Osteoarthritis is one of the leading causes of disability. Total knee arthroplasty (TKA) is a surgical intervention for patients with severe osteoarthritis. Post TKA rehabilitation is crucial for improving patient’s quality of life. However, traditional rehabilitation has only focused on physical function; a systemic analysis of other dimensions such as social participation and environmental factors of post TKA rehabilitation is lacking. The aim of this study was to develop a core set from the International Classification of Functioning, Disability and Health (ICF) to create a comprehensive rehabilitation program for patients with osteoarthritis post TKA. Before the Delphi-based consensus process, a literature review process was performed for related ICF categories selection. We used a three-round Delphi-based consensus among 20 physical therapists with orthopedic rehabilitation expertise in a university-based hospital. A five-point Likert scale was used to rate the importance of each item. The consensus of ratings was analyzed using Spearman’s rho and semi-interquartile range indices. The ICF core set for post TKA rehabilitation was determined based on a high level of consensus and a mean score of ≥4.0 in the third Delphi-based consensus round. The ICF core set comprised 32 categories, with 13 regarding body function, four regarding body structures, nine regarding activities and participation, four regarding environmental factors, and two regarding personal factors. Our ICF core set for post TKA rehabilitation can provide information on effective rehabilitation strategies and goal setting for patients post TKA. However, further validation and feasibility assessments are warranted. Osteoarthritis (OA) is a leading cause of walking and stair-climbing limitations among older adults, as well as of disability worldwide ,2. PatieDespite significant advancements in surgical and prosthesis placement techniques, numerous patients present a limited range of motion (ROM), pain, limited physical function restoration and impaired quality of life . EffectiThe ICF provides disease classification and a systemic approach to identify health-related problems and conditions. However, it includes over 1450 categories, which limits its clinical application . RehabilThe Delphi-based consensus method was used to determine the core ICF categories relevant to rehabilitation among patients with TKR . All posArticles concerning rehabilitation and TKR were searched using the keywords “osteoarthritis”, “rehabilitation”, and “knee replacement”. All relevant articles in English were included for further evaluation, and quality assessment was performed. The selected articles were then reviewed independently by two reviewers (Huang and Liao), who selected the TKR rehabilitation-related factors. In case of conflict of opinion among the reviewers, a third reviewer (Liou) judged and determined whether the factors should be included. All relevant factors were then defined and linked to TKR rehabilitation categories based on systematic and standardized procedures. Forty-seven factors related to TKR rehabilitation were linked with ICF categories, with 14, 4, 17, and 12 categories belonging to the codes for body function (b), body structure (s), activities and participation (d), and environmental factors (e), respectively [The ICF categories related to post TKR rehabilitation were evaluated over three formal rounds of Delphi-based consensus surveys. From 1 August 2019 to 31 December 2019, Delphi-based consensus surveys were administered to 20 physical therapists with expertise in the orthopedic and sports rehabilitation fields. The therapists were invited to participate through emails containing information on the study aim and consensus methods. The questionnaire was mailed to those who agreed to participate. The first questionnaire contained the second-level ICF codes for potential TKR rehabilitation-related categories and detailed descriptions of these categories. The participants were asked to rate the importance of selected categories in post TKR rehabilitation programs on a five-point Likert-type scale . The results of each item in the first round were considered reference data for the second round, including the participants’ scores, all participants’ mean scores and the participants’ standard deviations (SDs). Based on these results, all participants were requested to reevaluate their previous ratings, all participants’ mean scores, SDs, and rate each item again in the second round. Similarly, the results of each item in the second round were considered reference data when answering the five-point Likert-type scale of each item for the third round. The consensus formation was complete upon completion of the three rounds of the Delphi-based consensus method .p < 0.05 was considered statistically significant. The dispersion of each participant’s score was quantified using the semi-interquartile range (SIQR) by dividing between the third and the first quartiles . SIQRs were calculated for each item; SIQR ≤ 0.5 indicated a high level of agreement. The importance of each item was based on the mean Likert score; categories with a mean score of ≥4.0 in the third round of the Delphi-based consensus were considered the ICF core set. Data analyses were performed using SPSS .To identify appropriate brief ICF core set categories for patients post TKR, we performed serial data analysis. Analysis of the Spearman’s rank correlation coefficient (rho) was performed to compare participants’ scores with the mean scores of all participants for each ICF category over the three rounds of the Delphi-based consensus process. A Spearman’s rho of >0.7 indicated strong agreement between individual participants and all participants of each panel; We recruited 20 physical therapists (11 women and nine men), with expert experience of over five years. All participants completed the three rounds of the Delphi-based consensus. Percentage of agreement and disagreement of importance of ICF core set for post TKA rehabilitation is added in The WHO provided the ICF framework in 2001. Although the ICF provides disease classification and a systemic approach to identify the health-related problems and conditions, it includes more than 1450 categories, hindering effective clinical application . TherefoDespite the post TKA pain relief, patients may continue to present muscle atrophy and ROM limitation, which limit daily living activities such as walking, climbing stairs, squatting and exercise . TraditiIn the aspect of body structures, motion-related structures other than the knee joint, such as the pelvic region, are also critical for post TKA rehabilitation. A study mentioned that trunk control can be improved post TKA . HoweverThe ICF core set included nine categories associated with activities and participation. These categories were as follows: carrying objects (d430), walking (d450), moving around (455), washing oneself (d510), toileting (d530), dressing (d540), participating in remunerative employment (d850) and participating in recreation and leisure (d920). Daily activities and participation are paramount in enabling patients receiving TKA to return to their previous lifestyle and in improving their life quality. Studies have reported that TKA care generally improves the quality of life and leads to favorable functional outcomes ,25. HoweOur TKA rehabilitation core set contained four environment aspect categories, which were as follows: products and technology for personal indoor and outdoor mobility and transportation (e120); design, construction, and building products and technology of buildings for public use (e150); transportation services, systems, and policies (e540) and health services, systems, and policies (e580). We determined that health service and health policy systems were included in the core set in addition to transportation and building technology. Rehabilitation goal-setting can be related to the use of transportation and a safe environment for daily living. Furthermore, health policy support systems were associated with effective rehabilitation post TKA. Transportation and building technologies were related to a higher quality of life after TKA rehabilitation. However, public health medical resources are crucial for post TKA rehabilitation programs. Environmental factors should also be considered to regain function after surgery and thus obtain effective and efficient rehabilitation post TKA.Compared with previous studies about ICF comprehensive core sets with 55 categories for osteoarthritis, which contained 13 categories from the component body functions, six from the component body structures, 19 from the component activities and participation and 17 from the component environmental factors, we presented more concise ICF core sets with 32 categories . CompariThis study reported an ICF core set that was specifically designed for the post TKA rehabilitation program. However, several limitations must be addressed. First, the perception of the importance of post TKA rehabilitation factors could differ among participants of this study. The different circumstances post TKA and rehabilitation intervention periods could cause perceptional variations in the importance of certain ICF categories. To avoid this discrepancy, the situations of patients with TKA were described before answering the questionnaire. Second, participants in the ICF core set were physical therapists, and TKA may be related to various fields of professionals. However, post TKA rehabilitation is mostly performed by physical therapists in our country; we supposed that makes them more familiar with post TKA rehabilitation. Further studies of Delphi process by other fields of professionals are recommended in the future. Third, the feasibility and validity of the ICF core set were not obtained from patients post TKA. The feasibility and validity of patients post TKA under rehabilitation should be investigated to identify clinical applications in the further study. Finally, the participating experts were limited to Taiwan. The opinions of post TKA rehabilitation programs may vary across countries. Nevertheless, we believe that our core set is applicable to patients not only in Taiwan but also those in other countries with similar medical system. However, further study is needed to investigate the feasibility of this core set for those countries with different health care system and environments.Effective post TKA rehabilitation is related to social participation and environmental factors, as well as physical functions. The ICF, a systematic framework, reveals interactions between various dimensions of the rehabilitation of TKA patients. Our Delphi consensus-based ICF core set for patients with TKA can provide information on effective rehabilitation strategies, multidisciplinary team intervention and goal-setting for post TKA rehabilitation programs. Moreover, it could be helpful to develop individualized telerehabilitation program with weight-bearing biofeedback, neuromuscular electrical stimulation and balance control system for outpatient therapy, with personalized intensity and intervention by related professionals under the framework of this core set.


