This review intends to observe those perspectives through three different lenses: the goal and type of interaction, the physical implementation, and the sensorimotor pathways targeted by robotic devices. The ways that researchers approach the problem of restoring gait function are grouped together in an intuitive way. Seeing robot-assisted rehabilitation in this unique light can naturally provoke the development of new directions to potentially fill the current research gaps and eventually discover more effective ways to provide therapy. In particular, the idea of utilizing the human inter-limb coordination mechanisms is brought up as an especially promising area for rehabilitation and is extensively discussed.Stroke affects one out of every six people on Earth. Approximately 90% of stroke survivors have some functional disability with mobility being a major impairment, which not only affects important daily activities but also increases the likelihood of falling. Originally intended to supplement traditional post-stroke gait rehabilitation, robotic systems have gained remarkable attention in recent years as a tool to decrease the strain on physical therapists while increasing the precision and repeatability of the therapy. While some of the current methods for robot-assisted rehabilitation have had many positive and promising outcomes, there is moderate evidence of improvement in walking and motor recovery using robotic devices compared to traditional practice. In order to better understand how and where robot-assisted rehabilitation has been effective, it is imperative to identify the main  Stroke is typically caused by a long-term lack of oxygen to the brain through a blood vessel bursting or clotting. Since this event usually occurs on one side of the brain, the effects are generally seen on the contralateral half of the body in the form of hemiparesis. This partial paralysis is common after stroke and makes a significant impact on daily life. After initial onset, recovery in the early stages is crucial to mitigate the long-term effects of stroke. More people are in need of stroke rehabilitation every year, and the cost for post-stroke patients with a need for continuous care is still high and projected to substantially increase in the next decade  signals  has been proposed to implement electrical excitation directly onto the muscle. When coordinated, induced muscle contractions can be useful for drop-foot prevention  depolarizes cortical nerve membranes and discharges groups of neurons by an induced magnetic field near the cortex of the brain , shown in An example of how this categorization could lead to new methods and approaches is illustrated in visual) while walking on a split-belt treadmill with body-weight support , is experiencing unexpected unilateral walking surface stiffness perturbations (error augmentation), that specifically evoke contralateral leg responses (inter-limb coordination mechanisms) by disturbing proprioceptive and balance feedback mechanisms (equilibrioception). Preliminary results with these tools suggest that muscle and brain activity is evoked on one leg when the stiffness of the walking surface for the other leg is perturbed (Skidmore et al., According to the protocol followed in this study, a subject wearing a virtual reality headset (The above combination of methods and approaches is not unique, and by no means exclusive to what needs to be included in a comprehensive approach in gait rehabilitation. Ideally, selection of approaches ought to be done in the context of a review of gaps and weaknesses found in the empirical evidence. These gaps can be identified using the categorization of approaches this paper introduces. More specifically, In conclusion, this paper provides a potential solution to the overwhelming number of gait therapy methods based from the need for utilizing the methods that work and combining them in organized ways to produce new methods, which can potentially have improved outcomes. An example of using this categorization to come up with new methods for rehabilitation, such as perturbation-based approaches using inter-limb coordination mechanisms, is demonstrated. However, this is only one of the possible seeds of new approaches that could sprout from this framework. The authors strongly believe that this new perspective of mixing and matching hardware, procedures, algorithms, and intended neural pathways could lead to more focused research and eventually significant advances in lower-limb robot-assisted stroke rehabilitation.BH and PA contributed conception of the paper. BH organized the database of the references included and wrote the first draft of the manuscript. PA wrote sections of the manuscript. All authors contributed to 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.


This study aimed to evaluate the prognostic role of AR-V7 in terms of prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) in CRPC patients treated with novel hormonal therapy (NHT)  or taxane-based chemotherapy (Docetaxel and Cabazitaxel).A comprehensive literature search was conducted on PubMed, Embase, and the Web of Science from inception to February 2020. Studies focusing on the prognostic values of AR-V7 in CRPC patients treated with NHT or chemotherapy were included in our meta-analysis. The OS and PFS were analyzed based on Hazard ratios (HRs) and 95% confidence intervals (CIs). Furthermore, Odds ratios (ORs) and 95% CIs were summarized for the AR-V7 conversion after treatment and the PSA response.The AR-V7 positive proportion increased significantly after NHT treatment , however, it declined after chemotherapy . AR-V7-positive patients showed a significantly decreased PSA response rate after NHT  but not statistically significant for chemotherapy . Notably, PFS  and OS  were worse in AR-V7-positive ttreated with NHT. Similarly, AR-V7 positivity correlated with poor prognosis after chemotherapy as evidenced by shorter OS  and a significantly shorter PFS .NHT treatment increased AR-V7 positive proportion whereas chemotherapy decreased it. Moreover, AR-V7 positivity correlated with lower PSA response, poorer PFS, and OS in CRPC treated with NHT, and shorter OS in patients receiving chemotherapy. Taxane-based chemotherapy (Docetaxel and Cabazitaxel) and novel hormonal therapy (NHT) such as Enzalutamide and Abiraterone have been proven to improve overall survival (OS) and possess favorable safety profiles in metastatic castration-resistant prostate cancer (mCRPC) , 2. The via several mechanisms. Previously, high expression of AR-V7 was linked to NHT resistance, but its expression level declined after chemotherapy  The study reported on CRPC and AR-V7; 2) The results were expressed as a positive rate in percent of AR-V7 before and after treatment in CRPC. Other included results were the PSA response rate, PFS, or OS after NHT or chemotherapy; 3) The results were reported from clinical trials including RCTs and nonrandomized studies. Studies were excluded if: 1) treatment was neither novel hormonal therapy nor chemotherapy, or not clearly mentioned; 2) studies reported only the AR-V7-positive proportion before or after treatment in CRPC patients; 3) studies lacked results of therapy response rate, PFS, or OS; 4) studies involved non-human subjects; 5) studies were published in languages other than English except when a translation was provided; 6) case reports, comments, editorials, letters, or reviews. Notably, when more than one publication was retrieved from the same trial, the most recent or most complete report was used.1) The following baseline patient characteristics were collected for each eligible trial: age, tumor stage, Gleason score, baseline PSA and alkaline phosphatase, and the median time from diagnosis to sampling. 