How have musculoskeletal rehabilitation needs changed globally during the past 30 years?In this cross-sectional study of 191 countries and territories, prevalent cases and years lived with disability (YLD) counts of musculoskeletal disorders in need of rehabilitation increased substantially, with 55 countries and territories increasing annually in age-standardized prevalence and 18 in YLD rates. The changing patterns of age-standardized prevalence and YLD rates differed by sex and health condition.The findings of this study suggest that musculoskeletal rehabilitation needs have increased, with nearly 1 in every 4 people needing rehabilitation, and coping strategies should be developed. This cross-sectional analysis evaluates secular trends in global musculoskeletal rehabilitation needs by sex, age, region, country, and health condition. It is hard for policy makers and health professionals to develop musculoskeletal rehabilitation strategies because secular trends for musculoskeletal rehabilitation by region and country remain unknown.To evaluate the secular trends in global musculoskeletal rehabilitation needs by sex, age, region, country, and health condition.This cross-sectional study included data from 191 countries and territories from the World Health Organization Rehabilitation Need Estimator between January 1, 1990, and December 31, 2019. Data analyses were performed from February to May 2021.Prevalence and years lived with disability (YLDs) of musculoskeletal disorders in need of rehabilitation, overall and by sex, age, region, country, and health condition. Trends in rehabilitation needs were evaluated by the estimated annual percentage changes (EAPCs) in age-standardized rates. Pearson correlation analysis was used to examine the associations between EAPCs and the age-standardized rates in 1990. The associations between the age-standardized rates and universal health coverage (UHC) effective coverage index were assessed by fitting a restricted cubic spline in a linear model.P < .001; YLD: ρ = −0.55; P < .001), except for those of neck pain and rheumatoid arthritis. Excess rehabilitation needs were observed in countries with both higher and lower UHC effective coverage indexes .From 1990 to 2019, the global number of prevalent cases of musculoskeletal disorders in need of rehabilitation increased from 1060.6  million to 1713.6  million, with a steady increase in the number of YLDs from 93.9  million to 149.0  million. Overall, 55 countries and territories (28.8%) had annual increase in age-standardized prevalence rates, and 18 countries and territories (9.4%) had annual increase in YLD rates. The global age-standardized prevalence and YLD rates of musculoskeletal disorders decreased annually with EAPCs of 0.34  and 0.42 , respectively. Specifically, the global age-standardized prevalence and YLD rates decreased for low back pain , fractures , other injuries , and amputation . The age-standardized prevalence rate decreased for neck pain  but increased for osteoarthritis  and rheumatoid arthritis . In contrast, the age-standardized YLD rates remained stable for neck pain , osteoarthritis , and rheumatoid arthritis . The age-standardized prevalence rate of neck pain decreased faster in male individuals, with an EAPC of −0.10 , while the age-standardized prevalence rate of low back pain decreased faster in female individuals, with an EAPC of −0.55 . EAPCs were significantly associated with the baseline age-standardized rates (prevalence: ρ = −0.49; In this cross-sectional study, substantial increases in musculoskeletal rehabilitation needs were found across locations, suggesting rehabilitation needs have become a global health concern. Mitigating risk factors, strengthening rehabilitation in primary health care, and allocating sufficient funds are encouraged to satisfy rehabilitation needs. Moreover, there is a traditional belief that only individuals with certain disabilities need rehabilitation.10 Therefore, it is critical to alter this perspective and track changes in rehabilitation needs to guide rehabilitation resource allocation. However, to the best of our knowledge, only 1 study has comprehensively reported the rehabilitation needs attributed to 25 health conditions, including musculoskeletal disorders, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019.10 However, the secular trends in musculoskeletal rehabilitation needs by region and country have not been described. In addition, no study has estimated the annual percentage changes in musculoskeletal rehabilitation needs by category over a specific time interval. A better understanding of the secular trends in musculoskeletal rehabilitation needs at the regional and national levels helps to identify the areas with high rehabilitation needs and discover the potential areas requiring additional attention, which will facilitate the development of strategies tailored to rehabilitation needs. Therefore, in this study, we presented the secular trends in prevalence and years lived with disability (YLDs) of musculoskeletal rehabilitation needs by sex, age, region, country, and category between 1990 and 2019 using data from the GBD 2019 study.The heavy burden of musculoskeletal disorders and their health consequences necessitate additional efforts for the appropriate provision of rehabilitation services. However, rehabilitation services are often insufficiently provided in many countries.STROBE) reporting guideline for cross-sectional studies. The GBD 2019 study comprehensively analyzed causes of 369 diseases and injuries and 87 risk factors in 204 countries and territories between 1990 to 2019 by using data from population censuses, household surveys, civil registration and vital systems, hospital and clinical records, and other sources, which were collected from published literature, institutional websites, international and national surveys, and the GBD collaborative network.12 As a coping strategy to deal with physical, psychological, and social dysfunction, rehabilitation is needed at some stages of diseases and injuries.10 Importantly, for estimating musculoskeletal rehabilitation needs, published studies that described or calculated rehabilitation needs in populations with health conditions were reviewed without language restrictions. However, only those population-based original studies with a large sample  and showing national representative results were included.10According to the Hong Kong Hospital Authority’s Investigator’s Code of Practice, ethical approval was not needed because this study conducted secondary analyses of publicly available data and participants’ information was not individually identifiable. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  by age, sex, region, country, and year were calculated for 191 countries and territories by using the GBD’s Bayesian meta-regression tool, Disease Modeling–Metaregression (DisMod-MR) version 2.1.10 Briefly, DisMod-MR 2.1 was used to fit a global model on data from all countries and territories.14 The global model accounted for extra covariance within each of 7 GBD super-regions  in age-standardized rates to measure and quantify the trends of rehabilitation needs. The lower bound of an EAPC greater than 0 suggests an increasing trend, and the upper bound of an EAPC smaller than 0 indicates a decreasing trend. However, 95% CIs of an EAPC that include 0 suggest the age-standardized rate has remained relatively stable during the study period. We mapped the age-standardized rates and EAPCs in musculoskeletal rehabilitation needs for each country and territory. Subsequently, sex and age differences in global musculoskeletal rehabilitation needs were compared. The associations between EAPCs and the age-standardized rates of musculoskeletal rehabilitation needs in 1990 were then examined by ρ coefficients in Pearson correlation analysis to determine the potential factor of EAPCs.20 Furthermore, given that health spending per capita , and a 2-sided P < .05 was considered statistically significant. Data analyses were performed from February to May 2021.The changing patterns of age-standardized prevalence and YLD rates of rehabilitation needs were compared in World Bank high-income countries and low- and middle-income countries in the 6 WHO regions, including Africa, the Americas, Southeast Asia, Europe, the Eastern Mediterranean, and the Western Pacific regions.Globally, the number of prevalent cases of musculoskeletal disorders in need of rehabilitation increased significantly from 1060.6  million in 1990 to 1713.6  million in 2019, which contributed to a steady increase in the number of YLDs from 93.9  million in 1990 to 149.0  million in 2019. The global age-standardized prevalence and YLD rates of musculoskeletal disorders in need of rehabilitation decreased annually during the entire period with EAPCs of −0.34  and −0.42 , respectively. The Western Pacific region had the largest increases in the prevalent cases and YLDs. Despite this, the highest rehabilitation needs were in the World Bank high-income countries in 2019. Overall, the age-standardized rates of rehabilitation needs decreased across all regions during this period annually. The fastest decreasing speeds were noted in Europe, with EAPCs of −0.47  and −0.57  in age-standardized prevalence and YLD rates, respectively . At the Based on the proportion of prevalent cases and YLD counts, low back pain contributed most to musculoskeletal rehabilitation needs over the past 3 decades across regions. In 2019, low back pain accounted for 568 444 532 of 1 713 557 313 global prevalent cases of musculoskeletal disorders (33.2%), followed by fractures (436 288 796 [25.5%]), osteoarthritis (343 943 653 [20.1%]), other injuries (305 001 551 [17.8%]), neck pain (222 718 453 [13.0%]), amputation 175 731 751 [10.3%]), and rheumatoid arthritis (13 487 835 [0.8%]) A. From 1From 1990 to 2019, age-standardized prevalence and YLD rates of low back pain, other injuries, and amputation in need of rehabilitation showed steady declining trends, whereas those of neck pain, fractures, osteoarthritis, and rheumatoid arthritis largely stabilized. Notably, age-standardized rates due to neck pain, fractures, other injuries, and amputation increased steadily overall from 2014 to 2019. The age-standardized prevalence and YLD rates of fractures, other injuries, and amputation were higher in male individuals, whereas those of low back pain, neck pain, osteoarthritis, and rheumatoid arthritis were higher in female