Results show that the effect of an arrest on playercareers is negligible, though it has become slightly more detrimental over time.Player value and performance are stronger predictors of post-arrest careertrajectories, and average or better performance negates any detrimental impactof an arrest.This article examines whether arrests for an act of violence against women have anegative impact on National Football League (NFL) player careers and whetherthis impact has become more negative over time. Framed by criminologicaldeterrence and conflict theories, I conduct a Bayesian multi-level negativebinomial regression on a matched pairs sample of all 117 NFL players arrestedfor an act of violence against women between 2000 and 2019( While m , one whi  and foot  commit a . While r , manysp . While scholars have examined the specific one-time sanctions  given to professional athletes involved in violent acts . I matched each of these players witha player who was not arrested but was as similar as possible in terms of their age,race, position, draft position, career achievements, and relevant player statistics.Examining the career duration of these players in subsequent years thus allowed forthe examination of the common notion that players pay a substantial price merely forbeing accused of a violent act and arrested for it, even if they are not eventuallyconvicted.To examine the effects of arrests following VAW on NFL player career outcomes, Icollected data on all the NFL players who were arrested on such charges between theyears 2000 and 2019 .VAW falls explicitly under the NFL’s list of prohibited conduct, providing for “aspecial form of discipline that applies specifically to violations regardingassault, battery, domestic violence, dating violence, child abuse and other forms offamily violence, or sexual assault” . This caCriminological deterrence theory  providesnot punished, especially when itis committed publicly, “norms are weakened and shown to be less universal intheir binding force” , it is not clear howseriously teams take these accusations when assessing whether to retain oracquire an accused player. Unlike in general crime deterrence situations, whereit is only those who commit the crime (and their family and friends) who arenegatively impacted by the decision to punish, in this situation both theaccused (the player) and the sanctioning body (the team) can be negativelyimpacted by the team’s decision to punish. If an NFL team punishes a talented,valuable player by releasing them from the team or by not signing them to asubsequent contract, both the team and the player likely suffer. For teams, thedesire to retain or acquire a talented, productive, and/or valuable playeraccused of an act of VAW may supersede their desire to release the player andhelp deter future incidents of VAW. While the link between more certain andharsher punishment for acts of VAW and deterrence of future acts of the samenature may be clear, it is less clear whether teams will actually punish theseplayers in the first place.While deterrence theory provides a framework for understanding the importance ofpunishment in deterring future incidents of VAW, NFL teams’ actual commitment todeterring such incidents cannot be taken for granted. While one can assume NFLteams Criminological conflict theories and theories of Black masculinity highlightpotentially contrasting results to the question of whether NFL players arelikely to suffer negative career consequences when accused of an act of VAW.While most NFL players belong to a traditionally over-criminalized and highlysanctioned racial group , conflicAcademic literature is littered with studies demonstrating the unequal treatmentof Black men in legal and criminal justice contexts . This inIt is also important to highlight the treatment and framing of Black athletes andBlack masculinity . ThesucThe sample of arrested players used in this study consists of 117 NFL playersarrested for an alleged act of VAW between 2000 and 2019. This samplenecessarily excludes NFL players who were accused in civil lawsuits, or thoselinked to incidents of VAW but never formally arrested, such as BenRoethlisberger and Richie Incognito. It is possible that the lack of formalcriminal charges laid against these players is reflective of certain race-basedprivileges . HoweverUSA Today NFL Arrests Database, which tracks all NFL playerarrests from the year 2000 until the present, and has been used in past academicwork micwork .USA Today ArrestsDatabase, I corroborated the database by searching for the player’s name, theirarrest or criminal charge , and the team they wereplaying for at the time of the arrest  on ProQuest’sNorth American journalism search engine. For each player, I found multiple newsstories that corroborated the arrest information in the database and was able tofill in other key information regarding the relationship of the alleged victimto the athlete, the formal charges laid, and the conviction, sentence, or anydisciplinary action doled out by the team or the NFL (if applicable). I thenused data from pro-football-reference.com  to record the age of the player at the time of the arrest, their race, andtheir player statistics (described below).I included in the sample players arrested for domestic violence, domesticassault, domestic battery, domestic abuse/assault, battery, or sexual assault ofa woman. To ensure the accuracy of the A matched-pairs research design is effective in assessing the impact that oneintervening factor can have on an outcome, by comparing the results of anaffected research subject with those of an unaffected, matched subject .In thisMatched, non-arrested athletes were chosen based on similarities to arrestedathletes on criteria that are most likely to determine NFL player longevityand salaries . These iI first matched players on their race and the position they played. Arrestedplayers were labeled as either quarterback, running back, fullback,receiver, tight end, offensive lineman, defensive lineman, linebacker,cornerback, safety, and kicker. I then examined the players’ age, which hadto be within two years of each other at the time of the arrest.Next, I considered the players’ statistics. Due to the vastly different rolesthat players have in American football , there are few statistics that could be systematically usedacross the sample to match players. I thus used games played, games started,approximate value per game, and participation in the Pro Bowl as matchingcriteria, due both to their capacity to predict salary  andto tThe following example illustrates the matching process: Ahman Green wasarrested for domestic violence on April 25, 2005. I thus recorded Green’srace (Black), age at the time of arrest (27), position (running back),whether he participated in a Pro Bowl (he had), draft round (third), andplayer statistics for his seven seasons in the NFL preceding the arrest. Inthe seven seasons preceding the arrest, Green played in 107 games, starting72. His per-game approximate value was 0.81, one of the highest recorded inthe sample. His per-season approximate value was 12.4.n = 234) is available as a supplemental file.Using pro-football-reference.com’s player season finder tool, I then searchedfor a matched player based on as many of these parameters as possible,focusing the search on the seasons immediately preceding his arrest. ForGreen’s match, I searched for seasons played by Black running backs betweenthe ages of 26 and 28, who played between the 2003 and 2004 NFL seasons,with an approximate value of 10 or higher. This initial search yieldedseasons played by Shaun Alexander, Reuben Droughns, Edgerrin James, FredTaylor, and Ricky Williams. While these players had seasons that matched theparameters described above, Alexander was the same age as Green (27)following the 2004 season, participated in a Pro Bowl, had started a similarpercentage of games, and was closest in terms of his per-game approximatevalue. The original, self-created dataset with all 117 matched pairs. Iperform a slight adjustment on the (AfterYears) variable to createthe (AAfterYears) variable, adjusting for situations where players’intervention date was in 2014 or later, and they played in 100% of theiravailable post-intervention seasons. In these few cases, without adjusting, theamount of post-intervention years these players participated in would beright-censored relative to players from earlier years, because more recentplayers necessarily could only have played up to the 2019 season (even if theyare still currently NFL players), compared to players arrestedin years prior who had more potential seasons to play post-intervention. Thisadjustment only applied to 17 of the 234 players in the sample.While post-intervention seasons do not directly account for player earnings fromNFL salaries and endorsement and sponsorship contracts, it is a strong proxy forplayer career outcomes, as it measures how long a player remains employed by anNFL team. To measure post-intervention seasons, I recorded the number of seasonsin which both arrested and matched players were paid a salary in the NFL(Arrests). This isrecorded as 1 if the player was arrested for an act of VAW, and 0 if they werenot. This arrest coefficient is impacted by second-level time variables,explained below. I also control for whether the player’s VAW arrest represents arepeat arrest .The primary explanatory variable is VAW arrests Repeat variable is coded as 1 if a player had been arrestedonce, 2 if they had been arrested twice, and 3 if they had been arrested threetimes in the past. There are also several other independent variables used tocontrol for the impact of arrests on player outcomes at the individual-playerlevel.This In the first level of the model, I control for the effect of player value, usingboth pre-intervention and post-intervention approximate values. As with thepre-intervention approximate value, I transform the post-intervention statisticso that it can be assessed on a per-game basis. Both approximate valuestatistics are standardized to have a mean of 0 and a one-unit standarddeviation. I also include a covariate for how often players started games, bothbefore and after the intervention. These “start percentage” statistics are bothcentered at their respective medians.While it is generally common practice not to control for post-treatmentvariables, in this case it is vital to control for both pre-intervention andpost-intervention player value when assessing the impact of arrests on aplayer’s career length. If post-intervention player value  were not controlled for, a player’scareer-ending shortly after their arrest could mistakenly be attributed to thisarrest, rather than their lack of performance. Because the result of the outcomevariable in question (career length) does not occur immediately after the arrestor intervention date, but rather over the rest of a player’s career, it isimperative that their performance and value over the rest of their career iscontrolled for. Arrests also do not directly impact a player’s performance, asarrested players had a mean start percentage (after-intervention) of 48.5% and amedian start percentage of 54.6%, compared to 46% and 45.3%, respectively, fornon-arrested players. Arrested players also had a mean approximate value pergame of 0.26 (median 0.22), compared to 0.25 (median 0.24) for non-arrestedplayers.