitation approach using treadmill training combined with non-immersive VR seems to induce changes in cortical cholinergic activity, which enables functional gait improvements and reduces the fall rate in comparison to a traditional rehabilitation method .A reduction in static and dynamic balance is a major risk factor for falls also in stroke survivors . In factA recent review on post-stroke rehabilitation therapy  providedMore promising effects seem to be evident in the case of upper limb motor impairments in stroke rehabilitation , but furVR technology has considerable potential for detecting functional limitations in IADL performance in AD patients, beyond that of current neuropsychological measures, as shown by Allain et al. . MoreoveVR cognitive training for individuals with MCI and dementia has proven to result in improvements in the cognitive domains of attention, executive function, and visual and verbal memory. Moreover, significant reductions in depressive symptoms and anxiety were evident, with a delay in the progression of cognitive impairment .Additionally, the VR format might help in training adherence, as individuals with MCI and dementia patients seem to prefer the VR format of a task over the paper version, as confirmed by a feasibility study with image-based rendered VR in patients with mild cognitive impairment and dementia .Some recent studies have suggested that rehabilitation treatment interventions might be useful and effective in treating motor and cognitive symptoms in different neurological disorders, including traumatic brain injury , multiplFinally, VR represents an effective tool that could improve the traditional cognitive and motor rehabilitation in patients that are affected by a neurological disease. Moreover, home-based VR might offer a promising addition or alternative to existing rehabilitation programs, and a chance to provide and/or prolong the required therapy after discharge in a more accessible setting, potentially improving clinical outcomes.Future research needs to improve the study design by including larger samples, longitudinal designs, long term follow-ups, and different outcome measures, including functional and quality of life indexes, to better evaluate the clinical impact of this promising technology in healthy old subjects and in neurological patients. In particular, the next challenge for the research on VR and rehabilitation can be summarized in the following questions:1. Does an innovative intervention enriched with VR provide a significant improvement in mobility, compared to traditional physiotherapy?2. Is the intervention cost-effective for the health management systems?To answer to these questions, it is crucial to understand how to improve the rehabilitation path of older people, through multidisciplinary multicomponent and person-centered intervention, integrated with VR.The evidence reported in the paper are in line with the aims that were expressed by the National Plan for Health Research, whose priorities are defined in accordance with the indications contained in the regulation of the European Parliament and of the Council on the establishment of the “Health for growth” program, which pursues as a goal the achievement of a strong potential for economic growth thanks to the improvement of the state of health, through the facilitation of innovation in health care, the improvement of skills and information on specific diseases, and the identification of good practices for effective prevention . In lineAs it is shown by the numerous studies in the field, the application of VR has a positive impact on the rehabilitation of the most predominant geriatric syndromes. The level of realism of the virtual stimuli seems to have a crucial role in the training of the cognitive abilities. Nevertheless, semi-immersive or non-immersive VR systems have the advantage of being more accepted by the users, as they experienced less cybersickness after the training. Moreover, the integration of these devices in the health management systems are still lacking despite the evidence and the peculiarity of VR technologies with different level of immersivity. A tentative explanation can be found, not only in the cost of technology that seems to be more affordable in the recent years, but, most of all, in the absence of a standardized protocol and procedure, to harmonize traditional rehabilitation therapies and innovative VR systems. For this reason, it will be necessary to improve the research in the field, adopting RCTs study design as well as indicators of health technology assessment, to understand the effectiveness and efficacy also in terms of optimization of the clinical pathways. In addition, as VR systems can be easily adopted at home, it can be considered to be useful for the continuity of care.