individuals  (P < .001)  A. Likewi < .001) B. Given  < .001) . For cat < .001) .P = .01) (P = .03)  A. ObservP = .03) B. The mo4 People in Australia with low back pain experienced work incapacity, productivity decline, and early retirement, which accounted for approximately 66-fold less accumulated wealth (AUS $5038 vs $339 121) compared with their healthy counterparts working until the usual retirement age of 65 years.4 In addition to accumulated wealth reduction, being dependent and lack of social identity also affect people experiencing low back pain. As a result, they struggle to maintain a decent living and to take social responsibilities.22 Moreover, with population growth and aging, the number of people experiencing low back pain is expected to increase significantly in the following decades. Notably, in our study and supported by a previous study,23 the most rapid increasing trends of low back pain were in low- and middle-income countries. Therefore, the increasing disability related to low back problems contributed to productivity loss, which may perpetuate the cycle of poverty in those countries.23To our knowledge, this is the first study to present the secular trends in musculoskeletal rehabilitation needs over the past 3 decades at the global, regional, and national levels. From 1990 to 2019, although the global age-standardized prevalence and YLD rates of musculoskeletal disorders decreased annually with EAPCs of −0.34  and −0.42 , respectively, substantial increases in prevalent cases and YLDs of musculoskeletal disorders were found, which was a result of population growth and aging. Importantly, nearly 1 in every 4 people needs musculoskeletal rehabilitation, which challenges the common belief that rehabilitation is needed by only a small population. Particularly, low back pain was the leading contributor to musculoskeletal rehabilitation needs worldwide. Additionally, low back pain is also the leading cause of early retirement among adults.25 For example, male individuals need more rehabilitation resources due to fractures, as male individuals generally report a higher rate of severe traumas with increased morbidity and mortality, such as motor vehicle collisions, work-related bone overloading, and recreational injuries,26 although female individuals, especially those at postmenopausal stages, show a higher risk of fractures due to lower levels of bone density, declines in estrogen levels, and a higher fall rate.27 Similarly, higher rehabilitation needs due to amputation are found in male individuals, given that males show a higher rate of road traffic crashes28 and peripheral arterial disease29 as well as a higher risk of diabetes,30 which are also closely associated with individuals’ hormone levels and immune response. Notably, the age-standardized prevalence rates have increased faster in the Syrian Arab Republic, Palestine, and Pakistan, which may be an indication that traumatic events have contributed to the increasing needs of musculoskeletal rehabilitation, as those areas have been affected by conflict in recent decades. Rehabilitation needs increased with age, and rehabilitation needs due to low back pain, neck pain, and rheumatoid arthritis peaked at older ages. These results are confirmed by the GBD 2017 study findings.34 This has implications for health service delivery and rehabilitation resource distributions, as more attention should be paid to specific age and sex groups.For fractures, other injuries, and amputation, more rehabilitation resources were needed in male individuals, while for low back pain, neck pain, osteoarthritis, and rheumatoid arthritis, opposite patterns were found. This gender disparity could be explained by the combined effects of anatomic, hormonal, immunological, and traumatic factors on the development of musculoskeletal disorders.35 In addition, it is essential to improve the effectiveness and efficiency of health systems.17 This reveals the importance of incorporating rehabilitation services into health systems and promoting rehabilitation, especially in primary health care.10 Furthermore, allocating sufficient funds will facilitate the provision of rehabilitation services, given that attaining UHC effective coverage indexes of 80 and greater requires $1398 per capita spending with the most effective health systems.17In our study, the age-standardized prevalence and YLD rates of rehabilitation needs are found to be generally higher in those countries with higher UHC effective coverage indexes. Despite this, remarkable gaps exist between observed and expected rehabilitation needs across countries. More importantly, excess rehabilitation needs reflect the limitations of health systems, and the burden of musculoskeletal disorders has exceeded health care capacity in these locations. This phenomenon existed in countries with higher and lower UHC effective coverage indexes, although countries with higher UHC effective coverage indexes tended to outperform those countries with lower UHC effective coverage indexes in terms of health care provision. One possible resolution is to identify and control risk factors, such as less exercise, overweight and obesity, an unbalanced diet, smoking, and alcohol consumption, and mitigate their impacts on the development of musculoskeletal disorders.10 Therefore, people in the early stages of health conditions might have less serve manifestations but in need of rehabilitation resources were excluded.10 Although this calculation might not be thorough, the aggregated results accounted for a considerable proportion of total YLDs attributable to chronic diseases and injuries in need of rehabilitation. Third, it is essential to assess the associations of risk factors with musculoskeletal disorders to provide better evidence for clinical practice and decision-making. However, these risk factors were not available from the WHO Rehabilitation Need Estimator, and thus their contributions were not assessed. Future studies may collate and assess the effects of these factors. Fourth, great variations in the effectiveness of promotion, prevention, and treatment approaches for musculoskeletal disorders among countries may affect individuals’ experience of health conditions.This study has several limitations. First, the accuracy and precision of our research findings mainly relied on the quality and availability of data sources. For this reason, estimates for countries without available data but derived from modeled results using the GBD’s Bayesian metaregression tool, DisMod-MR 2.1, should be interpreted with caution. To ensure reliability and accuracy of results, these countries are encouraged to make additional efforts to collect data from statistics systems and sustain data quality, which may be difficult in some resource-limited areas and may warrant international cooperation. Second, rehabilitation needs were calculated based on 7 health conditions, which were included given their prevalence, severity, and the necessity of rehabilitation.This study found that the number of prevalent cases and YLD counts in need of musculoskeletal rehabilitation has increased considerably during the past 30 years. High rehabilitation needs have become a global public health concern, although overall decreasing trends were found in age-standardized rates. Mitigating risk factors, strengthening rehabilitation in primary health care, and allocating sufficient funds for rehabilitation services are possible ways to meet the needs of rehabilitation.


The proportion of children who never received rehabilitation was 49.8% (n = 1411) in Bangladesh, 45.8% (n = 82) in Nepal, 66.2% (n = 86) in Indonesia, and 26.7% (n = 74) in Ghana. The mean (Standard Deviation) age of commencing rehabilitation services was relatively delayed in Nepal (3.9 (3.1) year). Lack of awareness was the most frequently reported reason for not receiving rehabilitation in all four countries. Common predictors of not receiving rehabilitation were older age at assessment , low parental education and family income, mild functional limitation, and associated impairments . Additionally, gender of the children significantly influenced rehabilitation service utilisation in Bangladesh. Conclusions: Child’s age, functional limitation and associated impairments, and parental education and economic status influenced the rehabilitation utilisation among children with CP in LMICs. Policymakers and service providers could use these findings to increase access to rehabilitation and improve equity in rehabilitation service utilisation for better functional outcome of children with CP.Background: We assessed the rehabilitation status and predictors of rehabilitation service utilisation among children with cerebral palsy (CP) in selected low- and middle-income countries (LMICs). Methods: Data from the Global LMIC CP Register (GLM-CPR), a multi-country register of children with CP aged <18 years in selected countries, were used. Descriptive and inferential statistics  were reported. Results: Between January 2015 and December 2019, 3441 children were registered from Bangladesh ( Cerebral palsy (CP) is a group of disorders of movement and posture caused by non-progressive lesions in the developing brain . GloballDespite the large burden, there is little information describing the rehabilitation needs of children with CP in LMICs ,8. The eUnderstanding the magnitude of rehabilitation needs and potential factors influencing service utilisation is essential for planning, policymaking, and developing a comprehensive rehabilitation program in order to address the future needs of children with disabilities in LMICs . To meetThis study utilised data collected as part of the Global LMIC CP Register (GLM-CPR), an ongoing collaboration between CP registers based in LMICs. A protocol clearly outlining case definition, methodology, and definition of core variables has been used to allow harmonisation of country-specific CP register data to the GLM-CPR dataset. As part of the GLM-CPR, detailed information related to rehabilitation service receipt among participating children is also documented since different types of services with varied cost, scope, and access are available for children with disability  in the respective countries. In this study, data from four countries  included in the GLM-CPR were analysed to report the rehabilitation status and predictors of utilisation of the available rehabilitation services among children with CP in LMICs.The GLCMPR follows the case