Gamification has become increasingly important both in research and in practice. Particularly in long-term care processes, such as rehabilitation, playful concepts are gaining in importance to increase motivation and adherence. In addition to neurological diseases, this also affects the treatment of patients with musculoskeletal diseases such as shoulder disorders. Although it would be important to assist patients during more than one rehabilitation phase, it is hypothesized that existing systems only support a single phase. It is also unclear which game design elements are currently used in this context and how they are combined to achieve optimal positive effects on motivation.This scoping review aims to identify and analyze information and communication technologies that use game design elements to support the rehabilitation processes of patients with musculoskeletal diseases of the shoulder. The state of the art with regard to fields of application, game design elements, and motivation concepts will be determined.We conducted a scoping review to identify relevant application systems. The search was performed in 3 literature databases: PubMed, IEEE Xplore, and Scopus. Following the PICO  framework, keywords and Medical Subject Headings for shoulder, rehabilitation, and gamification were derived to define a suitable search term. Two independent reviewers, a physical therapist and a medical informatician, completed the search as specified by the search strategy. There was no restriction on year of publication. Data synthesis was done by deductive-inductive coding based on qualitative content analysis.A total of 1994 articles were screened; 31 articles in English, published between 2006 and 2019, were included. Within, 27 application systems that support patients with musculoskeletal diseases of the shoulder in exercising, usually at home but also in inpatient or outpatient rehabilitation clinics, were described. Only 2 application systems carried out monitoring of adherence. Almost all were based on in-house developed software. The most frequently used game components were points, tasks, and avatars. More complex game components, such as collections and teams, were rarely used. When selecting game components, patient-specific characteristics, such as age and gender, were only considered in 2 application systems. Most were described as motivating, though an evaluation of motivational effects was usually not conducted.There are only a few application systems supporting patients with musculoskeletal diseases of the shoulder in rehabilitation by using game design elements. Almost all application systems are exergames for supporting self-exercising. Application systems for multiple rehabilitation phases seem to be nonexistent. It is also evident that only a few complex game design elements are used. Patient-specific characteristic are generally neglected when selecting and implementing game components. Consequently, a holistic approach to enhance adherence to rehabilitation is required supporting patients during the entire rehabilitation process by providing motivational game design elements based on patient-specific characteristics. In Germprovider ,” it is provider . A multiprovider .Today’s situation is characterized by a high number of patients with musculoskeletal diseases of the shoulder, low adherence to long-term therapies, and a resulting enormous financial burden on health care systems. This motivates finding modern solutions for supporting patients during rehabilitation and thus reducing costs. Among other things, health-enabling technologies are being developed, which are defined as “sensor-based information and communication technologies, aiming at contributing to a person’s health and health care as well as to his or her quality of life .” An increhabilitation process, gamification, and motivation. As part of these, this review attempts to answer the following questions:Within this scoping review, information and communication technologies utilizing game design elements will be identified to obtain an overview of the fields of application, the game design elements, and motivation concepts. Accordingly, 3 categories should be analyzed: 1. Rehabilitation ProcessScope: What is the scope of the identified application systems?Phase: In which phase of rehabilitation processes are the identified application systems used?2. GamificationGeneral implementation: How is the concept of gamification generally implemented in the application systems?Game design elements: Which game design elements, that is game components, mechanics, and dynamics, are used?3. MotivationMotivation concepts: Which motivation concepts are addressed?Evaluation and outcome: Which aspects of the application systems are evaluated, in particular, motivation and adherence?The overall aim of this review was to identify and analyze existing technology-based approaches using game design elements to support rehabilitation processes of patients with musculoskeletal diseases of the shoulder. For this purpose, this scoping review was conducted in accordance with the extended PRISMA checklist for scoping reviews (PRISMA-ScR) . Given tIn general, peer-reviewed articles, reviews, and conference articles published between 1997 and mid 2019 were included. For literature not written in English or German, a translator was involved. If, despite all efforts, it was not possible to translate a relevant publication, it was excluded retrospectively. Reviews were only used additionally as part of a citation pearl growing.outcome and comparison were not considered. In terms of population, all publications focusing on patients with musculoskeletal diseases of the shoulder joint were included. This covered patients with following conditions: fractures, dislocations, inflammatory diseases, and degenerative diseases [intervention, all publications describing an application system used to support patients within the rehabilitation process were included. It should be noted that only application systems in which game design elements were used, that is, game components, game mechanics, and game dynamics, were included. Hardware-based systems such as robots, exoskeletons, and orthoses were not considered.The eligibility criteria were determined on basis of the PICO  framework ; howeverdiseases . Due to For a comprehensive overview, we searched 3 databases: the medical literature database Medline via PubMed, the technical research database IEEE Xplore, and the multidisciplinary database Scopus.population  and intervention were crucial for this review. Patients with musculoskeletal diseases of the shoulder are described by various terms  for the shoulder or upper extremities . There was no specific search for musculoskeletal diseases of the shoulder, as it was assumed that these are rarely mentioned explicitly. Intervention describes a variety of different interventions, all of which are subsumed under the term rehabilitation. Rehabilitation ranges from diagnosis and acute treatment to therapy planning, medical, or vocational rehabilitation to subsequent rehabilitation services. Therefore, apart from general terms such as rehabilitation, computer, or technology-assisted therapy, more specific therapeutic terms were searched . Additional terms, such as therapy planning or self-management, were added to allow a more comprehensive search. Technical aspects were considered by a fourth search block including both specific terms such as game, gamification, and exergame, as well as unspecific terms such as virtual and augmented reality. For more details on the search queries see A proper search term was defined iteratively following PICO. According to the objectives, the key elements Following qualitative content analysis , full teThe search request was made to PubMed on June 17, 2019 and to IEEE Xplore and Scopus on June 18, 2019. Overall, the search returned 2595 matches. After excluding duplicates, title screening and abstract screening of the remaining 1994 publications were conducted by 2 independent reviewers  with different expertise—physical therapy and medical informatics. Checking of predefined exclusion criteria was done sequentially. Whenever disagreements arose, a third reviewer (BSa) was consulted for decision making. Thus, a total of 95 publications were included in the full-text screening. Full-text screening was carried out in the same way as the title and abstract screening. Finally, 31 publications were included in the full-text analysis .Qualitative content analysis was performed by a single reviewer (BSt) using the predefined search tree. During the analysis, 17 inductive subcategories were added ; 11 others outlined the target group only vaguely—there were 5 application systems for shoulder injuries, 2 for musculoskeletal shoulder pain, and 4 for musculoskeletal diseases of upper extremities, in general; and the remaining 4 were intended to be used for treatment of musculoskeletal diseases of the shoulder as well as of one of the following diseases: paraplegias with spinal cord injuries , cerebroAll 27 application systems assist in the execution of exercises, mostly physiotherapeutic self-exercises. Of them, 5 were explicitly described as telerehabilitation systems ,29-32. TMost of the application systems were developed for the outpatient sector as part of conservative therapy or subsequent rehabilitation services . Only MaOf the 27 application systems, 24 were based on self-developed software products. Only 3 made use of commercial games, namely Wii Sports ,40; EyeTWhereas 11 publications focus on the implementation of a single, sometimes incredibly broad game ,38,43-48The most frequently used game components are those that are easy to implement, such as points, tasks, avatars, and information messages . When plMost application systems implement training as playful tasks. Apart from being more fun, this is more interesting than doing the same monotonous exercises on a daily basis . In addiNearly all application systems used game components, such as points, progress bars, leaderboards, and achievements to provide feedback or represent a current state . Since aAccording to García-Martínez et al , all impEncouraging motivation, as well as enhancing engagement, is one of several goals of gamification ,57. CertExcept for 3 publications presenting purely application systems or approaches ,47,59, aA previous review  has alreThe few application systems that can be found are mostly exergames supporting physiotherapeutic self-exercises, usually at home (20 of the 27). Application systems to assist prevention, diagnostics, acute treatment, or inpatient rehabilitation seems to be almost nonexistent. The same applies to application systems supporting multiple rehabilitation phases. Here, not even one could be discovered.disease management.There is also little variation in the scope of application systems. All application systems support the training of patients, but only a few can be used to create training plans (8 of the 27), or even, to adjust them during the rehabilitation process (6 of the 27). Also, functionalities for monitoring therapy adherence and progress are quite rare (9 of the 27). Just 2 offer possibilities for monitoring therapy adherence, although adherence is a crucial factor for sustainable rehabilitation success , wherebyAlmost all application systems are based on in-house developed software (24 of the 27). They offer flexibility in terms of the therapeutic needs of patients with shoulder diseases as well as of the game design elements used to enhance motivation and adherence. Selection and implementation of adequate game design elements depend substantially on the target group and its individual characteristics, such as age, gender, personal preferences, level of knowledge, and intrinsic motivation ,42. HoweAnalyzing the application systems in terms of the game design elements used, it is obvious that more complex game components are used only rarely or not at all. Usually, easy to implement game components are selected and combined. Since the realization of game mechanics is based on the game components implemented, even here, little variation is found. Accordingly, 22 application systems used diverse simple game components to provide feedback. Astonishingly, education was also rarely included, although this is a meaningful aspect for patient empowerment. Overall, it seems that only little attention has been paid to the factual effect of individual game components and game mechanics when selecting and implementing them. No publications deal with respective motivation models and theories to demonstrate or prove the effects of single game design elements on user behavior.Almost all application systems had been evaluated. Mostly, this concerned the technical feasibility, efficacy, or acceptance but rarely the motivation and adherence of patients. Factual evidence of increased motivation or adherence caused by the developed application systems or game design elements as part of clinical trials was lacking.There were only a few application systems for the rehabilitation of patients with musculoskeletal diseases of the shoulder using game design elements. Excluding hardware-based systems limited the search considerably. The same applied to the exclusion of publications due to insufficient descriptions of game design elements during title and abstract screening. Here, numerous publications were excluded (n=150). Given an inadequate description of game design elements in the abstract, it is not possible to determine for certain that such elements had not been implemented. However, this indicated that gamification does not have a central role in these publications. For analyses with regard to the motivational effects of game design elements, this is nevertheless, an essential prerequisite.Whereas all screenings were performed by 2 independent reviewers, the qualitative content analysis was done by a single reviewer. A second reviewer might have ensured the correct identification and classification of relevant game design elements, rehabilitation phases, and motivation aspects. Particularly in classifying game mechanics and game dynamics, there is some margin for interpretation. Consequently, it was not possible to provide details on game dynamics in the sense of conceptual structures, such as constraints, emotions, or relationships . Howeverself-management, prevention, and patient pathway was not sufficient. Therefore, a complementary mobile health app analysis is planned using the Google Play Store to examine whether there are other application systems beyond exergames and subsequent rehabilitation services for musculoskeletal diseases of the shoulder.Overall, it is striking that only exergames supporting outpatient or inpatient rehabilitation could be identified. There was just one application system for prevention and one for disease management. This restricted result might be caused by the common meaning of rehabilitation as medical and vocational rehabilitation including subsequent rehabilitation services. Even searching for terms such as The concept of gamification is gaining importance in the context of health care to enhance motivation and support therapy in general. Especially for chronic diseases and thus long-term care processes such as rehabilitation, gamification reveals particular potential. However, for rehabilitation of musculoskeletal diseases of the shoulder, only a few application systems that use game design elements to increase motivation and adherence exist. Beyond that, all identified application systems focus on the support of self-exercises, mainly in the outpatient sector. Application systems for inpatient rehabilitation, other rehabilitation phases, or multiple rehabilitation phases seem to be nonexistent. Only the fewest application systems provide additional functionalities, for example, provision of information or monitoring of adherence to assist patients during rehabilitation and increase their self-management skills. Altogether, the selection, combination, and implementation of game design elements appears somewhat impetuous. Indeed, gamification is generally used to motivate, avoid boredom, and distract from pain and anxiety. But it seems that only a little attention has been paid to the factual effect and thus benefit of individual game components and game mechanics. Furthermore, patient-specific characteristics are mostly neglected when selecting game components. It remains exciting to learn about the effects that future developments will report, including patient-specific game design elements.


Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol  produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC. Prostate cancer (PCa) is the most common non-cutaneous cancer among men. Although it is slow growing, often with no symptoms and being highly treatable in early stages, the American Cancer Society predicts in 2020 that there will be around 33,000 deaths due to PCa . Most of1) and dihydrotestosterone (DHT) (2)  2) , for gro , for gr3), apalutamide (4), or darolutamide is inevitable. Several mechanisms have been attributed to these resistances including overexpression of the AR, mutations in the AR ligand-binding domain (LBD), loss of AR (neuroendocrine PCa), constitutively active AR splice variants (AR-SVs), increase in intratumoral hormonal synthesis, and activation of growth factor pathways [Resistance to ADT such as gonadotropin-releasing hormone agonist or antagonist  results in progression to CRPC. Subsequent or concomitant resistance to AR blocking agents such as the androgen synthesis inhibitor; abiraterone; and/or antiandrogens such enzalutamide (pathways . Over tipathways . The AR-pathways . Notablypathways .3 or abiraterone showed enhanced AR-V7 protein expression [5) [3 or abiraterone treatment in vitro and in vivo [Endocrine therapy-resistant PCa cells generated by chronic treatment with pression ,12. Knocsion [5) , has bee in vivo ,14.Elucidation of the crystal structures of the AR DNA binding domain (DBD) and the LBD provides a new framework for understanding the functions of this receptor and has led to the development of rational drug design for the treatment of prostate cancer. Despite the lack of any specific structural characterization, N-terminal domain (NTD) inhibitors are also in preclinical development.6) and oxandrolone (7) and steroidal antagonists such as cyproterone acetate (8) were approved.Early ligand-based drug design was based on modification of structure of testosterone, the most prevalent endogenous androgen. Starting in the 1930s, many steroidal agonists such as methyltestosterone (1) to DHT (2) as a local amplification of the AR axis in certain tissues such as the skin and prostate [2 and other the steroidal AR ligands [2 bound to the AR via an internalized, i.e., not solvent-exposed, hormone binding pocket (HBP) in the C-terminal LBD.Unfortunately, cross-reactivity with other nuclear hormone receptors, liver toxicity, and inability to separate anabolic (muscle/bone building) from androgenic  activity has limited the utility of steroidal ligands. In the 1960s, it was discovered that 5α-reductase converted testosterone (prostate . Not unt ligands . The end9), was discovered as an AR antagonist in the 1980s [10), were the first in a series of agents termed as antiandrogens, including bicalutamide (11), the first diphenyl nonsteroidal AR ligand [11 in which the sulfonamide of 11 was replaced with thioethers (not shown); however, the thioethers lacked in vivo agonist activity [12), which acted as agonists in anabolic tissues such as the musculoskeletal system (as reflected by the levator ani muscle) and weak partial agonists (or antagonists) of the anabolic tissues such as ventral prostate and seminal vesicles [The first nonsteroidal AR ligand, flutamide  or F876L for 3 or 4), which destabilizes AR, is accomodated by mutation to a smaller amino acid [10) co-crystal structure serves as a representative escape mutation  and DHT (2) to the HBP of the LBD continues to be productive, but antiandrogen resistance via agonist switch and AR truncation  mutations limits their duration of efficacy. Correspondingly, innovative new approaches to provide hormone therapy in CRPC are needed. This review seeks to briefly outline a variety of novel small molecule ligands with AR antagonist activity and/or noncanonical AR binding sites with the goal of stimulating interest in further discovery of noncanonical ligands that may overcome known mechanisms of FDA-approved endocrine therapies.3 or 4 resistance. Another small molecule downregulator is AZD3514 (16), which was demonstrated to bind to AR LBD and downregulate AR. In two phase I clinical trials, moderate anti-tumor activity was observed in CRPC patients as judged by significant PSA declines, but the drug was not well tolerated. Although development was discontinued, 16 provided a rationale for future development of SARD compounds [An emerging alternative approach to relying on competitive binding of the HBP to prevent endogenous androgen action is to downregulate (decrease expression or destroy (destabilize or proteolyze)) the AR, thereby eliminating AR-mediated signaling . Selectiompounds .17) [Galeterone (17)  is a ste17) ,33,34.17)  was developed by Tokai Pharmaceuticals and tested in a phase III clinical trial (ARMOR3-SV) in 2016 for AR-V7-positive mCRPC [17 has poor oral bioavailability, which undoubtedly contributed to its clinical failure in phase III. The multi-targeted lyase inhibitor and direct AR antagonist/SARD 17 is a novel approach that is still in clinical development by the University of Maryland, Baltimore (NCT04098081), with a next-generation lead 18 still in preclinical development [Galeterone  [21 is derived from enzalutamide (3).Nonsteroidal AR ligands offer greater nuclear receptor selectivity as well as being relatively amenable to synthetic modification. Examples of nonsteroidal AR warheads include arm (12) , whereasEarly PROTACs possessed peptide-based linkers, but non-peptide-based linkers are preferred, or various lengths of polymers such as polyethylene glycol (PEG)-based  to connect the warheads. The complexity of PROTAC design has increased as more complex linker segments are now commonly employed (see black atoms in ARD-266 (25) and ARCC-4 (26)).A wide variety of E3 ligase warheads has been explored. A representative sample of four different E3 ligases are shown in AR-targeted PROTACs in 26) is shown here as an exemplary SARD [26) in 3 as the AR ligand and VHL as the ubiquitin ligase, thereby targeting AR to the protease for degradation. ARCC-4 (26) was able to degrade AR in VCaP cells  to ETS-related gene (ERG)) translocation) at 5 nM with maximal degradation of 98%. ARCC-4 (26) was able to degrade wtAR and a variety of escape mutants with nanomolar potencies including F876L (confers resistance to 3 and 4) [11)) [11) [9), glucocorticoids, and progesterone) [9, glucocorticoids, and progesterone) [26, PROTACs tend to be large compounds that do not comply with standard rules for oral bioavailability, and thus attaining this broad scope of antiandrogen activity in vivo may be difficult. Another disadvantage with PROTACs, assuming full oral bioavailability, is the limitation of requiring an LBD  to destroy the AR, indicating that AR-SVs may not be destroyed by these PROTACs. Lastly, PROTACs do not eliminate the possibility of PR- or GR-mediated AR-axis signaling, referred to as AR bypass resistance. A reportedly orally bioavailable SARD whose structure is undisclosed, ARV110, developed by Arvinas, was initiated in phase I trials in 2019 in a late-stage mCRPC patient population, and recently released an interim data update . Dose escalation of ARV110 produced PSA responses at 280 mg, and at 420 mg attained sufficient exposure to have antitumor effects as judged by analogy to preclinical models. Two of five patients (40%) with H874 or T877 mutations had PSA reductions >50% compared to 2 of 15 wtAR patients, supporting testing of a molecularly defined late-line patient population. Additionally, Arvinas is considering testing in a less pre-treated population. This data established the proof-of-concept that it is possible to have clinical efficacy with an orally active AR-directed PROTAC; however, the high dose (420 mg) to achieve efficacious exposures in contrast to the low nanomolar preclinical potencies suggests that pharmacokinetic (PK) properties could be improved.Many AR-degrading PROTACs exist, however, ARCC-4  , W741L (4) [11)) , M896V (1)) [11) , T877A (sterone) , H874Y (sterone) ,51, and sterone) . As illu9) was less potent than bicalutamide (11), and both were susceptible to resistance due to AR overexpression. Enzalutamide (3) and apalutamide (4) could overcome AR overexpression and demonstrated the novel ability to inhibit nuclear translocation of the AR; however, all these antiandrogens were susceptible to escape mutations [Two generations of (competitive) antiandrogens have been approved, and with each new approval, the scope of antiandrogen activities was expanded and/or antiandrogen potencies improved. For example, flutamide  activating function (AF)-2 and (2) binding function-3 (BF-3) sites that reside in the LBD, DBD sites include (3) the DNA recognition helix  and (4) The LBD consists of the C-terminal residues from 676 to 919 and, in addition to the internal HBP, also possesses the AF-2 function, which forms an external binding surface for interactions with co-regulatory proteins recruited upon agonist binding. The noncanonical LBD inhibitors have had weak antiandrogen potencies but nonetheless provide novel ways to modulate the AR axis by directly blocking (AF-2 inhibitors) or modulating (BF-3 inhibitors) the protein–protein interactions that occur between AF-2 and its cofactors . Direct 31), an exemplary small molecule inhibitor of the AF-2 site, was discovered on virtual screening for ligands that bind to the AF-2 site. IMB-A6 (31) demonstrated the ability to inhibit binding of co-factor PELP-1 (proline-glutamic acid- and leucine-rich peptide) at 10 µM range (noncompetitive with HBP ligands) [32), was shown unequivocally by X-ray crystallography to bind the BF-3 domain [32) was recently tested in a model of spinobulbar muscular atrophy (SBMA), a neurodegenerative disorder in males characterized by expanded length CAG trinucleotide repeat (long poly-Q tract). In SBMA, the long poly-Q tract results in toxic neurodegenerative effects upon androgen stimulation of defective AR. MEPB (32) caused increased recruitment of co-repressors such as nuclear receptor corepressor (NCoR) to the AF-2 domain and ameliorated neuronal loss, neurogenic atrophy, and testicular atrophy in a mouse model of SMBA, validating AF-2 modulation as a potent androgen-sparing strategy for SBMA therapy [IMB-A6 (ligands) . Another3 domain . MEPB  or LBD truncations . A theoretical disadvantage is that the DBD is the most conserved domain between steroid receptors, and thus obtaining steroid receptor selectivity might be challenging.33), which suppressed PSA expression comparable to enzalutamide (3) (0.17 μM vs. 0.12 μM) in LNCaP cells [Characterizing DBD by X-ray crystallography provided structures that facilitated the discovery of surface-exposed regions of the AR that might serve as a noncanonical ligand binding site. In silico virtual screening of residues S579 to K610 identified candidate molecules that were effective at abolishing transcription in LNCaP cells . ScreeniaP cells .33 and 3 again displayed similar potency (0.340 μM vs. 0.314 μM) [3 but not by 33, supporting the proposed binding site. VPC14449 (33) fully inhibited wtAR at 5 μM but only partially affected estrogen receptor at 15 μM and did not affect glucocorticord receptor or progesterone receptor at <25 µM, demonstrating surprising nuclear receptor selectivity (similar to 3). On the basis of this in vitro characterization, the researchers deemed 33 to be a useful prototypical DBD inhibitor and was tested in models of CPRC [In an artificial in vitro transcriptional activation assay, .314 μM) . To vali of CPRC  such LNC34)) [35)) [Two separate groups are developing antiandrogens that bind to the AF-1 region. Mutational analysis has revealed two regions in the NTD, encoded by amino acid residues 141-338 (transcription activation unit (Tau)-1) and 380-529 (Tau-5), to be essential for this transcriptional activation, being termed as the AF-1 . AR has 34))  and tau-)) [35)) . Deletio)) [35)) . In cont)) [35)) . Binding)) [35)) .34 was discovered in 2010 in vitro assays. Unlike bicalutamide (11), these antagonists had noncompetitive activity as judged by the lack of a right shift with increasing concentrations of an agonist such as R1881 and were not able to displace fluoromone from the HBP  [38 was the active component of a mixture of hydroxyl group