Overexpression of the androgen receptor (AR) mRNA and protein is the most prevalent alteration in castration-resistant prostate cancer (CRPC) that is due to amplification of the AR gene and/or an upstream enhancer in a non-coding region in up to 81% of cases  and by iCurrent treatment strategies aim to control AR-driven CRPC by blocking the AR ligand-binding domain (LBD), decreasing alternative sources of ligands or by employing an antagonist that alters AR conformation. However, since these measures do not affect AR mRNA synthesis, increasing levels of AR protein have been shown to shift the abundance and ratios of co-activators over repressors assembled on the promoters of AR target genes and decrease bicalutamide binding, generating resistance , 4. The in vitro and tumor growth in vivo in all CRPC model systems [Generally, treatment strategies aiming to suppress aberrant gene transcription have met limited success. However, CRPC with its essential component of resistance development to antiandrogen agents after prolonged treatment, that result in strong dependence on AR overexpression, independently or through cross-talk with associated oncogenic pathways, may be unusually susceptible to this strategy. In particular, broadly-targeted epigenetic mechanisms affecting chromatin acetylation status by the opposing actions of histone acetylases (HATs) and deacetylases (HDACs) are critically involved in fine-tuning regulation of AR mRNA transcription and splicing, as well as the transcriptional activation of AR protein target genes . Althoug systems . UnfortuAn alternative perspective is that HDACIs might be more effective in overcoming the prevalent acquired resistance to anti-androgenic agents in CRPC compared to their direct anti-tumor effects.We demonstrated in preclinical experiments with CRPC culture/xenograft models that overexpress AR and ARSv7 that there is synergistic inhibition of cell growth by Panobinostat in combination with the antiandrogen bicalutamide in cells resistant to bicalutamide . NotablyIn contrast to Panobinostat monotherapy, these results are consistent with a model in which rewriting the epigenetic code by a HDACI resensitizes the CRPC to the antiandrogen they became resistant to  by suppr


Neuromyelitis optica (NMO), also known as Devic syndrome, is a central nervous system demyelinating disease consisting of optic neuritis and myelitis. Several studies have reported the effects of rehabilitation programs and specific exercises on outcomes in individuals with multiple sclerosis, but few have considered individuals with NMO. We present 2 cases of paraplegia due to NMO with rehabilitation outcome.The first case corresponds to a 65-year-old woman with NMO presented with C4 incomplete American Spinal Injury Association (ASIA) scale D, and the second case is a 41-year-old woman with NMO presented with C1 incomplete ASIA-C.Two cases were confirmed by positive anti-aquaporin-4 antibody and presence of T2-weighted hyperintense lesion in spinal cord on magnetic resonance imaging.The first patient planned for focusing on left hand fine motor training through occupational therapy by strengthening and stretching muscle using E-link  during 4 weeks, and the second patient received strengthening lower extremity and gait training using a lower-body positive pressure treadmill  during 4 weeks.After a 4-week rehabilitation, the first patient's manual muscle testing was improved to grade 2/5 to 3+/5 in left upper limb specifically. Also, Spinal Cord Independence Measure (SCIM) was improved 79 to 88. Functional gains were made in bathing, upper-extremity dressing, and using chopsticks independently. Also, the second patient's manual muscle testing improved to grades 1 to 2/5 to 3 to 4/5 generally, and ASIA scale improved C5 incomplete ASIA-D. SCIM was improved to by allowing walking independently and increasing lower-extremity dressing and toileting ability.An intensive, multidisciplinary rehabilitation program may lead to neurological and functional gains in patients with NMO. In 2006, Wingerchuk et al's study proposed the criteria to define the syndrome, reporting an impressive 99% sensitivity and 90% specificity. The diagnostic criteria characterize NMO by optic neuritis, myelitis, and at least 2 of the following 3 criteria must be present: longitudinally extensive cord lesion, magnetic resonance imaging nondiagnostic for MS, and NMO-IgG seropositivity.–6 The serum autoantibody NMO-IgG, which targets aquaporin-4, is a good candidate because it is >90% specific for NMO in patients presenting with an optic-spinal syndrome and is not detected in patients with classic MS. The specificity of the antibody as a marker for NMO and its immunoreactive sites in the spinal cord occurs in NMO.Neuromyelitis optica (NMO), also known as Devic syndrome, is a central nervous system demyelinating disease consisting of optic neuritis and myelitis. The onset of the syndrome varies, from young adolescence to adulthood, with a median peak incidence among individuals aged in their late 30s. In United states, NMO occurs in Caucasian individuals, but there is an over-representation among Native Americans, Hispanic Americans, Asians, and individuals of Mediterranean and African descent. The prevalence of MS is lower in Japan than in the Western Europe, and the ratio of classic, monophasic NMO to MS is higher.Like MS, NMO is more frequent in women than in men.