PSA gene, suggesting a role for p68 in facilitating RNAP II transcription of AR mediated genes. These results suggest p68 is important in facilitating β-Catenin and AR transcriptional activity in PCa cells.The DEAD box RNA helicase p68 (Ddx5) is an important androgen receptor (AR) transcriptional co-activator in prostate cancer (PCa) and is over-expressed in late stage disease. β-Catenin is a multifunctional protein with important structural and signalling functions which is up-regulated in PCa and similar to p68, interacts with the AR to co-activate expression of AR target genes. Importantly, p68 forms complexes with nuclear β-Catenin and promotes gene transcription in colon cancer indicating a functional interplay between these two proteins in cancer progression. In this study, we explore the relationship of p68 and β-Catenin in PCa to assess their potential co-operation in AR-dependent gene expression, which may be of importance in the development of castrate resistant prostate cancer (CRPCa). We use immunoprecipitation to demonstrate a novel interaction between p68 and β-Catenin in the nucleus of PCa cells, which is androgen dependent in LNCaP cells but androgen independent in a hormone refractory derivative of the same cell line (representative of the CRPCa disease type). Enhanced AR activity is seen in androgen-dependent luciferase reporter assays upon transient co-transfection of p68 and β-Catenin as an additive effect, and p68-depleted Chromatin-Immunoprecipitation (ChIP) showed a decrease in the recruitment of the AR and β-Catenin to androgen responsive promoter regions. In addition, we found p68 immunoprecipitated with the processive and non-processive form of RNA polymerase II (RNAP II) and show p68 recruited to elongating regions of the AR mediated  The onset and progression of prostate cancer (PCa) is driven by the transcriptional function of the androgen receptor (AR), and ablation of androgens is an effective strategy at early stages of the disease β-Catenin is an integral component of the Wnt pathway, playing a role in signal transduction. The cytoplasmic stabilisation and nuclear accumulation of β-Catenin is the ‘hallmark’ of the activation of the Wnt signalling pathway (see reviews The RNA helicase p68 (Ddx5) is a growth- and developmentally- regulated prototypic member of the DEAD box family of helicases. p68 functions in many cellular processes commonly dysregulated in cancer including processing of pre-mRNA and alternative splicing, cell proliferation, microRNA processing  associates independently with β-Catenin and p68 in PCa cells in-vitro conditions, p68 and β-Catenin are able to directly bind independently of AR and androgens. (N.B. the higher band in the β-Catenin immunoprecipitation blot is a non-specific band detected by the myc antibody). However, endogenous protein immunoprecipitated from nuclear LNCaP extracts showed the β-Catenin-p68 interaction was facilitated in the presence of androgens , but conversely in the LNCaP-AI cell line the interaction was facilitated in the absence of androgens   . (N.B. tPSA gene PSA gene (in-between the enhancer and promoter region (E-P), exon 1, intron 2, exon 3, intron 3, exon 5 and 3′dsF regions), to establish whether p68 was recruited to sites other than transcriptional initiation. (N.B. The primer location and sequence information for these regions can be found in PSA gene). p<0.05*) differential enrichment of AR upon R1881 treatment (10 nM) at set time points  to the ARE III region of the PSA gene, as demonstrated previously p<0.005**) cyclical dissociation-association recruitment of p68 upon R1881 treatment (10 nM) to the ARE III region, although recruitment was not limited to this region as E-P, Exon 3, Intron 3, Exon 5 and 3′dsF regions also showed significant enrichment. Recruitment did not reach significance at ARE I, Exon 1 and Intron 2 regions. These findings imply p68 is associated with both transcriptional initiation and elongation forms of RNAP II and enriched not only at the transcriptional start sites of a AR regulated gene but at exonic, intronic and 3′dsF regions, indicating a possible function for p68 in facilitating the processing of AR gene transcription by RNAP II.We have previously described p68 as functioning as an ‘adaptor’ or ‘coupling’ protein that may coordinate the tightly integrated processes of transcriptional initiation, elongation and mRNA splicing in AR-regulated gene expression PSA gene upon p68 knockdown by siRNA p<0.0494* and protein∼90% at 72 hrs post transfection), did not significantly alter β-Catenin mRNA or protein expression levels compared to control  siRNA in LNCaPs cells, in the presence or absence of R1881 (PSA promoter in control (NS) siRNA transfected LNCaP cells as expected (p<0.0077**). Similarly, androgen stimulation increased AR recruitment to the ARE III enhancer region of the PSA gene 9 fold in control (NS) siRNA transfected cells (p<0.0008***). A similar pattern of attenuation in AR recruitment was also seen at KLK2 . Interestingly, a similar pattern in attenuation of β-Catenin recruitment upon p68 targeted siRNA knockdown was also seen. Increased β-Catenin recruitment to both ARE I (0.6 fold) and ARE III (0.8 fold) regions was observed upon androgen stimulation in control (NS) siRNA transfected cells compared to non-treated cells . A similar pattern of β-Catenin de-recruitment was repeated at the KLK2 and TMPRSS2 promoter in p68 depleted cells  androgen treatment (3 Luc reporter activity in the presence or absence of R1881 demonstrating that β-Catenin does not directly affect p(ARE)3 Luc reporter activity in the absence of AR. However, co-expression of AR and β-Catenin showed an 8 fold increase in p(ARE)3 Luc reporter activity upon R1881 treatment, confirming β-Catenin as a co-activator of the AR consistent with previous findings 3 Luc reporter activity following R1881 treatment, also confirming p68 as a co-activator of the AR consistent with previous findings. (N.B. p68 has been shown to not affect p(ARE)3 Luc reporter activity directly in the absence of AR p<0.0011**) increase in p(ARE)3 Luc reporter activity upon R1881 treatment, 10 fold higher than AR and β-Catenin co-expression, demonstrating p68 has a significant additive effect on AR and β-Catenin transcriptional activity. This was also seen with another androgen regulated PSA promoter luciferase reporter (p(PSA) Luc), whereby co-expression of AR, β-Catenin and p68 constructs showed a significant 8 fold (p<0.0057**) increase in reporter activity, 5 fold higher than AR and β-Catenin co-expression, confirming the additive effect of p68 on β-Catenin and AR transcriptional activity . This is similar to a previous report that found p72 was unable to enhance AR transcriptional activity of the p(ARE)3 Luc reporter Given that p68 and β-Catenin interact in PCa cells and p68 facilitates the recruitment of β-Catenin to androgen responsive gene promoters. We next chose to investigate the combined effect of co-expression of p68 and β-Catenin on the transcriptional activity of the AR using androgen-dependent luciferase reporter assays in COS-7 cells. The AR-mediated p(ARE)PSA luciferase reporter data to confirm an interaction between p68, β-Catenin and the AR in PCa cells. We initially confirmed a direct in-vitro p68-β-Catenin interaction by transient transfection of constructs into the AR negative COS-7 cell line (which was not androgen dependent). However, upon further investigation we found under endogenous conditions the p68-β-Catenin interaction was facilitated in the presence of androgens in the LNCaP PCa cell line, but conversely in the hormone refractory (LNCaP-AI) derivative of this cell line (representative of the CRPCa disease type), the interaction