(BeforeSeasons). Playerswho had only played 1 or 2 seasons before the intervention date could have manymore years of NFL service ahead of them, while players whose intervention dateis following their 8th or 9th season may have been already nearing retirement orthe end of their careers. However, it is also possible that early in theircareers, players are not yet established as stable performers in the NFL, andcould be more likely to be out of the league soon. There could be a curvilinearrelationship between pre-intervention seasons and post-intervention seasons. I,therefore, use both pre-intervention seasons (BeforeSeasons_c) andthe square of pre-intervention seasons2) also likely has an impact ontheir career length, even post-intervention. However, as a player's careeradvances and they get further away from their draft year, the importance oftheir draft position on their career longevity likely decreases. I, therefore,include an interaction effect between pre-intervention seasons and draft round,to account for this potential effect (DraftRound × BeforeSeasons). Draft roundis recorded from 0 to 8 (though the draft only has seven rounds), with eightdenoting undrafted players. I also control for the fixed effects of the race(White) and age (Age_c) of a player. White iscoded as 1 if the player is white and 0 if not, while Age_c iscentered to its median of 25.Where a player was drafted Year variable is standardized for thepurpose of the analysis so that 1999 is recorded as 0, and 2019 (the lastpossible season) is recorded as 20. I also include a dichotomous variable forwhether the arrest occurred before or after the Ray Rice assault and arrest(Ray Rice). As explained above, this incident was a heavilycovered media story, and in response, the NFL passed a new PCP, with specificclauses pertaining to acts of off-field violence. The effect of arrests(Arrested) on player seasons may also be impacted by the timeat which they occur. The coefficient measuring the effect of arrests thereforeis included at the second (time-based) level, with the same Yearand Ray Rice variables. Including covariates at the second levelfor the effect of arrests will provide insight into the effect of arrests oncareer length, and how this effect has changed over time. While this does notensure that the pre- and post-Ray Rice periods are of equal length, as inSpencer and Limperos’ (2018) study of media coverage, this strategy allows foran observation of year-over-year change as well.The second level of the model examines the impact of the specific calendar yearon the number of seasons a player plays post-intervention. This is done toassess whether the impact of an arrest on career length has changed over time,in line with perceived changing societal norms regarding VAW. The time levelincludes the intervention year, which denotes the last season a player playedbefore intervention. This The specifications of the model are shown below:it ∼ GamAAfterYearsit) = α#t + α$tArrestedit + α2BeforeSeasonsit + α&BeforeSeasons2 + α4BeforeAVit(λ(AfterAVit + α)eStartPctCit + α*AfterStartPctCit + α+DraftRound+ it + α9AgeMit + α$#Whiteit + α$$DraftRoundit + α$2Repeatit∗BeforeSeasons#t = γ## + γ#$InterventionYear + γ#2RayRicet + η#tα$t = γ$# + γ$$InterventionYear + γ$2RayRicet + η#tαThe model fixed effect estimates are found in The baseline player in this analysis is a Black player of median age (25) who was afirst-round draft pick, played the median number of seasons before the interventionyear (3), and started a median percentage of his games both pre (52%) and post (49%)intervention. This baseline player’s last pre-intervention season was in 1999, withmedian per game approximate value statistics both pre (0.40) and post (0.24) intervention.Most of the fixed effects model estimates, for both the variables of interest andcovariates, do not have a significant negative or positive effect on player careeroutcomes. The 95% credible intervals in positive impact on a player'scareer. This confidence level is calculated using posterior predictive samples,which establish that 96.5% of the probability distribution for the “arrested”coefficient is above 0, indicating a positive effect. Without accounting forwhen the arrest happens, a baseline player (whose interventionyear is in 1999) who has been arrested for an act of VAW is therefore likely to haveplayed in approximately 35.9% more post-intervention seasons. Giventhat the baseline non-arrested player is expected to play in three seasons, anarrested counterpart is expected to play in 4.07 seasons, just over a one-seasonincrease.Having been arrested for an act of VAW does not have a statistically significantpositive or negative impact  onpost-intervention career length. However, with a one-tailed test, the model produces96.5% confidence that an arrest has a intervention year:arrested shows that the effect of a VAW arrest on career lengthbecomes more negative over time. As with the arrested coefficient,while a two-tailed test of significance does not yield 95% certainty that the effectof an arrest worsens over time, a one-tailed test produces 95.2% confidence thatthis effect is negative.While an arrest may have a positive impact on a player's career without accountingfor when it happens, the coefficient for morepost-intervention seasons than non-arrested players, over time, arrests have anincreasingly negative impact on post-intervention seasons. This analysis indicatesthat the later  a player is arrested, the more this arrestnegatively impacts their career length. Using the mean estimate of theintervention year: arrested variable, an arrested player isexpected to play 3.8% fewer post-intervention seasons for every year later thattheir arrest occurred. A baseline player arrested in 2006 therefore is expected toplay 3.29 post-intervention seasons (compared to 4.07 for a player in 1999), while abaseline player arrested in 2015 is expected to play 2.34 post-intervention seasons.Up to and including players arrested in the year 2008, arrests are predicted to haveeither a slightly positive effect or no effect on a player's post-interventionseasons. For players arrested in 2009 and after, they are expected to participate inslightly fewer post-intervention seasons, with the negative impact of arrestsincreasing for every year following, as shown in While players arrested in the early 2000s are predicted to play The impact of arrests on career outcomes was not clearly affected by whether thearrest occurred after the Ray Rice incident. Arrests that occurred after 2013 didhave a more negative effect on the number of post-intervention seasons than arreststhat happened in years prior, but this change was consistent with the year-over-yearlinear change described above. This analysis does not suggest that the effect of ayear change between 2013 and 2014 (2013 being the last season before the Ray Riceincident occurred) was any different than the change between 2001 and 2002, 2007 and2008, or any other 2 years in the sample.Beyond the uncertain and changing (with time) impact of arrests, age has a clearnegative impact on post-intervention seasons. For every year older a player was atintervention, they are expected to play 9% fewer seasons. Compared to a baseline25-year-old player who is expected to play 3 seasons, a 29-year-old player isexpected to play 2.1 seasons, a nearly one-season decrease.Player value and player performance also both have a positive effect on careerlength. Players who start a higher percentage of their games post-intervention areexpected to play more post-intervention seasons, as the estimated coefficient forstart percentage is 0.877, and its exponentiated coefficient is 2.40. To put this incontext, this means that a baseline player who starts 25% of their games (a backup)is expected to play 1.95 seasons, while a player who starts 75% of their games (astarter) is expected to play 4.05 seasons. A baseline player who starts 0% of theirgames, who is in an exclusively backup role post-intervention, is only expected toplay 0.9 seasons post-intervention. Even when the changing impact of an arrest overtime is considered, an arrested starter in 2019 is expected to play more seasonsthan either an arrested or non-arrested backup in any year .Intervention Year:Arrested coefficient) in later calendar years also disappearscompletely, even at lower credibility interval thresholds.From a player performance perspective, for every one-unit standard deviation increasein post-intervention approximate value per game, a player is expected to play 30%more post-intervention seasons. Further, in analyses of subsamples where only thelowest-performing players—i.e., those who were more than 1 standard deviation belowaverage in both approximate value and start percentage—were removed, theincreasingly negative impact of arrests , both Bayesian and simple frequentistregression analyses show that arrested players do I assessed the popular claim that accusations and arrests for alleged acts ofviolence “ruin a person's career” . The results from this Bayesianmulti-level model point to negligible consequences for arrested athletes, especiallyhigher performing players. Moreover, the model most conclusively demonstrates thaton-field productivity and value have a much stronger and clearer impact on playercareers. While it seems that the penalty for arrested athletes has increased overtime, to the point that arrests for acts of VAW are predicted to have a smallnegative impact on career outcomes starting in the year 2009 (with this negativeeffect increasing in the following years), this change only affects lower-performingand lower-valued players., a player's performance and value on thefield seem to negate any negative impact that an arrest may have. Recent NFL historyis littered with examples of higher-performing players who have been given second orthird chances following incidents of off-field violence in both college and the NFL,including Tyreek Hill, Adrian Peterson, Antonio Brown, Brandon Marshall, and BenRoethlisberger, among others .While the impact of arrests seems to become increasingly negative over time for thefull population of players, perhaps due to “much less tolerance for domesticviolence than there was a decade ago” , a playe5It is important to note that in this study, the “higher performance” subsamplesanalyzed did not include only top-performing players like Brown or Hill, but ratheronly excluded players in the bottom 25% of both start percentage and approximatevalue. Lower-performing players are much more likely to see their careers cut short,regardless of whether they have been arrested or not. This points to the possibilitythat NFL teams may be making examples of arrested lower-performing players bycutting them from their team or refusing to sign them to future contracts, to showthat they are taking a stand against VAW. Jacobs (2021) makes this point with regardto the Seattle Seahawks’ January 2021 release of backup offensive lineman ChadWheeler immediately following reports of a disturbing domestic violence incident. AsJacobs notes, “he's an easy one for the league to cast aside and use as an exampleof taking gender-based violence seriously” (2021), given that Wheeler's value to theteam was not high to begin with .Cynics of sports and sports business may find these results unsurprising, as wouldsome proponents of conflict perspectives, who could classify professional athletesas part of the wealthy, dominant class of people who are often not impacted by thelaw. While one should be cautious when generalizing the results beyond the group ofNFL players analyzed here, this finding echoes the results of Sailofsky and Shor'sanalysis (2022) of NBA athletes, which shows that NBA players do not seem to benegatively impacted by arrests for acts of VAW if they are performing at even anadequate level. For most players, the