–12 This is most likely due to the low incidence and prevalence of NMO, and also a poor understanding of the disease. However, NMO is a progressive neurologic disease with an uncertain course, and it is important to devise a rehabilitation strategy to reduce the neurological sequelae that occur after an episode.Several studies have reported the effects of rehabilitation programs and specific exercises on outcomes in individuals with MS, but few have considered individuals with NMO.In this article, we present 2 cases of NMO and discuss the rehabilitation program used.22.1This case report conforms to all CARE guidelines and reports the required information accordingly. The study was approved by the Institutional Review Board and Ethics Committee of Jeju National University Hospital. Written consent was obtained from both patients.2.2 revealed that the patient had muscle weakness in the left upper and lower limbs  and no sensory abnormality, and the American Spinal Injury Association (ASIA) classification was C4 incomplete ASIA-D.A 65-year-old woman was admitted to the department of rehabilitation medicine after experiencing chronic left hand dystonia and weakness for 1 year. A diagnosis of NMO was confirmed by positive anti-aquaporin-4 antibody and the presence of a T2-weighted hyperintense lesion in the spinal cord and left optic nerve on magnetic resonance images. The spinal cord lesion was at the level of C2 to C5, and was roughly 3 segment lengths in size. Neurological assessment according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI)At the time of admission to the department of rehabilitation medicine, maximal grip strength and pinch strength were measured using a dynamometer, and her grip strength was 5.4 kg for the left hand and 11.8 kg for the right hand. The box and block test score was 8 for the left hand and 21 for the right hand. The 9-hole test time was 64.3 seconds for the left hand and 32.0 seconds for the right hand. The Spinal Cord Independence Measure (SCIM) was 79, and the patient was in need of help from others to perform daily activities such as dressing or eating.The patient received conventional occupational therapy focusing on upper-extremity stretching, strengthening, and performing daily activities for 30 minutes, hand fine motor training using E-link  Fig.  for 30 mAfter 4 weeks of rehabilitation, when she was re-evaluated, manual muscle testing score in the left upper limb had improved from grade 2 to grade 3+, and the SCIM had improved from 79 to 88. Functional gains were made in all activities of daily living, especially bathing, dressing independently, feeding, and going to the toilet. Maximal grip strength and pinch strength increased to 7 kg for the left hand and 15 kg for the right hand. The box and block test improved to 12 for the left hand and was maintained at 21 for the right hand. The 9-hole test time reduced to 42.2 seconds for the left hand and 28.3 seconds for the right hand. These results indicate that fine motor control was improved and clumsiness decreased. The patient was discharged home and scheduled to attend outpatient rehabilitation twice a week.2.3A 41-year-old woman was admitted to the department of neurology medicine after developing weakness, an inability to independently ambulate, and impaired vision in the left eye. Two years before the admission, the patient had been diagnosed with NMO by positive anti-aquaporin-4 antibody; however, she did not take the azathioprine that had been prescribed. Neurological work-up confirmed that she had relapsed, and she was prescribed steroid pulse therapy and azathioprine. After 12 days, she was transferred to the department of rehabilitation medicine. revealed that the patient had muscle weakness in the right upper and lower limbs , and sensory abnormality to light touch and pinprick without a clear sensory level, and the ASIA classification was C1 incomplete ASIA-C. SCIM was 42. The patient was able to walk a short distance using a rolling walker, and the Berg balance scale score was 22. The 6-minute walk test (6MWT) distance was 110 m, and the timed up and go (TUG) test time was 31.7 seconds.At the time of transfer, neurological assessment according to the ISNCSCIAs an inpatient, the patient received conventional occupational therapy focusing on upper-extremity stretching, strengthening, and performing daily activities for 30 minutes, and physical therapy including lower-extremity muscle strengthening and aerobic exercise for 30 minutes. In addition, the patient received gait training for 30 minutes using a lower-body positive pressure (LBPP) treadmill  Fig. —a medicaAfter 1 month, manual muscle test scores generally improved from grades 1–2 to 3–4, and the ASIA classification improved to C5 incomplete ASIA-D. SCIM improved to 84 due to improvements in independent walking, lower-extremity dressing, and toileting. The Berg balance scale score improved to 50, the 6MWT distance improved to 260 m, and the TUG test time improved to 8.6 seconds. The patient was discharged home and scheduled to attend outpatient rehabilitation twice a week.3 but there are few studies on the effects of rehabilitation in patients with NMO in Oriental and Asia. This study is the first to report the rehabilitation effect of NMO patients in the Oriental or Asian region treated with inpatient intensive rehabilitation program.Tables  described 3 patients with NMO who were treated in an inpatient rehabilitation unit in United states for 1 to 1.5 months. Although all 3 patients improved, the authors did not state what exercise devices the patients were treated with during rehabilitation. In the current report, both cases were treated using devices (E-link for case 1 and LBPP treadmill for case 2).Schreiber et al Although E-link is a useful tool for assessing hand function,–18 there are no studies of its utility for treating dystonia and weakness in patients with musculoskeletal and neurological diseases. This is the only study that has