was facilitated in the absence of androgens. This is similar to a finding of increased endogenous AR/β-Catenin complex formation in a castrate resistant PCa mouse xenografts model, where no interaction between AR and β-Catenin was detected in the presence of androgens PSA luciferase reporter data showed co-transfection of p68 and β-Catenin constructs had an additive effect on the transcriptional activity of AR in the presence of androgens. These data suggest that p68 and β-Catenin work together as co-activators to additively enhance the transcriptional activity of the AR which interestingly, may have implications in the progression of the CRPCa disease type.In this study, we describe a functional interaction between p68, β-Catenin and the AR in the nucleus of PCa cells. The AR has been shown to signal through the Wnt/β-Catenin pathway in PCa as an adaptation to castrate levels of androgens PSA promoter, and KLK2 and TMPRSS2 promoter regions in control (NS) siRNA transfected LNCaP cells, which was subsequently attenuated in p68 depleted cells. The observed β-Catenin recruitment to the same androgen regulated promoter regions was reduced in p68 depleted LNCaP cells upon androgen treatment, but to levels lower than non-treated cells (similar to the IgG control). This is an interesting finding as it suggests that a reduction in the recruitment of β-Catenin to the promoter regions of androgen regulated genes in p68 depleted cells is not just a consequence of less AR available for recruitment, and implies that p68 function is required to load β-Catenin to transcriptionally regulated regions of androgen responsive genes.We also showed using knockdown of p68 expression by siRNA oligonucleotide combined with ChIP, that p68 was required for optimal recruitment of the AR and β-Catenin to promoter regions of androgen regulated genes. Androgen stimulation facilitated recruitment of the AR to both ARE I and ARE III regions of the PSA gene, but also in-between the enhancer and promoter region and at exonic and intronic regions. Collectively, this suggests p68 has the potential to support RNAP II function at elongating regions of the PSA gene. ChIP recruitment data was gathered at set time points of androgen stimulation and recruitment to all areas of the PSA gene was seen in the absence of androgens. Immunoprecipitation data also showed p68 interacted with both forms of RNAP II in the absence of androgens. This suggests that p68 is possibly pre-loaded to transcriptionally active areas of the PSA gene ready for the start of transcription in a similar mode by which RNAP II is found ‘poised’ at transcriptionally active gene regions prior to transcriptional initiation PSA gene suggesting a role for p68 in the termination and polyadenylation of AR mediated transcripts, consistent with a previous report that described p68 involved in transcriptional deactivation in Drosophila promoting mRNA transcript release et al. published a manuscript which demonstrated p68 (Ddx5) and the highly homologous p72 (Ddx17) protein have a dual role in the control of transcription of the pro-migratory NFAT5 transcription factor (in addition to their role in facilitating the inclusion of NFAT5 exon 5), in breast cancer cells The role of p68 in alternative mRNA splicing is well documented , but also during elongation and transcriptional progression and may have the potential to influence the expression of AR regulated genes through direct interaction with RNAP II. Taken together, these data provide evidence that p68 is required for transcriptional regulation of AR mediated genes and is of importance in the recruitment of AR co-factors to the AR transcriptional complex. This may be of significance in the progression of the CRPCa disease type.2. LNCaP and PC3 cells , were cultured in RPMI-1640 and COS-7 cells (ATCC) in D-MEM media, both supplemented with 1% L-glutamine (Invitrogen) and 10% foetal calf serum (FCS) (Invitrogen). LNCaP-AI cells derived from the LNCaP cell line following continuous passaging in steroid depleted media for 8 months to gain androgen independence have been described previously All cells were grown at 37°C in 5% CO3 Luc, PSA promoter Luc, pCMV-β-galactosidase, pcDNA3-AR, pcDNA3-p68, pcDNA3-p72 3+-Myc6-β-Catenin and pSG5-AR constructs were kind gifts from Professor Ralf Janknecht  The following plasmids have been described previously, p(ARE)3Luc or p(PSA)Luc, pcDNA3-AR or pSG5-AR and pCMV-β-galactosidase using Superfect (Qiagen), as described previously 3-p68, pcDNA3-p72 and pCS3+-Myc6-β-Catenin fusion constructs were co-transfected into cells as detailed in figure legends. The range of plasmid levels indicated in figures (+ and ++) corresponds to 50 and 100 ng respectively. Luciferase activity was corrected for corresponding β-galactosidase activity to give relative activity. All reporter assays are the mean of at least three independent experiments ± standard error.Luciferase reporter assays were performed in COS-7 cells co-transfected in triplicate with 0.1 µg of p(ARE)LNCaP or LNCaP-AI cells were cultured in SDM for 48 hours prior to 10 nM R1881 treatment, (8 hours). Cells were nuclear extracted using CelLytic™ NuCLEAR™ Extraction kit  with an extraction buffer salt concentration of 330 mM in the presence of protease inhibitors , and RNase A (100 µg/ml - Sigma). All immunoprecipitation experiments were performed as described previously AGGCTACTGTTGGATTGATTCGAA and Reverse CATGATTTGCGGGACAAAGG), p68 and GAPDH oligonucleotides  small interfering RNA (siRNA) . The following regions were assessed for p68, AR and IgG (control antibody) occupancy: AREIII, AREI, in between the enhancer and promoter regions (E-P), Exon I, Intron 2, Exon 3, Intron 3, Exon 5 and the 3′dsF. The primer sequences for ARE III, ARE I and E-P have been described previously PSA gene. ChIP sonication products were optimised to robustly yield fragments of less than 500 bp to allow discrimination between all regions examined. ChIP results are representative of at least three independent experiments ± standard error. IgG control ChIP was performed on the longest androgen treatment set time point (120 min).LNCaP cells seeded in 90mM dishes were reverse transfected with p68 or NS siRNA as described above and cultured in SDM for 48hours prior to 10 nM R1881 treatment for 90 minutes. ChIP was undertaken on siRNA treated cells using both AR and β-Catenin antibodies and an IgG antibody was included as a control, as described previously t test was used with GraphPad Prism 6 software , to compare differences as stipulated in figure.The independent sample Figure S1Immunoprecipitation of endogenous p68 and β-Catenin in an AR negative PC3 cell line do not interact. Cropped immuno-blot images of PC3 whole cell lysates, immunoprecipitated (IP) with either p68 or β-Catenin antibody and probed sequentially with β-Catenin and p68. Extract samples contain whole cell lysate and protein G sepharose with no antibody present, and Control (Con) samples contain antibody and protein G sepharose in extraction buffer only.(TIF)Click here for additional data file.Figure S2Over-expression of p68 additively enhances the activity of β-Catenin mediated AR transcription by an AR mediated PSA promoter luciferase reporter. COS-7 cells were transiently transfected in triplicate with 0.1 µg of p(PSA)Luc reporter, 0.1 µg pSG5-AR, 0.1 µg of pCMV-β-galactosidase and 0.05 µg of pcDNA3-p68 or pCS3+-Myc6-β-Catenin constructs (+10 nM R1881). Luciferase activity was corrected for the corresponding β-galactosidase activity to give relative activity. The range of plasmid levels (+ and ++) corresponds to 50 and 100ng respectively. Data is shown relative to AR activity alone (set as 1) and from at least three independent luciferase assay experiments (+/− SE).(TIF)Click here for additional data file.Figure S3Over-expression of p72 does not enhance the activity of β-Catenin mediated AR transcription. COS-7 cells were transiently transfected in triplicate with 0.1 µg of p(ARE)3 luciferase reporter, 0.1 µg pcDNA3-AR, 0.1 µg of pCMV-β-galactosidase and 0.05 µg of pcDNA3-p72, p68 or pCS3+-Myc6-β-Catenin constructs (+10 nM R1881). Luciferase activity was corrected for the corresponding β-galactosidase activity to give a relative activity. The range of plasmid levels (+ and ++) corresponds to 50 and 100 ng respectively. Data is shown relative to AR and β-Catenin activity alone (set as 1) and from at least three independent luciferase assay experiments (+/− SE).(TIF)Click here for additional data file.Table S1Sequences for primers used in ChIP experiments and location of primers on the PSA gene.(TIF)Click here for additional data file.