2) The description of the study design included the author’s name, year, country, study design, type of therapy, description of interventions, and outcome measures. 3) The number of patients assigned to different treatment regimens and follow-up duration. 4) The AR-V7-positive percentage before and after treatment in CRPC samples and the methods of detection. 5) The number and proportion of patients with therapy response to NHT or chemotherapy and its detailed definition. 6) The prognosis outcome data were the hazard ratios (HRs) with 95% confidence intervals (CIs) and P-values of PFS, detailed in the subgroup analysis of NHT or chemotherapy. 7) For OS, HRs with 95% CIs and P-value, detailed in the subgroup analysis of NHT or chemotherapy.2 statistic. Odds ratio (OR) and hazard ratio (HR) estimates were weighted by the Mantel-Haenszel method. The pooled effect was calculated using either the fixed effects model (I2 < 50%) or the random-effects model (I2 ≥ 50%) based on heterogeneity level. All statistical tests were bilateral with a significance p value of 5%.Summary statistics were generated using Review Manager Software . All patients were included and analyzed on an intention-to-treat basis. The AR-V7-positivity conversion after treatment and the association between AR-V7 expression and the response rate of NHT or chemotherapy were assessed. The primary endpoints of the meta-analysis were OS and PFS. Patients were grouped by AR-V7 status and compared in terms of the PSA response rates, PFS, and OS after NHT or chemotherapy in CRPC. The summary measure for OS and PFS was HR (95% CI). Statistical differences among studies were evaluated using the chi-square test and the IArticle selection process is shown in Nine trials including 897 patients were used to compare AR-V7 conversion after treatment. Their clinicopathological features are listed in 2 = 71%, P<0.001), and thus a random-effects model was used. The proportion of AR-V7 positivity significantly increased after Abiraterone or Enzalutamide treatment  whereas, it significantly declined after chemotherapy .A total of 897 patients from nine trials were enrolled. Of note, 154 out of 433 patients were AR-V7 positive before treatment, however, the proportion converted to 243 out of 464 after treatment. Subgroup analysis of different treatment strategies was performed Figure 22 = 0.0%, P=0.80). In subgroup analysis, the OR of a PSA response in AR-V7-positive CRPC was 0.07  for Abiraterone-treated group, 0.06  for Enzalutamide group, and 0.14  for Abiraterone or Enzalutamide subgroup. Similarly, 65 out of 165 AR-V7 positive patients showed therapeutic response to chemotherapy whereas, in AR-V7 negative patients, the proportion was 48.5% (83 of 171), .In total, 61 out of 347 AR-V7-positive men showed good response to NHT whereas, 544 out of 985 AR-V7-negative CRPC showed good response to PSA  where a random effect model was applied for this analysis. Further subgroup analysis revealed that AR-V7 positive patients had worse PFS following Abiraterone treatment , Enzalutamide treatment , and Abiraterone/Enzalutamide treatment . However, patient with AR-V7-negative status tended to have a better PFS although not significantly , , therefore, the fixed-effects model was applied.AR-V7 negative patients benefited more from NHT in terms of PFS compared with the positive patients , , thus a random effect model was applied. Further subgroup analyses indicated that AR-V7 positive patients had a worse OS after Abiraterone treatment , Enzalutamide , and Abiraterone/Enzalutamide treatment . For patients who received chemotherapy, AR-V7 positive patients had a worse OS than negative patients ,  mRNA , 18, 20.The different conversion of AR-V7 expression after NHT and chemotherapy indicates different treatment mechanisms. These findings show that taxane-based therapeutic combination may be effective against drug resistance in CRPC , particuFurther analysis showed that, among patients who received NHT, the PSA-response proportion was lower in AR-V7-positive patients than negative. This indicated that AR-V7 could potentially predict NHT resistance. In our previous study, taxane-based chemotherapy tended to be highly beneficial than NHT in AR-V7 positive patients whereas the efficacy of NHT and taxane in AR-V7 negative patients was similar . Recent Sub-analysis was carried out to delineate the association of AR-V7 expression with the PFS and OS. The NHT group was further sub-classified into Abiraterone, Enzalutamide, or a combination of both. Of all patients receiving NHT, AR-V7-positive patients had worse PFS and OS than AR-V7-negative patients. Since the first report by Antonarakis et al. that AR-V7 in CTCs was associated with NHT resistance and poor survival in CRPC patients , 11, theThis study is limited by the different comprised sample sizes ranging from 14 to 277 patients, and the statistical power is restricted by the following: First, small sample size and limited follow-up time of some studies would yield less reliable results due to the size effect. The risk of publication bias among the studies cannot be ignored. We plotted low statistical power trials in We attempted to minimize these limitations. First, we performed a comprehensive systematic literature search on major online databases with a reproducible strategy to minimize publication bias. Second, although selection bias could not be eliminated, strict inclusion criteria were applied to minimize bias caused by different AR-V7 test assays, treatment response definition, and therapy history. Third, a subgroup analysis was performed according to different therapies and it was reported that the correlation between AR-V7 and therapy outcomes was consistent across the subgroup stratified by NHT and chemotherapy. Fourth, the type of trial, tumor stage, AR-V7 test assay, therapy strategy, prior-treatment PSA, and surveillance time are detailed in tables for further analysis and reference. Biomarkers that provide accurate prognostic information for CRPC are urgently required. Several randomized clinical trials (RCTs) have indicated the benefits of early inclusion of docetaxel to androgen deprivation therapy in hormone-sensitive metastatic prostate cancer –57. BesiThe significant prognostic value of AR-V7 in CRPC patients treated with NHT or chemotherapy was determined in this meta-analysis. The AR-V7 expression significantly increased after NHT but remarkably decreased after chemotherapy. Moreover, AR-V7 positive CRPC patients portend worse prognosis of NHT with a lower therapy response, poorer PFS, and OS. Besides, for chemotherapy, AR-V7 positive patients acquired fewer benefits of prognosis with a lower PSA response, shorter OS, and a nearly significantly worse PFS. Based on these results, AR-V7-positive CRPC should be considered as a specific subtype with a worse prognosis and be treated with a highly active anti-tumor therapy. Furthermore, the AR-V7 status should be consistently monitored and AR-V7 targeted therapy strategies are needed. However, cross-institutional studies are still needed to validate AR-V7 as a selection treatment marker. Future studies should aim to improve AR-V7 detection to validate the clinical utility in CRPC.All datasets presented in this study are included in the article/ZW: project development, data collection, data analysis, manuscript writing. HS: data collection, data analysis, manuscript writing. NM: data collection, data analysis. QL: data collection, data analysis. YM: data collection, data analysis. CW: project development, manuscript editing. LX: project development, manuscript editing. 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.