shown an improvement in hand function after using E-link as part of the rehabilitation of a patient with NMO.The E-link allows standardized pinch and grip measurements, and is a flexible rehabilitation method that can be tailored to specific patient needs in isometric strengthening, motor learning and control, and pinch and grip exercises, and is thus appropriate for a wide spectrum of injuries. Although the LBPP is an effective and safe method to improve functional ability in very weak patients with musculoskeletal and some neurological diseases,–23 there are no studies showing its effectiveness in patients with NMO. By controlling the pressure in the enclosure, between 20% and 100% of the patient's body weight can be unloaded, in precise 1% increments for low-impact, pain-free movement. The LBPP supports normal walking and running biomechanics, unlike a conventional treadmill, and provides real-time gait data and video monitoring to help patients improve their experience and results. In this study, we showed that rehabilitation that included LBPP training improved lower limb performance and locomotion in a patient with NMO.The LBPP is a treadmill surrounded by a pressure chamber. The user wears a special pair of shorts that zip at the waist into a pressurized airtight enclosure, which is suspended over the treadmill surface.–12 few have considered individuals with NMO.,24 Nechemia et al's study showed that individuals with NMO had better outcomes after rehabilitation than individuals with MS, regardless of the initial functional status; this was shown to be because they had better cognitive function and communication abilities. Thus, individuals with NMO have better prognosis after rehabilitation than individuals with MS.Although many studies have reported the effects of rehabilitation on outcomes in individuals with MS,The clinical course of NMO is either monophasic or relapsing. The initial presentation of monophasic NMO is more severe than that of relapsing NMO, but recovery is better. Relapsing NMO has a poor prognosis, with more than half of patients developing severe visual loss and an inability to ambulate without aids within 5 years of disease onset.Moreover, it revealed that patients with relapsing NMO are at high risk for cervical myelitis, which can cause respiratory failure and death. In patients with relapsing NMO, such as case 2, we propose that early rehabilitation would minimize complications and improve function.,26There are few articles emphasizing the importance of early rehabilitation in patients with NMO; however, many studies in stroke and Parkinson disease have revealed that early intensive rehabilitation is associated with greater and faster improvement in performance of activities of daily living and quality of life.This report has several limitations. First, it was a retrospective report of only 2 cases, and the results may not generalize to all patients with NMO. Second, we did not consider the impact of medical treatment of NMO. The impact of medical treatment affected the outcome of the patients presented in this report. Thus, further studies addressing these limitations are warranted.4An intensive, multidisciplinary rehabilitation program may lead to neurological and functional gains in patients with NMO. Further studies are needed to validate rehabilitation protocols and their effects.Conceptualization: Won Bin Kim, So Young Lee.Data curation: Won Bin Kim.Formal analysis: Won Bin Kim.Investigation: Won Bin Kim.Methodology: Won Bin Kim, So Young Lee.Project administration: So Young Lee.Resources: So Young Lee.Software: Won Bin Kim.Visualization: Won Bin Kim.Writing – original draft: Won Bin Kim.Writing – review & editing: Won Bin Kim, So Young Lee, Bo Ryun Kim, Youn Ji Kim.


Ar knockout mouse models have established that AR-mediated androgen actions have a part in regulating female fertility and ovarian function. Considerable evidence from human and animal studies currently reinforces the hypothesis that androgens in excess, working via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). Identifying and confirming the locations of AR-mediated actions and the molecular mechanisms involved in the development of PCOS is critical to provide the knowledge required for the future development of innovative, mechanism-based interventions for the treatment of PCOS. This review summarises fundamental scientific discoveries that have improved our knowledge of androgen actions in PCOS etiology and how this may form the future development of effective methods to reduce symptoms in patients with PCOS.Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-age women. By comprising reproductive, endocrine, metabolic and psychological features—the cause of PCOS is still unknown. Consequently, there is no cure, and management is persistently suboptimal as it depends on the ad hoc management of symptoms only. Recently it has been revealed that androgens have an important role in regulating female fertility. Androgen actions are facilitated via the androgen receptor (AR) and transgenic  Polycystic ovary syndrome (PCOS) is a heterogeneous condition, which affects approximately 6% to 20% of women of reproductive age. It is the most common endocrine condition in women of this age group ,2,3. AltNotwithstanding the pervasiveness of PCOS and its noteworthy health impact, a cure for PCOS does not exist, and current strategies for its management are insufficient, as they depend on ad hoc and imperfect treatment of symptoms. Given no drug has ever been approved specifically for the PCOS condition , the maj4) and dehydroepiandrosterone sulfate (DHEAS), as well as the enzyme required to convert pro-androgens to bioactive