results of this study suggest that theargument that accusations that do not result in conviction  are nearly or just as dangerous as acts of violence themselves ismisplaced.While I was not able to discuss how arrests may impact the public image andendorsement opportunities of players, for most players, their employment in the NFLis largely unaffected. Moreover, given the size of NFL rosters, the frequentturnover of players on teams and in the league more generally, and the NFL's generalstrategy of branding and promoting teams rather than individual players, mostplayers have very little opportunity for sponsorship to begin with. The retention ofplayers on teams and their continued presence in the league is a much more suitableindicator of career consequences.For those who argue that players’ careers should indeed not suffer from arrestsbecause the North American legal system operates under the premise that the accusedis innocent until proven guilty, it is important to note that professional athletesare generally convicted at lower rates than those in the general population .MoreoveThese general findings also stand in contrast with research on other employmentcontexts, which show that criminality has a significant negative effect onemployment, particularly for Black men . Even thAccording to the logic of deterrence and expressive theories of punishment, the lackof career punishment faced by NFL players accused of acts of violence against womencould stunt efforts to reduce this violence, both at the professional and amateurlevels. Studies from various non-sport contexts also suggest that the threat offuture extralegal consequences and adverse effects in the labor market related toarrests may serve as a deterrent to future crime and violence . Given tbelieved thesearrests hurt their careers. Second, from a more practical perspective, one must alsobe cautious about how much power is granted to the NFL and its organizations topunish players without any sort of legal or investigatory process. As privateorganizations that are largely unaccountable to the public, there is a danger inproviding these organizations with carte blanche to disciplineplayers without due process, even in cases of alleged violence. This tension—betweenensuring accountability for players’ bad behavior and ensuring that these playersare treated fairly as workers by their powerful employers—is especially salient inthe case of VAW by NFL players, as these situations usually involve both a group ofalleged perpetrators who historically have been mistreated (young Black men) and agroup of victims who historically have been ignored and underserved (women victimsof men's violence).However, two notes of caution are important here. First, though my analysis indicatesthat the fear that allegations of VAW hurt player careers is empirically false formost NFL players, if this fear nevertheless exists, there could still be a deterrenteffect among these players. To know whether NFL policies or team decision-makingregarding violence has a deterrent effect on players’ likelihood to commit acts ofVAW, one would need to assess whether players It is also important to note that even changes in the extralegal sanctioning of NFLplayers are unlikely to eliminate off-the-field violence. There are many reasons forthe continued prevalence of VAW perpetrated by athletes, and only some of them maybe related to a lack of sufficient response and consequences. Professional sports,and professional football especially, is in many ways a breeding ground forfraternal, toxic masculinity that promotes violence and domination . StartinAnother complicating factor in explaining how football might lead to violence is therisk of chronic traumatic encephalopathy (CTE) among players, due to repeated blowsto the head and to concussions . NFL plaNonetheless, social-control mechanisms do not seem to carry much weight in the NFL,which has implications for football players at all levels. While one must becautious about generalizing the results of this study to other sports or employmentcontexts, which could have context-specific rules, policies, and cultures thataffect how these arrests impact career outcomes, this analysis emphasizes the wayelite performers are differentially impacted by legal and extralegal systems ofcontrol. As Jacobs (2021) writes, “if you’re exceptionally gifted at football, theNFL will almost always find a place for you no matter what you do in your sparetime.”At the very least, an arrest for an act of VAW does not spell the end of anNFL player's career. In fact, when assessing his future in the league, an NFL playershould be much more concerned with their performance on the field than theirbehavior off of it.There are some limitations to this research that must be noted. As mentioned above,while the 117 arrested players represent the full population of NFL players arrestedfor an act of VAW over the past 20 years, this population remains relatively small.It is possible that this small sample explains the lack of statistical significanceon some of the variable coefficients, and in the coefficients for some of theinteraction terms. However, even with this relatively small sample, the models usedstill had good predictive power, and the interaction term for how the impact of anarrest changes over time was statistically significant.It is also important to reiterate that career length only represents one importantproxy for career outcomes. While this variable accounts for how long a playerremains employed and earning a salary in the NFL, it does not account for the dollaramount of that salary, and whether they earn any other income through endorsement orsponsorship.do impact athlete careers, as well as why other cases do not.Interviews of sport decision makers, as well as content analysis of media and socialmedia, may be effective methodological tools for this type of analysis.The qualitative analysis could also be used to examine why certain specific cases ofVAW Finally, future research could examine how the #metoo movement has impacted prominentathletes accused of acts of VAW. While the most highly publicized stories from thismovement have revolved around those in the entertainment industry, professionalathletes are part of a similar group of famous, economically powerful men who areoften protected from legal and extralegal consequences.


Research in healthcare is increasingly focused on quality assurance and continuous quality improvement aiming to promote service quality. Satisfaction is a key endpoint in outcomes research and service benchmarking, along with “traditional” clinical outcomes. What controls stroke survivors’ satisfaction differs among qualitative studies’ conclusions, but there is general consensus on the importance of communication, improvement in activity, and engagement in goal setting. This review aims to collect and synthesise studies of the satisfaction of stroke survivors with rehabilitation services. A systematic search was conducted in seven electronic databases, including CINAHL, OVID, Pedro, Scopus Midline, Web of Science, and PubMed. The database search yielded 1339 studies, while one additional work was identified through hand searching. After removing duplicates, 74 studies were read in full, and after resultant exclusions, 12 qualitative studies were systematically reviewed, extracted, and appraised by two reviewers independently (HAS and RT) and the third reviewer (CS) was available for any disagreement. Five analytical themes were identified: Healthcare Professional–Patient Relationship (HCP), Delivery Service, Perceived Patient Autonomy (PPA), Expectations Shape Satisfaction, and Culture Influences Satisfaction. The studies of survivors’ satisfaction, experiences, and their rehabilitative needs with the services they receive have provided different factors that influence their satisfaction during rehabilitation in different countries worldwide. However, the context in which the studies were conducted is quite limited, and more detailed studies are required for many underexplored contexts. Survivors commonly report being dissatisfied with the rehabilitation services they receive in various contexts . FactorsPeoples et al.  providedThis qualitative SR will be reported and presented in a Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for SR (PRISMA-ScR) flow diagram ,13. To sThe reference list of included studies was screened to identify additional studies. All databases were accessed via the Nottingham University (NUsearch) platform, and study authors were contacted via email by the researcher whenever there was missing information or any need for clarification. Identified citations were checked and uploaded into EndNote Insert X9/2018 , and duplicates were removed .This protocol is now registered on PROSPERO with ID: CRD42022376532.Two reviewers (HAS and RT) appraised the studies, and they were blinded to each other’s assessments. This review used the standard JBI Checklist for Qualitative Research (JBICQR). Based on a comparative analysis of three online appraisal instruments’ ability to assess validity in qualitative research, the domains examined in the JBICQR were found to be more coherent and sensitive to the assessment of validity than other commonly used tools in qualitative studies . Table 2The standardized data extraction tool from JBI SUMARI was used to extract the qualitative data from papers included in the review. This was completed by the primary reviewer (HAS) and was checked by the second reviewer (RT).Qualitative research findings in this review underwent thematic synthesis to create new themes related to the SR question and objectives. This approach enables the author to produce new concepts and hypotheses while staying close to the primary finding from the studies . Figure n = 9) were published during the last 15 years. The studies represent a broad geographical distribution over nine countries, including one each for Canada  just took my cigarettes and lighter away from me” .“You know you won’t walk again” .Survivors expressed their satisfaction with their therapists during the rehabilitation process in different settings, including the outpatient department, physiotherapy, occupational therapy, and during their stay in the hospital:“He tried to help me”.“[Named occupational therapist] was very good. She helped me to move my fingers” .“They were more of a support” .On the other hand, a sense of disappointment and dissatisfaction was reported, such as a lack of therapist attention to patients’ needs:“He was busy chatting with others about other issues”.“She was more interested in people who had got motor neuron diseasesI think rather than … aphasia” .Concerns were also expressed regarding the amount of rehabilitation input:“If I could get more therapy I might improve” .Time is needed to develop better relationships between HCPs and their patients during rehabilitation; however, survivors reported dissatisfaction with lack of HCP continuity during their rehabilitation and described this experience as “time lost”:“To me, it is like it is [negatively] affecting the treatment” .Participants expressed their satisfaction with the equipment available to them in the rehabilitation setting because it allowed for better training and good movement during training:“Using equipment such as springs, pulleys… very useful” .Conversely, younger stroke patients commonly reported a lack of flexible rehabilitation training, and those who were offered such services found that they did not match their needs and desires, which affected their experiences and thoughts about getting better in rehabilitation:“Later, when I got home and faced reality, I realised that I needed more support” .One participant was placed in a geriatric ward despite being only 52 years old. Consequently, the surroundings and activities that were offered did not match the participant’s needs, and they felt that they were “walking alongside” the process of rehabilitation . Additio“The clinic in our area has nothing for my disease, no exercises” .Moreover, the privacy and crowding in other rehabilitation settings were reported as factors of dissatisfaction among survivors:“So crowded with no privacy”.