We report a case of a 61-years-old woman in remission of psoriasis for 20 years. She presented recurrence of psoriasis in the form of plaques few days after taking L-methylfolate 15mg/day. The L-methylfolate was prescribed as an adjuvant for the treatment of depression in a patient with the methylenetetrahydrofolate reductase gene polymorphism (MTHFR). Folate, a B vitamin, is essential to the brain for noradrenalin syntheses, serotonin, and dopamine. Three forms of folate are commonly used: folic acid, 5- methyltetrahydrofolate  and folic acid. The BH4 is a pterin that acts as a mandatory cofactor for the activity of hydroxylase phenylalanine, tyrosine hydroxylase and tryptophan hydroxylase, which catalysis the initial stages of degradation of phenylalanine in the liver, therefore, as well as the limitation stages of biosynthesis of dopamine neurotransmitters and serotonin.The biologically activated form of folate, the L-methylfolate, is the only folate metabolism that cross the blood-brain barrier, and regulate the formation of tetrahydrobiopterin cofactor (BH4).Because folate performs a crucial role in the central nervous system, it is believed that individuals with reduced levels can achieve higher rates of depression and poor response to antidepressants treatment.Individuals with polymorphism of MTHFR gene of C677T and A1298C types, both associated with metabolism or folate absorption, may better benefit from 5-MTHF, instead to the folic acid.versus placebo.Some findings add to evidences that implicate in methylation disorders of nervous system in biology of some forms of mental disease. In a sample of 123 psychiatric patients (diagnostic of higher depression or schizophrenia), 41 had borderline deficiency or defining folate (serum folate below 200µg/L). In this double-blind placebo study a total of 15mg daily of L-methylfolate was administered for 6 months, in addition to the psychotropic coadjuvant treatment. Patients presented significant clinical and social recovery to the use of L-methylfolate Other studies added 5-MTHF to antidepressant to people with low folate concentration or to individuals whose depression did not respond to drugs. The increase of folate during treatment with antidepressant may improve the efficacy of antidepressant not responding and allows that those that responded partly to the monotherapy with antidepressant to reach abetter response.Psoriasis, common inflammatory systemic disorders, affects mainly the skin and nails and, occasionally, joints. The prevalence of psoriasis in different population ranges between 0 and 12%.Methotrexate drug has been indicated for erythrodermic psoriasis, moderate to severe arthropathic psoriasis, acute pustular psoriasis, severe plaque psoriasis or disabling psoriasis and to cases with poor response to phototherapy and/or retinoids.There are suggestions in the published literature that L-methylfolate may cause reduction of efficacy of methotrexate for treatment of psoriasis, such as the case of a 53-yeard-old man who presented worsening of psoriasis after it had solved almost completely 2 years before, although under continuing therapy with methotrexate. In addition, he had recurrence of psoriatic lesions and new psoriatic lesions covering 80% of his body, approximately 4 to 5 weeks after the beginning of L-methylfolate 15mg daily for depression treatment.Hospital Israelita Albert Einstein , and registered under the protocol number 3.930.986 and CAAE: 30171919.2.0000.0071.Study submitted and approved by Research Ethics Committee of the A 61-year-old white women, married, mother of two children, reported worsening of psoriasis symptoms after using L-methylfolate 15mg daily for coadjutant treatment of depression. She reported depression and psoriasis since she was 20 years old. The patient was without recurrent lesions of psoriasis since 41 years of age.Due to the history of depression, she was prescribed to use lithium carbonate, however, because of psoriasis the substance was avoided. In 2000, she had improvement in the depression by taking venlafaxine 225 mg once a day. In 2016, because of humor oscillations, lamotrigine 100 mg to day was added and, to improve her sleeping quetiapine 50mg daily was prescribed. These were the current dosages, with improvement of the depression, quality of life and significant adverse effects.In January 2019, polymorphism in MTHFR gene was detected, with mutation of heterozygous for C677T, and the patient received a prescription for 15mg daily from L-methylfolate. Before finishing the first week of the use of L-methylfolate, psoriatic lesions had appeared, which did not occurred for 20 years. The occurrence was reported in psychiatric that removed the medication, and, 4 days later, psoriatic lesions begun to recovery, and disappeared completely after few weeks. The patient remained without new changes up to beginning of 2020.After 20 years of being asymptomatic, there was recurrence of psoriasis with less than 1 week of the use of L-methylfolate 15mg daily. The patient reported not experience stress or recurrence of depression, which confirmed the stable picture. There were no changes in the patient's eating habit and medicines, expect to the L-methylfolate. Differently from cases already reported, our patient did not use methotrexate concomitantly, therefore, disregarding the hypothesis of possible interaction between methotrexate and L-methylfolate.The importance of this report relays on the coadjuvant psychiatric therapy of high doses of L-methylfolate in patients with history of psoriasis. The present case seems to be the second case reported in the published literature that associate L-methylfolate and worsening of psoriasis.The similarity between cases and possible correlation between L-methylfolate and psoriasis had drawn our attention, a fact that led to the hypothesis of high doses of L-methylfolate in direct relationship. high dosage of L-methylfolate, approximately 15 times to the tolerable upper intake levels (UL) for folate, described by the Food and Nutrition Board do Institute of Medicine; and the fact that methylcobalamin 1mg corresponds to commonly prescribed dosage for supplementation for B12 vitamin deficiency, which in this case was already used by patient without reporting of adverse effect.Although L-methylfolate 15mg has been formulated with 1mg of methylcobalamin, we believe that the first has a direct relationship and triggering role in psoriasis recurrence. Some reasons that may support this believe: close relationship with clinical cases already reported;Considering the increase of cases treated with higher doses of L-methylfolate as coadjuvant for individuals with MTHFR gene polymorphism, the use of this substance must be carefully evaluated for patients with history of psoriasis. O folato, uma vitamina B, é necessário ao cérebro para síntese de noradrenalina, serotonina e dopamina. Três formas de folato são comumente usadas: ácido fólico, 5-metiltetrahidrofolato  e ácido folínico.A BH4 é uma pterína que atua como cofator obrigatório para a atividade das enzimas fenilalanina hidroxilase, tirosina hidroxilase e triptofano hidroxilase, que catalisam as etapas iniciais da degradação da fenilalanina no fígado, assim como as etapas limitantes da biossíntese dos neurotransmissores dopamina e serotonina.A forma biologicamente ativa de folato, o L-metilfolato, é o único metabólito do folato que atravessa a barreira hematoencefálica, regulando a formação do cofator tetraidrobiopterina (BH4).Como o folato desempenha papel crucial no sistema nervoso central, propõe-se que os indivíduos com níveis reduzidos possam ter taxas mais altas de depressão e resposta fraca ao tratamento com antidepressivos.Portadores de polimorfismo do gene MTHFR dos tipos C677T e A1298C, relacionados ao metabolismo ou à absorção do folato, podem se beneficiar melhor do 5-MTHF, ao invés do ácido fólico.versus placebo.Algumas descobertas se somam às evidências que implicam em distúrbios da metilação do sistema nervoso na biologia de algumas formas de doença mental. Em amostra de 123 pacientes psiquiátricos (diagnóstico de depressão maior ou esquizofrenia), 41 tinham deficiência limiar ou definida de folato (folato sérico abaixo de 200µg/L). Nesse estudo duplo-cego, placebo, administraram-se 15mg ao dia de L-metilfolato, durante 6 meses, além de tratamento psicotrópico coadjuvante. Os pacientes apresentaram significativa recuperação clínica e social ao uso de L-metilfolato Outros estudos adicionaram 5-MTHF a antidepressivos para pessoas com baixo teor de folato ou em indivíduos cuja depressão não era responsiva às drogas. O aumento de folato durante o tratamento com antidepressivos poderia melhorar a eficácia dos antidepressivos em não respondedores e permitir que aqueles que respondem parcialmente à monoterapia com antidepressivos alcancem melhor resposta.A psoríase, distúrbio inflamatório sistêmico comum, afeta principalmente a pele, as unhas e, ocasionalmente, as articulações. A prevalência de psoríase em diferentes populações varia entre zero e 12%.O medicamento metotrexato vem sendo indicado