androgens, 3β-hydroxysteroid dehydrogenase (3β-HSD) in serum [Hyperandrogenism represents a chief attribute of PCOS as elevated androgen levels are the most constant feature, with the majority (−60%) of patients exhibiting hyperandrogenism (Rotterdam definition) . Women win serum ,13. Excein serum ,15. The in serum , or exogin serum ,18. Addiin serum . These oAndrogen receptor antagonists have proven useful in the treatment of PCOS phenotypes. Through its actions on the hypothalamus, pituitary and ovarian steroidogenesis, the use of the oral contraceptive pill has the overarching effect of reducing hyperandrogenism . These eFlutamide, a competitive antagonist of the AR, is most widely used and has been reported to have a favourable effect in women with PCOS as it decreases hirsutism and acne ,26,27. PAlternative anti-androgens include spironolactone and cyproterone acetate, steroidal AR blockers that compete with T and DHT for binding the AR. Both of these AR blockers are observed to be effective in significantly decreasing levels of hirsutism and acne in PCOS patients ,21. MoreTaken together, results from the use of anti-androgenic drugs in PCOS patients either alone or in combination have demonstrated that targeted inhibition of hyperandrogenism, and therefore androgenic actions, has a beneficial effect with improvements observed in numerous PCOS traits. Since the AR facilitates the actions of androgens, these observations provide support for an association between hyperandrogenism and the development of an extensive array of PCOS traits. Nevertheless, these treatments are not restorative, and such pharmacological interventions simply provide an opportunity for PCOS women to alleviate PCOS symptoms. However, evidence suggests that antiandrogens have unacceptable hepatotoxicity , which oA powerful method to study PCOS is through animal models that mimic the features present in the human condition of PCOS. Animal research is necessary as research in humans is hampered due to the inability to perform fully controlled human studies that have considerable ethical and logistical restrictions. Studies using animal models provide insights into basic biological mechanisms stimulating the development of PCOS, and thus provide the opportunity to locate novel targets for the treatment of PCOS that surpass current medical practice of symptom-based treatments. While animal models of PCOS have been developed using different approaches including treatment with androgens, estrogens, antiprogestins and genetic manipulation ,36, the Hyperandrogenism has been postulated to play a key role in the origins of PCOS, as PCOS animal models created through the induction of hyperandrogenism consistently produce animals that present a broad range of reproductive, endocrine and metabolic features of PCOS . These oPCOS is most closely recapitulated in animal models with either prenatal exposure to testosterone or DHT, or early postnatal exposure to DHEA or DHT in rodents, and in sheep and nonhuman primates by excess prenatal exposure to testosterone . These aMetabolic features of PCOS are also present in animal models of PCOS with obesity and aberrant adipose function observed in several androgen-induced PCOS animal models. Androgenized female mice display increased fat mass, enlarged adipocyte cells accompanied by decreased adiponectin levels inferring adipose tissue dysfunction ,45,46,47Additional evidence promoting androgens as significant drivers in the etiology of PCOS come from studies reporting that treatment with AR antagonists on PCOS animal models prevented or reversed the manifestation of some PCOS traits. For example, the prenatally androgenized PCOS sheep model with ovulatory dysfunction, displayed restoration of LH surges necessary for ovulation when co-treated with the AR antagonist flutamide . In a moRecent research has focused on identifying the site(s) of androgen action involved in the development of PCOS. A number of recent studies have incorporated the use of androgen receptor knockout (ARKO) mouse models as a means to explain the direct role of androgens in PCOS development, since androgen actions are directly mediated via the AR. It was observed in global ARKO female mice exposed to androgen excess that PCOS could not be induced ,53, confTo explore the location of these sites, recent studies have used PCOS mouse models in combination with global and cell-specific ARKO mouse models to better understand the mechanisms behind the androgen-induced PCOS environment. To locate the main sites of AR actions, PCOS has been induced in mice with a non-functional AR in either ovarian granulosa cells, theca cells or in the brain. Female mice with a loss of AR function only in the granulosa cells displayed the majority of PCOS characteristics and were only safeguarding against increased granulosa cell degeneration in antral follicles . InactivThere is significant evidence advocating for androgen excess mediated actions through the AR in the origin of PCOS. However, current generations of anti-androgens are systemic and, as mentioned earlier, lead to unacceptable liver toxicity, which disqualifies them for use in non-lethal chronic disorders such as PCOS. Therefore, the focus of current research has been directed at identifying ways to specifically target and suppress hyperandrogenic effects in women with PCOS.A potentially effective strategy is to target AR-signalling in neuroendocrine pathways, as specific loss of AR actions in the brain prevented hyperandrogenized mice from developing PCOS traits, identifying the brain as a main site involved in experimental PCOS . Women wSpecific loss of AR signalling in the brain also protects hyperandrogenized