“Waited a long time”.“Prefer to have my therapy at home” .In terms of follow-up, either in a rehabilitation setting or in participants’ homes, patients showed dissatisfaction with the lack of follow-up meetings with their regular therapist and“Got annoyed with [having] no follow-up when I got back [home]” .Looking at the studies conducted in remote areas, such as in Northern Australia, revealed a more acute lack of supportive care. For instance, Aboriginal people appeared to struggle to receive appropriate follow-up and transportation to attend rehabilitation appointments:“It was just my wife at home, and my son”.“A taxi was sent for me, but it wasn’t on a regular basis”.“Family members provided support to patients” .In Quebec, survivors reported a lack of assistance when getting home or follow-up care, so they had to engage family members during the recovery process, and they experienced difficulties finding an appointment for rehabilitation sessions:“Difficulty obtaining assistance or care at home”.“Had to be very persistent before receiving an outpatient appointment” .These findings indicate the struggles that survivors experienced and the dissatisfaction they consequently experienced with the healthcare services they received.PPA is a term that refers to a person’s right to be involved in their care journey and to express their ability to participate . In thisConversely, a sense of low PPA was commonly reported in relation to patients’ perceptions of how they were treated during their rehabilitation:“It has something to do with being… We’re just sick people, nothing else” .Elderly survivors stressed their special rehabilitative needs; they needed more information and education about their status (“I’m not well educated”)  to be inSatisfaction with rehabilitation appears to be met when certain factors relating to the survivor’s expectations from the services provided or from HCPs are achieved. Three of the included studies reported that participants were very optimistic regarding recovery following the stroke:“With physiotherapy, we can have full recovery” .More adherence and compliance with therapy inherently promote stroke recovery improvement. However, some participants did not expect much by the end of their therapy journey and held a grim view that it would be difficult to resume a “normal” life after the rehabilitation process. This was particularly acute among those who had initially experienced high levels of optimism, which they subsequently came to regard as unrealistic:“There will be no treatment for a patient that can be adequate”.“You wonder how you are going to cope”.“I thought I’d just come out and be as good as gold” .Importantly, patients who expected to return to complete normality  were notably less satisfied with the services they received. Lawrence et al.  reported“Care providers seemed to know little about stroke and its consequences, such as aphasia” .The previously reported findings reflect how expectations may influence the sense of survivors’ satisfaction.Two of the included studies highlighted the influence of cultural background on survivors’ satisfaction. Gender preferences in therapy sessions were also highlighted in one study conducted in the Middle East, because female patients expressed difficulties in being treated by males. If they needed home care therapy, they might ask for a non-HCP women to help because only male therapists are able to provide home care:“Only male therapists work with survivors in their homes in Jordan” .Religious or spiritual needs could be one factor contributing to patients’ satisfaction in rehabilitation. In China, for example, participants expressed their need to pray, which reflects the possible benefits of spiritual care for stroke patients, a hitherto underexplored area of stroke rehabilitation:“Often pray to have peace and good health; it’s helpful to pray at that time and I feel better psychologically. Good, it’s helpful to pray” .A key aspect found in this review was the collaboration between patients and HCPs. Thompson  suggesteIt is essential to explore survivors’ satisfaction with rehabilitation services because of the importance of reflecting on the actual views of survivors and improving the level of care provided in practice. The relationship between the findings in this SR were identified in terms of five overarching themes: HCP–Patient Relationship, Delivery Service, Perceived Patient Autonomy (PPA), Expectations Shape Satisfaction, and Culture Influences Satisfaction. Survivors expressed their satisfaction with the help and support they received in different settings, such as physiotherapy ,23 and oIn this review two studies reported that patients were dissatisfied either with the amount of rehabilitation provided or the type of training ,21, whicp < 0.001). This indicates the importance of regular follow-up, not only to reduce readmission , but also to keep survivors motivated to recover and to stay satisfied.An enriched Service Delivery environment seems to draw positive impressions from survivors during rehabilitation, and increases their satisfaction and hopes of possible recovery . As prevPPA refers to patients’ right to express thoughts and choices during decisions related to their medical status . In thisDespite rehabilitation satisfaction studies tending not to consider the age of patients and time post-stroke, some researchers noted that elderly survivors had rehabilitative needs that differed from their younger counterparts, including with regard to autonomy, and information delivery  . This suThe convenience that survivors require in rehabilitation is not only linked to the training program, but also to being acknowledged as individuals and being involved when decisions are made . HoweverAnother finding was concerning how expectations can shape satisfaction; what survivors expect of their experience with rehabilitation, and the healthcare services provided in general must be considered by healthcare planners, policy makers, and managers because this experience, as much as the technical Quality of Care, will determine how people use the system and how they benefit from it . In thisExpectations about what healthcare services can provide to patients have been studied widely in different contexts, such as in emergencies, during which 70% of healthcare dissatisfaction was related to real or perceived problems involving physician communications, which influence patients’ expectations . Not meeCultural differences include factors related to beliefs, languages, behaviours, and prevailing national cultural characteristics . The infLimitations of this review are related to the nature of the studies included and therefore include the factors discussed in the above analysis. For example, in terms of study design, a lack of theoretical framework, and an absence of details concerning data collection time and analysis were prevalent problems. Other limitations concerned the trustworthiness of data relate to the qualitative and subjective analysis of participants’ descriptions, for example, the rich presentation of participants’ responses, reliability checks, and detailed information on how the analysis were performed. Furthermore, the time post-stroke  was not mentioned in four studies, which raises questions regarding the accuracy of the reported satisfaction and experience with rehabilitation ,22,23,26Despite the generally good quality of the reviewed studies, some did not provide a clear definition of satisfaction with rehabilitation itself, given that it is a subjective experience among individuals. Further, a pragmatic decision was made to include only papers published in the English language, which led to the exclusion of four potentially relevant studies due to being published in other languages.Studies of survivors’ satisfaction and their rehabilitative needs with the services they receive yielded different factors influencing their satisfaction during rehabilitation in different countries worldwide, but the context in which the studies were conducted were quite limited, and more detailed studies are required for many underexplored contexts.


The oxidized low-density lipoprotein receptor 1 (LOX-1) is one of the most important receptors for modified LDLs, such as oxidated (oxLDL) and acetylated (acLDL) low-density lipoprotein. LOX-1 and oxLDL are fundamental in atherosclerosis, where oxLDL/LOX1 promotes ROS generation and NF-κB activation inducing the expression of IL-6, a STAT3 activator. Furthermore, LOX-1/oxLDL function has been associated with other diseases, such as obesity, hypertension, and cancer. In prostate cancer (CaP), LOX-1 overexpression is associated with advanced stages, and its activation by oxLDL induces an epithelial-mesenchymal transition, increasing angiogenesis and proliferation. Interestingly, enzalutamide-resistant CaP cells increase the uptake of acLDL. Enzalutamide is an androgen receptor (AR) antagonist for castration-resistant prostate cancer (CRPC) treatment, and a high percentage of patients develop a resistance to this drug. The decreased cytotoxicity is promoted in part by STAT3 and NF-κB activation that induces the secretion of the pro-inflammatory program and the expression of AR and its splicing variant AR-V7. Here, we demonstrate for the first time that oxLDL/LOX-1 increases ROS levels and activates NF-κB, inducing IL-6 secretion and the activation of STAT3 in CRPC cells. Furthermore, oxLDL/LOX1 increases AR and AR-V7 expression and decreases enzalutamide cytotoxicity in CRPC. Thus, our investigation suggests that new factors associated with cardiovascular pathologies, such as LOX-1/oxLDL, may also promote important signaling axes for the progression of CRPC and its resistance to drugs used for its treatment. Lipoproteins are macromolecular complexes that transport lipids in a soluble form through blood circulation . LipoproProstate cancer (CaP) is the most prevalent malignancy among adult men in the developed world . AdvanceHigh concentrations of oxLDLs were observed in patients with advanced CaP, and the overexpression of LOX-1 has been associated with high Gleason scores and clinicopathological stages III and IV ,32. NotaLOX-1 activation by oxLDLs increases ROS generation in different cellular models associated with atherosclerosis progression, and has been described as an important signal for NF-κB activation . To evalTo determine the effect of LOX-1 activation by oxLDLs on the NF-κB signaling pathway, C4-2B and 22RV1 cells transfected with siRNA control or siRNA LOX-1 were treated with 50 μg/mL oxLDLs for 1 h, and the phosphorylation of p65 and IκB-α were analyzed by Western blot. The results showed that oxLDL induces p65 phosphorylation by 1.37- and 1.33-fold on C4-2B and 22RV1 cells (siRNA control), respectively. In IκB-α, the oxLDL induces the phosphorylation by 1.40- and 3.19-fold on C4-2B and 22RV1 (siRNA control) cells, respectively. In contrast, the oxLDL-induced phosphorylation of p65 and IκB-α was prevented in the LOX-1 knockdown