para psoríase eritrodérmica, psoríase artropática moderada a grave, psoríase pustulosa aguda, psoríase em placas grave ou incapacitante e em casos com má resposta à fototerapia e/ou retinoides.Há sugestões na literatura de que o L-metilfolato pode causar diminuição da eficácia do metotrexato para tratamento da psoríase, como o caso de um homem de 53 anos que apresentou piora da psoríase após tê-la resolvido quase 100% nos 2 anos anteriores, apesar da continuação da terapia com metotrexato. Houve recorrência de lesões psoriáticas e novas lesões psoriáticas, cobrindo 80% de sua superfície corporal, aproximadamente 4 a 5 semanas depois que começou a usar L-metilfolato 15mg ao dia para tratamento da depressão.Estudo submetido e aprovado pelo Comitê de Ética em Pesquisa do Hospital Israelita Albert Einstein, e registrado com o número de protocolo 3.930.986 e CAAE: 30171919.2.0000.0071.Paciente do sexo feminino, 61 anos, caucasiana, casada, dois filhos, relatou piora dos sintomas da psoríase após início de L-metilfolato 15mg ao dia para tratamento coadjuvante de depressão. Relatava depressão e psoríase desde os 20 anos. Desde os 41 anos, a paciente estava sem recidivas das lesões psoriáticas.Pelo histórico de suas depressões, teve indicação de carbonato de lítio, mas foi evitado devido à psoríase. Em 2000, apresentou melhora do quadro depressivo, com venlafaxina 225mg ao dia. Em 2016, devido a oscilações de humor, foi acrescida lamotrigina 100mg ao dia e, para melhora do sono, foi usada a quetiapina 50mg ao dia.Essas eram as doses atuais, com melhora da depressão, da qualidade de vida e sem efeitos adversos significativos.Em janeiro de 2019, detectou-se polimorfismo no gene MTHFR, com mutação heterozigótica no C677T, e a paciente recebeu prescrição de 15mg ao dia de L-metilfolato. Antes do término da primeira semana de uso do L-metilfolato, surgiram lesões psoriáticas, que há 20 anos não se manifestavam. O transcorrido foi relatado ao psiquiatra, que retirou a medicação, e, 4 dias após, as lesões psoriáticas começaram a remitir, desaparecendo completamente após algumas semanas. A paciente permanecia sem novos registros de manifestações até início de 2020.Depois de 20 anos assintomática, houve recidiva da psoríase com menos de 1 semana de uso do L-metilfolato 15mg ao dia. A paciente relatou não passar por nenhum estresse e nem recaída da depressão, confirmando quadro estável. Não houve mudança no hábito alimentar e medicamentoso, além do L-metilfolato.Diferentemente do caso já relatado, a paciente deste caso não fez uso concomitante de metotrexato, descartando a hipótese de possível interação entre este e L-metilfolato.A importância deste relato refere-se à terapêutica psiquiátrica coadjuvante de altas doses de L-metilfolato em pacientes com histórico de psoríase. O presente caso deve ser o segundo relatado que associa L-metilfolato e piora de psoríase.A semelhança entre os casos e a possível correlação entre L-metilfolato e psoríase despertaram nossa atenção, o que levanta a hipótese da alta dose de L-metilfolato em relação direta.dosagem alta de L-metilfolato, aproximadamente 15 vezes a tolerable upper intake levels (UL) de folate, descrita pela Food and Nutrition Board do Institute of Medicine ;e o fato de a metilcobalamina 1mg corresponder à dose comumente prescrita na suplementação para insuficiência ou deficiência da vitamina B12, já utilizada pela paciente sem relato de efeito adverso.Embora 15mg de L-metilfolato tenham sido formuladas com 1mg de metilcobalamina, acreditamos que o primeiro tenha relação direta e papel desencadeante na recidiva da psoríase. Alguns motivos nos convergem a esse pensamento: estreita relação com o caso clínico já relatado;Com o aumento de casos tratados com doses elevadas de L-metilfolato como coadjuvante em portadores de polimorfismo do gene MTHFR, seu uso deve ser cuidadosamente avaliado em pacientes com histórico de psoríase.


The androgen receptor (AR) is the main therapeutic target in advanced prostate cancer, because it regulates the growth and progression of prostate cancer cells. Patients may undergo multiple lines of AR-directed treatments, including androgen-deprivation therapy, AR signaling inhibitors , or combinations of these therapies. Yet, tumors inevitably develop resistance to the successive lines of treatment. The diverse mechanisms of resistance include reactivation of the AR and dysregulation of AR cofactors and collaborative transcription factors (TFs). Further elucidating the nexus between the AR and collaborative TFs may reveal new strategies targeting the AR directly or indirectly, such as targeting BET proteins or OCT1. However, appropriate preclinical models will be required to test the efficacy of these approaches. Fortunately, an increasing variety of patient-derived models, such as xenografts and organoids, are being developed for discovery-based research and preclinical drug screening. Here we review the mechanisms of drug resistance in the AR signaling pathway, the intersection with collaborative TFs, and the use of patient-derived models for novel drug discovery. Prostate cancer is one of the most common causes of cancer-related death among men in Western countries. At diagnosis, most prostate cancers rely on the androgen receptor (AR) signaling for growth and survival. In this pathway, the AR is bound by ligands, such as dihydrotestosterone (DHT), and regulates the expression of target genes –5. In adIn normal prostate epithelium, the AR suppresses proliferation and promotes differentiation ; howeverAn important step in developing novel therapies is testing their effectiveness in preclinical models. Although there is a longstanding paucity of preclinical models of CRPC, larger collections of patient-derived models are providing new tools to validate and prioritize candidate treatments for clinical trials. In this review, we examine mechanisms of castration-resistance involving the AR and collaborating TFs, new strategies for targeting tumors with these features, and the use of different patient-derived models for testing these novel treatments.The AR gene on Xq11-13 consists of 8 exons encoding the N-terminal domain , DNA-binding domain , hinge region , and ligand binding domain  , 16. BinAR locus are one the most common mechanisms of castration-resistance, and they often encompass an enhancer located ~700 kilobases upstream  can mediate castration resistance . IncreasIn an effort to overcome resistance to current treatments, new therapies are being developed to target the AR. Some compounds have a similar mechanisms-of-action to existing AR-directed treatments. Like abiraterone actetate, the new compound VT464 (seviteronel) is a CYP17A1 inhibitor that suppresses androgen biosynthesis . Unlike AR pre-mRNA transcripts  or SNIPERs (specific and non-genetic inhibitor of apoptosis protein [IAP]-dependent protein erasers). These heterobifunctional small molecules contain a ligand that binds to the target protein, such as an AR antagonist, linked to another ligand that engages the ubiquitin ligase complex –71. Sincin vitro and in vivo, and had increased activity in combination with docetaxel , by mimicking the LXXLL motif in the AF2 domain of the AR C-terminus . By blococetaxel , 75. Howocetaxel . EPI-506ocetaxel , but wasocetaxel .Compounds are also being developed to block the interaction of the AR with DNA. This could target both full-length and variant forms of the AR, which contain the DBD. For example, AR binding to specific androgen response element sequences can be blocked using PI polyamides, N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids that bind to the minor groove of DNA with high affinity and sequence specificity –81. PI pCofactors, including coregulators and TFs, are also necessary for AR-regulated gene expression. Whilst coregulators directly bind to activation function (AF) 1 or 2 domains of the AR, TFs bind to DNA elements near AR binding sites . Some TFThe importance of cofactors and collaborative TFs makes them potential therapeutic targets for indirectly targeting the AR. There are numerous strategies for targeting different AR interacting proteins, so here we focus on two notable examples, bromodomain and extra terminal domain (BET) proteins and OCT1  that collaborate with MYC.The BET family of epigenetic readers, including BRD2/3/4  and BRDT (bromodomain testis associated), bind to acetylated histones and regulate the expression of downstream genes such as MYC .BET proteins are therapeutic targets in different tumor types, but are of particular interest in prostate cancer because they affect the expression and activity of the AR pathway . BET proThe promising preclinical data for BET inhibitors suggests that they are potential new treatments for CRPC, functioning in part by indirectly targeting the AR. Numerous BET inhibitors are clinical development and some are in phase I/II clinical trials enrolling men with CRPC, such as ABBV-075 (mivebresib) and MK-8628/OTX015 (birabresib) . So far,in vitro and in vivo  is the mostly highly differentially expressed . ACSL3 iAlthough there are few drugs