epimers, irreversibly bound to the N-terminal domain of the AR via the 20S chlorohydrin [38 inhibited AR-V7-dependent genes, i.e., genes shown to be uniquely upregulated by AR-V7 and not AR-FL [34 was tested in patients that had failed enzalutamide (3) or abiraterone therapy, finding only a reduction of PSA by <30% for a short period of time. Further, very high doses of up to 3.6 g were required. Due to the poor pharmacokinetics, the trial was stopped. This was interpreted as a proof-of-principle but insufficient potency and drug exposure  to inhibit the heterogenous and resistant ARs present in this difficult-to-treat patient population, and new agents were prepared.A new generation of androgen receptor antagonists including the HBP) , supportrohydrin , and wasot AR-FL . Althoug39), a semi-synthetic sulfonamide NTD antiandrogen derived from the bisphenol A (37) nucleus, was reported to provide synergistic activity in AR-V7 PCa when combined with the canonical antiandrogen 3. A very recent new drug, EPI-7386 (structure unknown), has been characterized preclinically in VCaP and several other xenografts. EPI-7386 demonstrated a significant inhibition of VCaP tumors in castrated mice with a tumor growth inhibition of close to 100%. ESSA Pharma reported the compound to have entered clinical trials (NCT04421222) for PCa. The reported irreversibly binding NTD inhibitor mechanism of the EPI series, if preclinical activities translate to the clinic and sufficient bioavailability is possible, suggests broad scope AR antagonism in prostate cancers expressing escape and/or truncation mutant; however, poor pharmacokinetics of this template suggest that AR overexpression may be difficult to overcome. Phase I dose escalation trials are expected to end in 2022.Compounds from this template with 20-fold greater potency and improved pharmacokinetics have been reported . For exa40) was one of the first natural products reported to block the NTD transactivation of the AR in prostate cancer cells [41. Another agent, niphatenone B (42), was isolated from the marine sponge Niphates digitalis that represents a novel structural class of AR antagonist. Research found that 41 binds covalently to the AF-1 region of the AR NTD and blocks the proliferation of prostate cancer cells that are dependent on functional AR, and many analogs have been prepared and examined [Sadar et al. have also reported chemically unrelated natural products that interact with the NTD. For example, sintokamide A , or antiandrogen bicalutamide (11), these were full-antagonists with a tertiary amine or nitrogenous B-ring that were discovered to be SARDs. Leads inhibit and degrade a broad scope of expressed ARs to include wtAR, all point mutations tested, and all AR-SVs tested. These molecules bind to the LBD and NTD of AR, but are believed to target AR for degradation via the NTD binding site [3) [A series of NTD-binding compounds emerged from propanamide structure–activity relationship studies. Unlike the structurally similar SARM, enobosarm   resistan35) . Despite having reduced AR inhibitory potency, 35 was found to possess improved pharmacokinetic properties such that in vivo activity was observed. Subcutaneously administered 35 reduced tumor weights and degraded full-length AR and AR-SV (AR-V7) in 22RV1 cells, unlike 3, and further suppressed PSA in LNCaP (T877A) tumors [These metabolic liabilities were eliminated by cyclicizing the amine into a series of indoles and indolines , exempliBiophysical interaction experiments using NTD-only peptides co-incubated with these SARDs and monitored by NMR, fluorescence polarization, and the like ,77,78, h45) (low affinity for LBD (>10 µM in purified LBD); 199 nM inhibition of wtAR), which was the first well-characterized orally bioavailable SARD from this group [45 has low binding affinity to LBD but maintained AF-1 binding as supported by steady-state fluorescence emission spectra. Like previous SARDs, 45 requires the tau-5 region of AF-1 for promoting AR degradation through the ubiquitin proteasome pathway to degrade both AR-FL and AR-SVs [In order to improve oral bioavailability and reveal the pharmacodynamics possibilities accessible with an NTD-directed SARD, the same research group developed and reported the second generation of these SARDs, which nearly maintained potency but dramatically improved in vivo efficacies . A serieis group ,79. Unlid AR-SVs .50 in the low nanomolar range, preferably below 50 nM) and high efficacy (>70%) degradation of both AR-FL and AR SV. Similar to the indoles discussed above, these studies demonstrated that the stronger the electron-withdrawing moiety is on the pyrazole ring, the more potent the AR inhibitory activity, with the potency order of 46  > 47  > 48  > 49  > 45 , but SARD efficacy did not necessary correlate with these AR-FL inhibitory activities (IC50). Disubstitution of the pyrazole ring was tolerated without loss of AR inhibitory potency and possibly enhanced bioavailability, as exemplified by 50 . Research showed that 50 retained high potency AR inhibition (IC50 of 84 nM) and was among the highest efficacy degraders of the pyrazole template with greater than 70% degradation of both AR FL and AR SV at 1 and 10 µM. By comparison, 45 was a less potent wtAR inhibitor (199 nM) but was a full efficacy degrader of AR-FL and AR-SV. We have listed the compounds that are in clinical and preclinical development in SAR studies of these pyrazol-1-yl-propanamides successfully improved potency while retaining oral bioavailability. NTD SARDs were screened in vitro for high potency inhibition of wtAR  or NTD-binding AR ligands also have the ability to degrade AR-FL or AR-SV, providing additional advantages in AR axis suppression over traditional canonical antiandrogens. The field of noncanonical inhibitors and SARDs have exerted AR antagonism profiles commensurate in scope to the function of the site blocked , but are


Objective: Co-occurrence of chronic psychotic disorders and substance use disorder (SUD) is clinically challenging and increasingly prevalent. In 2000, legislation was passed in Israel to foster rehabilitation and integration in the community of persons with mental health disorders. In 2010, the need to allocate resources for patients with these co-occurring disorders (COD) was officially recognized. Yet, most rehabilitation services were not specifically designed for COD. This study examines the relationship between duration of community rehabilitation and number of psychiatric hospitalization days among persons with/without COD in Israel.Methods: Data from the National Psychiatric Case Register on 18,684 adults with schizophrenia/schizoaffective disorders hospitalized in 1963–2016, was merged with data from the Israel Mental Rehabilitation Register. Associations and interactions between COD-status (COD/non-COD), time-period , duration of housing or vocational rehabilitation on hospitalization days per year were analyzed using repeated-measures ANOVA.Results: The proportion of non-COD chronic psychotic patients who received rehabilitation services increased from 56% in Period1 to 63% in Period2, as it did among COD patients—from 30 to 35%. The proportion of non-COD patients who received longer-duration vocational rehabilitation (≥1 year) was significantly higher (43%) than among COD patients (28%) in both time periods. For housing rehabilitation, these proportions were 79 and 68%, respectively. Persons with COD experienced more hospitalization days annually than non-COD patients. Duration of rehabilitation (less/more than a year) was inversely associated with annual number of hospitalization days (p < 0.0001). This pattern was noted in both COD and non-COD groups and remained significant after controlling for age, sex, COD group, percent of hospitalizations with SUD, and age at first hospitalization.Conclusions: COD patients with prolonged rehabilitation seemingly achieve long-term clinical improvement similar to non-COD patients, despite most rehabilitation settings in Israel not being designed for COD patients. Yet, COD patients receive overall less rehabilitation services and for shorter periods than non-COD patients. Long-term rehabilitation services should be provided to COD patients, who may need more time to commit to treatment. To achieve better long-term mental health improvements, a continued expansion of community-based integrative treatment and rehabilitation services for COD patients is needed in Israel. One-fourth to two-thirds of patients with schizophrenia in the US and in Europe have a co-occurring Substance Use Disorder (SUD) –6. AnalyThe co-occurrence of schizophrenia/schizoaffective disorder and SUD  is often characterized by a chronic relapsing course of illness. The recurrence or worsening of the SUD can also trigger relapse of a psychotic episode . SUD worThe positive effect of community rehabilitation services on patients with severe mental illness, and schizophrenia in particular, has been widely reported –19. CommCommunity Rehabilitation of Persons with Mental Disability Law was enacted in Israel in the year 2000 with the aim to foster “the rehabilitation of persons with mental health disorders and their integration in the community, in order to enable them to attain the maximal degree of functional independence and quality of life, while maintaining their dignity.” This law initiated a reform in hospitalization services with the aim of reducing the number of psychiatric hospital beds alongside the establishment of community rehabilitation services, which began operating in 2001.The Of the rehabilitation services offered , vocational and housing rehabilitation are the most common, offer the greatest support and are usually the longest in duration. The aim of housing rehabilitation is to enhance social and housekeeping skills for independent-living in the community, by means of finding suitable and dignified housing conditions, with provision of support and on-going contact with community services. Vocational rehabilitation services promote finding and maintaining employment adapted to the wishes and capacities of the individual . RehabilUntil recently no rehabilitation services were available for persons with co-occurring disorders of severe mental illness (SMI) and SUD, and those with active drug use were generally denied services. It was only in 2010 that the Israeli parliament officially recognized the need to allocate additional resources for patients with COD . These rEnactment of the Community Rehabilitation law lead to the opening of private community-based rehabilitation services regulated and funded by the Ministry of Health  and was Regrettably, the treatment of addictions and the care of COD patients of SMI and SUD were excluded from the mental health reform of 2015. Patients with COD remained under the responsibility of the Ministry of Health, and are not entitled to receive treatment for their disorders from their HMO . Thus, tThe present study, the first in Israel, examines the relationship between mental rehabilitation in the community and hospitalization characteristics of people with chronic psychotic disorder with and without SUD. We hypothesized that the rate of COD (comorbid chronic psychotic disorders and SUD) patients receiving rehabilitation services will be lower than that of non-COD patients, and that rehabilitation will be associated with a decrease in the number of hospitalization days over time for both groups, with a more substantial decrease among those without SUD.Data were extracted from Israel's Mental Rehabilitation Register (IMRR) and merged with the National Psychiatric Case Register (NPCR) of the Ministry of Health. The NPCR is the official register of all psychiatric admissions and discharges countrywide since 1950 . As descFor each hospitalization, a SUD diagnosis is recorded based on an ICD-10 diagnosis of F10–F19 in the categories of dependence and abuse (excluding F17—nicotine dependence) and/or a psychiatrist-documented indication of alcohol and/or drug abuse at admission or discharge. Patients were classified as COD if they had a SUD diagnosis in two or more hospitalizations, or in at least 20% of their hospitalizations.Each person's hospitalization history was documented from his/her first hospitalization until