C4-2B and 22RV1 cells. This suggests that activation of LOX-1 by oxLDLs induces the NF-κB signaling pathway activation A–C. To cNF-κB activation significantly increases the expression and secretion of pro-inflammatory cytokines, such as IL-6, which has been described as an important cytokine in CRPC generation and enzalutamide resistance ,50. To dOverexpression and increased activity of AR and its splicing variant AR-V7 have been widely associated with CRPC and enzalutamide resistance . In the The mechanism associated with AR and AV-V7 overexpression has been correlated with NF-κB and STAT-3 activation, to this part, our data suggest that oxLDLs through LOX-1 induce ROS/NF-KB/IL-6 and STAT3 axis, which indicates that AR and AR-v7 could be overexpressed by LOX-1/oxLDL. To determine this, 22RV1 cells were transfected with siRNA control and siRNA LOX-1 for 48 h and then treated with 50 μg/mL of oxLDLs. The expression of AR and AR-V7 was analyzed by Western blot, the AR activity was analyzed through its translocation to the nucleus by immunocytochemistry assay, and the expression of prostate-specific antigen  was analyzed by real-time PCR. The results showed that oxLDL induces by 1.65- and 1.7-fold the AR and AR-V7 expression in C4-2B (siRNA control) cells, respectively, and by 1.75- and 1.60-fold in 22RV1 (siRNA control) cells, respectively, compared with untreated cells. The effect of oxLDL-induced overexpression of AR and AR-V7 expression was prevented in LOX-1 knockdown C4-2B and 22RV1 cells A. Furthe50 for enzalutamide by 1.8- and 2.7-fold in C4-2B and 22Rv1 cells, respectively  of enzalutamide resistance in CRPC ,57. Our ectively . Moreoveectively A,B. In tectively A,B, sugg50 for enzalutamide in CRCP cell lines. The ROS generation induced by oxLDL/LOX-1 has been reported in many studies associated with atherosclerosis, endothelial dysfunction, and macrophage activation [LOX-1 receptor and oxLDLs are associated with the development and progression of several pathologies, such as atherosclerosis, obesity, type 2 diabetes, and different cancers ,30,31,32tivation . We extetivation . In conttivation . In conttivation ,64. In tSeveral authors have described that the activation of NF-κB by ROS induces IκBα phosphorylation-dependent or independent of IKK ,66,67. NOur results demonstrated that oxLDL treatments decrease enzalutamide cytotoxicity, an effect that is prevented when LOX-1 is silenced. These results confirm that the expression of enzalutamide resistance markers, such as AR and AR-V7, are associated with oxLDL-mediated LOX-1 activation. Our analysis demonstrated that CRPC cells co-treated with oxLDLs, and enzalutamide maintain the expression of AR and AR-V7 at the level of cells without enzalutamide treatment, strongly supporting that oxLDL decreases enzalutamide cytotoxicity mediated by LOX-1 activation.50 of AR-targeting drugs, such as enzalutamide. Thus, our results in conjunction with other investigations, demonstrate a relevant role of LOX-1 in cancer progression. These allow us to propose LOX-1 as a target in cancer therapy or, as in our study, as a target for the prevention of the resistance to enzalutamide in CRPC. In this regard, statins, an HMG-CoA reductase inhibitor, positively prevent cancer progression [Based on this evidence, it is reasonable to propose that oxLDL/LOX-1-mediated AR and AR-V7 expression in CRPC cells is a result of the NF-κB pathway activation. However, it is relevant to note that this effect could occur directly through oxLDL/LOX-1/ROS/NK-kB/AR axis activation or indirectly through the overexpression and secretion of proinflammatory cytokines, such as IL-6, which in turn act in an autocrine fashion to activate STAT3/AR axis. From this perspective, even if either of these events could justify the AR and AR-V7 overexpression, LOX-1 activation should induce an increase in the ICgression . Likewisgression . Thus, FIn conclusion, treating CRPC patients is a complex process involving using different drugs for its control. However, resistance to drugs used in CRPC, such as enzalutamide, is observed in a large percentage of patients. Our results showed for the first time that LOX-1 and oxLDLs, two critical factors associated with pathologies of lipid metabolism and CaP tumor progression, are also determinants in the resistance to enzalutamide in human CRPC cell lines through NF-κB or STAT3 signaling pathway and AR and AR-V7 overexpression. Human prostate cancer cells C4-2B and 22RV1 were grown in RPMI 1640 medium, supplemented with 2 mM L-glutamine (Hyclone), 10% fetal bovine serum, and 1% penicillin-streptomycin (GIBCO). The cell lines were maintained at 37 °C with 5% CO2. The C4-2B and 22RV1 cell lines are cell lines widely used in castration-resistant prostate cancer research. The C4-2B cell line is from LNCaP (androgen sensitive), co-inoculated in a nude mouse with human fibroblasts derived from osteosarcoma. The nude mice were castrated after eight weeks of incubation, and castration-resistant tumor cells (C4 cells) were isolated and characterized. The process was repeated to obtain the C4-2B cell line. The 22RV1 cell line is derived from xenograft that was serially propagated in mice after castration-induced regression and relapse of the parental, androgen-dependent CWR22 cell line xenograft. Both cell lines are androgen-independent but can respond to testosterone or DHT, and are able to secrete PSA. The cell lines express AR and its variant AR-V7. In this sense, it has been reported that 22RV1 expresses high levels of AR-V7 and other variants compared to C4-2B ,82. The LDL isolation and oxLDL generation were carried out, according to our previous reports ,32. The siRNA against LOX-1 were acquired from ThermoFisher Scientific (S9842). For silencing the LOX-1 RNA expression, C4-2B and 22RV1 prostate cancer cell lines were transfected with 150 pmol of siRNA/LOX-1 or siRNA/control using Lipofectamine 3000 . Two days post-transfection, LOX-1 silencing was verified by Western blot. Western blot and immunostaining were performed using standard protocols . Anti-LO® FAST qPCR KIT  and Agilent AriaMx real-time PCR system equipment. The results were analyzed as 2−ΔΔCT relative quantification. The comparative threshold cycle values were normalized for b-actin  and prostate-specific antigen (PSA)  were performed using KAPA one step SYBRC4-2B and 22RV1 cells were transfected (20.000 cells) with siRNA control or siRNA LOX-1. Then, after 48 h, cells were seeded in 96-well black plates for fluorescence analysis. Cells were pre-incubated with 5 µM CM-H2DCFDA general oxidative stress indicator  for 15 min at 37 °C and then treated with 50 µg/mL of oxLDLs during 3 h at 37 °C. As a control, C4-2B or 22RV1 cells were treated with 25 µM Trolox for 2 h and then incubated with 50 µg/mL oxLDLs for 3 h. Two experimental approaches were used to determine the effects of oxLDL/LOX-1 on NF-κB activation. On the one hand, C4-2B and 22RV1 cells transfected with siRNA control or siRNA LOX-1 for 48 h were treated with 50 µg/mL of oxLDLs for 1 h and the phosphorylation state of p65 and IκB-alpha subunit was analyzed by Western blot. On the other hand, transcriptional activity assays were performed using the luciferase reporter pHAGE NFKB-TA-LUC-UBC-dTomato-W  . To thisFurthermore, co-treatment with 50 µg/mL of oxLDLs and ROS inhibitor Trolox, three NF-κB inhibitors: triptolide (TLP) , bay 11-7082 (BAY) , caffeic acid phenethyl ester (CAPE)  and a chemical inhibitor of STAT3 activity Stattic  were used in the ROS and pathways inhibition. Enzalutamide  was dissolved at 40 mM in DMSO and stored at −20 °C. The cytotoxic effects of enzalutamide on C4-2B and 22RV1 LOX-1 knockdown cells were determined by clonogenic assay. C4-2B and 22RV1 parental or LOX-1 knockdown cells were seeded on 6-well plates and pre-incubated with or without 50 µg/mL of oxLDL. Then, the cells were incubated with increasing concentrations of enzalutamide (0–50 mM) and cultured for 14 days at 37 °C. Colonies were stained with crystal violet, images were photo-documented using the LI-COR ODYSSEY CLX equipment, and total colony numbers were counted for each condition.


Current strategies to inhibit androgen receptor (AR) are circumvented in castration-resistant prostate cancer (CRPC). Cyclin-dependent kinase 7 (CDK7) promotes AR signalling, in addition to established roles in cell cycle and global transcription, providing a rationale for its therapeutic targeting in CRPC.The antitumour activity of CT7001, an orally bioavailable CDK7 inhibitor, was investigated across CRPC models in vitro and in xenograft models in vivo. Cell-based assays and transcriptomic analyses of treated xenografts were employed to investigate the mechanisms driving CT7001 activity, alone and in combination with the antiandrogen enzalutamide.CT7001 selectively engages with CDK7 in prostate cancer cells, causing inhibition of proliferation and cell cycle arrest. Activation of p53, induction of apoptosis, and suppression of transcription mediated by full-length and constitutively active AR splice variants contribute to antitumour efficacy in vitro. Oral administration of CT7001 represses growth of CRPC xenografts and significantly augments growth inhibition achieved by enzalutamide. Transcriptome analyses of treated xenografts indicate cell cycle and AR inhibition as the mode of action of CT7001 in vivo.This study supports CDK7 inhibition as a strategy to target deregulated cell proliferation and demonstrates CT7001 is a promising CRPC therapeutic, alone or in combination with AR-targeting compounds. Prostate cancer is the second most common malignancy in men worldwide and a leading cause of cancer-related death . The andCyclin-dependent kinase 7 (CDK7) is a recognised anticancer drug target due to its regulatory roles in cell division and transcription , 12. As The multiple roles of CDK7 commend it as a drug target for CRPC. However, a fundamental understanding of the mechanistic effects of selective CDK7 inhibition in CRPC is currently lacking. In a previous study, the covalent CDK7 inhibitor THZ1 was used , howeverCT7001 was provided by Carrick Therapeutics. Apalutamide, enzalutamide, darolutamide and bavdegalutamide were purchased from MedChemExpress. Mibolerone was purchased from PerkinElmer.2. Cell line authenticity was confirmed using short tandem repeat analysis performed through the MWG Eurofins Human Cell Line Authentication service. All cell lines were regularly tested for Mycoplasma infection using the MycoAlert Detection Kit (Lonza).LNCaP, C4-2, VCaP, DU145, PC3, PNT1A, BPH-1 cell lines were obtained from the ATCC as frozen stocks. 