targeting OCT1, PI polyamides have been developed that block the interaction between OCT1 and specific DNA binding sites. A PI polyamide targeting the OCT1 binding sites of ACSL3 suppresses ACSL3 expression and inhibits the growth of CRPC by repressing global OCT1 chromatin association and AR signaling . These pAR gene and expression of several AR isoforms in 22Rv1 cells  from patient tumors has advanced with the use of more highly immune-deficient strains of mice. Yet, PDXs are often more difficult to establish from prostate cancer compared to other malignancies, due to low take rates (10–40%) and long latency periods (up to 12 months) . Neverthin vivo drug responses, but the experiments are expensive, labor-intensive, low throughput and have long timeframes. Explants and organoids are complementary models that address these limitations. Explants are intact pieces of tissue maintained for several days ex vivo on filters or gelatin sponges, so they retain the native tissue architecture and microenvironment (ex vivo and in vitro cultures are also useful for testing tool compounds that have poor bioavailability or are not available in sufficient quantities for in vivo experiments. Explants and organoids can also be used for experiments that are challenging with PDXs, including large-scale dose responses of single or combination treatments, genetic manipulation, and short-term time points for mechanistic studies (in vivo treatments with PDXs. Therefore, by combining different patient-derived models established from different cases of CRPC, it will be possible to test the next generation of therapies with greater rigor and efficiency to help prioritize them for further clinical trials.Like all experimental models, PDXs have limitations, so they can be integrated with other patient-derived models to maximize the advantages and offset the limitations of each approach . PDXs prironment , 131. Orironment , 133. Th studies , 135. ThOver the last decade, the introduction of new treatments for CRPC has extended patient survival, but tumors still eventually fail treatment. The increasingly detailed understanding of the underlying mechanisms of resistance has facilitated the development of novel compounds that use alternative approaches to target the AR pathway, directly or indirectly. Two examples of drug targets are BET proteins, with BET inhibitors in ongoing clinical trials for prostate cancer, and OCT1, with novel compounds in preclinical development. Whether these compounds are effective as monotherapies, or should be used in combination with other treatments is still under investigation. Nevertheless, growing collections of patient-derived models, spanning xenografts, organoids and explants, are providing ways to test the efficacy of these candidate drugs across a wider spectrum of tumors. Collectively, this ongoing effort will provide a rich pipeline of new treatments for further validation in clinical trials.DO, ST, and SI: conceived the concepts. DO, ML, and NC: wrote the first draft of the manuscript. KT and GR: revise the first draft. All authors reviewed and approved of the final manuscript.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.


Background: As the population ages, the rate of hip fractures and the need for rehabilitation increases. Home-based rehabilitation (HBR) is an alternative to classic inpatient rehabilitation (IR), which is an expensive framework with non-negligible risks.Methods: A retrospective study of patients 65 years and above following surgery to repair a hip fracture who underwent HBR or IR between 2016 and 2019. The two rehabilitation frameworks were compared for rehabilitation outcome and factors predicting successful rehabilitation. The outcome was determined with the Montebello Rehabilitation Factor Score-Revised (MRFS-R).Results: Data were collected for 235 patients over 3 years. The mean age was 81.3 ± 8.0 and 172 (73.3%) were women. Of these, 138 underwent IR and 97 HBR. The HBR group had better family support and fewer lived alone. There were also differences in the type of fracture and surgery. The medical condition of the IR group was more complex, as reflected in a higher Charlson's comorbidity scores, higher rates for delirium and more infectious complications, a lower Norton score, lower serum hemoglobin, and albumin levels, and higher serum creatinine and urea levels. It also had a more significant functional decline after surgery and required a longer rehabilitation period. However, no difference was found in the rehabilitation outcomes between the two groups (MRFS-R ≥ 50). The independent predictors for rehabilitation in the IR group were serum albumin level, comorbidity, and cognitive state. There were no independent predictors in the HBR group.Conclusions: In this retrospective study, there was no significant difference in short-term rehabilitation outcomes between the HBR and IR groups event though the patients in the IR group were medically more complex. This result should be taken into account when planning rehabilitation services after hip fracture and tailoring rehabilitation frameworks to patients. Hip fracture, a common problem in elderly patient populations, is associated with functional impairment, reduced quality of life, and even mortality . The aimIn recent years, the Clalit Healthcare Services, the largest in Israel, developed an HBR program in its Southern District. The aim of the present study was to compare patients who had surgery for femoral neck fractures and underwent HBR with those who were rehabilitated in the Geriatrics Department of a tertiary university hospital with IR. There were three primary study questions:Is there a difference between patients who underwent rehabilitation in these two frameworks in a real-life setting?Is there a difference in rehabilitation outcome between the two frameworks?Are there different predictors of success in the two rehabilitation settings?In the Southern District of the Clalit Healthcare Services recently established a Geriatric Sector including a Geriatrics department in the tertiary Soroka University Medical Center, and a community Geriatrics Service with an HBR unit.The Soroka University Medical Center is a 1,150-bed tertiary hospital, the biggest in southern Israel and the third largest in Israel. The hospital has a 25-bed Geriatrics ward that was established over 30 years ago. The staff includes specialists and residents in geriatric medicine, nurses and aides, physiotherapists, an occupational therapist, a dietician, and a social worker. It provides consultation services for the medical center's wards and units. The ward admits patients with acute illnesses referred from the emergency room and patients in need of rehabilitation, some following surgical repair of a femoral neck fracture. The process for admitting these patients begins with a geriatric consultation in the two Orthopedic Surgery wards of the hospital over the 1st days following surgery, including an initial geriatric assessment. Patients who meet criteria for HBR are given this option. Those who do not meet the criteria are referred for IR. Based on criteria including available space in the Geriatrics ward, health insurance from an HMO that does not support rehabilitation in the Geriatrics ward, the patient's or the family's decision to undergo rehabilitation elsewhere than the Soroka Medical Center, and the anticipated need for a prolonged rehabilitation due to a very poor functional or cognitive state, the patient is transferred either to the Geriatrics ward in the medical center or to another rehabilitation center outside of the hospital. Over the course of their stay in the Geriatrics ward each patient undergoes a comprehensive geriatric assessment. All healthcare professionals in the unit take part in this assessment, with an emphasis on medical problems, drug therapy, the patient's cognitive and affective state, and the patient's functional and social condition, including support resources and living conditions. In accordance with the assessment findings an interventional rehabilitation plan is developed.This plan is adjusted during the course of the day's work and at weekly meetings of the multidisciplinary staff. The rehabilitation process includes mobilization facilitated by all staff members, physiotherapy five times per week (average 45 min per session), occupational therapy several times a week (average 30 min per session), and a psychosocial intervention by the social worker. Preparation for discharge from the ward begins at the early stages of hospitalization. It includes interaction with relevant community services to adjust living conditions, nursing help, and ongoing rehabilitation at home. Patients with femoral neck fracture are discharged when the goals of rehabilitation are achieved such as independence using accessories in passageways, and mobility and independence in toileting, or when the patient reaches a plateau based on the Functional Independence Measure (FIM) .This unit includes a multidisciplinary staff with geriatric specialists, nurses, occupational therapists, physiotherapists, a