the end of 2016. A total of 18,684 patients with 168,377 hospitalizations were included in the analysis after exclusion of 29 patients who had an anomalous number of hospitalizations (≥80).1) and 2010–2016 (Period2). We divided the periods before and after 2010, the year in which the Israeli parliament officially recognized the need to allocate additional resources to treat patients with COD  and the total length of time the person actually received the service in each of the two time periods 2001–2009  and in Period2 (2010–2016)] and mean annual number of hospitalization days were assessed using χ2 and t-tests, as appropriate. Repeated measures ANOVA was used to track changes in hospitalization variables across the two time periods. Multivariate ANCOVA modeling for mean hospitalization days per year was performed to identify predictors including rehabilitation length, age, age at first hospitalization, sex, COD-status and percent of hospitalizations with SUD. Statistical significance level was set at p < 0.05 to help guide interpretation of the results. The data were analyzed using IBM® SPSS® Statistics, version 24.0.Associations between the independent variables [COD-status and length of housing/vocational rehabilitation in Periodp < 0.0001). The rate of vocational rehabilitation service approval was identical in both groups (93%).Of the 18,684 persons with a psychiatric hospitalization between 2001 and 2016, 28.8% had a co-occurring disorder . The CODp < 0.0001). In both groups, an increase over time was observed. Among patients without COD, 35% received rehabilitation services in Period1 and this rate increased to 56% in Period2, and among patients with COD the rehabilitation service rate increased from 30 to 48% across the two time periods .As seen in Overall, non-COD patients also received vocational rehabilitation for longer duration than COD-patients. 43% of people without COD who received vocational rehabilitation for more than a year in both periods, compared to 28% of people with COD . Also, 11 and Period2, duration of rehab was inversely associated with annual number of hospitalization days. As seen in 1 the mean number of hospital days was lowest among those who did not receive any rehabilitation, whereas in Period2 those who received more than 1 year of rehab experienced the fewest hospital days per year. COD-status was also significantly associated with hospitalization days—the mean number of hospitalization days/year was consistently higher among those with COD. Comparing Panel A and Panel B, a decrease in hospitalization days from Period1 to Period2 was noted only among those who received rehabilitation over a year. People who received vocational rehabilitation experienced fewer hospitalization days than people with housing rehabilitation .People without COD received housing rehabilitation for longer periods−79% of people without COD who received housing rehabilitation, received rehabilitation for more than a year in both periods, compared to 68% of people with COD. Also, 2% of people without COD received housing rehabilitation for less than a year in both periods, compared to 6% of people with COD (p < 0.0001). Having received vocational rehabilitation for <1 year in either Period1 or Peroid2 was associated with a greater number of hospitalization days per year in 2010–2016 .People without COD received vocational rehabilitation for longer periods−43% of people without COD who received vocational rehabilitation received rehabilitation for more than a year in both periods, compared to 28% of people with COD. Also, 18% of non-COD people received vocational rehabilitation for less than a year in both periods, compared to 28% of people with COD (p < 0.0001). Numer of hospital days was independently associated with percent of hospitalizations with SUD (p = 0.025) and with male sex (p < 0.0001), and inversely associated with age at first hospitalization (p < 0.0001). Age at time of the study was not associated with annual number of hospitalization days.The association between mean number of hospital days and rehabilitation remained significant upon controlling for age, sex, COD group, percent of hospitalizations with SUD, and age at first hospitalization. Multivariate ANCOVA modeling revealed a significant independent association between mean hospitalization days per year during 2010–2016 and COD-status  of persons without COD and slightly over half (56%) of those with COD received rehabilitation services. The increase in the proportion of people receiving rehabilitation services reflects the development of the rehabilitation system in Israel, which over the years has recognized the need to expand rehabilitative care in the community, thus opening more rehabilitative frameworks. These findings are consistent with previous reports regarding the growth of community rehabilitation services in the country , 37.The percentage of people without COD who qualify for rehabilitation services was significantly greater than those with COD, although the difference is not large. We expected, in light of our clinical experience, a much larger disparity in rehabilitation eligibility in favor of persons without COD. In addition, until recently, and during most years of the current study, there was a declared policy of the Rehabilitation Committees of not providing services to people with active drug use . SeveralAnother possibility of the described discrepancy is related to the definition of the COD group in our study . We found that people from the COD group who received rehabilitation services, had SUD recorded in less than half of their hospitalizations. Approval for rehabilitation services might have been granted during hospitalizations without active SUD, whereas in other hospitalizations with active drug use, rehabilitation services were refused.In addition, hospital therapists who submit the patient to the Rehabilitation Committee may not always fully disclose drug use information when the use is not very intense (even in the presence of SUD diagnosis), out of a concern that the information would cause the Committee to reject the request for rehabilitation services.1 and/or Period2, had on average fewer hospitalization days annually in Period2 than those who received rehabilitation for <1 year. This finding corresponds with worldwide studies, including in Israel, which show that community rehabilitation services are associated with fewer hospitalization days and less frequent hospitalizations among people with schizophrenia (Our results indicate that persons who received rehabilitation for a longer duration (a year or more) in Periodophrenia –23.The finding that people who did not receive rehabilitation services had fewer days of hospitalization than people who received rehabilitation is surprising at first glance. A possible explanation for this could be better underlying clinical condition or stronger support from family or other sources, which enable these persons to manage in the community without rehabilitation services. Indeed, the group who did not receive services includes a small proportion (<10%) whose application for rehabilitation services was refused.The finding that those who received rehabilitation services for a short duration had, on average, more hospitalization days compared to people with longer rehabilitation, can be easily understood. People who dropped out from the rehabilitation setting may have been discharged from the hospital before a sufficient improvement was achieved and thus were not yet able to adapt to a rehabilitation community setting. It is also possible that joining a new therapeutic framework in the community posed a stressor they could not easily overcome, thus leading to a clinical exacerbation and re-hospitalization. Another explanation could be that some clinical or personality characteristic made it difficult for them to cope with the rehabilitation requirements and to benefit from the rehab services, and these same characteristics had an impact on the higher frequency of hospitalizations and greater number of hospitalization days per year.1 and then received longer rehabilitation in Period2, experienced fewer days of hospitalization. At the same time, the possibility of an underlying confounding clinical or personality characteristic, as mentioned, or higher levels of intrinsic motivation and better family relationship  were already diagnosed with SUD in PeriodIn addition, in our study, COD is defined as a SUD diagnosis present in at least two hospitalizations or in at least 20% of each patient's hospitalizations rather than the more commonly used “lifetime” or first-hospitalization SUD definition. We believe this enhances the COD diagnostic validity (specificity) as it describes a chronic comorbid drug use pattern. Indeed, on average, a SUD diagnosis was documented in more than half (54%) of all hospital admissions amongst those classified as COD. We did not adopt stricter COD criteria  out of a concern that the secondary SUD diagnosis may be under-recorded, as has been noted in other countries . FurtherTwenty-nine individuals with more than 80 hospitalizations were not included in the analyses. The decision to exclude them stemmed from an impression that the excessive numbers of hospitalizations might have been due to double reporting. Regrettably, the data for these individuals is unavailable and we are unable to rerun the analyses with them included to assess the impact of the exclusion. We believe the impact is negligible given the small number excluded.1 (2001–2009) and Period2 (2010–2016) may introduce some measure of confounding by factors differentially distributed across the two time periods. The periods were defined in accordance with the study objective to assess the government's decision to allocate additional resources toward the treatment and rehabilitation of persons with COD. We are unaware of any substantial temporal changes in treatment or quality of services, beyond the expansion of rehabilitation services. Defining the unit of analysis for number of hospital days as “per year” rather than per period, will have minimized the effect of any such confounding.Lastly, the unequal duration of PeriodIn summary, the results of our study show that people with COD appear to have the potential for significant rehabilitation when given the opportunity. Also, it seems that at least some people with COD can go through a prolonged rehabilitation process in the community even in settings that are not specifically designed for people with SUD. However, persons with COD are less likely to remain in rehabilitation for prolonged periods. Findings of this study show that when rehabilitation is prolonged and lasts for at least a year, there is a significant reduction in hospitalization days. These findings reinforce the clinical importance of sustained rehabilitation for people with COD, for whom longer rehabilitation may be required to commit to rehabilitation and to attain clinical stabilization than for persons without COD. It is likely that if rehabilitation frameworks are dedicated for people with COD, those with even more severe SUD may benefit from rehab and will be less likely to drop out early. The process of expanding the rehabilitation services designed for COD patients should be accelerated and more healthcare providers should be trained in evidence-based practices for COD. As this process continues to evolve, we will likely see a significant improvement in the clinical condition of these patients over time and in their ability to manage and re-integrate in the community, and as a result their need for hospitalizations is expected to decline.reuven.eliahu@moh.gov.il) Data Security Office, Ministry of Health.The datasets analyzed in this study were obtained from the Ministry of Health of Israel. Access to the data is highly restricted due to the sensitive nature of pyschiatric patient data. Requests to access these datasets should be directed to Mr. Reuven Eliyahu (All the authors designed the study. SF wrote the first draft of the manuscript. TB-A designed the methods for data analysis. YN and PR proofed and revised the manuscript. All authors contributed to the article and approved the submitted version.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.