definitions of the Surveillance of CP in Europe (SCPE) and the Australian CP Register (ACPR) for the inclusion of children with CP in respective registers ,19. ChilThe GLMCPR employs both population-based surveillance and hospital/institution-based surveillance mechanisms to recruit children with CP from LMICs.In the population-based surveillance mechanism, the key informant method (KIM) is being used to identify children with suspected CP from communities. The KIM is a validated method with a 77.6% case-ascertainment rate  and has The Bangladesh CP Register (BCPR), a population-based surveillance of children with CP, represents rural and semi-urban Bangladesh (where the majority of the population (76.7%) lives) in terms of demographic and other indicators . The surveillance site covers 18 sub-districts  of seven districts in Bangladesh. Children registered into the BCPR between January 2015 and December 2019 were included in this study.In Indonesia, a community-based KIM survey was conducted in eight districts of Sumba Island  in 2017. Children registered between March 2017 and August 2017 through the KIM survey were included in this study.Established in June 2018, the Nepal CP Register (NCPR) is an ongoing surveillance of children with CP in Nepal. The surveillance site covers six municipalities of Gorkha district . Children registered between June 2018 and October 2018 were included in this study.In the hospital/institution-based surveillance mechanism, children with CP are identified prospectively following a convenience/purposive recruitment strategy during regular service provision in health facilities/rehabilitation centres. This method is being used to register children with CP living in Begoro town of Fanteakwa district  in Ghana. Children recruited between October 2018 and May 2019 into the Ghana CP Register (GCPR) were included in this study. The details about the study settings of all four CP registers included in the GLM-CPR have been published elsewhere [In both types of surveillance mechanisms, children with suspected CP identified by key informants in the community or by trained health care professionals in the hospital setting undergo a detailed neurodevelopmental assessment by a multi-disciplinary medical assessment team including a paediatrician, a physiotherapist, and a counsellor for a confirmed diagnosis.Using a uniform template, data are collected on selected core variables by each CP register. Variables included in this study were: sociodemographic characteristics  and clinical characteristics  level, Manual Ability Classification System (MACS) level, predominant motor type, topography, and associated impairments). Information on rehabilitation  were also collected from primary caregivers. In this study, the main outcome variable was the rehabilitation status  of a child with CP recruited in any of the registers. Responses were collected as a binary variable with either ‘yes’ or ‘no’. Children who received at least one rehabilitation session were categorised as rehabilitation recipients and marked ‘yes’. Additionally, available medical records were reviewed for any documentation on rehabilitation services. Regarding reasons for not receiving rehabilitation, if a primary caregiver mentioned that s/he was not aware of the need or benefit of rehabilitation/intervention for her/his child with CP, or the availability of services, it was documented as ‘lack of awareness’. If a respondent mentioned financial hardship/lack of money for not receiving rehabilitation services of their child, we documented financial constraint as a reason for not receiving rehabilitation services. Similarly, if caregivers responded that they could not take their children to the available rehabilitation service centres because of the difficulties in transport use, then it was documented as a transport problem.p value < 0.05 was considered significant. All data were analysed using Statistical Package for the Social Sciences (SPSS) software version 26 .Continuous variables were collected as exact values and later recoded and categorised into groups . Similarly, the monthly family income data were collected in local currencies and then converted to USD and categorised into three monthly family income groups . Descriptive analyses were performed to report the overall rehabilitation status. Bivariate analysis was completed to identify the underlying factors of rehabilitation services. Factors that were found significant in unadjusted analyses were fitted into the adjusted model. Adjusted odds ratios (aOR) with 95% confidence interval (CI) were reported. A Ethical approval was obtained from the international/national/institutional Human Research Ethics Committee (HREC) for each of the countries registered with the GLM-CPR before the commencement of the registers. For the BCPR, ethical approval was taken from the Cerebral Palsy Alliance HREC (Reference no.: 2015-03-02) in Australia, the Asian Institute of Disability and Development (AIDD) HREC (Reference no.: southasia-irb-2014-l-01), and the Bangladesh Medical Research Council National Research Ethics Committee (BMRC/NREC/2013-2016/1267) in Bangladesh. For the NCPR, ethical approval was obtained from the Nepal Health Research Council Ethical Review Board (NHRC ERB) (Registration no.: 101/2018). In Indonesia, ethical approval was taken from the AIDD HREC (Reference no.: sothasia-irb-2017-1-01) and Hasanuddin University HREC, Indonesia (Reference no. 630/H4.8.4.5.31/PP36-KOMETIK/2017). For the GCPR, ethical approval was obtained from the Office of the Administrator Begoro Rehabilitation Centre. Prior to data collection, informed written consent was taken from primary caregivers of children with CP.n = 1331/3441) female.This study included 3441 children with CP . The mean age at assessment was 7 years (y) and 9 months (mo) (standard deviation (SD) 4 y and 6 mo; median 7 y 2 mo; interquartile range (IQR) 3 y 9 mo–11 y 4 mo); 38.7%, (n = 1653/3422) of the registered children with CP from all four countries had never received any type of rehabilitation services. However, the proportion of children who never received rehabilitation did vary significantly across countries, with 45.8% (n = 82/182) in Nepal up to 66.2% (n = 86/130) in Indonesia in the population-based settings (p = 0.001) and 26.7% (n = 77/277) in Ghana. Of those who received rehabilitation services, the majority received physical therapy . Access to assistive devices was low (6.3–16.3%) in Bangladesh, Indonesia, and Nepal, whereas, in Ghana, more than a third of children had received an assistive device. The mean (SD) age of commencing rehabilitation services substantially differed between the countries in population-based settings, ranging from 2.9 (3.0) y in Indonesia and 3.9 (3.1) y in Nepal. Most of the children received services between age 0 y and 4 y in both population-based  and institution-based settings. Hospital/health centre were the primary rehabilitation services provider in Nepal , Indonesia , and Ghana , while non-government organisation was the commonest service provider in Bangladesh . Lack of awareness regarding service needs and availability was the most commonly reported reason for not receiving rehabilitation in all four countries (84.2% (n = 1141/1355) in Bangladesh, 71.4% (n = 45/63) in Nepal, 70.9% (n = v61/86) in Indonesia, and 68.9% (n = 51/74) in Ghana)  .The proportion of children who received rehabilitation services gradually declined as age increased in Bangladesh, Indonesia, and Nepal. However, the findings were contradictory in Ghana .p = 0.013)  .p < 0.05) except Ghana. Similar findings were also found for the father’s education  was significantly associated with accessing rehabilitation services in all countries  and speech impairment (p = 0.032) in Ghana and children with hearing impairment (p = 0.016) in Indonesia. Comparatively, this rate was significantly lower for intellectual impairment (p = 0.020), visual impairment (p = 0.004), and hearing impairment (p < 0.001) in Bangladesh and for intellectual impairment (p = 0.006) in Nepal. The cohort of children with 3–5 associated impairments had significantly lower rehabilitation service utilisation in Bangladesh (p < 0.001) (The utilisation of rehabilitation services was significantly higher among children with epilepsy (< 0.001) .p < 0.001, respectively) and Indonesia (3 (3) y vs. 8 (5) y, p < 0.001, respectively) (The mean (SD) age of CP diagnosis was significantly lower among children who received rehabilitation compared to those who never received rehabilitation in Bangladesh (3 (3) y vs. 5 (4) y, ctively) .To assess the relationship between motor severity and rehabilitation service utilisation among children registered in the GLM-CPR, clinical characteristics of children with CP were assessed according to the GMFCS level I–II and GMFCS level III–V distinctly. Overall, children with GMFCS level I–II having dyskinetic or ataxic type of CP, tri/quadriplegia topography, MACS level III–V, 1–2 associated impairments, and early diagnosis had higher rehabilitation service utilisation. On the other hand, children with GMFCS level III–V having a dyskinetic type of CP, tri/quadriplegia topography, MACS level III–V, no associated impairments, and early diagnosis had greater rehabilitation service utilisation .The adjusted analysis shows that female children, illiterate and primary level completed mothers, illiterate fathers, monthly family income of USD 51–100, GMFCS level III–V, and hearing impairment significantly predict the rehabilitation service utilisation of children in Bangladesh. In comparison, intellectual impairment was significantly associated with rehabilitation service utilisation in Nepal. Amongst the Indonesian cohort, primary educated mothers and hearing impairment were found to significantly influencing rehabilitation service utilisation. In Ghana, 5–9 y age group and 10–14 y age group were significantly associated with rehabilitation service utilisation .This is one of the first studies reporting rehabilitation status and cross-cultural comparison of predictors of rehabilitation service utilisation among children with CP in four LMICs, i.e., Bangladesh, Nepal, Indonesia, and Ghana. Our study revealed that nearly half of the children with CP registered into the GLM-CPR had never received rehabilitation services in their lifetime, and the age of commencing rehabilitation was substantially delayed in all four countries. The study findings also suggest that the predictors of