dietician, and a social worker. This is a nuclear staff with tenured positions and do not work for extra income. Weekly staff meetings are held. The rehabilitation program begins with the receipt of patient data from the Orthopedic Surgery wards, an additional evaluation using criteria for HBR, and determination of the discharge date. At the time of discharge from the hospital the staff conducts a house visit including a comprehensive geriatric assessment, and determines the goals of the rehabilitation program, similar to the preparations made at the Geriatrics ward in the hospital. Over the course of rehabilitation the patient lives in the framework of home hospitalization under the responsibility of a geriatric specialist and receives comprehension care, including 24-h availability of the rehabilitation staff's doctor and nurse. The patient has a 45-min physiotherapy session 5 days a week, occupational therapy at least once a week (average 30 min per session), and psychosocial intervention by the staff social worker, as needed. In addition, the Clalit Healthcare Services pays for required nursing care for the patient during HBR.The decision to discharge from HBR is reached using the same criteria as in the Geriatric ward, when the goals of rehabilitation are achieved or the patient reaches a plateau based on FIM. In most cases, the patient then continues rehabilitation at home or in a rehabilitation center, but at a lower level of intensity.It is important to note that the staffs of the unit for intensive rehabilitation and of the Geriatric ward are in constant contact including convening weekly joint staff meetings. All the geriatric specialists in both frameworks undergo their training in geriatric medicine in the Geriatrics ward of the Soroka Medical Center.Criteria for admission to HBR. The unit for home-based rehabilitation adopted the criteria of Crotty et al.  for admiRehabilitation is indicated;Discharge from the hospital is appropriate;The patient's physical and cognitive condition enable active participation in a rehabilitation program;The home environment is suitable for home rehabilitation;There is a healthcare provider in the community who can provide for the medical needs of the patient, in this case the geriatrician on the HBR staff is the responsible medical provider;The main caregiver, if there is one, agrees with the decision to apply home-based rehabilitation.The study population consisted of patients 65 years or above who underwent surgical repair of a femoral neck fracture and were admitted for rehabilitation in the Geriatrics ward of the Soroka University Medical Center  or with the Unit for Home-based Rehabilitation (HBR) of the Clalit Healthcare Services between January 1, 2016 and December 31, 2019.Data on the study participants were obtained retrospectively from the electronic medical records (EMR) of the Soroka University Medical Center and the Clalit Healthcare Services. The following data were collected:Socio-demographic data—age, gender, education level, marital status, place of residence, having a staircase or elevator at home, information about the patient's main caregiver, nursing caregiver;Medical history—type of hip fracture, type of surgery, the patient's chronic diseases [the Charlson comorbidity index  score waLength of stay (LoS) at the orthopedic and geriatric wards or at the HBR unit, emergency room referrals and hospitalizations during rehabilitation (HBR group only) and six months after the rehabilitation process, and mortality rate;Functional status as assessed by the Functional Independence Measure—anamnestic FIM (anFIM), FIM on admission (FIMa), and FIM on discharge (FIMd). FIM is an 18-item ordinal scale with scores on each item ranging from 1 to 7  with the total score ranges from 18 to 126;Cognitive function was assessed with the Mini Mental State Examination (MMSE) , with thMood status was assessed by geriatricians during CGA and a diagnosis of depression was made based on the DSM 5 criteria ;The risk for pressure sores was assessed by the Norton screening tool for pressure ulcer risk, rated on a scale of 0–20 with higher scores indicating a lower probability for pressure ulcers ;Rehabilitation outcome was measured with the Montebello Rehabilitation Factor Score Revised (MRFS-R) . The MRFMRFS-R = ((FIMd – FIMa)/FIMd)/((an FIM – FIMa)/an FIM) × 100This index enables an appraisal of the degree that patients realized their rehabilitation potential. For example, a MRFS-R score of 55 indicates that the patient achieved 55% of the rehabilitation potential.T-Test or One-Way ANOVA were used. For continuous variables that were not normally distributed the Mann–Whitney or Kruskal–Wallis test were used. For quality variables the Chi-Square test was used.Data analysis was performed using the IBM SPSS Statistics Version 26 software. Univariate data analysis was performed to assess the relationship between the degree of functional improvement and rehabilitation in the IR and HBR groups and in the entire study population. For normally distributed continuous quantitative variables, the Student's p < 0.05), and (b) those with clinical significance . Before performing the model, we checked for interactions or confounders and removed them from the model. A logistic regression model was built for each type of rehabilitation to predict its success, which was defined as MRFS-R ≥ 50% for the study. We added a logistic regression model to predict the success of rehabilitation for the entire study population with the addition of the independent variable “Rehabilitation setting” (HBR vs. IR).The multivariate analysis included the following variables: (a) those with a statistically significant difference in the univariate analysis .A two-sided Data were collected for 235 patients with a mean age of 81.3 ± 8.0, of who 172 (73.3%) were women. The IR group included 138 patients and the HBR group 97.P = 0.001), more patients who lived alone , and fewer patients with a partner who played the role of main caregiver . The IR group had fewer patients with an intracapsular fracture , and there was a corresponding difference in the type of surgery: in the patients who had an intrascapular fracture, 51.2% in the IR group had total hip replacement (THR) while 88.1% of the patients in the HBR group did (P < 0.001). The IR group had more complex medical issues with a higher total score in the Charlson's Comorbidity Index (TCS) , they were taking more chronic mediations at admission to rehabilitation , their Norton score was lower , the serum hemoglobin level was decreased more after surgery , the admission serum creatine level was higher  as was the admission serum urea level , and the serum albumin level was lower . Although there were no statistically significant differences between the two rehabilitation groups in anFIM, the FIMa was lower in the IR group  and the FIM loss (anFIM-FIMa) following the femur fracture in this group was more prominent .The IR group had fewer married patients  and infectious diseases . However, patients in the HBR group had more pressure sores .Patients in the IR group had a higher occurrence of delirium . Over the 6 months following the end of the rehabilitation program 33% of the patients in the HBR group went to the emergency room at least once compared to 15.2% in the IR group (P = 0.002). There was no statistically significant difference between the groups in hospitalization over this follow-up period. Two patients in the IR group died during rehabilitation while all the patients in the HBR group survived the rehabilitation period (P = 0.513). There was no statistically significant differences between the groups in the three-month mortality rate .The period of rehabilitation was longer in the IR group , but the FIM gain (FIMd – FIMa) was lower . There were no statistically significant differences between the groups in the MRSF-R score  and there was no difference in the number of patients that had a score of MRFS-R ≥ 50. In the total study population of 235 patients in the two rehabilitation settings, 146 (62.1%) achieved a score of MRFS-R ≥ 50 . Only two independent variables were associated with rehabilitation success, TCS  and MMSE . Thus, in the multivariate analysis the rehabilitation setting was not associated with rehabilitation success.At the end of the rehabilitation process the FIMd score was higher in the HBR group , with lower co-morbidity , a higher MMSE score , a higher Norton score , a higher serum albumin level , a lower percentage of delirium , and fewer cases of periprosthetic fractures . The length of stay (LoS) in the orthopedic surgery ward prior to rehabilitation in the IR group was shorter among patients with MRFS-R ≥ 50, but this difference did not reach statistical significance . The picture was a little different in the HBR group. In patients with MRFS-R ≥ 50 the TCS score was lower , the MMSE was higher , and the Norton score was higher . At admission to rehabilitation their serum urea level was lower . Two other variables that showed a trend to difference that did not reach statistical significance were a