PRPF6 also promotes expression of AR-FL and AR-V7. Moreover, PRPF6 depletion reduces tumor growth in prostate cancer-derived cell lines and results in significant suppression of xenograft tumors even under castration condition in mouse model. Furthermore, PRPF6 is obviously highly expressed in human prostate cancer samples. Collectively, our results suggest PRPF6 is involved in enhancement of oncogenic AR signaling, which support a previously unknown role of PRPF6 during progression of prostate cancer and castration-resistant prostate cancers.Androgen receptor (AR) and its variants play vital roles in development and progression of prostate cancer. To clarify the mechanisms involved in the enhancement of their actions would be crucial for understanding the process in prostate cancer and castration-resistant prostate cancer transformation. Here, we provided the evidence to show that pre-mRNA processing factor 6 (PRPF6) acts as a key regulator for action of both AR full length (AR-FL) and AR variant 7 (AR-V7), thereby participating in the enhancement of AR-FL and AR-V7-induced transactivation in prostate cancer. In addition, PRPF6 is recruited to  Prostate cancer is one of the leading causes of male cancer-related deaths worldwide AR gene. AR-Vs are constitutively active and predominantly distributed in the nucleus, allowing them to drive gene transcription independent of ligand binding AR enhancer, AR amplification, overexpression of AR co-regulators, and generation of AR-Vs AR pre-mRNA and/or AR genomic structural rearrangement AR acting as a hormone inducible transcription factor is a member of the nuclear receptor superfamily. Full-length AR (AR-FL) mainly consists of ligand-independent activation function (AF-1) and ligand-dependent activation function (AF-2). By alternative splicing process, C-terminal truncated variants of AR (AR-Vs) are generated from In eukaryotic cells, mature messenger RNAs are formed by splicing from nascent precursor messenger RNAs, which is operated by spliceosomes cis-regulatory elements in AR target genes and associates with JMJD1A to enhance AR-induced transactivation. PRPF6 also promotes expression of AR-FL and AR-V7. Moreover, PRPF6 depletion reduces tumor growth in prostate cancer-derived cell lines and results in significant suppression of xenograft tumors even under castration condition in mouse model. Furthermore, PRPF6 is obviously highly expressed in human prostate cancer samples. Taken together, our results demonstrate that PRPF6 is involved in enhancement of oncogenic AR signaling, which provides an insight to potential therapeutic strategies for prostate cancer, especially for CRPC.Here, our results have demonstrated PRPF6 acts as a key regulator for action of both AR-FL and AR-V7, thereby participating in the enhancement of AR-FL and AR-V7-induced transactivation in prostate cancer. In addition, PRPF6 is recruited to Luciferase reporter plasmids and expression plasmids of Myc-tagged PRPF6, AR-FL and AR-V7 were described previously The antibodies used in this study were: anti-PRPF6 , anti-AR , anti-MLL1 , anti-JMJD1A , anti-PSA , anti-FASN , anti-UBE2C , anti-H3K4me3 , anti-H3K9me2 , anti-H3K36me3 , anti-FLAG , anti-Myc , anti-β-Actin (Proteintech 60008-1-Ig), anti-GAPDH . Other reagents used in this study were: normal mouse IgG , normal rabbit IgG . Transfections of plasmids and siRNAs were performed according to manufacturer's instructions of jetPRIME reagents (Polyplus-transfection). Charcoal/dextran-stripped serum (CSS) was prepared from fetal bovine serum  according to the standard protocol.Human PCa cell line LNCaP, CWR22Rv1 and VCaP were obtained from Kunming cell bank of Chinese Academy of Sciences, and were identified using PCR-STR analysis. LNCaP, CWR22Rv1 and VCaP cells were cultured in Roswell Park Memorial Institute medium 1640  with 10% (v/v) FBS (CLARK). HEK293, cells were cultured in Dulbecco's modified Eagle medium , and supplemented with 10%FBS. LNCaP-AI cells were cultured in media with 5% CSS. For the experiments with DHT stimulation, cells were cultured in medium with 5% CSS. Cells were incubated in a humidified incubator containing 5% CO2 at 37°C.For RNA interference (RNAi), chemically synthesized small interfering RNAs siRNA duplexes were purchased from Sigma (Sigma-Aldrich). The sequences of siRNAs targeting PRPF6 were: siPRPF6 1# 5'-GAGAAGATTGGGCAGCTTA-3', siPRPF6 2# 5'-GAUCUAAAUGACACCAAUU-3'. The sequence of negative control siRNA (siCtrl) was 5'- UUCUCCGAACGUGUCACGUTT -3'. For lentivirus-delivered RNAi, lentiviral productions targeting the same sequence as siPRPF6 1# were purchased from Shanghai GeneChem Company and performed following manufacturer's instructions.In dual-luciferase reporter assays, cells were co-transfected with the listed constructs. After 24 hrs, cells harvested and lysed in passive lysis buffer. Luciferase activities were analyzed by dual-luciferase reporter assay system using GloMax Multi Jr detection system (Promega). Firefly luciferase activity was normalized to the activity of control renilla luciferase. Data represent the mean ± SD from three experiments.For immunoprecipitation, equal protein amounts of the extracted whole cell lysates were immunoprecipitated with specific antibody or control IgG. The immunoprecipitated complexes were analyzed by western blot.Cells were fixed by paraformaldehyde and blocked in donkey serum albumin. Then cells were incubated with primary antibody and subsequently FITC- or Cy3-conjugated secondary antibody (Jackson ImmunorRsearch Labs Inc). Nuclei were stained with DAPI (Roche).Total RNA was extracted using TRIzol reagent (Thermo Fisher Scientific). cDNA synthesis was carried out with PrimeScript RT reagent kit with gDNA Eraser (TaKaRa), and then analyzed by SYBR Premix Ex Taq kit (TAKARA) according to the manufacturer's instructions in LightCycler96 system (Roche). Relative expression of genes was normalized by 18S rRNA. Data represent the mean ± SD of triplicate real-time PCR. Sequence of primers were list ed in Supplementary RIP experiments were performed using control IgG or antibodies using RIP assay kit  according to manufacturer's protocol. The immunoprecipitated RNA were converted to cDNA and quantified by real-time PCR. ChIP experiments were performed as previously described For growth curve assays, cells were seeded into 96-well plates at indicated densities. After indicated times, viability of cells were evaluated using the MTS assay (Promega) with the absorbance at 490 nm. For colony formation assays, cells were maintained in medium for indicated times, then cells were fixed with paraformaldehyde and stained with coomassie blue dye.5cells were suspended in 100ul medium with half Metrigel (BD Biosciences) and injected subcutaneously into the 6-week-old male NOD/SCID mice with or without castration operation. Tumor size were measured by electronic caliper and the volume were calculated according to the formula: Volume=(π/6)×(width×length)3/2. 21 or 27 days after inoculation, mice were killed in keeping with the policy of the humane treatment of tumor bearing animals.Animal works were approved and supervised by the Animal Ethics Committee of China Medical University. 5×10Formalin-fixed paraffin-embedded sections of PCa tissues and adjacent non-cancerous tissues were obtained from the first hospital of China Medical University. Ethical approval for sample collection and tissue use was approved by the Human Research Ethics Committee of China Medical University. A total of 162 tissues, including 20 PCa tissues without matched adjacent non-cancerous tissues, and 71 pairs of PCa and matched adjacent non-cancerous tissues, were collected to perform IHC staining. IHC experiments were performed as previously described t-test was used with Prism Graphpad program. SPSS software was used to analyze results of IHC. Student's t-test was used to determinate the significant difference between immunohistochemical expression of PRPF6.To determinate the significant difference in results of real-time PCR, dual-luciferase reporter assays and xenograft tumor growth assays, Student's To investigate the physiological role of PRFP6 in prostate cancer, we examined the endogenous protein expressions of PRPF6 in four cultured prostate cancer-derived cell lines as indicated Figure A. These in vivo tumor growth analysis in a mouse xenograft model with CWR22Rv1 cells. Results showed that PRPF6 knockdown reduced tumor burden, with smaller volumes and slower growth rate of the xenograft tumors  motifs. In addition, we generated expression plasmids encoding PRPF6 truncated mutants Figure . Our resWe next performed a series of luciferase assays to investigate the function of PRPF6 on AR-mediated transcription. By employing three luciferase reporter systems, including ARE-luc, MMTV-tk-luc and PSA-tk-luc reporters, we demonstrated that PRPF6 significantly enhanced AR-FL-mediated transactivation in the presence of DHT Figure A-3C. FurPSA, kallikrein related peptidase 2 (KLK2), fatty acid synthase (FASN), transmembrane protease serine 2 (TMPRSS2), UBE2C, bone morphogenetic protein type IB receptor (BMPRIB), ELOVL fatty acid elongase 5 (ELOVL5), 15‐hydroxyprostaglandin dehydrogenase (HPGD), solute carrier family 45 a3 member (SLC45A3), and acid phosphatase 3 (ACPP). Rea-time PCR results showed that lentivirus-mediated PRPF6 knockdown resulted in a significant decrease in the expression of 9 AR target genes, including PSA, KLK2, FASN, TMPRSS2, UBE2C, BMPRIB, HPGD, SLC45A3 and ACPP with DHT treatment in LNCaP cells  on its target genes to induce target gene transcription upon the treatment of androgen. We thus turn to examine the recruitment of PRPF6 or AR on the e Figure A. A growAR target genes to maintain the active chromatin state, subsequently promoting AR-mediated transcription.We then turn to ask whether PRPF6 associates with histone methyltransferase or demethylase to coactivate AR-mediated transactivation. It has been reported that JMJD1A, which is a histone H3K9 demethylase, acts as a coactivator for AR by epigenetic regulation of histone H3K9me marks AR itself transcription. In order to assess the effect of PRPF6 on endogenous expression of AR, we knocked down PRPF6 expression using two specific siRNAs targeting different sequences of PRPF6. In LNCaP cells, mRNA level of AR-FL was reduced after PRPF6 knockdown  AR transcription in clinical prostate cancer tissues (Figure Having revealed the involvement of PRPF6 in AR signaling and growth of prostate cancer cells, we next examined the expression of PRPF6 in clinical prostate cancer samples. In good agreement with upregulation of AR-FL and AR-Vs expression by PRPF6 Figure , we founs Figure A. We thes Figure B. The sts Figure C. Furthes Figure D. These cis-response elements on AR target genes, thereby modulating histone modification level and enhancing AR-induced transcriptional activity. On the other hand, PRPF6 promotes the expression of AR-FL and AR-V7 (Figure It has been demonstrated that several splicing factors are upregulated and drives the progression of prostate cancer CSF1JMJD1A functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks In line with the previous report that transactivation domain of PRPF6 exists within 78-495 aa residues AR genomic structural rearrangement AR-V7 couples with transcription of AR gene AR-FL and AR-V7 transcripts are often tightly correlated in individual clinical specimens and xenograft models AR-V7 splicing. U2AF65 and SRSF1 act as 'pioneer' factors, directing the recruitment of the spliceosome and increasing the expression of AR-V7AR-V7 expression by regulating the alternative splicing of ARcis-regulatory elements on AR gene to enhancing the transcription of AR gene itself, thereby promoting the expression of AR-FL or AR-V7 (Figure AR-V7 generation could be facilitated by aberrant splicing and/or In summary, our results have demonstrated that PRPF6 regulates oncogenic AR signaling pathway in prostate cancer-derived cell lines, PRPF6 depletion reduces tumor growth of prostate cancer-derived cell lines even under the castration condition in mice, and PRPF6 is highly expressed in clinical prostate cancer samples. Our data support a previously unknown role of PRPF6 during prostate cancer progression, which may provide an insight to potential therapeutic strategies for prostate cancer, especially for CRPC.Supplementary figures and tables.Click here for additional data file.