22Rv1 and 22Rv1 FL-AR KO were a gift from Dr Luke Gaughan (Newcastle University) . C4-2B cTm) of CDK targets were determined using a Boltzmann sigmoidal curve (least squares fit) fitted through the average normalised data points from all human lines available in the Meltome Atlas [The melting temperatures  [Cell number was assayed using the Sulforhodamine B (SRB) assay as previously described . To deteculator) .CT7001 combinations with AR-targeted therapies were tested in a 6 × 5 matrix in LNCaP, C4-2B, and PC3 cells. Cell numbers on days 0 and 3 were assayed using the SRB assay. Percent growth inhibition was calculated relative to vehicle control using day 3 values corrected by subtracting day 0 values. A file containing growth inhibition (%) data for each cell line was uploaded on the SynergyFinder 2.0 web application (synergyfinder.fimm.fi) . Bliss iCaspase 3/7 activation assays were performed using the Caspase-Glo 3/7 Assay System (Promega), 72 h after treatment with CT7001. Luminescence was measured using the VICTOR Light luminometer (PerkinElmer). Signal was normalised to cell number on day 3 measured by SRB assay.Total RNA was extracted from treated cells using the RNeasy Mini kit (QIAGEN). cDNA was synthesised from 1 µg of RNA with oligo-dT primers using RevertAid First Strand cDNA Synthesis Kit (ThermoFisher). Quantitative Polymerase Chain Reaction (qPCR) was performed in a QuantStudio 7 Flex Real-Time PCR System (Applied Biosystems) using SYBR Green Real-Time PCR Master mix (Invitrogen) and primers designed using Primer-BLAST , and analysed using the Guava Muse Cell Analyser (Luminex).GCTCCCACTTGTGTCAAAA-3’ for pSV-S515A-AR, 5’-GCAGAGTGCCCTATCCCGAGCCCACTTGTGTCAAAA-3’ for pSV-S515E-AR, and 5’-GCAGAGTGCCCTATCCCGATCCCACTTGTGTCAAAA-3’ for pSV-S515D-AR. Competent DH5α E. coli cells were transformed with the plasmids, plasmid DNAs were purified using QIAprep Spin Miniprep Kit (QIAGEN) and subjected to Sanger sequencing (GeneWiz) to confirm the presence of the expected mutations.The following plasmids have been previously described: pSV-AR encoding human AR, TAT-GRE-E1B-LUC encoding AR-responsive luciferase reporter, and BOS-β-galactosidase encoding a constitutive reporter . PlasmidCOS-1 cells were transfected as previously described  with 1 μLNCaP/Luc or transfected COS-1 cells were lysed with Reporter Lysis Buffer (Promega). Luciferase activity was assayed using the Steadylite Plus kit (PerkinElmer). β-galactosidase activity was assayed using the Galacto-Light Plus system (Invitrogen). Light emission was measured using a VICTOR Light luminometer (PerkinElmer). For LNCaP/Luc lysates, luciferase activity was normalised to protein concentration. For COS-1 lysates, luciferase activity was normalised to β-galactosidase activity.6 C4-2B cells resuspended in a volume of 100 µL serum-free media and Matrigel Basement Membrane Matrix High Concentration (Corning) in a 1:1 ratio. Animals were randomised into treatment groups (n = 10 per group) when tumour volume reached 90 mm3. Mice initiated on specific treatments were housed in separate cages. Individual mice were treated at 4 mL/kg body weight with vehicle (5% DMSO and 30% SBE-β-CD dissolved in distilled water), 50 mg/kg CT7001, 25 mg/kg enzalutamide, or 50 + 25 mg/kg CT7001 + enzalutamide (combination). Treatments were administered orally once daily for 21 days by two unblinded investigators. Tumour size was measured every 3–4 days using digital calipers by two unblinded investigators, and tumour volumes were calculated using the formula: length × width × height × π/6. Mice were sacrificed on the last day of treatment, 2 h after administration of the final dose.C4-2B cells were expanded by passaging twice weekly and harvested during the exponential growth phase. Cells were counted and viability was assessed using the trypan blue exclusion assay before implantation. Based on a priori sample size calculation using G*Power 3 software, a total of 40 male NSG mice (6-8-week-old) were purchased from Charles River (UK) and allowed to acclimatise for 1 week. Mice were injected subcutaneously with 2.5 × 10Whole blood was collected via cardiac puncture in EDTA-coated tubes and spun immediately at 7500 rpm for 5 min in a benchtop centrifuge. Plasma was collected, snap frozen in liquid nitrogen and sent to the Cambridge Biochemistry Assay Lab  for analysis. Mouse aspartate transaminase (AST), mouse urea, and human free PSA levels were measured using a Siemens Dimension EXL analyser.Dissected tumours were fixed in 4% paraformaldehyde for 48 h and embedded in paraffin blocks. Sections of 4 µm were stained with the following antibodies: Ki67 , P-S5 PolII , P-S2 PolII , and P-T161/T160 CDK1/CDK2 . Staining was visualised using Dako REAL DAB + Chromogen (Agilent Technologies). Slides were counterstained with haematoxylin. Staining was quantified in a blinded fashion in two different fields of view per tumour in three animals per group.t test. Multiple comparisons were carried out using one-way or two-way analysis of variance followed by Dunnett’s or Šídák’s multiple comparisons test unless otherwise stated. In vivo tumour growth rate was defined as the slope of the linear regression described by tumour volume data points over time. All experiments were conducted with at least two biological repeats. Significant p values are displayed as follows: *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Where no asterisks are displayed, no significant differences were found.Statistical analyses were carried out using GraphPad Prism v9.0. Pairwise comparisons were performed using the Student’s Total RNA was extracted from 30 mg frozen tumour using the Monarch Total RNA Miniprep Kit (NEB). RNA library preparation and sequencing was performed by Novogene (UK) using 1 µg total RNA. Briefly, sequencing libraries were generated using NEBNext Ultra RNA Library Prep Kit for Illumina (NEB). Library quality was assessed using the Ilumina Bioanalyser 2100 system (Agilent Technologies). The library preparations were sequenced on a NovaSeq 6000 System (Illumina) and paired-end reads were generated. Clean reads were obtained from raw reads in FASTQ format by removing adaptors, poly-N sequences, and low-quality reads. Paired-end clean reads were aligned to the reference genome (GRCh38) using STAR v2.5 software. HTSeq v0.6.1 was used to count the read numbers mapped of each gene. Raw sequencing data and a matrix containing raw counts were submitted to the GEO repository (accession number GSE198488).P values were adjusted using the Benjamini and Hochberg’s approach. Genes with an adjusted p value (padj) <0.05 were assigned as differentially expressed. Gene clustering was performed using the degPatterns clustering tool from the DEGreport package (v1.24.1) [Differential expression analysis was performed using the DESeq2 R package (v1.28.1) . Statistv1.24.1) .Gene set enrichment analysis (GSEA) was performed using GSEA 4.1.0 software (Broad Institute) using the normalised counts table estimated by DESeq2 for all genes and the Hallmark collection of gene sets (Molecular Signatures Database) . StatistPrevious in vitro kinase assays showed CT7001 selectively targets CDK7, although higher concentrations additionally inhibited the activities of other CDKs . TransitTm, defined as the temperature which aggregates 50% soluble protein. The Tm of the different CDKs ranged between ~47 and 53 °C  as well as the maximal measured GR value , and summarised these values for each prostate line tested in Fig. 50 ranged between 0.08 and 0.65 µM for malignant prostate cell lines, suggesting potent growth inhibition consistent with selective engagement with CDK7 based on CeTSA  were respectively 3.5-fold and 1.7-fold higher than the average GR50 for malignant lines. In LNCaP cells, inhibition of CDK7 activity was associated with markedly reduced retinoblastoma (Rb) phosphorylation, a downstream target of cell cycle CDKs, while levels of CDK7, cyclin H and MAT1 were unaffected  cells in LNCaP, C4-2B, and, to a lesser extent, in DU145 cells, consistent with Rb inhibition, and an increase in tetraploid (G2/M) cells in PC3 cells  inhibition studies. GR curves and associated GR metrics are not confounded by the number of cell divisions taking place over the course of the experiment  , and thuted Fig. . In contely Fig. . This inlls Fig. . The G2/ell line . Despiteell line . CollectA cytotoxic tendency was observed in GR studies in most prostate lines except DU145 and PC3 cells, which are p53-deficient. This prompted us to investigate whether CT7001 causes activation of the p53 pathway. Indeed, accumulation of p53 protein and increased serine-15 (S15) phosphorylation occurred in p53-intact LNCaP and C4-2B cells after 48 h of treatment, but not in loss-of-function p53-mutant DU145 cells or PC3 cells Fig. . ActivatGiven previous reports suggesting a coactivator role of CDK7 in AR-dependent transcription , 25, we To investigate whether the mechanism of AR repression involves the reported phosphorylation of AR by CDK7 at S515, we employed AR luciferase reporter assays in COS-1 cells transfected with expression vector encoding either wild-type AR or AR in which S515 was replaced either by non-phosphorylatable alanine (S515A-AR), or by the phosphomimetic aspartic acid (S515D-AR) or glutamic acid (S515E-AR). Cells were co-transfected with an androgen-responsive luciferase reporter and β-galactosidase reporter as internal transfection efficiency control. Androgen treatment stimulated the transcriptional activity of wild-type AR and mutant AR proteins in a concentration-dependent manner Fig. . Relativ50 of 0.68 µM, and by all AR-Vs tested, with EC50 ranging between 0.42 and 1.07 µM  or constitutively active AR-Vs that lack the LBD  and, additionally, a significant reduction in tumour growth rate in the combination arm compared to enzalutamide alone (p = 0.0156) but no significant difference between the growth-rates of CT7001-treated and combination-treated tumours (p = 0.3145)  male mice with established subcutaneous C4-2B xenografts were assigned into 4 treatment groups: vehicle, CT7001 (50 mg/kg) alone, enzalutamide (25 mg/kg) alone, or a combination of enzalutamide and CT7001. On day 21 of daily oral treatment, CT7001 and enzalutamide monotherapy reduced final tumour volume by 52% and 50% respectively, while combination therapy reduced final tumour volume by 73%, compared to vehicle treatment Fig. . A signi45) Fig. . Mean tu45) Fig. . Tumour 45) Fig. . All tre45) Fig. . Additio45) Fig. . There w45) Fig. . Immunoh45) Fig. . In addin = 3–4 per group). Unsupervised principal component analysis (PCA) captures 28.94% of the gene expression variance in the first two PCs and shows separation of the different groups, with the enzalutamide and combination groups clustering furthest from the vehicle group  prostate cancer cell lines to THZ1, an inhibitor of CDK7/CDK12/CDK13, has been previously reported . With reNotwithstanding, complete loss of AR expression is rare in CRPC, where reactivation of AR signalling drives resistance to androgen deprivation therapy. This frequently involves mutation or loss of the AR LBD. In this report, we demonstrate that CT7001 treatment successfully inhibits growth and AR-dependent transcriptomes of cell lines modelling these scenarios: LNCaP cells carry a point mutation in the AR LBD (T877A) which confers promiscuous activation by alternative ligands, VCaP cells display AR gene amplification in addition to expressing constitutively active AR-Vs, while the engineered 22Rv1 FL-AR KO line displays ligand-independent AR transcriptome driven by AR-Vs and intrinsic resistance to AR-targeting therapies. Direct inhibition of ectopically expressed AR-Vs was also demonstrated. As CT7001 mechanistically functions independently of the AR LBD, unlike all approved AR-targeted compounds, it is a good therapeutic candidate for CRPC tumours with AR reactivation. We also explored the therapeutic potential of combining CDK7 inhibition with the widely prescribed antiandrogen enzalutamide and found additive tumour growth repression in vivo, likely mediated largely through CT7001’s potent repression of cell cycle progression. Further research is warranted to determine whether, in models displaying resistance to antiandrogens, AR pathway suppression by CT7001 becomes essential for therapeutic efficacy.50 in LNCaP prostate cancer cells. Therefore, inhibition of the Rb and AR pathways may be sufficient to explain the growth inhibition observed at lower concentrations. This is in line with recent work using the CDK7-selective covalent inhibitor YKL-5-124, which