Most problems faced by modern human society have two characteristics in common - they are tragedy-of-the-commons type of problems, and they are global problems. Tragedy-of-the-commons type of problems are those where a commonly shared resource is overexploited by free riders at the expense of everyone sharing the resource. The exploitation of global resources such as clean air and water, political stability and peace, etc. underlies many of the most pressing human problems. Punishment of free riding behavior is one of the most frequently used strategies to combat the problem, but the spatial reach of sanctioning institutions is often more limited than the spatial effects of overexploitation. Here, we analyze a general game theoretical model to assess under what circumstances sanctioning institutions with limited reach can maintain the larger commons. We find that the effect of the spatial reach has a strong effect on whether and how the commons can be maintained, and that the transitions between those outcomes are characterized by phase transitions. The latter indicates that a small change in the reach of sanctioning systems can profoundly change the way the global commons can be managed. Many of the most pressing problems of human society are global problems: environmental pollution, overpopulation, nuclear proliferation, global warming, etc. At their core, most of these problems present a tragedy-of-the-commons-like situation th-order free rider problem” which cannot be solved by such a simple sanctioning system In order to prevent the tragedy of the commons caused by free-riding behavior, a number of strategies have been proposed. In particular, punishment of free-riding has received considerable attention. In its simplest form, punishment emerges from individuals who are willing to punish exploiters at a personal cost to themselves. If the threat and cost of being punished are greater than the potential gain from exploiting, such a simple sanctioning system can temporarily maintain the commons th-order free rider problem” and maintain the commons despite the apparent inefficiency caused by the continuous costs that accrue even in the absence of exploiters A more complex sanctioning system, where individuals contribute to a punishment pool, rather than paying the cost of punishment themselves, has shown to be a potential solution to this dilemma. In such a “pool punishment” system, exploiters are punished by an institution paid for by pool punishers As the commons of the 21st century have become increasingly global , a problem of scale has emerged M players on a square lattice with M cells (implemented as a torus), where each player occupies a cell. We assume that the players do not move between games. Players can participate in a game if they are no more than an interaction distance ip away from a focal player. To play a game, players can contribute and receive from the commons as described above. Punishers can only punish other participants that are no more than a punishment distance pp away from the punishing player. Since the game is non-compulsory, players are given the option to stay out of the game and instead receive a payoff σ. The probability that two randomly chosen players of a game are able to punish each other is parameterized as a coverage coefficient cC, which can be calculated asδ is a set of players within the interaction range of the initiating player, and α is one if and only if the distance between players i and j is less than or equal to pp and zero otherwise. From this we can calculate the effective values of b, β, g and γ such that Cb′ = b C, β′ = β, Cg′ = g C, and C.γ′ = γ C Note that the cost paid by pool punishers is unmodified because they contribute to the punishing pool even when there are no defectors within their punishment range.To investigate the effect of sanctioning systems with limited reach, we consider a spatial environment with a total of β>0, pool punishers have a lower payoff than the other cooperating strategies and thus can be invaded by cooperators or peer punishers. Then, defectors can invade a population of peer punishers ifFrom this, we can now determine under what circumstances the commons can be maintained by punishment . In a non-compulsory game, defectors will always be invaded by non-participants intained . If the intained .β even if they are not currently punishing any players, and thus they can be invaded as long asCC wheng = b), the range of CC for which (4) can be met will be non-zero  holds. Pool punishers have to pay  commons . If the  commons . It thennon-zero . Thus, uCC, β should be small whereas b should be large. That is, in order to protect the global commons with non-global sanctioning systems, the contribution cost to a sanctioning institution should be minimized while the costs imposed on non-cooperators should be maximized CC can have profound effects on whether the commons can be maintained, and if so, by which type of sanctioning system. Furthermore, while previous work has argued that peer punishment is outcompeted by pool punishment when second order punishment is permitted We've presented here a simple model of a spatial public goods game to address the problem of scale that has emerged as many of the most pressing issues facing modern societies have become global. While the simplicity of the model cannot capture every detail of the real world complexities inherent to governing the commons, it allows us to formalize the effects of some key parameters that are common to all sanctioning institutions, such as the costs associated with punishment. In particular, as can be seen from Eq. (4), in order for pool punishment to emerge under even small values of ip<∞)  . OverallN-1 other players that are no more than an interaction distance ip away from the focal player partake in a game with the focal player. In this model, a player cooperates by donating an amount c to a commons. This donation is then multiplied in value by a factor r and evenly distributed to the rest of the participants We developed a simple model implementing a spatial public goods game that reflects the fundamental dilemma of the tragedy of the commons. A public goods game models individuals' contributions to the common good. Specifically, each player is given the choice to donate to the common good or not. These contributions are then multiplied by a constant and evenly divided amongst the other players. Because a player receives the same amount regardless of its own donation, a rational player would not contribute to the commons. More formally: in each game, an initial focal player is selected randomly. Then a set of N players cooperate by contributing c which is then multiplied by a constant r and equally divided among the other players. In this case, all players will receive a