higher percentage of patients who underwent THR compared to other types of surgery  and a longer LoS in rehabilitation in the MRFS-R ≥ 50 group .P-value lower than 0.1 for MRFS-R ≥ 50 (P = 0.01), MMSE  and serum albumin level prior to the start of rehabilitation  predicted a successful rehabilitation outcome with MRFS-R ≥ 50.Separate regression models were built for the two study groups. The models included sex and variables that reached statistical significance in univariate analyses or had a S-R ≥ 50 . The modWhen the relevant variables, type of surgery, TCS, MMSE, Norton, and serum urea  were entIn the HBR group, there were more married patients, fewer patients who lived alone, and more patients whose partner/spouse was their main caregiver. These findings are not very surprising. It is clear that patients who live with a functioning partner, who can take responsibility for the patient as the main caregiver, are more likely to choose HBR over IR. Thus, it would appear that the living alone is a critical factor in the decision on the rehabilitation setting. Giusti et al. , who evaThe HBR group had more patients with intrascapular fractures and a higher rate of patients who underwent THR. These results would appear to reflect the functional and cognitive condition of HBR patients. On the one hand, patients with extracapsular fractures have longer LoS including rehabilitation and they have a higher chance of undergoing long-term care . On the Although the pre-surgery hemoglobin level was similar in both groups, the hemoglobin loss was more significant in the IR group. Previous studies have shown that perioperative blood loss is associated with lower mobility during physiotherapy , an incrThe serum albumin level was lower in the IR group. In the vast majority of cases pre-fracture albumin tests were not available so it is difficult to conclude whether hypoalbuminemia reflects a low premorbid nutritional level or whether it is associated with perioperative stress. In any event in previous studies hypoalbuminemia was associated with postoperative complications , 34, a lOver the course of rehabilitation more IR patients developed delirium and various infections, but had a lower rate of pressure sores. Caplan et al.  found thThere were more emergency room visits in the HBR group during the 6 months following the fracture than in the IR group. We see some possible explanations: Was the comprehensive geriatric assessment by the HBR medical staff less comprehensive than we thought with insufficient attention to all the patients' medical problems? Were there medical issues that were not taken into account by the Charlson index, so the medical condition of the HBR patients was actually more complex than the score reflected?The differences between the study groups in terms of type of surgery, TCS, rates of infectious diseases and delirium, laboratory tests, and postoperative functional decline, enabled us to answer the first study question. IR patients had fewer sources of support, more complex medical conditions, and apparently were more frail, at least as it relates to the choice of surgery.P < 0.001), this results appears to reflect the fact that their admission functional condition (FIMa) was better . In our opinion, the improvement in functional condition, which was significantly higher in the IR group , does not reflect a greater level of success in the IR group. The MRFS-R score, which has advantages that were presented in a previous publication from the Geriatrics ward of the Soroka University Medical Center , MMSE (every increase of one point increased the chance of success by 9%), and serum albumin .The issue of rehabilitation success has been investigated comprehensively in the past. For example, Cary et al.  in a stuWith MRFS-R as the measure of success in another study in our department , we founIn light of the results of the present study, the answer to the question “Do the results of rehabilitation in two different frameworks have similar predictor variables?” is negative. One cannot determine the predictor variables for success in HBR while the factors that predict successful rehabilitation in IR include sex, comorbidity, and postoperative serum albumin level.The present study has several advantages. It is a comparative study of two real-life situations among patients who underwent rehabilitation in two frameworks, both of which were affiliated with the same regional Geriatrics service whose rehabilitation staffs had an ongoing collaboration. We used computerized medical data systems that enabled us to collect a broad spectrum of data that could be introduced into a model with many relevant indices. The measure of rehabilitation success was determined in advance, using an instrument, MRFS-R, that we believe takes into account all the parameters of the patient's functional state prior to the fracture, at admission to rehabilitation, and at discharge from rehabilitation, and has the capacity of optimal adjustment for the rehabilitation potential of each specific patient .The study also has several limitations. The most significant limitation is its retrospective nature and the absence of randomization. For this reason, the conclusion that there were no significant differences in rehabilitation outcomes between the two rehabilitation settings was based on data extracted from the electronic medical record. It is possible that some important information was not included. Furthermore, the results of the multivariate logistic regression did not enable us to provide a complete answer to the study question. Of course, the ultimate solution to this problem would be a randomized controlled trial.Another significant limitation is the way the FIM questionnaires were completed. Although all the geriatricians working in the two frameworks underwent training in geriatric medicine in the Soroka University Medical Center and received a similar geriatric education, and there is a strong connection among the staffs including common staff meetings, we cannot rule out variance among the evaluators that could have affected the results of the study.The present study has several additional limitations. Data were not collected on Instrumental ADL, so we do not know if, and to what extent, this measure changed as a result of rehabilitation in the two study populations. It is possible that when the patients are in their natural environment this measure could improve more. The absence of information on quality of life and the cost of treatment are also study limitations.In addition, we accounted only for the number of medications that the patients were taking and not details on specific drugs. On the one hand, this information, for example, drugs for treatment of osteoporosis or sleeping pills, could add to our understanding of the causes of falls and fractures, while on the other information on drugs with anticholinergic activity could explain the differences in rehabilitation outcomes.In this study, we evaluated the results of the intensive phase of rehabilitation only. At the end of the intensive phase the patients continued with a process of non-intensive rehabilitation in various community frameworks, in a rehabilitation center, or by once-a-week rehabilitation at home. Lack of information on the patients' functional state at the end of this rehabilitation process weakens the study conclusions and indicates the need for continuing research.The methods used for HBR in the southern region of the Clalit Healthcare Services may be different from those used in other frameworks so, for example, every patient who is discharged to HBR receives an allowance for nursing care. In addition, the home rehabilitation staff includes a geriatrics specialist who took overall responsibility for 24/7 medical care. This is in contrast to most studies in this field where medical care was undertaken by a primary care doctor who was not an integral part of the rehabilitation staff . Thus, cIn summary, based on the results of this retrospective study that evaluated short-term outcomes of intensive rehabilitation among patients with femoral neck fractures, patients with more complex medical conditions that underwent IR had similar rehabilitation outcomes as patients with less medically complex conditions who underwent HBR. These conclusions can serve as an additional tool for the selection of a rehabilitation framework that is tailored to the individual patient's profile.yanp@bgu.ac.il.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Requests to access these datasets should be directed to The studies involving human participants were reviewed and approved by the Helsinki Committee of the Soroka Medical Center (SOR-0211-19). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.YL, BP, and YP designed the study, collected the data, and wrote the article. EZ, DS, DK, and EM designed the study, collected the data, and assisted with writing the article. TF designed the study, was responsible for the statistical design of the study and for carrying out the statistical analysis.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.