rehabilitation service utilisation vary between the studied countries, which could be partially attributed to the different cohort sizes of the CP registers included in GLM-CPR.The proportion of children receiving rehabilitation declined with increasing age in all studied countries except Ghana, which is most likely because of the institution-based recruitment . Young age has been reported as a positive predictor of rehabilitation service utilisation in earlier studies ,22. HoweIn terms of gender, female children with CP had a lower likelihood of receiving rehabilitation services when compared to male children in Bangladesh. Nuri et al.  describeWe observed that children of illiterate and primary educated parents, mainly mothers, in Bangladesh and Indonesia had a significantly lower likelihood of receiving rehabilitation. These findings are in line with earlier studies reporting a significant relationship between parental education and the exposure of physiotherapy service in the USA  and IndiAmongst the clinical predictors, children with GMFCS level III–V and MACS level III-V had a significantly higher likelihood of receiving rehabilitation services in Bangladesh and Nepal, respectively. These findings are in agreement with studies conducted in Canada , the USAThe chance of receiving rehabilitation was significantly lower among children with hearing and intellectual impairments in Bangladesh and Nepal, respectively. In Indonesia, however, children who had hearing impairment were more likely to receive rehabilitation services. Children with 1–2 impairments had a higher chance of receiving rehabilitation services compared to children with no associated impairments in Nepal. Like ours, a contradictory finding on the association between associated impairments and rehabilitation service use was reported in earlier studies. Liljenquist et al.  reportedOur study findings identified that most of the participating children in LMICs are diagnosed at an age when they are past the period for maximum neuroplasticity. On a positive note, the study also indicates that children who were diagnosed at an early age had a significantly higher probability of receiving rehabilitation services. These findings, once again, underscore the necessity of establishing early diagnostic and intervention facilities to improve access to rehabilitation services for children with CP in LMICs.Inadequate access to rehabilitation services is a major concern in low-resource settings ,33. In rDespite our extensive effort, there are some limitations in this study. (i) The number of children with CP included in this study from four countries varied largely due to different timepoint of the establishment of registers . However, over time, these CP registers and their cohort size would mature. (ii) Additionally, the type of surveillance mechanisms  might have impacted the findings of the study. For instance, institution/hospital-based surveillance systems are likely to overestimate the service access, while community-based surveillance in a rural setting may slightly underestimate service access. Despite these challenges, these CP registers are an important and essential source of information to better understand CP and service use in these developing countries—by bringing these data together, this innovative program provides us with a snapshot of CP in LMICs that would not otherwise be possible. (iii) The findings on whether children received rehabilitation reported in this study might be an overestimation of the true rehabilitation status, as data presented here reflects the proportion of children with CP who have ever received any rehabilitation service with a minimum of one session to be considered as a recipient of rehabilitation services. (iv) The KIM method has a 77.6% case ascertainment rate which indicates that there might be incomplete case ascertainment in this study, particularly for the milder form of CP . HoweverNearly half the children with CP do not have access to rehabilitation services in Bangladesh, Nepal, and Indonesia. Although the rate of a severe form of motor severity  was higher among the participating children, the utilisation of assistive devices is extremely poor in Bangladesh, Nepal, and Indonesia. Additionally, the age of rehabilitation service commencement is noticeably delayed, limiting the opportunity for neuroplasticity as well as functional recovery. To enable early intervention uptake and prevent functional limitations, the establishment of early diagnostic facilities is essential. This study revealed some socio-demographic  and clinical factors  that were significantly associated with rehabilitation service utilisation. Our study highlights that strong advocacy programs and policy-level work are essential to raise awareness for early childhood intervention and establish parents-led community-based rehabilitation facilities in LMICs. Policymakers and service providers could use these findings to increase access to rehabilitation, and improve equity in rehabilitation service utilisation for better functional outcomes of children with CP in these LMIC settings.


As robots move from the laboratory into the real world, motion planning will need to account for model uncertainty and risk. For robot motions involving intermittent contact, planning for uncertainty in contact is especially important, as failure to successfully make and maintain contact can be catastrophic. Here, we model uncertainty in terrain geometry and friction characteristics, and combine a risk-sensitive objective with chance constraints to provide a trade-off between robustness to uncertainty and constraint satisfaction with an arbitrarily high feasibility guarantee. We evaluate our approach in two simple examples: a push-block system for benchmarking and a single-legged hopper. We demonstrate that chance constraints alone produce trajectories similar to those produced using strict complementarity constraints; however, when equipped with a robust objective, we show the chance constraints can mediate a trade-off between robustness to uncertainty and strict constraint satisfaction. Thus, our study may represent an important step towards reasoning about contact uncertainty in motion planning. As robots move into the real world, accounting for model uncertainty and risk in motion planning will become increasingly important. While model-based planning and control has demonstrated success in designing and executing dynamic motion plans for robots in a variety of tasks in the laboratory , real woTrajectory optimization (TO) is powerful for planning continuous dynamic motions that obey constraints such as actuation limits, obstacle avoidance, and contact dynamics . While t• Design chance constraints for contact with uncertainty in contact distance and friction coefficient.• Provide a risk-bounded interpretation to the relaxed chance complementarity constraints.• Demonstrate that chance constraints, combined with a contact-sensitive objective, can control the trade-off between robustness to contact uncertainty and contact constraint satisfaction at fixed values of uncertainty.In this work, we explicitly investigate uncertainty resulting from the terrain contact parameters and develop a method for trading off between motion feasibility and robustness. In contrast to the previous work , which cPlanning motions for robots with intermittent contact can be achieved through either hybrid  or contaIn contrast, contact-implicit methods specify contact through a complementarity model which includes the nearest contact distance and friction coefficient , and thuTo trade-off between robustness and constraint satisfaction, chance constraints can be added to an optimization problem to enforce a probabilistic version of the uncertain constraints . Chance In this section, we present a robust contact-implicit TO with both contact-robust costs and chance constraints to provide robustness to contact uncertainties while maintaining the feasibility of physical contact models.q, velocities v, controls u, and contact forces λ through a discretized optimal control problem:L is the running cost, hk is the timestep, x =  is the state, M is the generalized mass matrix, C contains Coriolis and conservative force effects, B is the control selection matrix, Jc is the contact Jacobian, λN and λT are the normal and tangential contact reaction forces, ϕ is the contact distance, γ is a slack variable corresponding to the magnitude of the sliding velocity, μ is the coefficient of friction, and e is a matrix of 1s and 0s.Planning robot motions that are subject to contact reaction forces can be achieved through contact-implicit TO . The traThe contact Jacobian can be decomposed into normal and tangential components, a ⊥ b ≥ 0 represents the complementarity constraints a ≥ 0, b ≥ 0, ab = 0. γ and the corresponding relative tangential velocities to be nonzero. In sticking, however (1f) forces the variable γ to zero and (1e) requires the corresponding relative tangential velocity to also be zero. We replaced the friction cone with a polyhedral approximation (e in (1f), which contains only 1s and 0s, instead of the use of the 2-norm, and we consider λT to be the non-negative components of the friction force projected onto the polyhedron. The polyhedral approximation presented here can readily extend to the full three-dimensional case, although we do not study three-dimensional contact in this work.ximation , denotedλ, although this is purely a design choice. Quadratic costs are common in the optimal control literature  is a mathematical program with equilibrium constraints, a type of nonlinear program (NLP) that can be difficult to solve. Two approaches to solve the problem numerically using standard NLP solvers like SNOPT  include ab ≤ ϵ  and solvb ≤ ϵ  ≥ 0, ω ∈ Ω where z is a deterministic variable, and F(⋅) is a vector-valued stochastic function, and ω represents a random variable on probability space The complementarity constraints in (1) assume that perfect information about the contact model is available. However, if any of the model parameters are uncertain, the problem has stochastic complementarity constraints (SCP)  0 ≤ z ⊥ ψ that attains its roots when the complementarity constraints are satisfied: ψ = 0⇔z ≥ 0, F ≥ 0, zF = 0. Although this formulation is for scalars z and F, it generalizes to the case when z and F are vectors by applying the complementarity constraints and/or the residual function elementwise. In the Expected Residual