caused no change in PolII phosphorylation at growth-inhibitory doses [Considering the more widespread effects of CDK7 on PolII-dependent transcription, mounting evidence suggests targeting transcriptional kinases using selective inhibitors could provide a sufficient therapeutic window to be effective without the initially feared toxicity , 55. Ourry doses , 22, whiry doses . HoweverTP53 status is associated with response to CT7001 therapy in patients with metastatic hormone receptor-positive/HER2-negative breast cancer [Several questions remain regarding the mechanism of action of CT7001 in prostate cancer. Firstly, activation of p53 presumably contributes to CT7001-induced apoptosis. The highly metastatic PC3 cell line, which does not express p53 protein, appears resistant to apoptosis in response to CT7001 treatment. In addition, activation of p53 transcriptional programme has been demonstrated to sensitise some cancer cells to CDK7 inhibition by promoting pro-apoptotic pathways . As the t cancer . Secondlt cancer . This, iIn summary, the data presented here demonstrate that the orally bioavailable CDK7 inhibitor CT7001 impedes malignant cell growth by targeting proliferation pathways and, in addition, downregulates oncogenic AR signalling and induces apoptosis in CRPC models. This multifaceted mechanism of action drives additive combinatorial activity with the antiandrogen enzalutamide in the C4-2B xenograft model of advanced CRPC. Therefore, this study supports CDK7 inhibition as a therapeutic strategy for CRPC and provides a rationale for new combination regimens consisting of CDK7 inhibitors and antiandrogen therapy, all the more so as CT7001 demonstrated acceptable safety profile with evidence of target engagement in clinical trials.Supplemental FiguresSupplemental MethodsARRIVE checklist


The expression of androgen receptor (AR) is not commonly tested or studied in uterine cancers, unlike estrogen receptor (ER) and progesterone receptor (PR) which are positive in most endometrial carcinomas. In this series, we evaluated the expression of AR and its comparison to ER and PR in different types of endometrial cancers and have reviewed the literature.The status of AR, ER, and PR expression were evaluated in 71 cases which were categorized into endometrial endometrioid cancer (EEC), non-endometrioid endometrial cancers (NEEC), and metastatic carcinomas of endometrium. Expression of the receptors were compared to each other as well as to mismatch repair proteins (MMR), p53, and body mass index (BMI) using Fisher’s Exact test in the StatPlus software.In EECs, the positivity was 97% for all the three receptors. In NEEC, positivity rates were 68%, 48%, and 35% for AR, ER, and PR respectively. In Metastatic carcinomas, AR and ER positivity was seen in 100% while PR was positive in 75% of the cases. In all cancers, the rates were 17% (11/66) for MMR loss, 57% (30/53) for p53 aberrant expression, and 76% (54/71) for the patients with BMI of ≥ 25 (kg/m2).AR is expressed in a high percentage of endometrial cancers. Its significance is more evident in high-grade NEEC where ER and PR may not be expressed. These findings warrant further evaluation of AR expression and candidacy of this pathway as a potential therapeutic target in endometrial cancers. Endometrial cancers (ECs) are the most common gynecologic malignancies in the United States . The groThe effect of androgen action in endometrial cancer is poorly understood. ARs are expressed in the endometrium throughout the menstrual cycle, even as androgens play a role in the regulation of endometrial apoptosis . While iThe purpose of this study was to investigate the expression of AR and compare the findings to that in ER and PR among the different types of ECs.This retrospective study was approved by the Institutional Review Board (IRB #22–000672) at UCLA David Geffen School of Medicine. Since this project was a retrospective study on the archived information and the tissue blocks, no patients were involved and the need for patient’s consent had been waived by the UCLA IRB. The Epic Beaker laboratory information system was used to conduct a search for endometrial cancers between March 2016 to June 2022. The inclusion criteria for the search included cases who had ECs, had been tested for estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemical (IHC) stains for patient care and their results had been reported. Among which, mismatch repair (MMR) and p53 test results were also obtained if they had been ordered during the routine pathology practice. In addition, some demographic information, including age, body mass index (BMI), surviving months following the initial diagnosis, and the treatments, was recorded. For all primary endometrial malignancies, the nomenclature and FIGO  grades were recorded according to the established WHO guidelines [Leica BOND III auto-Stainer was used to carry out the staining steps. Rabbit monoclonal anti-AR antibody (clone: SP107) was obtained from Cell Marque and used at 1:100 dilution. The paraffin sections were deparaffinized and the epitopes were retrieved in BOND-ER-2 solution for 30 minutes followed by the antibody incubation for an additional 15 minutes. BOND Refine Detection kit was used to detect the bonded antibody molecules.The IHCs for ER, PR, mismatch repair (MMR), and p53 had already been performed for the clinical or diagnostic purposes on these cases and the data were available in the patients’ clinical records. Only AR IHC was carried out on the respective tissue sections for this study.For ER IHC, Epredia rabbit monoclonal anti-ER (clone SP1) was used. Additionally, anti-PR monoclonal mouse antibody (clone PgR-636) had been obtained from DAKO. ER and PR IHC staining was carried out according to the established methodology in our department which was similar to AR as described. Breast tissues were used as control for ER and PR, while prostate and testicular tissues were utilized as control for AR.For MMR IHC stains, MLH1  and MSH2  had been obtained from Cell Marque. PMS2  and MSH6  had been utilized from Epitomics and using normal cellular components as control.For p53 IHC, mouse monoclonal antibody (clone DO-7) by Novacastra, had been obtained from Leica using high-grade serous carcinoma tissue as control.Scoring for ER and PR had been carried out as per the current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for breast cancer where any cellular reaction of 1% or more is considered as positive , 17. An Loss of MMR protein expression is widely tested by IHC throughout the world . The staTP53 missense mutation tends to accumulate p53 protein in the nuclei of the cancer cells. Normally, the scattered nuclear IHC reaction which is present in less than 30% of the cells, is referred to as wild type (WT). There are two general IHC patterns when the mutation occurs, one is complete absence of the reaction and second is diffuse and strong nuclear and sometimes cytoplasmic staining of more than 80% of the cells. The two patterns are referred to as aberrant expressions (AE) . The AEs2) as defined in WHO guidelines: underweight (BMI < 18.5), normal or desirable weight (BMI = 18.5 to <25), over-weight (BMI = ≥25 to <30), and three classes of obesity (BMI ≥30) [We used body mass indices (kg/mBMI ≥30) . In thisp-values of 0.05 or less were used to indicate a significant difference between two data sets.Fisher’s Exact test, in a 2x2 contingency table , was useAndrogen, estrogen, and progesterone receptors’ stain results were tabulated based on three diagnostic categories: EEC , NEEC , and MET (metastatic carcinoma). The NEEC category included high-grade malignancies comprised of serous carcinoma (SCA), clear cell carcinoma (CCCA), malignant mixed Müllerian tumor or carcinosarcoma (CS), dedifferentiated/undifferentiated endometrial carcinoma (DECA), and mesonephric-like adenocarcinoma (MNCA). The three steroid hormone receptors were considered positive when the nuclear stains were present in 1% or more of the cancer cells , 17. TheIn the design and conduct of this work, we adhered to the parts of REMARK guidelines germane to our study . Since wAmong the 937 cases with endometrial cancers obtained during the search period, the computer returned 71 surgical pathology cases matching the inclusion criteria. For this study, AR stain was performed and evaluated on these 71 cases. Patients’ ages ranged from 41 to 88 years with a median of 65. All patients were postmenopausal except for three  where 60 cases were positive for AR as opposed to 49 for PR , Fisher Exact tests did not return significant 9 for PR .p-values of <0.0001) indicating non-concordance of MMR with 17% (11/66) losses as to 76% (50/66) for ER, 68% (45/66) for PR, and 85% (56/66) for AR expression  who had MMR IHC tests performed for patient care purposes. Mismatch repair gene proteins had been lost in 17% (11/66) of cases and were intact in 83% (55/66) of the patients . Cases wpression .p-value = 0.01), where p53 had an aberrant expression in 57% (30/53) whereas AR had been expressed in 81% (43/53) of the cases. The comparative differences between p53 and ER/PR were not statistically significant  had p53 IHC tests performed for patient care purposes. The cases with no p53 were excluded from the statistical test. There were 57% (30/53) of patients who had aberrant expression of p53 . The recnificant .2) or greater were observed in 76% (54/71) of the total patients, among which 48% (34/71) had a BMI of 30 or more falling in the obese classes [p-values when the receptor stains were compared to BMIs of ≥25 in the “All” category, indicating concordance of the BMIs with receptor stains .Twenty cases were FIGO grade-1, thirteen had grade-2, and three with grade-3. AR, ER, and PR stains were positive in 97% (35/36) of the patients as shown in Table 1 and represented in p-values of <0.0001) indicating lack of concordance with 17% MMR loss versus 97% ER/PR/AR expressions , again non-concordant with 13% versus 96% of the three receptors  intact proteins whereas loss of MLH1 and PMS2 were seen in 4 and loss of MSH2 and MSH6 were observed in 2 cases . MMR losressions . Other ceceptors .p-values of 0.003) by Fisher’s Exact test where 69% of the patients were overweight (BMI ≥ 25) as opposed to 97% ER, PR, and AR expressions  were overweight (MBI ≥ 25) of which 44% (16/36) were obese (BMI ≥ 30) in this category. Comparison of the BMI to the receptors, resulted in significant differences  when ER was compared to PR and AR stains  when the comparison was made between AR and PR (The cases were comprised of SCA (13 patients), CCCA (6 patients), CS (6 patients), DECA (5 patients), and MNCA (1 patient) as listed in Tables R stains . HoweverR and PR .p-value ≤ 0.03) when compared to each receptor except for PR  using Fisher’s Exact test . ER and PR, on the other hand, were significantly different  meaning a concordance between BMI and AR  cases of CCCA were negative for ER and PR staining whereas 50% of them had expressed AR. Also, one of the SCA cases while being positive for AR was negative for ER and PR . Only one case in this group had her primary carcinoma excised in our institution  loss is a frequent genetic finding in both prostatic and type 1 endometrial cancers that results in activation of AKT signaling , 31. Koip-value = 0.4) by the Fisher’s exact test  of cases as opposed to 85% of AR expression in this series. Although, BMI of ≥25 did correlate with the three receptors, there was an exception. In NEEC, AR did correlate with the BMI where there was no significant difference Click here for additional data file.