payoff ofXY defectors, a defector will receive a payoff of , and a cooperator will receive a payoff of ,σ instead of the part of the resource pool that a player would otherwise receive X cooperators, Y defectors, and Z nonparticipants, the probability that a participant will not be able to play with any other players isX+Y>1, there is a non-zero probability of a game taking place, and it is assumed that a game will take place given a sufficient number of attempted games.We begin by defining a very basic public good game where all of the g. To engage in this punishment, a peer punisher must pay γ per defector punished. In a game with X cooperators, Y defectors, and W peer punishers, a cooperator will receive a payoff ofWe will now allow for the possibility of peer punishment. A peer punisher is a cooperator that fines every defector that it plays with a penalty β each round to maintain a punishment pool. This punishment pool then fines every defector by amount b for every pool punisher the defector cheats. If a game is played with V pool punishers, W peer punishers, X cooperators, and Y defectors, a pool punisher will receive a payoff ofbV from (13) and (14). Since peer punishers can differentiate between pool punishers and themselves, it is possible that peer punishers can engage in second order punishment of pool punishers also. However, this does not effect the dynamics.We can also allow for pool punishment. A pool punisher contributes i and j with payoffs iP and jP. We can use a simple social learning functioni will imitate player j. We will assume that each player will randomly choose another player to consider updating. Note that if s→∞, player i will always imitate player j when j>PiP, and player i will imitate player j with a 50% probability when j = PiP. Otherwise, player i will not imitate player j. Furthermore, a player may randomly switch to a new strategy with a probability μ. We will assume that μ is small enough that mutation is rare and likely to occur only when the population's strategies are uniform Consider two players M players where M – 1 players have the same strategy, and one player has a new strategy. As before, the players divide into groups of N players to play a game. After these games have been played, a player is chosen to update using (16). We can model the frequency of the new strategy using a birth and death process M players with the new strategy are absorbing states. The probability that the new strategy successfully invades the population is the probability that the random walk reaches the latter state. We define this probability as i→jP.Now consider a world with M players that have the same strategy, one of the players must first mutate into the new strategy, then that strategy must replace the other M–1 players' strategies as shown above. In our model, there are a total of 5 strategies, so the probability that a mutation will result in a specific strategy is 1/4. From this, we can build a 5 state Markov chain where each state represents a uniformFor a new strategy to invade a world with We can then take the limiting distribution of the chain to find the long term average frequency of each of the strategies δ of players in that area. The N players that will play together are randomly chosen from this set. However, some of these players may not be within the punishment distance PP of each other, so their ability to punish will be lowered. The probability CC that two players randomly chosen from the set are able to punish each other isα is one if the euclidian distance between players i and j is less than PP and zero otherwise. Since the two players are not always able to punish each other, their effective values of b, β, g and γ areCC decreases.Given a location and a play distance, we can find a set CC is below the a certain point. Let us begin with a single defector trying to invade a population of peer punishers. If we assume that M is much larger than N, it is unlikely that the defector will try to imitate one of the players it cheated, but instead a peer punisher who's payoff was not lowered because of being cheated or having to pay to punish. The cheated peer punishers are also more likely to consider imitating someone other than the defector. If there is more than one defector, the probability of imitating a player that is not a defector or has not been cheated goes down, and defectors have an easier time spreading. Thus, the ability of peer punishers to sufficiently punish the initial defector determines which side of the phase transition the game is on. By combining (10) and (11) and using the effective parameters defined in (19), we can show that this transition occurs atCC and separates the values of CC where pool punishers are able to stop defectors from invading and where they are not. The reason that this transition happens at a higher value of CC than the one for peer punishers is because all pool punishers contribute to punishment, whereas only peer punishers that are actively punishing have their payoffs lowered. As with (20), we can use (12), (15) and (19) to show that this transition occurs atCC.Regardless of whether second order punishment is allowed, we see a sharp transition from a fairly even spread of strategies to peer punishers being the dominant strategy. This transition occurs because peer punishment is unable to prevent the invasion of defectors when


Regaining independent ambulation is the top priority for individuals recovering from stroke. Thus, physical rehabilitation post-stroke should focus on improving walking function and endurance. However, the amount of walking completed by individuals with stroke attending rehabilitation is far below that required for independent community ambulation. There has been increased interest in accelerometer-based monitoring of walking post-stroke. Walking monitoring could be integrated within the goal-setting process for those with ambulation goals in rehabilitation. The feedback from these devices can be downloaded to a computer to produce reports. The purpose of this study is to determine the effect of accelerometer-based feedback of daily walking activity during rehabilitation on the frequency and duration of walking post-stroke.Participants will be randomly assigned to one of two groups: feedback or no feedback. Participants will wear accelerometers daily during in- and out-patient rehabilitation and, for participants in the feedback group, the participants’ treating physiotherapist will receive regular reports of walking activity. The primary outcome measures are the amount of daily walking completed, as measured using the accelerometers, and spatio-temporal characteristics of walking . We will also examine goal attainment, satisfaction with progress towards goals, stroke self-efficacy, and community-integration.Increased walking activity during rehabilitation is expected to improve walking function and community re-integration following discharge. In addition, a focus on altering walking behaviour within the rehabilitation setting may lead to altered behaviour and increased activity patterns after discharge.NCT01521234ClinicalTrials.gov  Stroke results in sensorimotor impairments, reduced balance control, and reduced aerobic function, which can limit the capacity for independent community ambulation -3. RegaiGoal setting is an essential part of rehabilitation but its use may be more ‘common sense’ rather than being grounded in sound psychological theory -26. ScobResearchers have begun to investigate the utility of ambulatory monitoring using accelerometers . We deveThe primary objective of this study is to determine if feedback about characteristics of daily walking activity, provided to patients and their treating