Minimization (ERM) approach , the variable zk and the function F are generic decision variables and constraint functions, respectively. In our work, we consider uncertainty in the terrain geometry and in the friction coefficient separately. In the case of uncertain terrain geometry, F is the normal distance function ϕ(q) and z includes the normal forces λN. Likewise, in the case of uncertainty in friction, F is the linearized friction cone in (1f) and z includes the sliding velocity slack variable γ.Prior work using an ERM cost to plan for uncertainty in contact resulted in solutions that were robust to variations in the contact parameters . Howeverθ is the specified probability of violation , θ > 0.5) or a conservative (θ < 0.5) constraint.As F ≥ 0) ≥ 1 − β and Pr(zF ≤ 0) ≥ 1 − θ. Assuming that z is a deterministic variable, by To complement the robust ERM approach, in this work we investigate contact uncertainty by converting the stochastic complementarity constraints to deterministic, chance complementarity constraints. As with the Gaussian ERM, we assume the complementarity function is normally distributed Remark 1. If either σ = 0 or β = θ = 0.5, then the chance constraints recover the strict complementarity constraints.Remark 2. If β = 0.5 and θ > 0.5, we recover a relaxed version of the complementarity constraints  :Mz=1K∑knstraint  for fricnstraint  for cont–6. Unless otherwise noted, all of our robust and chance-constrained problems were initialized with the reference, non-robust solution, and we used the same value for uncertainty σ in the ERM objective as in the chance-constraints. Our code is available at https://github.com/GTLIDAR/ChanceConstrainedRobustCITO.We compared the chance-constrained risk-sensitive optimization approach to the ERM-only risk-sensitive approach  and the x =  includes the planar position and velocity of the center of mass of the block, pCoM and vCoM respectively, and the control u is a horizontal force applied at the center of mass. We optimized for a 1s trajectory, discretized with 101 knot points, to travel between the initial state x0 = ⊤ and final state xN = ⊤. The running cost had weight matrices R = 10 and Q = diag. We first solved the optimization to a tolerance of 10–6 and then to 10–8; in this example, solving to the tighter tolerance improves the visual quality of the solutions. In the reference trajectory, we used friction coefficient μ = 0.5. For the uncertain cases, we assumed a mean friction of σ ∈ {0.01, 0.05, 0.10, 0.30, 1.00}. When including chance constraints, we tested several combinations of the risk bounds θ, β ∈ {0.51, 0.6, 0.7, 0.8, 0.9} For completeness, we also tested the chance constraints without the ERM cost for uncertainties σ ∈ {0.1, 1.0}. We quantified the feasibility of our motion plans using the merit score  by testing 9 combinations of β, θ ∈ {0.51, 0.7, 0.9}.We evaluated the performance of the non-robust reference controls, the ERM controls, and the ERM with chance constraints controls in open-loop time-stepping simulations . To evalq includes the planar position  of the base pCoM and the angles of the hip θH, knee θK, and ankle θA; that is, q = . Thus, the state vector is R = diag and Q = diag.Our second example is a 2D single-legged hopper with collision points at the toe and heel. The configuration μ = 0.5 and uncertain terrain height with expected distance between initial hopper base height and terrain of 1.5 m. We tested the ERM and ERM with chance constraints approaches under 6 uncertainties roughly logarithmically spaced between σ = 0.001 and σ = 0.5 m. To more effectively utilize the ERM cost at high uncertainty, we scaled the normal distance by 10 during optimization, expressing the distance and its uncertainty in decimeters. At each uncertainty level, we tested 5 values of the chance parameters, θ ∈ {0.51, 0.60, 0.70, 0.80, 0.90}, with β = 0.5 in all cases to ensure no ground penetration. Note that when we apply chance constraints, we do not apply any other relaxation to the complementarity constraints. Instead, we use the strictly feasible solution from our progressive tightening procedure to warm-start the optimization with chance constraints. We quantified the feasibility of the hopping motion plans using the merit score  using chance constraints without the ERM cost produced trajectories that were nearly identical to the reference trajectory under moderate uncertainty (σ = 0.1)  . When σ  control , indicatσ < 0.1, the ERM with chance constraints method produced friction forces around 4.9 N during sliding, similar to those produced by the ERM method alone (σ = 1.0), the ERM produced friction forces at 0 N during the entire motion, which is infeasible for all friction coefficients except μ = 0. In contrast, the ERM with chance constraints produced nonzero friction forces, and the magnitude of the friction forces increased as the risk bounds decreased and converged towards the expected value for friction at 4.9 N  , although both had a similar range of position errors  . Howevern errors . By varyues of β . Moreoveσ = 0.5 m). However, the ERM also allows contact forces to be applied at a nonzero distance from the expected terrain; such motion plans are not physically realizable on the expected terrain, and could be dangerous to execute on real robots because the robot may expect a large force when one is not provided by the environment. Introducing chance constraints, however, reduced the foot height and reduced the distance at which the contact normal forces were nonzero, and the decrease in foot height trended with decreasing the risk parameters θ, β (θ = β = 0.5, the chance constraints eliminate force-at-a-distance from the expected terrain. Thus, although the chance constraints reduce the contact infeasibility, unless the risk bounds are made sufficiently close to 0.5, the planned motions could still be dangerous to execute. Nonetheless, by bringing the foot closer to the expected terrain, the chance constraints reduce the risk associated with expecting a large force at a distance from the terrain, as the robot would need to accelerate the foot over a shorter distance to make contact compared to the larger distance prescribed using the ERM only. Finally, we note that neither the ERM nor the ERM with chance constraints had much effect on the optimized reaction forces; in this example, the effects were limited mainly to the contact distance.In the hopping example with contact distance uncertainty, the ERM alone produced higher average foot height with increasing uncertainty, up to an average of 0.46 m at our highest value of uncertainty (ers θ, β . Across ers θ, β , althougBy using the merit score, we also observed that the contact distance infeasibility decreased with both decreasing uncertainty and decreasing the risk parameters . While tθ and β. The improved feasibility is achieved because the chance constraints limit the region of allowable solutions to the ERM to those near the non-negative mF and z axes, i.e., the solution set of the non-stochastic complementarity constraints; moreover, as the risk bounds are decreased, the allowable set approaches the complementarity solution under the mean values of the constraints, representing the limit of perfect feasibility under the mean but no robustness.In this work we proposed a novel framework for accounting for contact uncertainty in TO. As previously explored, the ERM cost represents a robust contact-averse objective but also results in infeasible trajectories as the contact uncertainty grows . Here weOur work with chance-constraints is similar to previous works which have applied chance-constraints to obstacle avoidance  or to moHere we considered solely the problem of accounting for uncertainty in contact during motion planning; we specifically have not investigated handling uncertainty in contact with control. Future work could convert our technique into a feedback control policy by re-planning in a receding horizon fashion; however, current methods for solving contact-implicit problems are too slow to be used reactively in real-time. Thus, advancements in efficient solvers for contact-implicit problems are necessary before our work can be used in a receding horizon control fashion, such as those used in hybrid optimization to generate gait libraries . Apart fIn this work, we parameterized uncertainty in the distance to the terrain and in the friction coefficient using Gaussian distributions, as this distribution provides analytical formulas for the ERM cost and for the chance constraints. Having access to analytical formulas means we only needed to generate one robust trajectory, instead of generating multiple samples to achieve robustness . Given tOne challenge in developing a contact-robust TO is in propagating contact uncertainty through the system dynamics as the state evolves, as contact events are intermittent. In this work, we introduced an ERM cost to improve trajectory robustness as the ERM cost minimizes the sensitivity of the solutions to variations in the contact parameters ; nonetheThe main advantage of our chance-constrained ERM approach is that we can generate trajectories with varying degrees of robustness to contact uncertainty without changing the uncertainty. Thus, when faced with uncertain terrain, we can choose between being robust to terrain variations or being optimal with respect to our original objective without artificially changing the uncertainty in the model. Our work here focused on investigating these behaviors in simple systems on 2-dimensional terrain. In future works we could scale up our approach to full-scale robots traversing 3-dimensional terrain. We expect the complexity of solving the ERM and chance constraints to scale only with the number of contacts and not with the state dimension of the robot, as the number of complementarity constraints, and therefore the number of ERM costs and chance constraints, is linear in the number of contact points and not dependent on the state dimension - for example, adding several contact points to the sliding block and putting obstacles in the environment would make the contact problem more challenging, even though the state dimension is the same. Once we have scaled up to three dimensions, we could also evaluate our methods experimentally on full-scale robots, such as a quadruped, and compare the performance of our robust motion plans against the traditional approach using a simple controller, and against other risk-sensitive control approaches such as .