Confirming the results of Démoulin et al.  contains supplementary material, which is available to authorized users. Hinode Extreme Ultraviolet Imaging Spectrometer (EIS), steady coronal plasma upflows have been observed to emanate from the edges of active regions , also using Fe xii , they demonstrated that upflows from AR 8100 extended into the intermediate corona to become outflows and persisted for the entire lifetime of the AR, which spanned five solar rotations.Typically, these large-scale upflows are located above monopolar regions of strong magnetic field  can take place at the coronal null, creating a steep pressure gradient and a rarefaction wave in the reconnected loops  projection effects from intrinsic flow evolution. It was shown that the upflows have a strong collimated stationary component.Démoulin et al.  used Hinet al. . In applying this simple model to EIS Doppler velocity data of AR 10978, it was assumed that the plasma upflows are continuously driven with the same velocity magnitude and orientation in the local solar frame. The main equations of the model are presented here for convenience. See Démoulin et al.  for a coIn spherical coordinates with the radial direction  velocities in Despite the complex configuration of AR 11575, its flow pairs exhibit strong apparent evolution comparable to that of AR 11589 and AR 10961 shown in Figure et al. , indicating that the magnetic field strength does not drive the stationary flows, i.e. there is no direct magnetic acceleration as there is with CMEs.In most cases, derived velocities [i.e. higher mean line-of-sight velocities, show stronger rotational effects.In general, ARs with stronger flows, e.g. AR 10953, Figures Intrinsic flow evolution that is due to activity, such as flux emergence, jets, flaring, and CMEs, appears as a deviation from the model fit  between overpressure AR loops and neighboring underpressure loops (MP4 File 22.8 MB)Below are the links to the electronic supplementary material.


Synechocystis sp. PCC 6803. The addition of lauric acid (12:0) to cells accelerated the photoinhibition of PSII by inhibiting the repair of PSII and the de novo synthesis of D1. α-Linolenic acid (18:3) affected both the repair of and photodamage to PSII. Surprisingly, palmitic (16:0) and stearic acids (18:0) enhanced the repair of PSII by accelerating the de novo synthesis of D1 with the mitigation of the photoinhibition of PSII. Our results show chemical potential of FFA in the regulation of PSII without genetic manipulation.Free fatty acids (FFA) generated in cyanobacterial cells can be utilized for the biodiesel that is required for our sustainable future. The combination of FFA and strong light induces severe photoinhibition of photosystem II (PSII), which suppresses the production of FFA in cyanobacterial cells. In the present study, we examined the effects of exogenously added FFA on the photoinhibition of PSII in  Synechococcus elongatus PCC 7942 (hereafter Synechococcus) raises the rate of FFA production up to 2 mg L−1 h−1 [Our sustainable future depends on new sources of renewable energy instead of limited petroleum. Free fatty acids (FFA), materials for biodiesel, are a new and prominent power resource. Microalgae, including cyanobacteria are suitable platforms for the production of FFA. Disruption of acyl-ACP synthetase (AAS) gene and expression of thioesterase (TE) gene are the most conventional methods for improving FFA production in microalgal cells . In addi L−1 h−1 ,4. To acaas mutant of Synechococcus, increased amounts of FFA inhibit cellular growth and accelerate the photoinhibition of PSII by accelerating the rate of photodamage to PSII [aas mutant [Light is a driving force for photosynthesis; however, excessive light is harmful for photosynthesis. Photosystem II (PSII) is particularly sensitive to light, and the inactivation by light (photodamage) occurs under any intensity of light . The red to PSII . Among F to PSII ,12. Furts mutant . These rs mutant . HoweverSynechocystis sp. PCC 6803 (hereafter Synechocystis) was incubated in the presence of various FFA molecules, and we examined the effects of exogeneous FFA on the photoinhibition of PSII. Lauric acid (12:0) suppressed the repair of PSII by inhibiting the de novo synthesis of D1, with the resultant acceleration of photoinhibition of PSII. α-linolenic acid (18:3) accelerated photodamage to PSII. On the other hand, palmitic (16:0) and stearic acids (18:0) alleviated the photoinhibition of PSII by enhancing the repair of PSII via the accelerating synthesis of D1. From these observations, we report here the FFA-related photoinhibition by affecting the de novo synthesis of D1.In the present study, 2 mg−1 Chl h−1 in the presence of 12:0, 14:0, 16:0, 18:0, 18:1, and 18:3, respectively. Since the PSII activity in the absence of FFA was 851 ± 45 μmol O2 mg−1 Chl h−1, the exogeneous FFA did not significantly affect the activity of PSII. It should be noted that exogeneous FFA are immediately absorbed by Synechocystis cells [Synechocystis, 12:0 and 18:3 inhibit cell growth, and 16:0 and 18:0 accelerate it [Synechocystis cells to strong light at 1500 μmol photons m−2 s−1 at 32 °C in the absence or presence of various FFA at the concentration of 0.1 mM. The activity of PSII in the absence of FFA decreased to 25% of the initial level in 80 min under strong light  such as 12:0 accelerated the photoinhibition of PSII by suppressing the de novo synthesis of thylakoid proteins including D1 . Fatty a4Cl or nigericin extends photodamage to PSII [Polyunsaturated fatty acids (PUFA), such as 18:3, accelerated photodamage to PSII . The acc to PSII ,22, whic to PSII ,24. A la to PSII ,26. TherSynechocystis does not have the complete metabolic cycle for the degradation of fatty acids, such as β-oxidation [a into pD1 during PSII repair. Biosynthesis of fatty acids is a rate-limiting step in lipid biosynthesis. The exogenously added 16:0 and 18:0 are incorporated into the cells and converted to 16:0-ACP and 18:0-ACP, respectively, by AAS, which are the substrates for lipid biosynthesis, and thus facilitate lipid biosynthesis. PG and DGDG are required for the construction of OEC, which contributes rapid repairing of PSII [The supplementation of 16:0 and 18:0 had positive effects on the photoinhibition of PSII . Synechoxidation , indicatxidation . Our obsxidation . Thus, t of PSII ,31, and  of PSII ,20. Ther of PSII . Thus, eIn the present study, we showed the diverse effects of FFA species on the photoinhibition of PSII. Our findings show a potential chemical regulation of photosynthesis with FFA or FFA-derived molecules. Numerous studies use genetically modified organisms (GMO) to improve the ability of photoprotection and the biomass yield ,34,35. HSynechocystis sp. PCC 6803 were grown photoautotrophically at 32 °C in liquid BG11 medium under light at 70 μmol photons m−2 s−1, with aeration by sterile air, as described previously [−1 chlorophyll a) were used for assays. White halogen light was used as the light source in all experiments.Cells of a glucose-tolerant strain of eviously . Cells i−2 s−1 at 32 °C for designated periods of time to induce the photoinhibition of PSII, as described previously [−1 lincomycin was added to the suspension of cells just before the onset of illumination. Cell cultures were also incubated in the dark at 32 °C for designated periods of time. The activity of PSII under 1500 μmol photons m−2 s−1 was measured at 32 °C in terms of the evolution of oxygen in the presence of 1 mM 1,4-benzoquinone and 1 mM K3Fe(CN)6 with a Clark-type oxygen electrode . FFA compounds are purchased from FujiFilm Wako .Cell cultures in the presence of 0.1 mM FFA were exposed to light at 1500 μmol photons meviously . For ass−2 s−1 in the presence of 0.1 mM FFA for 40 min. Then, pulse labeling of proteins was started by the addition of 5 μCi mL−1 35S-labeled methionine and cysteine . A total of 6 mL of culture was taken at the designed times, and the reaction was terminated by the addition of 2 mM cold Met and Cys each. Proteins in thylakoid membrane were isolated by breaking cells with beads-beater followed by the centrifugation, and proteins  were analyzed by 12.5% SDS-PAGE containing 6 M urea, as described previously [Prior to the labeling experiments, cell cultures were incubated at 32 °C under strong light at 1,500 μmol photons meviously . Labeled