therapists, will increase walking activity in a group of individuals receiving rehabilitation post-stroke. We hypothesize that, compared to a control group who do not receive feedback via the treating physiotherapists, those who receive accelerometer-based feedback of daily walking activity as part of a goal-setting process will show: increased total daily walking activity, as measured by number of steps per day, total duration of walking activity, and total distance walked; increased frequency of ‘long’ walking bouts (i.e. > 5 minutes in duration); and improved control of walking, as defined by increased self-selected walking speed, and improved symmetry in spatio-temporal characteristics of walking. While walking practice should be initiated during in-patient rehabilitation, problems with walking function may not be fully apparent until the patient is discharged home. Therefore, we will examine the effects of accelerometer-based feedback administered during both in- and out-patient rehabilitation. Under the assumption that accelerometer-based feedback will increase walking activity, the secondary objective of this study is to determine if increased walking activity during rehabilitation results in increased rates of goal attainment, increased satisfaction with rehabilitation, improved self-efficacy, and improved community re-integration post-discharge from rehabilitation.This is a single-blind randomized controlled trial with the assessor being blinded to the group allocation . Participants will be randomly assigned, using allocation concealment, to one of two groups: feedback or no feedback. The study will span three phases of rehabilitation and recovery post-stroke: in-patient rehabilitation, out-patient rehabilitation, and post-rehabilitation community reintegration. Outcome measures will be obtained at up to four time points Figure : 1) uponIndividuals with sub-acute stroke who are attending in-patient rehabilitation at Toronto Rehab will be recruited to this study and will provide written informed consent prior to participating. All participants will have identified improving walking function as a rehabilitation goal upon admission and will be able to walk without supervision at the time of recruitment into the study. Individuals unable to provide consent to participate in the study due to foreign language or cognitive impairment will be excluded. In order to ensure generalizability to the wider stroke population, no further exclusion criteria will be applied.Participants will be assigned using a blocked stratified randomization approach to one of two groups: 1) feedback of walking activity; or 2) no feedback of walking activity (i.e. control group). There will be two strata based on the factor walking speed. Walking speed predicts the level of community ambulation achieved following discharge from rehabilitation . A thresGroup allocation will be performed by the principal investigator. A computer-generated random sequence will be used to assign participants. The treating physiotherapists will administer the goal-setting/planning . A blinded research assistant will conduct the assessments and process data. Participants cannot be blinded to group allocation and will be informed of the chance of being allocated to one of two groups.Goal setting and planning form an important part of care at Toronto Rehab. Goal setting is a patient-centred and collaborative process ,28,35,36The ABLE system consists of two lightweight commercially-available triaxial accelerometers  block of out-patient rehabilitation. The third block is often either not completed at all or not completed immediately subsequent to the second block (i.e. there may be a gap of a number of months between the second and third block). Therefore, the duration of the out-patient phase of the intervention is 6–10 weeks.In order to ensure that all physiotherapists administer the intervention in a consistent manner, we will host a series of in-services concerning goal-planning of walking activity. These in-services will focus specifically on the output from the ABLE system, which is the new component of this study. Physiotherapists will learn how to interpret the output from the ABLE system and how to use this information to evaluate a patient’s progress towards their goals. Specific cases will be discussed based on pilot testing of ambulatory monitoring.Participants in both intervention groups will meet with their primary treating physiotherapist once per week to discuss progress towards their goals for rehabilitation that are relevant to physiotherapy, including goals for walking. All participants will wear the accelerometers every weekday during in-patient rehabilitation to monitor daily walking activity. Research personnel will meet with the patients each morning to ensure that the accelerometers are worn correctly.For those participants assigned to the feedback group, physiotherapists will receive a daily summary of patients’ walking activity as a tool to guide goal planning. Physiotherapists will use the information as a ‘homework checker’ to determine if patients are complying with an assigned walking program. In the case of non-compliance, the physiotherapist will discuss a coping strategy for better integrating walking activity into the patients’ day. In the event that the patient is meeting their specific sub-goals for walking activity, the physiotherapist will re-evaluate these sub-goals and suggest more challenging goals.For participants assigned to the control group, physiotherapists will not receive accelerometer-based feedback of daily walking activity. However, physiotherapists will still discuss the achievement of walking goals with their patient. The same strategies implemented in the feedback group will be implemented in the control group . This process is no different to usual care around goal planning at Toronto Rehab.Participants in both groups will meet with their primary treating physiotherapist regularly to discuss progress towards walking goals. All participants will wear the accelerometers daily during out-patient rehabilitation. For those in the feedback group, physiotherapists will receive a weekly summary of patients’ walking activity as a tool to guide goal planning. Participants in the control group will attend goal-planning meetings with their physiotherapists, as is usual care.A summary of the measures collected at each point in the study is included in Table The following demographic and medical information will be obtained from clinical charts on admission to rehabilitation in order to characterize the study cohort: age, sex, height, weight, date of stroke onset, lesion location, pre-morbid medical history & current medical conditions, prescription medications, the National Institutes of Health Stroke Scale (NIH-SS) , the CheIn addition to collection at admission to rehabilitation, medical conditions will be reviewed at all assessment time points to confirm that there have been no major changes in medical status between assessments. The CMSA, BBS, and ABC will be repeated at discharge from in-patient and out-patient rehabilitation as impaired balance control, impaired lower-limb function and reduced balance confidence could potentially be barriers to independent ambulation. The occurrence of falls will be documented for safety monitoring purposes.The primary outcome measures pertain to walking activity as averaged over three days around the first two assessment time points (i.e. enrolment into the study and discharge from in-patient rehabilitation), and over seven days before the last assessment time point (discharge from out-patient rehabilitation). A longer monitoring period will be used for the out-patient phase as patients have