Augmented reality (AR) has been developed rapidly and implemented in many fields such as medicine, maintenance, and cultural heritage. Unlike other specialties, ophthalmology connects closely with AR since most AR systems are based on vision systems. Here we summarize the applications and challenges of AR in ophthalmology and provide insights for further research. Firstly, we illustrate the structure of the standard AR system and present essential hardware. Secondly, we systematically introduce applications of AR in ophthalmology, including therapy, education, and clinical assistance. To conclude, there is still a large room for development, which needs researchers to pay more effort. Applications in diagnosis and protection might be worth exploring. Although the obstacles of hardware restrict the development of AR in ophthalmology at present, the AR will realize its potential and play an important role in ophthalmology in the future with the rapidly developing technology and more in-depth research. Augmented reality (AR) is a technology that enhances the natural environment with computer-generated information in real-time . AR is nAs a developing technology, AR has drawn the interest of researchers from different fields. Besides, AR has attracted companies like Google and Microsoft, which created AR devices such as Google Glass and HoloLens, providing hardware foundations for subsequent research. With the help of researchers and companies, AR has been developed rapidly and implemented in many fields such as medicine, maintenance, and cultural heritage .Healthcare has become one of the pioneers, especially for applications requiring guidance and assistance . For exaIn this article, we reviewed AR in ophthalmology, summarized the applications and challenges of AR, and provided some suggestions for further research. We illustrated the structure of an AR system in ophthalmology, presented essential hardware, and systematically introduced AR's applications in ophthalmology, including applications in therapy, education, and clinical assistance. The ocular diseases that have been applied with AR in therapy include visual field defects, color vision deficiency, low vision, blindness, nyctalopia, metamorphopsia, and amblyopia. Applications in education contain medical education and public education. Applications in clinical assistance involve combining optical coherence tomography (OCT) and AR in surgery, deep anterior lamellar keratoplasty surgery navigation, and slit-lamps examination assistance.As shown in There are many kinds of cameras for video capturing, depending significantly on the type of application. For instance, if developers need the function to evaluate the depth of the space, they probably will use a depth sensor camera. The stereo camera can support the 3D reconstruction of the real world.The AR systems used to use personal computers as their computing center. With the invention of smartphones and microcomputers, the computing center became portable and subtle or directly embedded in the display.The displays applied to AR in ophthalmology include head-mounted displays (HMDs) and handheld displays. HMDs are displays worn on the head to place images over the user's view. The display technologies can be video see-through (VST) or optical see-through (OST) . VST disThere are two major AR prototypes: HMD-based AR systems and smartphone-based AR systems . HMD-basTo meet the authoritative standard, we classified applications in therapy of ocular diseases according to the International Classification of Diseases 10th published by the World Health OrganizationSeveral ophthalmic diseases could cause visual field defects (VFD), including glaucoma, stroke, and retinitis pigmentosa . Visual Image remapping, overlaid window, visual multiplexing, and danger indicator has been developed to provide a visual aid . Sayed eDespite providing a visual aid for the VFD patient, improving searching capability is another direction. In Zhao's study, CueSee offered five visual cues for users who cannot finish visual search tasks . Among tColor vision deficiency (CVD), also known as color blindness, is a group of ophthalmic diseases that affect 8% of males globally. Patients have difficulties perceiving and distinguishing specific colors , 23. CVDSeveral commercial AR devices provide prototypes for CVD aiding research . OmnicolThe processing technologies can be classified into two categories: substituting colors and augmenting visual information . SubstitBlindness is defined as the best-corrected visual acuity of a patient's better-seeing eye is <20/400 . The domLow vision is defined as the best-corrected visual acuity of a patient's better-seeing eye is better than 20/400 and <20/60 . PatientIn contrast to color blindness, nyctalopia has problems with rods rather than cones . TherefoMetamorphopsia is a group of macular disorders that cause the patient's sight to twist . The comAmblyopia is a disorder that affects the spatial vision of monocular or binocular . It is aOphthalmic surgery and diagnosis are difficult to get started due to their meticulousness. As a result, medical students need to practice a lot to be qualified. However, many students cannot get enough chances to practice because of the lack of cases. The surgical or diagnostic training simulators based on VR or AR systems have been presented to solve this problem. Students can acquire adequate practice through simulators to improve surgical or diagnostic quality. An inevitable defect of the VR simulators is that VR blocks the connection with the real environment. On the contrary, the AR simulators can reserve the real environment while simulating the surgical or diagnostic information. The AR simulators have been implemented in direct or indirect ophthalmoscopy and microsurgery. Schuppe et al. presented EYESI, a training simulator for indirect ophthalmoscopy, in 2009 for the first time . EYESI cSince ophthalmic diseases might cause severe consequences and significantly impact life quality, prevention is more important than treatment . BesidesSurgery and diagnosis are important but challenging in ophthalmology since they require a quantity of experience . Except AR is a popular technology in ophthalmology and has developed rapidly in the recent decade since the appearance of commercial HMDs and smartphones. The applications of AR in ophthalmology introduced in this review involve therapy, education, and clinical assistance. In order to have a better understanding of AR's development in ophthalmology, we have counted the number of publications in each application according to our classification method in the Google Scholar database . The AR'Applications in therapy aim to improve patients' vision or activities closer to healthy people. The common symptoms of eye disease are visual disturbances, and AR equips the ability to process visual information to enhance vision. Therefore, the therapy is a unique application in ophthalmology compared to other diseases. Besides, as a non-invasive treatment method, AR has great potential in alternative therapy. For patients with ocular diseases who cannot tolerate surgery or drugs, AR is a better choice. In addition, AR provides visual aids to patients suffering from incurable diseases to improve their quality of life. However, efforts are still needed to pay in ophthalmology treatment. Most AR applications in ophthalmology still lack adequate clinical research to evaluate the effectiveness, especially in ophthalmic disease aid. Although a few of research have held evaluation, the problems with insufficient sample size and selective bias still exist , 62. It The applications of AR in ophthalmic education involve public education and medical education in this review. Their common mechanism is simulating the vision vividly in real-time. The applications of AR in education can provide medical students with a lot of opportunities for practice. AR also allows healthy people to experience the vision of patients. In addition, compared to VR, the vision of AR simulation is more realistic and vivid because it is based on the natural environment. However, the evaluation of AR simulators is still lacking . In publSimilarly, the applications of AR in clinical assistance lacks effective evaluation. At present, AR is providing additional information to guide clinical activities in order to improve accuracy. However, AR technology includes not only adding information but also reducing and processing information. Therefore, AR technology can also be considered to remove things overlaying surgery or inspection targets in vision.In addition to the three areas summarized in this article, AR also has potential in diagnosing and protection. There have been some researches well-developed on VR but lack exploring in AR in the diagnosis of strabismus . It mighSince AR applications in ophthalmology integrate medicine and engineering, the development of AR in engineering is also critical. The most significant restriction of the ophthalmic AR system is the hardware. The resolution of the image is an unavoidable question troubling cameras and displays. A 20/20 vision requires a display system with 60 pixels per degree resolution in theory . Most ofIn conclusion, applications of AR in ophthalmology have been implemented in therapy, education, and clinical assistance. However, there is still a large room for development, which needs researchers to pay more effort. Applications in diagnosis and protection might be worth exploring. Although the obstacles of hardware restrict the development of AR in ophthalmology at present, the AR will realize its potential and play an important role in ophthalmology in the future with the rapidly developing technology and more in-depth research.HL, TL, and XZ designed the study. TL, CL, and XZ co-wrote the manuscript. WL, YC, and YY discussed and edited the paper. HL supervised this study. All authors discussed the results and commented on the paper.This study was funded by the National Natural Science Foundation of China (81770967 and 81822010). The funders had no role in the study design, interpretation, and writing of the paper.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. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Drosophila. However, mechanisms for controlling the level and the nuclear localization of Foxo in developing organs are not well understood. Here, we investigate the role of Drosophila Translationally controlled tumor protein (Tctp) and its interacting partner 14-3-3 in Foxo regulation during organ development. Foxo overexpression in the developing eye disc results in growth inhibition. We show that Tctp overexpression antagonizes the Foxo effect by downregulating the Foxo level in the eye disc. Foxo overexpression or knockdown of Tctp in the larval salivary gland results in reduced gland size, mainly due to reduced cell size by defects in endoreplication. Whereas 14-3-3ζ knockdown has a negligible effect, knockdown of 14-3-3ε mimics the effect of Foxo overexpression or Tctp knockdown, suggesting an isoform-specific role of 14-3-3. Unlike nuclear enrichment of the endogenous Foxo in the salivary gland, overexpressed Foxo protein is largely distributed in the cytoplasm, and this mislocalization is restored by Tctp overexpression. Opposite to the effect of Tctp overexpression, Tctp knockdown increases cytoplasmic Foxo levels while decreasing nuclear Foxo levels. Together, our data suggest that Tctp and 14-3-3ε play critical roles in cell growth by reducing cytoplasmic Foxo levels. Knockdown of human TCTP also elevates the level of cytoplasmic FOXO1 in HeLa cells, suggesting that human TCTP may have a conserved role in downregulating FOXO in human cells.Regulation of cell size is crucial for organ development. Insulin signaling regulates organ size by antagonizing the subgroup O of forkhead box transcription factor (Foxo) through 14-3-3 in  Translationally controlled tumor protein (TCTP) is a family of conserved proteins that play diverse functions ranging from protein synthesis to allergic responses . TCTP isDrosophila TCTP (labeled Tctp) is essential for organ growth by regulating both cell size and number in imaginal discs, the primordia for adult organs. Studies in Drosophila and Arabidopsis have revealed the roles of TCTP in the Target of rapamycin (TOR) signaling pathway for tissue growth [Drosophila, 14-3-3ε and 14-3-3ζ, are functionally redundant in organ development [e growth –6. Our pe growth . 14-3-3 elopment , 9.Drosophila, where they are involved in the negative regulation of the Foxo transcription factor [Drosophila and mammalian proteins are labeled as Foxo and FOXO, respectively). Phosphorylated FOXO proteins are excluded from the nucleus, thus resulting in reduced nuclear FOXO function as a transcription factor [Drosophila eye might be related to an activation of the nuclear Foxo function. However, it remains unclear whether the effects of Foxo overexpression are solely dependent on the nuclear function of Foxo in vivo.14-3-3 proteins have additional functions in insulin signaling for retinal differentiation and aging in n factor . In the n factor –13 -Gal4 instead of GMR-Gal4 to drive overexpression or silencing of genes in proliferating cells anterior to the morphogenetic furrow (MF). Compared to control   resulted in a ~40% reduction of the eye size  Fig. , Tctp RNize Fig. , whereasize Fig. . Overexpize Fig. . Tctp RNion Fig. . This stund Fig. , it sligund Fig. . Hence, foxoORF overexpression by ey-Gal4 strongly increased Foxo level in the anterior to the furrow, with weaker Foxo signals in the posterior region   Fig.  and reduFP) Fig. . These rTctp knockdown in the salivary gland by two independent UAS-Tctp RNAi lines using the AB1-Gal4 driver [Tctp RNAi only slightly increased the cell number  did not considerably affect salivary gland development  showed similar results , which has been used in other studies [foxoORF overexpression  also showed a weaker but significant reduction of the salivary gland size , BrdU signal was enriched in cell nuclei  in imaginal discs . Oscillaeus Fig. ''. Tctp and Fig. ''. 14-3-ycE Fig. . In contion Fig. ''. ThesefoxoORF severely reduced the gland size  siRNA, there was a strong increase in the hFOXO1 protein . 96 ± 4.0% of survived YWHAE-depleted cells showed strong enrichment of FOXO1 in the cytoplasm  antibody detected a major band at about 85 kDa. After 72 h treatment with human ein Fig. . To examion Fig. ''. 94 ± els Fig. . We alsoasm Fig. . These dOverall, these results suggest that Tctp is involved in regulating the level and the localization of Foxo. In addition, the role of Tctp in the Foxo regulation may be conserved in human cells.We have addressed the roles of Tctp and 14-3-3 isoforms in regulating Foxo functions in the developing eye and the salivary gland. Our data suggest that Tctp and 14-3-3ε play roles in tissue growth by regulating the level and the localization of Foxo protein.ey-Gal4-driven Foxo overexpression in undifferentiated cells of the eye disc is suppressed by Tctp overexpression  is enriched in the nucleus of HeLa cells, like Drosophila Foxo in the salivary gland. Furthermore, knockdown of hTCTP or YWHAE causes cytoplasmic localization of hFOXO  and AB1-Gal4 (1824) were obtained from Bloomington Drosophila Stock Center (BDSC). UAS-RFP (30556 on the second or 31417 on the third chromosome) (BDSC) was used for marking the Gal4 expression region. UAS-Tctp, UAS-Tctp RNAi, and UAS-hTCTP lines were as described [Drosophila Resource Center (VDRC). For 14-3-3 knockdown, UAS-14-3-3ε RNAi  and UAS-14-3-3ζ RNAi  were used. UAS-myc-14-3-3ε was a gift from Dr. Efthimios Skoulakis. For double knockdown of Tctp and 14-3-3, ey > Tctp RNAi/CyO recombinants were crossed with 14-3-3ε RNAi or 14-3-3ζ RNAi lines. UAS-foxoORF  and UAS-foxo  were used for dFoxo overexpression. The cross of UAS-foxo  was carried out at 18 °C to reduce the severe phenotype of small salivary glands. All other flies were grown at 25oC.The Gal4 drivers, AB1-Gal4 24 were oDrosophila imaginal discs were dissected from third instar larvae and stained as described [°C overnight sequentially in the primary and secondary antibody mix diluted in washing buffer . Finally, samples were stained with DAPI and mounted with a mounting medium (Vectashield). The following primary antibodies were used for immunohistochemistry: rabbit anti-Foxo  and mouse anti-Arm . Stained images were acquired using Zeiss confocal microscope LSM 710. Analysis of cell number and size of salivary glands was performed using the Image J program, and the data were presented with standard deviation (SD). Statistical significance was determined by a t-test of Microsoft Excel.escribed , 34. S2 °C overnight. Glands were blocked in 0.1% PBTr with 5% normal goat serum for 1 h before incubating with the secondary antibody of goat anti-rabbit Alexa 488  for 2 h at RT. The samples were washed four times, 15 min each with 0.1% PBTr. DAPI (1:2000) and/or phalloidin (1:250) was added during the second wash.For CycE immunostaining, late 3rd instar larvae were dissected in 1X PBS, then fixed in 1X PBS with 2% paraformaldehyde for 30 min. After washing three times 5 min each with 0.1% PBTr, the glands were incubated in 0.1% PBTr with rabbit anti-CycE  at 4 °C overnight. Glands were blocked in 0.1% PBTr with 5% normal goat serum for 1 h before incubating with the secondary antibody of goat anti-mouse Alexa 488  for 2 h at RT. The samples were washed four times 15 min each with 0.1% PBTr. DAPI (1:2000) was added during the second wash.For BrdU labeling, third instar larvae were raised in food vials containing 0.25 mg/ml BrdU for 24 h before dissection. Wandering 3rd instar larvae were dissected for salivary glands in 1X PBS, then fixed in 1X PBS with 2% paraformaldehyde for 30 min. After washing three times 5 min each with 0.1% PBTr (1X PBS with 0.1% Triton X-100), glands were treated with 3 N HCl for 30 min to denature the BrdU-labeled DNA. The glands were neutralized by washing with 0.1% PBTr for three times, 5 min each before incubating in 0.1% PBTr with mouse anti-BrdU (1:50) at 4 Drosophila S2 (stock #6) was obtained from Drosophila Genomics Resource Center (DGRC). The cells were maintained with 10% artificial serum in M2 media (Sigma-Aldrich). To knock down endogenous Tctp in S2 cells, dsRNA was designed and synthesized in vitro using MEGAscript RNAi Kit (Ambion): anti-Tctp forward 5'-GAGATGTTTGCCGACACCTAC-AA and reverse 5'-GCCGTCGCAGTCCATAGATTC primers conjugated downstream of T7 promoter sequences according to the manufacturer’s instructions. S2 cells were treated twice with 40 nM Tctp dsRNA every 3 days and harvested on day 6.°C for 10 mins. The total protein samples were loaded on 7.5% or 10% SDS-PAGE gel and transferred to a nitrocellulose membrane. After blocking at RT, membranes were probed sequentially in primary antibody solution and HRP-conjugated secondary antibody solution diluted with 2% dry milk or 2% BSA in TBST . Pierce ECL western blotting substrate (Thermo) was used to detect immunostained proteins. A cytosolic fraction from salivary glands was isolated as described [Late third instar larvae or S2 cells were lysed with lysis buffer  chilled on ice. The lysates were boiled with sample loading buffer at 95 escribed . Primaryescribed , mouse aoC, 5% CO2 condition. The sense strand of siRNAs was synthesized using target sequences for hTCTP (5′-GGTAACATTGATGACTCGC-3') [The human HeLa cell line was cultured with high glucose DMEM, 10% fetal bovine serum, 1% penicillin/streptomycin at 37TCGC-3')  and for °C overnight. Finally, cells were stained with DAPI.For immunostaining of human cells, HeLa cells were seeded on cover glasses coated with 0.01% poly-L-lysine 24 h before siRNA treatment. Cells were treated with 100 nM hTCTP or YWHAE siRNA for 72 h and fixed in 4% paraformaldehyde. Fixed cells were in blocking solution  for 1 h, then incubated with rabbit anti-FOXO1  diluted in washing buffer  followed by secondary antibody at 4 Supplementary Info