Purpose: The aim of this study was to assess the reliability and validity of the Arabic version of the patient-specific functional scale (PSFS-Ar) in patients with multiple sclerosis (MS) disorder. Materials and Methods: Reliability and validity were examined in patients with multiple sclerosis using a longitudinal cohort study design. One hundred (N = 100) patients with MS were recruited to examine the PSFS-Ar, test–retest reliability ), construct validity (using the hypothesis testing method), and floor–ceiling effect. Results: A total of 100 participants completed the PSFS-Ar . The PSFS-Ar showed an excellent test–retest reliability score . The SEM of the PSFS-Ar was 0.80, while the MDC95 was 1.87, indicating an acceptable measurement error. The construct validity of the PSFS-Ar was 100% correlated with the predefined hypotheses. As hypothesized, the correlation analysis revealed positive correlations between the PSFS-Ar and the RAND-36 domains of physical functioning (0.5), role limitations due to physical health problems (0.37), energy/fatigue (0.35), and emotional well-being (0.19). There was no floor or ceiling effect in this study. Conclusions: The study results showed that the PSFS-Ar is a self-reported outcome measure that is useful for detecting specific functional difficulties in patients with multiple sclerosis. Patients are able to express and report a variety of functional limitations easily and effectively, as well as to measure their response to physical therapy. The PSFS-Ar is, therefore, recommended for use in Arabic-speaking countries for clinical practice and research for patients with multiple sclerosis. Multiple sclerosis (MS) is an autoimmune disease that attacks the myelin sheaths around the axons of the central nervous system, leading to reduced mobility and adversely affecting the patient’s quality of life ,2. MS coPeople with MS typically experience a range of disabilities, as described in the International Classification of Functioning, Disability, and Health (ICF) Core Set for MS ,17. AccoPatient-reported outcome measures (PROMs) fall under the category of outcome measurements, in which patients report changes in their health status without influence from healthcare providers ,25,26,27The PSFS has been validated for use in many patient populations, such as individuals with musculoskeletal problems, spine conditions, and Parkinson’s disease . Recent Patients with MS usually suffer from functional limitations . The PSFIn the study of patients with MS, the reliability and validity of the PSFS-Ar were examined using a longitudinal cohort study method. The study was ethically approved by the Institutional Review Board at King Saud University (no. E-19-4530). Informed consent was obtained from all the participants involved in the study.Participants in this study were recruited if they had a confirmed diagnosis of MS from a neurologist at King Khalid University Hospital (KKUH). Patients with MS were invited to participate in the study. All patients with MS signed the consent form and completed the study without recording any withdrawals. Patients with MS were included in the study, regardless of the stage of the disease. The study included participants who were 18 years of age or older and who were capable of communicating, understanding the questions, walking with or without assistance, and reading and writing in Arabic. The study excluded participants with other neurological diseases and relapses less than 30 days prior to assessment. The study was conducted at King Khalid University Hospital’s (KKUH) Physical Therapy Outpatient Clinic in Riyadh, Saudi Arabia.A total of three to five activities were listed as difficult or impossible by participants . Each paThe RAND-36 assesses general health, addressing concepts relevant to people of all ages, diseases, and treatments. . It is aThe Global Rating of Change (GRC) scale is a commonly used outcome measure to monitor changes in patients’ health status . A GRC sDuring the first session, participants completed the RAND 36-item Health Survey and PSFS-Ar for the first time (T1). In the second session, which was 4 to 7 days after the first session, participants completed the PSFS-Ar for the second time (T2) to assess the test–retest reliability of the PSFS-Ar. In the second session, participants were also asked to rate the change in their health status using the Global Rating of Change (GRC) scale to determine that the patient’s health status did not change between T1 and T2. Participants signed inform consent forms prior to participation.2,1), with a 95% confidence interval for absolute agreement, whereby an ICC value equal to or greater than 0.7 was considered to indicate sufficient reliability [Test–retest reliability for the PSFS-Ar was examined among participants who completed the PSFS-Ar twice and reported no change in their condition between the two testing sessions. Test–retest reliability was examined using the Intraclass Correlation Coefficient model 2,1 (ICCiability . To ensu95) was used to quantify the true change in the PSFS-Ar beyond the measurement error. The MDC95 was calculated using the following formula: MDC95 = SEM × 1.96 × √2 [To examine the measurement error associated with repeated measurements using the PSFS-Ar, the standard error of measurement (SEM) and the Bland–Altman plot were used. The SEM was calculated using the formula SEM = SD × √(1 − ICC), where SD is the pooled standard deviation and ICC is the test–retest intraclass correlation coefficient . The min.96 × √2 .Floor and ceiling effects of the PSFS-Ar were considered present if more than 15% of the participants reached the lowest score (0) or the highest score (10). If the floor or ceiling effects are present, this leads to limited content validity .The construct validity of the PSFS-Ar as a measure of activity and participation in patients with MS was assessed by examining the following four pre-defined hypotheses: (1) the PSFS-Ar was hypothesized to have at least a moderate positive correlation with the physical functioning domain of the RAND-36; (2) the PSFS-Ar was hypothesized to have at least a moderate positive correlation with the role limitations due to the physical health problems domain of the RAND-36; (3) the PSFS-Ar was hypothesized to have at least a moderate positive correlation with the energy/fatigue domain of the RAND-36; (4) the PSFS-Ar was hypothesized to have a weak correlation with the emotional well-being domain of the RAND-36.The strength of the correlation was considered moderate if the absolute value of the correlation coefficient ranged from ≥0.3 to <0.6 and a weak correlation if it was <0.3, with ≥0.60 indicating a good correlation . For norThe minimum required sample size was based on the consensus-based standards for the selection of health measurement instruments (COSMIN) that recommended a sample size of 50 as the minimum requirement to investigate floor and ceiling effects and construct validity . For tesA total of 100 patients with MS participated in the current study. Their demographic characteristics are presented in 2,1 = 0.87; 95% confidence interval 0.75–0.93). The mean score and standard deviation values for the PSFS-Ar were 5.43 ± 2.19 and 5.33 ± 2.10 for the first and second testing sessions, respectively . The relative reliability of the PSFS-Ar was excellent , and no participants achieved the lowest score of 0, representing 0% of the total sample. Thus, the PSFS-Ar did not have any floor or ceiling issues.The purpose of this study was to evaluate the measurement properties of the PSFS-Ar for patients with MS, including test–retest reliability, measurement error, construct validity, and floor and ceiling effects. The results of the current study support the test–retest reliability and construct validity of the PSFS-Ar and suggest that the scale has acceptable measurement error with no floor or ceiling issues.The test–retest reliability of the PSFS-Ar was evaluated using the ICC model 2,1. An ICC greater than 0.70 is considered to have acceptable retest reliability according to current recommendations . In the For the purpose of quantifying the PSFS-Ar measurement error, the SEM and MDC were used . In order = 0.64) in comparison to (r = 0.50) in this investigation. In a systemic review, the PSFS and RAND-36 physical functioning were correlated between r = 0.22 and r = 0.83 in lower-extremity conditions [r = −0.79) [The correlational findings in this study support the construct validity of the PSFS-Ar as a measure of activity limitation in patients with MS, as 100% of the pre-defined construct validity assumptions were supported . Given tnditions . Moreove= −0.79) . Hobrat r = 0.19). The PSFS-Ar and the emotional well-being domain of the RAND-36 measure different constructs and, thus, were expected to show a low correlation. The low correlation reported in our study is in line with a previous study (r = 0.13) [r = 0.37). This correlation was expected, as physical health problems could affect, and be related to, the PSFS score that reflects a similar construct (activity limitation). Furthermore, the correlation of the PSFS-Ar with the energy/fatigue domain of the RAND-36 was moderate (r = 0.35). Fatigue is one of the most common symptoms of MS [As expected, this study showed that there is a weak correlation between the PSFS-Ar and the emotional well-being domain of the RAND-36 ( = 0.13) . The corms of MS . The resThere were no floor or ceiling effects in the PSFS-Ar, where only 3% of participants achieved the highest score and 0% achieved the lowest score. In the presence of a floor and ceiling effect, 15% of participants will achieve the highest or lowest score . In the There are many practical implications of the PSFS-Ar. It can be used in daily clinical practice as well as in research studies to measure activity limitations in Arabic-speaking patients with MS. The PSFS-Ar allows rehabilitation specialists to quantify activity limitation, according to the culture and lifestyle of Arabic speakers with MS. Moreover, rehabilitation specialists can confidently interpret patient’s scores in the PSFS-Ar to represent the extent of activity limitation.In this study, there are some limitations. Participants were not objectively assessed on their cognitive abilities. During interaction with the participants, researchers subjectively checked that all participants were cognitively capable of completing the outcome measures. Moreover, the responsiveness of the PSFS-Ar in patients with MS has not been examined. Thus, research on the responsiveness of the PSFS-Ar to patients with MS is needed in the future.To the best of our knowledge, this is the first study to assess PSFS-Ar measurement properties in patients with MS. The study results show that the PSFS-Ar is a self-reported outcome measure that is useful for detecting specific functional difficulties in patients with multiple sclerosis. Patients are able to express and report a variety of functional limitations easily and effectively, as well as measure their response to physical therapy. The PSFS-Ar has excellent test–retest reliability, acceptable measurement errors, and evidence supporting its construct validity with no floor or ceiling problems. The PSFS-Ar is, therefore, recommended for use in Arabic-speaking countries for clinical practice and research for patients with MS.