PCOS mice from developing metabolic PCOS traits, suggesting that metabolic dysfunction in PCOS patients may also be mediated via central mechanisms regulated by the AR . There iAndrogen receptor-driven actions occurring in adipose tissue are also of interest for the development of new strategies to treat PCOS. Studies have shown that the observed increase in intra-abdominal fat mass in women with PCOS, is positively correlated with circulating androgen levels . ChangesAnother potential androgen excess-AR-driven mechanism leading to aberrant adipose tissue function in PCOS could be the inability of adipocytes to generate adequate levels of the adipokines. Adiponectin, an adipokine involved in glucose and lipid metabolism, has been observed to be lower in women with PCOS , and sevNew innovative approaches aimed at reducing overall androgen excess have been tested in pre-clinical research and some clinical trials. One compound tested is dietary medium-chain fatty acid (decanoic acid), which reduces androgen biosynthesis in vitro by modulating the actions of the steroidogenic enzyme 3β-HSD leading to androgen reduction . A studyThere is significant evidence from human and animal studies demonstrating that excess androgens through the AR play a key role in the origin of PCOS . Researc


Active Rehabilitation (AR) is a community peer-based concept for people with spinal cord injury (SCI) that is primarily delivered through brief residential training programmes. Despite a plethora of positive anecdotal evidence of AR programmes as life-changing experiences, the effects of AR-programmes have not been evaluated scientifically. Here, we present the protocol of the INTERnational Project for the Evaluation of “activE Rehabilitation” (inter-PEER) aiming to evaluate the effects of AR training programmes on community-dwelling individuals with SCI.International prospective cohort study that recruits consecutive participants in AR training programmes. Evaluation is conducted through a web-based survey at 3 time-points: at the commencement and completion of the training programme, and 3 months after the end of the training programme. Evaluation also includes a practical wheelchair skills test at the first two time-points.The primary outcome measures are the Spinal Cord Independence Measure Self-report (SCIM-SR), the Queensland Evaluation of Wheelchair Skills test (QEWS), the Wheelchair Skills Test Questionnaire (WST-Q) and the Moorong Self-Efficacy Scale (MSES). The secondary outcome measures are the 11-item Life Satisfaction Questionnaire (LiSat-11), the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-Participation), the Leisure Time Physical Activity Questionnaire for people with SCI (LTPAQ-SCI) and the 10-item Connor-Davidson Resilience Scale (CD-RISC-10).We piloted the implementation of the protocol in Sweden in 7 participants with diverse SCI and sociodemographic characteristics and collected feedback from participants and peer-mentors about study procedures through interviews, a workshop and field observations.Inter-PEER is the first initiative to propose a systematic evaluation of the effects of AR training programmes among individuals with SCI. The project is a collaborative work of multiple stakeholders, including researchers, clinicians, peer mentors with SCI, and administrators of organisations providing AR programmes. The inter-PEER uses standardised outcome measures relevant to the AR context, it will facilitate quality evaluations of community peer-based programmes, stimulate international collaborations, and inform the design of randomised controlled trials on the effects of AR training programmes. Despite access to specialised acute care and in-patient rehabilitation, newly injured individuals with spinal cord injury (SCI) often feel unprepared physically and psychologically to transition to home , 2. HighActive Rehabilitation (AR) is a community peer-based concept for people with spinal cord injury (SCI) that was developed in Sweden 40 years ago. Since then, aspects of the concept have been implemented in more than 20 countries worldwide . The objAnecdotally, participants with SCI have described AR programmes as a life-changing experience, but scientific evidence of the effects of such programmes is lacking. Recent systematic and scoping reviews identified very few scientific publications evaluating community peer-based programmes for people with SCI, and none evaluating outcomes of AR programmes , 7. ThisThe current paper presents the protocol of the INTERnational Project for the Evaluation of activE Rehabilitation (inter-PEER), which is the first comprehensive scientific evaluation of the AR training programmes for participants with SCI. The primary objective of inter-PEER is to measure the effects of AR training programmes on physical independence, self-efficacy and wheelchair skills among individuals with SCI. The secondary objective is to measure the effects on community participation, life satisfaction, level of physical activity and resilience. The purpose of this protocol is to present the methodology of inter-PEER to facilitate the utilisation of homogenous research methods across organisations that use aspects of the AR programmes, and to facilitate comprehensive programme evaluation and international pooling of data. The inter-PEER protocol could be used as a whole or in part to evaluate AR programmes across countries.Inter-PEER is an international prospective cohort study that has commenced in Sweden and will later be implemented in other European countries. It involves participants with SCI taking part in AR training programmes that last for 7 days or more. Participant evaluation takes place at 3 time-points: at the commencement (baseline) and completion of the training programme, and 3 months after the end of the training programme. The reporting for studies following this protocol will be guided by the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement for cohort studies . AdditioAll participants in AR training programmes are invited to participate in the study, if they meet the following inclusion criteria: (1) having a SCI ; (2) being 16 years or older; (3) being able to comprehend and answer written questions. From a technical point of view, the inter-PEER protocol can only be implemented in AR programmes where there is availability of laptops or tablets with Internet access.Before the training programme, all registered programme participants receive an e-mail with information about the programme evaluation, emphasizing that participation is voluntary. On the first day of the programme, the on-site data collection coordinator approaches participants as they arrive, provides an information letter, offers to provide more information about the programme evaluation and then asks participants to provide a written informed consent. The on-site data collection coordinator has some research experience and has received training in the data collection procedures of Inter-PEER. An online platform, such as Survey Monkey, is used to collect data. For the start and completion of the programmes, laptops or tablets with Wifi or cellular connection are provided to participants to complete the survey. For the 3-month follow-up, participants are provided with an individualised link that they use to complete the survey in their own time and their own laptop or tablet device.During the first 24 h of the AR programme, consenting participants complete the online survey and also conduct a practical wheelchair skills assessment that is administered by peer mentors. A similar process takes place on completion of the programme. At the end of the programme, the on-site data collection coordinator completes a form with the fidelity criteria for the specific programme. Three months later, participants are provided with an individualised link and are asked to complete the follow-up online survey. Participants complete the 3-month follow-up evaluation in their own time online. Because participants often live far away from the training programme location, the practical wheelchair skills test is not included in the 3-month follow-up evaluation for practical reasons.The 3-month period after completion of an AR training programme was chosen as the optimal time for final evaluation. We believe that a shorter period would be insufficient to see potential progress after the AR training. On the other hand, a longer period (e.g. 6 or 12 months) may increase drop-outs and introduce confounding factors which would be difficult to control for given that the study does not have a control group. At 3-month follow-up, participants are asked to indicate whether any new training (other than the AR programme) and any other events  may have positively or negatively impacted their status. Respondents have the opportunity to explain further through free text.The inter-PEER has a strong focus on embedding the outcome evaluation in the schedule of AR programmes. Better integration of the evaluation in the schedule and greater engagement of peer mentors and non-disabled members in the evaluation processes can promote sustainability, increase participation and retention rates, and improve quality of data.If sufficient funding and resources are available, organisations can consider employing a multiple baseline design, for example by including an additional baseline assessment several weeks prior to start of the programme. In that case, it is recommended that the primary outcome measures are administered rather than the full survey. The latter would improve the design of the study and would provide more confidence in inferring causation as a result of the programme.Each country has their own data collection and steering team and can decide if they provide data for pooling. Organisations may choose to adopt and implement the full protocol and battery of outcome measures, or may choose a part of it based on their resources, needs and context.The full list of outcome measures and the scheme for administering each one of them are presented in Table Seventeen questions about sociodemographic and injury related factors are included in the survey. The phrasing of the questions has been adapted from that used in the International Spinal Cord Injury (InSCI) Community Survey . AdverseFunctional level is assessed through the SCIM-SR . SCIM isThe QEWS is used to measure wheelchair skills. QEWS was initially designed for use in people with SCI in the acute hospital setting as well as in the community without extensive or specialized testing equipment . It is sThe WST-Q version 4.3 for manual wheelchairs operated by their users is a self-reported survey measuring capacity (“Can you do it?”), confidence (“How confident are you?”), performance (“How often do you do it?”) and goal attainment  for a list of wheelchair skills . The WSTSelf-efficacy is assessed through the MSES . The MSEBased on the focus and content of the AR programme, the Spinal Cord Independence Measure self-report (SCIM-SR), the QEWS, the Wheelchair Skills Test Questionnaire (WST-Q) and the Moorong Self-efficacy Scale (MSES) are the primary outcome measures.Life satisfaction is assessed through the Life Satisfaction Questionnaire-11 (LiSat-11) . This wiParticipation is assessed through the Utrecht Scale for Evaluation of Rehabilitation participation (USER-Participation) . This InParticipation in moderate and vigorous