Correction to: BMC Health Serv Res 21, 811 (2021)https://doi.org/10.1186/s12913-021-06462-9Following publication of the original article , the autbold typeface.1. In the first paragraph of the Background section, some content is missing due to a typesetting error. The updated first paragraph is given below and the missing part has been highlighted in which respectively cost Medicare $28 billion (USD 2016) [3] and $8 billion (USD 2018) . In Australia, there are half a million public and private rehabilitation hospital admissions per year [6–8], with the 91,000 public admissions costing the public health care system $1.2 billion (AUD 2015/16) annually . There is also evidence that the cost and demand for inpatient rehabilitation is increasing [9]. This growth is thought to be driven by the ageing population, increasing survival following acute illness and injury, greater comorbidity in patients, and higher expectations of recovery within the general population [9].Globally, inpatient rehabilitation costs are substantial. In the UK, there are 2.2 million NHS-funded inpatient rehabilitation admission across Complex Specialised, Specialist and Non-specialist Services annually, which cost the NHS £858 million (GBP 2018/19) . In the US, Medicare is the main insurer for inpatient rehabilitation within skilled nursing facilities [3] and intensive rehabilitation within hospital settings . There are 2.5 million funded skilled nursing facilities admissions [3] and 408,000 hospital inpatient rehabilitation admissions annually  2. In Table 1 – The Process Evaluation Protocol should be referred to as Reference 35, instead of Reference 36.3. In the Data collection and management section, the third sentence should start with “REDCap” instead of “EDCap”.4. In the second paragraph of the Statistical analyses part in the Data Analysis section, the reference in one sentence needs to be corrected from  to . The updated sentence should be: will be analysed using mixed effects logistic regression, and the change in FIM™ score and utility index will be analysed using mixed effects linear regression.The proportion of people who achieve a MCID of 22 points in FIM™ The original article  has been


This enhancer-driven mechanism is remarkably dynamic and undergoes significant alterations during PCa progression. In this review, we discuss the AR mechanism of action in PCa with a focus on how cis-regulatory elements modulate gene expression. We explore emerging evidence of genetic variants that can impact AR regulatory regions and alter gene transcription in PCa. Finally, we highlight several outstanding questions and discuss potential mechanisms of this critical transcription factor. Androgen receptor (AR)-mediated transcription is critical in almost all stages of prostate cancer (PCa) growth and differentiation. This process involves a complex interplay of coregulatory proteins, chromatin remodeling complexes, and other transcription factors that work with AR at  Prostate cancer (PCa) is one of the leading causes of cancer-related death in men . In almocis-regulatory elements (CREs), the AR recruits coregulators [c-Myc, EVT1, and EIF5A2 (eukaryotic translation initiation factor) [GRHL2 (grainyhead-like transcription factor 2) [DNM1L (dynamin-related protein 1) [SCAP [mTOR  [NFKBIA , an inhibitor protein of NF-κB and p53 [The AR is a 919 amino acids (110 kDa) protein that contains an N-terminal domain (NTD), DNA-binding domain (DBD), and C-terminal ligand-binding domain (LBD) ,13. The gulators , remodelgulators , and othgulators ,18,19,20gulators . These g factor) ,23,24. Wactor 2) ; metabolotein 1) , SREBP (1) [SCAP  and mTORpamycin) ; and tra and p53 .Before the AR binds to DNA, the ARBS is first “primed” by pioneer factor (PF) proteins that interact with heterochromatin and increase chromatin accessibility . Given tKLK3/PSA  gene [KLK3/PSA, demonstrated that AR primarily drives transcription through enhancers rather than promoters [PSMA (prostate-specific membrane antigen) [p21 [AR induces gene transcription by binding to specific CREs in the genome. Identifying the location of ARBS is therefore critical to understand how AR functions. The first ARBS identified were found at the promoter of the rat probasin ,66 and Ken) gene ,68,69. Tromoters ,71. Enharomoters ,73. AR-dantigen)  and p21 en) [p21 . Large-sen) [p21 ,77,78.AR in vitro has been shown to sensitize binding and alter ARBS [FOXA1 expression alter the global chromatin accessibility and generate both pseudo-AR hypersensitivity and an increase in open chromatin ARBS [The AR cistrome, or genome-wide binding sites, is not static, and clinical ARBS display remarkable plasticity and significant reprogramming during both tumor initiation and disease progression . During ter ARBS . Furthertin ARBS . This cotin ARBS ,82. Potein vitro SELEX-seq  with recombinant AR-DBD protein [in situ [in situ AR motifs.ARBS are enriched for a conserved androgen response element (ARE) binding motif that is made up of two 6-bp asymmetrical elements separated by a 3-bp spacer (5′-AGAACAnnnTGTTCT-3′) ,69,83. T protein . Nonethe[in situ . Whole-g[in situ ,78,79,86[in situ , whereas[in situ ,88. Furt[in situ . However[in situ . Our rec[in situ . These fKLK3/PSA and rat probasin expression [BRM/BRG1 mutant cell lines showed limited AR activity at KLK3/PSA and rat probasin enhancers [Once bound to DNA, the AR recruits chromatin-modifying enzymes that stabilize accessibility and provide a platform for coregulators and TFs . This inpression . Overexpnhancers . In ER-mnhancers . The kinCHPT1 (choline phosphotransferase 1) and drive resistance [Once bound to chromatin, AR forms a complex with numerous coregulatory proteins to activate enhancers and alter the expression of target genes  89,110,,112. Thisistance . In addisistance . Althougsistance . For exasistance . Howeversistance . Furthersistance .in vivo [While poorly understood, AR-mediated gene downregulation has been proposed to occur through both direct repression and indirect coactivator sequestering, also known as squelching . In direin vivo ,127. Calin vivo ,129. In in vivo . c-Myc [c-Myc repression by AR is largely independent of AR binding to its target sites and primarily occurs via the redistribution of AR coactivators [c-Myc regulation by histone methyltransferase, DOT1L (disruptor of telomeric silencing 1-like), and AR through an enhancer has also been reported [p53, PTEN (phosphatase and tensin homolog deleted on chromosome 10), and LRIG (leucine-rich repeats and immunoglobulin-like domains). AR inhibits p53 expression, while p53 directly represses the expression of AR by binding to target promoters [PTEN is inversely correlated with AR in PCa tumors, and AR is reported to directly inhibit PTEN expression [LRIG is associated with increased overall survival in PCa cohorts [LRIG expression is also affected by SUMOylation of AR in which small ubiquitin-related modifiers (SUMOs) covalently bind to the AR and alter the downstream transcription events [Regardless of the mechanism, gene downregulation is believed to be important for the growth and progression of advanced stage PCa . Importac-Myc , which hc-Myc . c-Myc rtivators . Furtherreported . Decreasromoters ,137. PI3romoters . Expresspression . Finally cohorts ,141. LRIn events . Interesn events .in vitro annotations and H3K27Ac in clinical PCa samples. Unexpectedly, when these ARBS classes were functionally tested, both inactive and constitutively active enhancers, in addition to inducible enhancers, were frequently required for AR-mediated gene transcription. Supporting this functional role, each ARBS class demonstrated equivalent evolutionary conservation, suggesting that each enhancer type is required for gene transcription [AR primarily drives gene expression through enhancer CREs. Located at euchromatin , enhancecription . Apart fThere is increasing evidence that multiple ARBS work together to drive gene transcription. More than 60% of the AR-regulated genes have >2 ARBS within 200 kb proximity a. For exde novo [de novo loops can be formed through TF interacting structural proteins such as YY1 (Yin Yang 1) [in situ HiC maps of RWPE1, C4-2B, and 22Rv1 cell lines showed that common TADs found in all cell lines were much smaller than those TADs unique to a single cell line [n = 12) and benign prostate tissues (n = 5) demonstrated that, unlike cell lines, there was no significant difference in the number of TADs called or in TAD borders between samples [AR-regulated enhancers are brought in close physical proximity to the target gene promoter by chromatin looping . These Ade novo ,172. Prede novo , whereas Yang 1) ,175. Gen Yang 1) . Work fr Yang 1) . However Yang 1) . A recen Yang 1) . Similarell line . Using “ell line . However samples . CombiniTP53 (tumor protein 53) and PTEN (phosphatase and tensin homolog), as well as prostate-specific recurring mutations such as SPOP (speckle type BTB/POZ protein) and FOXA1 [TMPRSS2 is a prostate-specific AR-regulated gene, whereas ERG is a critical regulator of proliferation, differentiation, and apoptosis [ERG gene expression becomes regulated by AR signaling and is highly expressed in PCa. Similar complex rearrangements between the AR-regulated gene NRF1 and BRAF have also been observed [n-Myc and c-Myc expression have also been attributed to enhancer hijacking of distal enhancers in neuroblastoma [p53 gene separates a well-defined TAD that occurs in normal cells into two distinct TADs, with significant changes in CRE usage [PCa has a relatively low somatic mutation frequency compared with other cancer types . Common nd FOXA1 . Given tnd FOXA1 . Severalnd FOXA1 ,187,188.nd FOXA1 ,190,191,nd FOXA1 . For insnd FOXA1 ,194. Furnd FOXA1 ,196,197.nd FOXA1  and thennd FOXA1 . TMPRSS2poptosis ,200. As observed . n-Myc ablastoma ,203. ChaRE usage . FurtherRE usage . HoweverRE usage . Large-sRE usage ,207. GivRE usage ,209. FurRE usage .There is conflicting evidence for the role of non-coding SNVs in PCa initiation and progression. The vast majority of PCa point mutations are non-coding and found in intergenic (46%), intronic (44%), and promoter (9%) regions . Most ofCurrent PCa therapies target AR through either direct antagonism  or by reducing the synthesis of androgenic steroids  . HoweverIn this brief review, we discuss the mechanism of AR-regulated gene expression in PCa. Numerous studies characterizing the AR cistrome have revealed that the vast majority of ARBS are located at enhancer CREs that regulate the transcriptional activity via chromatin looping. However, while these ARBS are well characterized, there are still many outstanding questions, particularly, related to the expansion of ARBS in CRPC where there is a broad reactivation of early developmental transcriptional processes. There is emerging evidence that ARBS can influence gene transcription even without episomal enhancer activity, suggesting that AR directly or via other TFs can potentially stabilize CRE chromatin interactions and influence transcription. From this perspective, there is a need for additional chromosomal genome organization datasets to improve our understanding of phenotypic events in the different stages of PCa. With high-throughput dataset initiatives such as ENCODE ,219 and