more options for mobility post-discharge. Summary, whole day, outcome measures will be used in the analysis; i.e. total walking duration, total number of steps taken and total distance walked. However, it is most relevant to community ambulation and aerobic fitness to show increased duration of continuous walking ,47; therIncreased walking practice should improve control of walking. Spatio-temporal features of self-selected walking will be measured using a 4 m-long pressure sensitive mat . Participants will start walking at least 1 m away from the mat and will be instructed to walk across the mat until they reach a mark 1 m from the end of the mat. Participants will be instructed to walk at their normal pace. Participants will complete three passes across the mat and measures will be averaged across the three passes. Walking speed, cadence, step length, and symmetry of spatio-temporal measures  will be The Stroke Self-Efficacy Questionnaire (SEQ)  will be The Community Integration Questionnaire (CIQ) will be used as a measure of integration and participation post-discharge from in- and out-patient rehabilitation ,52 and hGoal attainment will be determined from patient charts at discharge from both in-patient and out-patient rehabilitation. Goals are classified ‘achieved’, ‘partially achieved’, ‘not completed’, or ‘discontinued’. Satisfaction with progress towards goals will also be extracted from patient charts . We will interview patients in order to determine barriers to walking. A single open-ended question will be used: “what, if anything, do you think is preventing you from walking more than you are at the moment?”.The following potentially confounding measures will be compared between the two intervention groups: CMSA, BBS, NIH-SS, ABC, and length of stay (in-patient rehabilitation). Measures that differ significantly between the two groups will be included as covariates in statistical models comparing interventions. Repeated-measures analysis of variance (ANOVA) or analysis of covariance , with group-by-time interaction, will be used to evaluate the effect of the interventions on walking activity, spatio-temporal characteristics of walking, and SEQ. Separate ANOVAs will be used for each outcome measure. The ‘group’ term is the intervention group; the ‘time’ term is the assessment time point. The group-by-time interaction effect will reveal if there is a greater change over time in one group compared with the other. Separate analyses will be conducted to compare measures at the first three time points; i.e. discharge from in-patient will be compared to study enrolment, and discharge from out-patient will be compared to discharge from in-patient. One-way ANOVA or ANCOVA will be used to compare the CIQ and satisfaction between the two groups at discharge from rehabilitation and three months post-discharge from in-patient. The frequency of goal attainment between the two groups will be compared at discharge from both in-patient and out-patient rehabilitation; intent-to-treat analysis will be employed for this outcome for all participants initially randomized, including those who withdraw from the study ,57. BarrFor sample size estimates, we used change in total walking duration from the initial assessment to discharge from in-patient rehabilitation (i.e. the first phase of the study) as our primary outcome of interest. In our pilot work, we observed an average increase in total daily walking activity of 20 minutes from the initial assessment to discharge in a group of stroke in-patients. We expect that an average increase in daily walking activity of 40 minutes in the feedback group would be clinically meaningful (i.e. 20 minutes more than expected with no feedback). The standard deviation for change in daily walking time was 23 minutes in our pilot work. Using a sample size formula for repeated measures ANOVA , an imprWhile there has been interest in using accelerometers for walking-related goal-setting and goal-planning in rehabilitation, the effectiveness of this technology in clinical practice to improve walking activity has not been shown. This study may demonstrate that accelerometer-based feedback of walking activity can increase walking activity, improve walking outcomes, and potentially improve community re-integration following discharge from stroke-rehabilitation. The study design deliberately integrates the novel intervention into current practice; therefore, the results will be immediately generalizable to other stroke rehabilitation settings.ABC: Activity-specific balance confidence questionnaire; ABLE: Accelerometry for Bilateral Lowe Extremities; ANCOVA: Analysis of co-variance; ANOVA: Analysis of variance; BBS: Berg balance scale; CIQ: Community integration questionnaire; CMSA: Chedoke-McMaster Stroke Assessment; ICC: Intraclass correlation coefficient; SEQ: Stroke self-efficacy questionnaire.The authors declare they have no competing interests.AM conceived of the study and drafted the manuscript. All authors participated in the design of the study and helped to draft the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/13/93/prepub


In BC, pediatric patients with spina bifida are followed by a multidisciplinary clinic at BC Children’s Hospital. Upon graduation, patients transition into the adult healthcare system where they must coordinate their own care. The purpose of this study is to determine the functional and health outcome of graduates transitioning from the spina bifida clinic at BC Children’s Hospital.Graduates of up to 10 years (1999-2008) from the pediatric spina bifida clinic were mailed a questionnaire. It consisted of 11 sections, including two standardized questionnaires on quality of life (QOL), the Medical Outcomes Study 36-item short-form (SF-36) and Spina Bifida-specific Health Related QOL (SBHRQOL).113 graduates were identified; 19 were lost to follow-up. 27 (29%) questionnaires were returned. 96% graduated from high school; 63% went on to post-secondary education. 30% had never been employed. 85% lived with parents. 48% had never been in a relationship. 81% were satisfied with their present bowel care; 38% were always clean and 15% had no bowel control. 85% were satisfied with their present bladder care; 22% were always dry and 11% had no bladder control. 19% voided independently and 78% self-catheterized. The wheelchair (58%) was most commonly used for community ambulation. 74% drove or utilized public transit. 93% were satisfied with life in general. The SF-36 physical function domain had the lowest average score (56/100). SBHRQOL mean score was 191. Overall, 89% were satisfied with their ambulation. 96% were satisfied with the care from the pediatric clinic; 52% were satisfied with their adult care. 96% of patients had a family physician; of these, 61% felt that their physician understood spina bifida.Health and functional outcomes may indicate the level of independence of adults living with spina bifida. Physical and financial dependence may limit these graduates from full independence. Most patients completed high school; fewer pursued higher education. Many patients demonstrated independence in the community by driving or using transit. Although largely satisfied with their bladder and bowel function, patients continued to have episodes of incontinence. Bladder function was mostly managed by self-catheterization.Overall, the majority of patients were satisfied with life in general, however, our results suggest that more physical support is required for adult graduates. Our results show that fewer adults were satisfied with adult care than in the pediatric clinic; this may result from a perception that their adult healthcare providers inadequately understood spina bifida.