physical activity is assessed through the Leisure Time Physical Activity Questionnaire for people with SCI (LTPAQ-SCI) . This isResilience is assessed through the 10-item Connor-Davidson Resilience Scale (CD-RISC 10) , 29. ThiDue to the brief duration of the intervention and short follow-up period, we do not expect to see major changes in life satisfaction, resilience, physical activity and community participation. However, we decided to include these areas as secondary outcomes. The main reason for the latter was to compare our cohort characteristics with those from other studies and prepare for assessing these areas in longitudinal and controlled studies in the future.http://www.gpower.hhu.de/en.html). Assuming a two-sided test with alpha = 0.05 and beta = 0.05 (power 0.95), a small effect size of 0.4 and expecting a 20% attrition rate, we would need 101 cases in each country. Effect size of 0.5 for SCIM-III  has been shown to be a meaningful change  made me think why I am here and what I could achieve”. The practical wheelchair skills test was seen as “…a good way to see your progress”. Participants also suggested to “use the findings from the QEWS to inform the focus of wheelchair skills training”. In regard to the follow-up, participants indicated that “follow-up survey and phone call are good ways to be motivated to continue to improve”.Feedback from peer mentors highlighted the benefits from using QEWS: “It is good to evaluate the effects in an objective, easy and meaningful way”. Also, peer mentors indicated that “results from the wheelchair skills test could be used in the goal setting discussion during the AR programme”. Lastly, the benefits of involving peer mentors and the programme coordinator with follow-up was highlighted by stating that “follow-up assessment is a good way to keep in touch with participants, and identify if there is anything major that they need help with”.Findings of the Inter-PEER will be shared with academics and the wider scientific community through peer-reviewed publications, seminars and conference presentations. There will be a series of articles specific for each country and articles based on pooled data. Findings will also be communicated to people with SCI through lay language articles in consumer-oriented magazines and newspapers, as well as on the websites of the community organisations. Procedures and findings will be further disseminated to community organisations through workshops and technical reports.At an operational level, findings from the inter-PEER will be utilised to modify the design of existing AR programmes to better serve the needs of future participants. Furthermore, findings may strengthen the case for developing such programmes in countries with limited availability of community rehabilitation. This is aligned with Objective 2 of the WHO Global Disability Action Plan 2014–2021 “to strengthen and extend community-based rehabilitation” [itation” .At a research level, inter-PEER will establish the use of standardised, internationally accepted outcome measures in the AR context, which will encourage organisations offering AR services to evaluate outcomes. Organisations will find it easier to conduct research as they will have a scientific toolkit that they can consider using. The availability of a battery of outcome measures and of standardised research processes will stimulate international collaborations and inform the design of future studies in this area. This protocol and the findings from prospective cohort studies will also inform the design of future controlled and potentially randomised studies that will explore the effectiveness of the AR training programmes. This is aligned with the WHO initiative “Rehabilitation 2030” that has called for action to upscale rehabilitation and highlighted the importance of building research capacity in order to expand the availability of robust evidence for rehabilitation [litation .At the health system level, inter-PEER will provide evidence for the role of AR programmes in the continuum of SCI care, i.e. acute care and in-patient rehabilitation, which may have further implications for policy and organisation of health care systems. In turn, this may help organisations that provide AR programmes to integrate better into the health care system, strengthen and streamline referral processes, secure funding and reach more community-dwelling individuals with SCI who could benefit from such services. Better integration does not mean merging with the health care system, but rather the opportunity to establish joint goals and responsibilities, close partnership, high degrees of mutual trust and respect, joint arrangements for streamlining processes including referrals, funding allocation and joint arrangements encompassing strategic and operational issues [remove barriers and improve access to health services and programmes” [l issues . This isgrammes” .international level, inter-PEER can assist with implementing similar evaluations of AR programmes in countries where these programmes are available. The protocol would need to be adapted to suit the processes, needs and resources of the respective organisations and an ethics approval would be needed to be obtained. This could facilitate the implementation of larger and more robust studies by pooling data across countries. This is aligned with Objective 3 of the WHO Global Disability Action Plan 2014–2021 to “strengthen collection of relevant and internationally comparable data on disability and support research on disability and related services” [At an ervices” .Additional file 1. The Template for Intervention Description and Replication (TIDieR) for Active Rehabilitation programmes.