Aortic regurgitation (AR) may lead to left ventricular (LV) dilatation, cardiac arrhythmias and heart failure. Close follow-up of horses with AR is therefore paramount to detect onset of cardiac decompensation. The aim of this study was to examine whether two-dimensional speckle tracking (2DST) can be used to detect altered myocardial function in horses with chronic AR compared to control horses. Speckle tracking was performed on short axis and long axis images of the LV in 29 healthy Warmblood horses and 57 Warmblood horses with AR. Radial, circumferential and longitudinal strain, strain rate and displacement were measured for each segment separately and the average was calculated over all segments. Data generated from the apical segments were not included in the analysis.Radial (SR) and circumferential (SC) strain were significantly higher in horses with moderate AR  but not in horses with severe AR , compared to control horses . Longitudinal strain did not show significant differences, but longitudinal displacement (DL) was larger in horses with moderate (average DL 29.5 ± 4.1 cm) and severe AR (DL 32.4 ± 6.1 cm) compared to control horses (DL 25.7 ± 4.0 cm), especially in the interventricular septum. Diastolic longitudinal strain rate was lower in early diastole in horses with severe AR (0.93 ± 0.18/s) compared to controls (1.13 ± 0.13/s).2DST is able to detect altered myocardial motion in horses with AR, which showed significantly higher radial and circumferential strain. Further research is needed to determine whether these findings contribute to a more accurate diagnosis and prognosis in clinical cases. Aortic regurgitation (AR) is quite common in horses, especially in older animals . In most2D speckle tracking (2DST) is an ultrasound technique that tracks speckles in the myocardial wall and allows evaluation of radial, circumferential and longitudinal wall deformation in horses. The technique has been shown to be feasible in horses, although diastolic measurements show a higher variability than systolic measurements –12. 2DSTThe aim of this study was to investigate whether 2DST is able to detect changes in radial, circumferential or longitudinal LV function in horses with different stages of AR severity, compared to healthy control horses.Descriptive statistics of all groups are listed in Table S of the LVFW was higher in horses with moderate AR. SC of the cranial LVFW was significantly higher in horses with moderate AR.Table E and SrCE were significantly lower in horses with severe AR compared to the control group. SrRE and SrRA showed no significant differences.In Table This study examines the ability of 2DST to detect altered myocardial function in horses with different stages of AR severity compared to control horses. In horses with moderate AR, radial and circumferential strain were significantly higher compared to healthy horses. In horses with severe AR, the radial and circumferential strain values did not differ from control horses, but the early diastolic longitudinal strain rate was significantly lower.Speckle tracking is an ultrasound technique that allows quantification of the myocardial strain in two dimensions by tracking the speckles in the ultrasound image. The manually determined ROI is automatically divided in segments and the software calculates deformation of the wall for all segments separately and for the global ROI. The software algorithm is designed to analyse images obtained in human patients. For longitudinal function, a human apical image algorithm is being applied to a parasternal long axis image at nearly 90 degrees to the apical plane. For radial and circumferential function, the LV segment designations are assigned by the algorithm based on the human heart orientation which is different from the equine anatomy. The effect of these differences is unknown as the commercial software algorithms are undisclosed. In addition, segmental measurements could be influenced by alterations of LV geometry or loading. Therefore, the clinical value of segmental strain and strain rate values remains unknown. These indices of myocardial deformation might indicate both effects of ventricular loading, as well as changes in myocardial contractility.Speckle tracking allows evaluation of the longitudinal function of the LV and the feasibility of the technique in horses was demonstrated . In humaHorses with moderate to severe AR did have a larger longitudinal displacement, however the difference was only significant in the IVS. This is probably a result of the increased ventricular length in horses with AR. Systolic radial strain increased significantly in all segments, especially in horses with moderate AR. This is in accordance with results from a study using tissue Doppler imaging  and mighE was not significantly different from control horses. This probably results from the combined effects of age and AR. Horses with AR were significantly older than control horses and with increasing age the ventricle becomes stiffer and less compliant, resulting in a slower early filling (lower SrLE) [E [E was found and this might be an indication of onset of decompensation. However, without an age matched control group no definite conclusions can be drawn. Averaged diastolic radial strain rates showed no significant differences, however measurement of SrRE and SrRA have been demonstrated to have a moderate variability and thus results should be interpreted with caution [Previous studies have demonstrated a moderate to high variability for diastolic segmental measurements with 2DST , 11. 2DSer SrLE) –22. AR iSrLE) [E . In hors caution .This study was intended to screen for variables that might be of interest for detecting myocardial dysfunction in horses with AR. Therefore a large number of variables was included, which may lead to false positive results. A post-hoc Bonferroni correction was applied to correct for multiple comparisons, but results should be interpreted with caution and more research is needed to determine the clinical usefulness of the variables that showed significant differences in this study. Ideally, a longitudinal follow-up study should be performed to evaluate which variables have prognostic value to predict further LV dilatation, ventricular arrhythmias and/or heart failure.The main limitation of our study was the significant difference in age between the horses with AR and the control horses, which reflected the fact that horses usually develop AR at older age. This may have confounded our results, since several indices of myocardial function might be age dependent –23. A reHorses were divided in groups of different AR severity partially based on subjective criteria. Currently, there is no gold standard for quantification of AR in horses. The criteria used in this study are commonly used in clinical practice , but migThe last limitation is related to the 2DST technique. Adequate image quality is paramount for accurate tracking of the speckles. The software also performs extensive smoothing of the curves , 26. Vis2DST is able to detect altered myocardial movement in horses with AR. Radial and circumferential function show more significant differences than longitudinal function. Further research is needed to determine whether these findings contribute to a more accurate diagnosis and prognosis in clinical cases.This is an observational cross-sectional study. All horses involved were privately owned horses. Twenty nine healthy Warmblood horses  aged 8 ± 4 years with a bodyweight (BW) of 566 ± 48 kg represented the control group. These horses were recruited prospectively. In order to be included, control horses had to be deemed healthy according to their owner and trained regularly. The AR group consisted of 57 Warmblood horses with AR  aged 15 ± 6 years with a BW of 548 ± 68 kg, presented at the Faculty of Veterinary Medicine  for cardiac examination. All control horses and 35 AR horses were also included in previous studies [Physical examination including thoracic auscultation was performed in all horses to exclude other cardiovascular and respiratory diseases. The study was approved by the ethical committee of the Faculty of Veterinary Medicine and Bioscience Engineering . Owner informed consent was obtained for all horses.After the study, all horses were discharged from the hospital.Echocardiography was performed in all horses without sedation, using a GE Vivid 7 Dimension ultrasound with 3S phased array transducer  at a frequency of 1.6/3.2 MHz with simultaneous recording of an electrocardiogram. Images were stored for off-line analysis.Standard 2DE, M-mode and color flow Doppler images were recorded. Horses with AR were not included if they had more than mild regurgitation of another cardiac valve. Valve regurgitation was subjectively graded taking into account the jet duration, the number of images in which the jet was visible and the area of the receiving chamber covered by the jet . For 2DSOff-line analysis was performed using dedicated software . For each image, 3 cardiac cycles were analyzed and then averaged. End-diastole was defined as the peak R wave on the ECG. To evaluate the longitudinal LV wall deformation, the right parasternal four-chamber long axis images were analyzed and the region of interest (ROI) was set by tracing the LV endocardial border from the septal insertion of the mitral valve until the insertion point on the lateral myocardial wall. The width of the ROI was set to cover the myocardial wall but not the epicardium  scaled to a BW of 500 kg . The scoStatistical analysis was done using commercially available software . Distribution of all variables was verified by evaluation of the residuals by visual inspection, the Kolmogorov-Smirnov test and Shapiro-Wilk test. Levene’s test for equality of variances was performed to check homogeneity of variance across groups. Variables with normal distribution and homogeneous variances were evaluated by one-way ANOVA with Bonferroni correction to compare means of the four groups . A non-parametric Kruskal-Wallis test with post-hoc pairwise comparison using the Dunn test was applied to compare all non-normal distributed variables. Level of significance was 0.05.Variables with normal distribution are reported as mean ± standard deviation (SD), non-normally distributed variables are reported as median (range).Additional file 1. Scoring method for AR severity.