Objective. The effectiveness of an individualized and everyday approach to cognitive rehabilitation for schizophrenia was examined in a case study. Method. After cognitive and functional assessment, concrete objectives were targeted for the person's everyday complaints. Strategies were constructed based on an analysis of the cognitive profile, daily life functioning, and processes involved in activities. They included a memory strategy for reading, a diary to compensate memory difficulties, and working memory exercises to improve immediate processing of information when reading and following conversations. Efficacy was assessed with outcome measures. Results. The program had beneficial effects on the person's cognitive and everyday functioning, which persisted at a 3-year follow-up. Conclusion. Findings provide suggestive evidence that an individualized and everyday approach may be a useful alternative in order to obtain a meaningfully lasting transfer of training to daily life, compared to the nomothetic ones which dominate the field. Cognitive rehabilitation therapy refers to “a behavioral training based intervention that aims to improve cognitive processes … with the goal of durability and generalization” . RecentlGeneralization and the ability to produce a meaningfully lasting effect represent two major goals of cognitive rehabilitation. Unfortunately, however, a large number of cognitive rehabilitation studies have overlooked both issues. In terms of the ability to produce a meaningfully lasting effect, Wykes et al.  report tThe issue of generalization has also been neglected by studies, yet the ultimate goal of remediating cognitive deficits is not simply to improve cognitive test scores but to generalize improvements to durable real-world application . In WykeIn our opinion, there are at least two major reasons why cognitive rehabilitation, until now, has had a limited effect on functional outcome. First, specific difficulties in patients' everyday lives have not been given the importance they deserve when designing and proposing cognitive rehabilitation programs, yet it is these difficulties that should be the main focus of interventions. Few current cognitive remediation programs take functioning into account in their design. Persons with specific functional difficulties (rather than cognitive difficulties) are included in two of these programs. Among those, the “Thinking Skills for Work program” by McGurk et al. , 5 has wThus, in addition to identifying the impaired and preserved cognitive domains in a patient with schizophrenia, it is equally important to define the consequences of the cognitive deficits on daily life activities and to develop ecological rehabilitation strategies  based on concrete objectives in daily life. Consequently, the efficacy of a cognitive rehabilitation should be based not only on the results of cognitive measures but also on everyday life measures. Moreover, cognitive rehabilitation programs have generally not focused on the real-world difficulties of persons with schizophrenia, but rather, on patients' cognitive difficulties. This has been based on the supposition that the trained cognitive tasks share some common cognitive processes with daily life activities, such that improvement of performance on a cognitive task will lead to beneficial effects on everyday functioning. However, due to the complex nature of the relations between cognitive and real-life functioning, such an approach might not necessarily lead to a significant improvement in daily life functioning. Therefore, we favor an approach which identifies patients' difficulties on everyday activities and endeavors to understand the nature (cognitive or otherwise) of these difficulties and thus to be able to identify which (cognitive or otherwise) processes to remediate see , 8). . 8]). Secondly, schizophrenia is unmistakably a vastly heterogeneous disorder e.g., , 10), bu, bu10]),In sum, the beneficial effects of cognitive rehabilitation in schizophrenia could be improved by adopting an approach that individualizes treatment and that directly focuses on decreasing the person's everyday difficulties. For this purpose, we concretely propose four steps. (1) The patient's goals and needs are identified, in addition to specific activities that pose problems in everyday life. This information can be assembled using various methods such as open discussions , observations , or questionnaires of psychosocial functioning. (2) Detailed evaluations are carried out, which include cognitive assessments of both defective and intact processes and the identification of the optimizing factors . 3) Based on these cognitive and functional evaluations, reasons are established as to why the patient might have difficulties in the various everyday activities. (4) Ecological rehabilitation strategies, which are combined and chosen according to the rehabilitation objectives, are then proposed to the patient and a “rehabilitation contract” is mutually agreed upon between the patient, and the mental health professional. Such a contract may include information such as what will be remediated and why, how it will be remediated, and the duration and frequency of sessions. In this approach, the patient's needs are directly addressed in a treatment context, thus undoubtedly increasing intrinsic motivation, which is a central issue in treatment programs [ Based onD.S. is a 42-year-old woman without a profession and who lives with her husband. She completed one year of superior studies in chemistry when her first psychotic episode appeared at 22 years of age leading to a diagnosis of paranoid schizophrenia according to DSM-IV criteria. She has had approximately 20 hospitalizations; the last one being approximately two years before the rehabilitation program. During acute phases of the disease, D.S. presented delusions, visual and auditory hallucinations, stereotypies, and obsessions. D.S. was clinically stable for at least six months before the rehabilitation apart from occasionally experiencing auditory hallucinations. At the time of the study, her treatment consisted of two atypical antipsychotics  and one benzodiazepine (lorazepam: 1 × 2.5 mg), and she was seen by her psychiatrist about twice a month. D.S. expressed a desire to be more autonomous and to not have to rely on her husband all the time. She described a number of difficulties in everyday activities: following and retaining television or radio programs, following and retaining conversations, reading and maintaining text information , remembering appointments, dates, activities (forcing her to write everything down on sheets of paper in order not to forget). These difficulties had a deleterious impact on her everyday functioning, such as social withdrawal. For instance, D.S. did not dare communicate with others as she feared that she would not be able to follow and understand the discussions. Also, if she constantly asked people to repeat what was said, she feared this will get on peoples' nerves or lead them to suspect that she is insane. z-score and at <10 for the percentile score . Performance was impaired on working memory tests assessing processing load and updating, while storage was preserved. Analysis of executive functioning revealed deficits related to flexibility and planning, but not inhibition. Performance was impaired on the verbal episodic memory tests, but not on the visual episodic memory test. Performances in divided and sustained attentional functions were all impaired. Processing speed was slow, but not impaired. An extensive cognitive battery was administered to D.S., which covered various aspects of cognitive functioning see . A scoreThe rehabilitation consisted of two 90-minute sessions per week  and lasted three months. The intervention plan was designed to evaluate the effect of cognitive rehabilitation on functional targets. For this purpose, outcome measures at two different times were used: pre-rehabilitation and post-rehabilitation assessment. Based on an analysis of D.S.'s daily functioning complaints and cognitive assessment, three rehabilitation target objectives were defined to improve her daily life functioning. Rehabilitation strategies were constructed according to processes involved in these target activities, analysis of preserved and impaired processes, and the optimizing factors.  Based on cognitive assessment, D.S. presented verbal episodic memory deficits, and in particular encoded text information in an unsystematic way. These impairments could explain difficulties she had in reading and remembering the contents of books or newspapers. In order to improve her memory for texts, a structured encoding strategy was proposed to D.S. This involved extracting the main information of a text in an organized manner, by omitting unimportant details and by highlighting significant elements. This strategy could help D.S. both at encoding and consequently at retrieval of a text .  D.S. also expressed difficulties in following conversations, and TV or radio programs. These difficulties, in addition to difficulties in maintaining information from texts from books or newspapers, could be related to a reduction of working memory resources observed in D.S. Thus, improving D.S.'s capacity to process immediate information in working memory could favor the extraction of main information and the binding between external information and mental representation in reading or conversational activities. Consequently, working memory training was implemented with several processing load and dual-task monitoring exercises.  Memory (working and episodic) and planning deficits were observed in D.S., which were implicated in her difficulties to remember and plan everyday activities. Thus, an external aid was proposed to compensate for memory and planning deficits and to decrease the anxiety related to forgetting. A personalized diary was created, which was structured with various headings according to her activities, and was implemented in D.S.'s daily life.  The macrostructure consisted of six headings: (1) title; (2) spatial context (where?); (3) temporal context (when?); (4) person(s); (5) facts; (6) results and conclusions. Two types of texts that D.S. had particular difficulties with were chosen by her: chapters from a book and newspaper articles. These texts did not differ according to their difficulty, length, and number of essential information contained in the six headings. In total, 17 chapters and 13 articles were used for the rehabilitation sessions (1 chapter and 1 article per session). They were analyzed in order to extract the total number of essential information contained in each of them and in order to construct a scoring grid (according to the six headings). After reading a text, D.S. was asked to complete the various headings of the macrostructure  were proposed to D.S. : (1) 10-word reconstruction exercises: a word was orally spelt to D.S. beginning with the last letter and she had to find the correct word; 10-number reconstruction exercises: a series of digits were orally read to D.S. who was then asked to provide the number formed by the digits; the words and numbers were of different lengths  ; (2) 3 alphabetical ordination exercises of orally presented words (3 to 4 words) ; (3) 8 exercises from a Brown-Peterson task: a number of four digits and then three words were read to D.S. who had to repeat the words and then recall the number ; (4) 5 exercises from a market task: D.S. received a list containing the price of articles in a market. The name of a person and the purchases (2 to 3 articles) were orally presented to D.S. who had to memorize them and calculate the total price .  The diary consisted of four headings based on D.S.'s daily functioning: “important dates” , “outings” , “shopping list,” and “housework”. On one sheet of the diary representing a week, the four headings were positioned on top horizontally and the days of the week were positioned to the left vertically. During the first session, D.S. was taught how to use the diary correctly. Two main objectives were proposed: (1) to gather all the information to be remembered in one place by respecting the headings and (2) to consult this diary at the same time of the day . For the following sessions, D.S. was asked to bring her diary with her in order to examine whether it was used in a regular and correct manner in daily life. If this was not the case, a discussion of how to improve diary use followed . In total, interviews concerning diary use were carried out in 10 sessions and lasted about 10 minutes each.Outcome measures (administered before and after the rehabilitation program) consisted of assessing macrostructure use, working memory performance, and diary use . The Subjective Scale to Investigate Cognition in Schizophrenia  was als The post-rehabilitation results see  revealedPerformance of pre- and post-rehabilitation outcome measures was compared see  for macrχ2(1) = 35.17; P < .001) and articles (χ2(1) = 200; P < .001). The mean immediate recall percentage for chapters and for articles was calculated. Significant improvements were noted for chapters (χ2(1) = 6.5; P = .01; χ2(1) = 12.53; P < .001). The scores on the Brown-Peterson task did not significantly improve from pre-rehabilitation to post-rehabilitation (χ2(1) = .08; P = .78). Finally, the market task improved significantly (χ2(1) = 56.23; P < .001). Scores on the word reconstruction task and the number reconstruction task improved significantly .χ2(1) = 1.79; P = .18). The decrease essentially concerned attentional complaints that showed a significant decrease (χ2(1) = 28.57; P < .001), while memory (χ2(1) = .74; P = .39) and executive complaints (χ2(1) = 1.73; P = .19) did not significantly diminish.  The total SSTICS score decreased (nonsignificantly) at post-rehabilitation , thus decreasing her anxiety level. She reported being better organized when everything was gathered in one place. Finally, she had the feeling of having made progress and was very satisfied with the rehabilitation.A follow-up assessment took place three years after the end of the cognitive rehabilitation. During this period, D.S. remained clinically stable without any hospitalizations. As previously, she continued to see her psychiatrist twice a month, and her treatment consisted of two atypical antipsychotics  and one benzodiazepine (lorazepam 1 × 2.5 mg). Moreover, she did not take part in any kind of rehabilitation  during this follow-up period. Assessments carried out at the follow-up were the same as those for pre- and post-rehabilitation. The results of the follow-up cognitive assessment see  indicatePerformance on pre-rehabilitation and follow-up baseline measures were compared see  for macrThe same types of texts (book chapter and newspaper article) as those used for pre- and post-rehabilitation were administered: one chapter from another book of the same author and one new article. χ2(1) = 9.68; P = .002; for articles: χ2(1) = 110.08; P < .001).  Significant improvements on immediate recall scores for the chapters and the articles persisted  were structured according to the various macrostructure headings and respected the chronological order of the events. The same tasks as those carried out at pre- and post-rehabilitation were administered albeit parallel versions  were used in order to minimize test-retest effects.χ2(1) = 2.92; P = .087) and for the number reconstruction task (χ2(1) = .53; P = .47). On the contrary, scores on the Brown-Peterson task significantly improved (χ2(1) = 7.99; P = .005), and the significant improvement on the market task persisted (χ2(1) = 14.86; P < .001). The significant post-rehabilitation improvement disappeared for the word reconstruction task , on the day page, the activities realized during the day in order to have a better awareness of past personal events. χ2(1) = 42.42; P < .001). Stable scores were noted on the total score (χ2(1) = .81; P = .37) and specifically for memory complaints (27/44 versus 27/44) and executive complaints (χ2(1) = 1.55; P = .21). The significant decrease after rehabilitation concerning attentional complaints persisted , which are less capable of establishing a causal relation. However, a protocol with multiple outcome measures or other designs  was not possible to implement for practical reasons: such a protocol requires numerous assessments and, consequently, is very tiresome and tedious for the patient and such protocol is difficult to design, especially when ecological measures are involved. Moreover, the quality of the case study would have been improved with the inclusion of measures defining the severity of psychiatric symptoms pre- and post-rehabilitation. This will be taken into account in future cognitive rehabilitation studies.Finally, it is also important to underline that the other psychological dimensions , which had an impact on D.S.'s everyday functioning, would also have been important to take into account in the individualized rehabilitation program in order to further increase its efficacy. Indeed, cognitive functioning is by far not the sole factor involved in functional outcome in schizophrenia. Fett et al. , in theiTherefore, we advocate an individualized, integrative, and everyday rehabilitation approach, which includes interventional strategies that help improve, in addition to cognitive factors, other factors that also play a significant role in functional outcome in schizophrenia. Further, we propose to carry out multidimensional evaluations, which include not only cognitive and functional assessments, but also comprise a large array of other dimensions. This integrative approach is important to take into account as schizophrenia is a disorder that affects many different areas and levels of functioning. Moreover, these areas are complementary and interdependent. That is, patients will have difficulties in a number of different areas  at the same time, and one area may have an impact on the other .