Chemotherapy-induced polyneuropathy (CIPN), one of the most severe and incapacitating side effects of chemotherapeutic drugs, is a serious concern in breast cancer therapy leading to dose diminution, delay, or cessation. The reversibility of CIPN is of increasing importance since active chemotherapies prolong survival. Clinical assessment tools show that patients experiencing sensorimotor CIPN symptoms not only do they have to cope with loss in autonomy and life quality, but CIPN has become a key restricting factor in treatment. CIPN incidence poses a clinical challenge and has lacked established and efficient therapeutic options up to now. Complementary, non-opioid therapies are sought for both prevention and management of CIPN. In this perspective, we explore the potential that digital interventions have for sensorimotor CIPN rehabilitation in breast cancer patients. Our primary goal is to emphasize the benefits and impact that Virtual Reality (VR) avatars and Machine Learning have in combination in a digital intervention aiming at (1) assessing the complete kinematics of deficits through learning underlying patient sensorimotor parameters, and (2) parameterize a multimodal VR simulation to drive personalized deficit compensation. We support our perspective by evaluating sensorimotor effects of chemotherapy, the metrics to assess sensorimotor deficits, and relevant clinical studies. We subsequently analyse the neurological substrate of VR sensorimotor rehabilitation, with multisensory integration acting as a key element. Finally, we propose a closed-loop patient-centered design recommendation for CIPN sensorimotor rehabilitation. Our aim is to provoke the scientific community toward the development and use of such digital interventions for more efficient and targeted rehabilitation. Breast cancer remains the most prevalent chronic disease in women, with a predicted 5 million new cases reported annually and among those with higher survival rates . Following the initial diagnosis, the increasing number of survivors for relatively long periods highlights the need for adequate supporting rehabilitation interventions. Chemotherapy-induced polyneuropathy(CIPN) is among the most severe side effects of many regularly used chemotherapy drugs with a direct impact on the autonomy and quality of life of patients –3 with iThese studies have laid the foundation for using technology in assessing, monitoring and controlling sensorimotor deficits associated with CIPN. Yet, none of them considered whole-body kinematic assessment of deficits and closed-loop deficit compensation. Our perspective sheds the light on the possibility to use commodity digital technologies, such as Virtual Reality (VR) and Machine Learning (ML), in combination, for personalized CIPN sensorimotor rehabilitation. We discuss the applicability of such a digital intervention facilitating motor deficits  in breast cancer patients.We start our perspective by evaluating the impact chemotherapy has upon patient's sensorimotor system. We briefly introduce the typical metrics in sensorimotor deficits assessment and motivate the need kinematics assessment. Afterwards, we analyse the rehabilitation facilitating effects that VR offers, highlighting aspects, such as validity, multisensory integration, and neuroplasticity. Finally, we consolidate this thesis and propose a patient-centered design recommendation for CIPN sensorimotor rehabilitation.CIPN defines the harm to the peripheral nervous system experienced by a patient who has been administered a neurotoxic chemotherapeutic agent. The substances that most frequently cause CIPN in breast cancer are: vinca alkaloids, taxanes, and platin derivates.Independent of the mechanisms of action, the targeted impact of such agents is on axonal transmission , 23, 24 Joint deficits and dysfunction in the sensorimotor domain due to neurotoxicity can influence everyday activities, including gait, posture, and induce falls , 30. AnyIn rehabilitation, the severity of such sensorimotor effects induced by CIPN is traditionally measured with subjective scales, such as the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) and the European Organization for Research and Treatment in Cancer Quality of Life Quest CIPN 20/30 (EORTC QLQ—CIPN 20/30) . Their aContinuous monitoring after initiation of a neurotoxic intervention is critical for the formation and advancement of CIPN related symptoms . A largePhysical training can attenuate CIPN symptoms and reduce deficits manifested in both sensory and motor domains. Streckmann et al. supports such hypothesis by evaluating the adaptations of the neuromuscular system through EORCT-QLQ-CIPN20, FACT/COG-Ntx and a batch of sensorimotor exercises . MoreoveProviding a richer depiction of patient's motion parameters, the next level in CIPN sensorimotor rehabilitation focuses on the use of wearable sensors in physical training , 17, 19.Targeting a closed-loop approach, the most advanced rehabilitation systems to date look at interactive motor adaptation training programs based on wearable sensors and visual animation . Such apVR enables a rich patient-centered and patient-tailored interaction with the virtual environment via tools, such as head mounted devices which require less set-up and effort than would be needed to train a patient for a rehabilitation routine in the real environment . MoreoveHuman perception of motion and bodily self involves multisensory integration, with vision playing an especially important role –58. The In this final section, given the generous frame we already unfolded, we provide a concept VR system for CIPN sensorimotor rehabilitation. Our aim is to provoke the scientific community to develop and use digital technologies for efficient patient-centered rehabilitation interventions.The conceptual architecture depicted in Such an architecture has the potential to influence multisensory processes in the brain that account for both the perception of the surrounding space and self-motion. We hypothesize that this is possible through a series of processes that can also account as effects of VR stimulation, namely: the predictive adaptation of internal models, motion memory as adaptation to a changing body and optimal feedback control, respectively.Under CIPN, peripheral nerves controlling muscles and tendons stiffness change, altering the kinematic and dynamic coupling between motor commands  and motion of the limb . Along such progressive variations, the patient's body dynamics change. Hence in order to maintain a desired level of performance, the brain needs to be “robust” to such changes. This robustness may be attained through continuous update, or adaptation, of the internal kinematic model that predicts the sensory consequences of motor commands.Human brains exhibit patterns of learning and forgetting. Such processes unfold over different timescales where motion memory is consolidated as a consequence of the adaptation to a changing body. Chemotherapy neurotoxic effects, induces such changes in both sensory and motor systems. When considering sensorimotor rehabilitation, if a patient performs a task and observes an error, the brain tries to estimate the source of the error and to evaluate if the sensory encoding is still valid or exposed to aberrations.Our perspective is that under VR stimulation the patient's brain can act as a feedback compensator for sensorimotor deficits. This view taps into a core postulate of sensorimotor learning, namely optimal feedback control. In this framework, based on previously acquired experience, the brain computes a time-varying mapping from its internal states  into actions that minimize a total expected cost of responding to the incoming sensory input. Such learnt mappings/associations are essential to tune future motor responses to sensory information and, implicitly, compensate for eventual deficits.Virtual environments facilitate the transfer and generalization of sensorimotor learning into the physical environment. Transfer is promoted if the avatar engagement with the virtual environments is equivalent to that expected in the physical world and the patient cognitive processing involved in task completion similar to the one required in the physical instantiation. Validating this hypothesis yields kinematics assessment and at the same time a rich multimodal stimulation.Such a system could bring unique advantages through cost reduction for the clinics and an easy deployment for home-based rehabilitation. This offers an important advantage to the patients that will not need to visit the clinic often, rather focus on their daily lives allowing the system to non-intrusively monitor and learn their deficits and adaptively compensate for them. Our belief is that such a digital intervention holds the promise of offering truly personalized rehabilitation for life after cancer through a unique combination of technologies, such as VR and ML.CA and DK contributed the conception and design of the perspective. CA wrote the first draft of the manuscript. DK wrote the sections of the manuscript. All authors contributed to the manuscript revision, read, and approved the submitted version.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.