Deep brain stimulation (DBS) is an electrical therapy that modulates the pathological activity to treat the motor symptoms of PD. Although this therapy is currently used in clinical practice, the sufficient conditions for therapeutic efficacy are unknown. In this work we develop a model of critical motor circuit structures in the brain using biophysical cell models as the base components and then evaluate performance of different DBS signals in this model to perform comparative studies of their efficacy. Biological models are an important tool for gaining insights into neural function and, in this case, serve as effective tools for investigating innovative new DBS paradigms. Experiments were performed using the hemi-parkinsonian rodent model to test the same set of signals, verifying the obedience of the model to physiological trends. We show that antidromic spiking from DBS of the subthalamic nucleus (STN) has a significant impact on cortical neural activity, which is frequency dependent and additionally modulated by the regularity of the stimulus pulse train used. Irregular spacing between stimulus pulses, where the amount of variability added is bounded, is shown to increase diversification of response of basal ganglia neurons and reduce entropic noise in cortical neurons, which may be fundamentally important to restoration of information flow in the motor circuit.Parkinson's disease (PD) is a neurodegenerative disorder which follows from cell loss of dopaminergic neurons in the  Although deep brain stimulation (DBS) may be used to treat motor symptoms of PD, there remains a poor mechanistic understanding of the therapeutic action of electrical modulation of the neural activity in the BG and other nuclei in the motor circuit.Parkinson's disease (PD) is a neurodegenerative disorder which stems from dysfunction in the basal ganglia (BG), a group of deep brain nuclei that play a prominent role in the regulation of motor movement. This disorder follows the loss of dopaminergic neurons in the subthalamic nucleus (STN) has been found in humans with PD , as well as in the striatum and motor cortex  are prominent biomarkers of parkinsonian activity. Dopamine-dependent beta band coherence between the cerebral cortex and the globus pallidus externa (GPe), thalamus, and motor cortex decrease  of the STN reduced low-frequency coherence within and across the GPe and Previous theories about the mechanism of action of DBS centered on the idea of regularizing pathological activity through entrainment and synaptic modifications  of the primary motor cortex (M1) and the thalamus, which relays information from the BG to the cortex. These models are used to examine new stimulation signal designs and their influence on firing rate changes and patterns. Biological models are an important tool for gaining insights into neural function and, in this case, serve as an effective test bed for innovative DBS paradigms. The integrity of the model is confirmed through comparison with j flow across the membrane of cell i is represented by the form:jg is the maximal conductance for ion j, and jm and jh are the activation and inactivation variables, respectively. In the following, the above current may be notated as jI, dropping subscript i when the cell type is clear. The single cell models are based on previous works, though parameter adjustments have been made to accommodate the network architecture described in the following section and conform to the spiking activity of experimental data. Additionally, we add small noise currents to the individual cells to account for inputs that are not explicitly modeled.Biophysical models, along the lines of conductance-based Hodkin-Huxley cell models, provide a mathematical description of how synaptic, ionic, and injected currents influence the membrane voltage potential over time through a set of differential equations. Single-compartment cell models with multiple input currents are used here to model the spiking behavior of neurons which serves as the basic components in a larger scale model of structures within the motor circuit of the brain. By adjusting parameters we can model properties exhibited in a variety of phenotypic states, namely neural activity in the healthy, parkinsonian and parkinsonian with DBS states. Six cell types are modeled here: cortical pyramidal cells, cortical interneurons, STN cells, GPe, and GPi cells, and thalamic neurons. The intrinsic ionic current due to ion in vivo data. A recurrent network architecture, shown in Figure The two main cell types that make up the cortex are excitatory pyramidal cells (PY) and inhibitory interneurons (IN). Both cell types are modeled here using single compartment models based on prior work  cells. The main output of the basal ganglia is the GPi, projecting to the thalamus which in turn relays signals to the cortex. The voltage equation for the membrane potential, y receives a fixed number x,yn of inputs from a presynaptic cell type x. This is done independently for each cell y. We chose the number of inputs per cell type, x,yn, to match empirical data and previous reports of approximate connectivity density between nuclei , can be described as:To simulate the effect of DBS on the model network, the STN neurons receive a current input that represents injected current from a microelectrode located at the center of the STN model neuron modulation. In practice, current pulses are biphasic, so current flow alternates directions between two electrical contacts to ensure that charge does not accumulative in neural tissue and cause irreversible damage. The DBS electrode here is modeled as a point source with the current signal consisting of a train of current pulses of width ω seconds and amplitude αpA/μmf is the stimulation frequency. To create an irregular pattern of stimulation, bounded noise is added to the timing of these pulses. Irregular DBS current, irrstimI(t), can be written as:nz are i.i.d. uniform random variables over the range  for some s ϵ ℝ for all n. The period is irregular and stochastic, but the average inter-pulse period between pulses is still 1/f and the maximum and minimum time between pulses is bounded, ensuring that the average rate of pulses is high and there are never long periods between pulses.Hence, an infinite train of such pulses can represented as:n = 6), we stimulated the STN using regular and irregular stimulation patterns at two frequencies in order to capture frequency- and regularity-dependent effects of stimulation. Subjects behaved spontaneously and both single-unit and local field potential (LFP) activity was captured bilaterally during the DBS sessions.The 6-hydroxydopamine (6-OHDA) rodent model has frequently been used to study PD and DBS  of Rice University.The amplitude and pulse width of the current pulses were 100 μA and 60 μs, respectively, which are parameters that have previously been established as effective , as well as for spike rate measured in response to irregular stimulation . For all stimulation frequencies, there was no significant difference in modulatory effect on average firing rate of the cells produced by regular vs. irregular stimulation patterns (One-Way ANOVA: p > 0.05). However, the spike patterns were differentially altered as a function of frequency and regularity of the stimulus pulse train. To characterize this, we computed the entropy of the interspike intervals (ISIs) for the orthodromic spikes from the PY cells. For a discrete random variable x, this entropy can be written as:The resultant firing rate of the PY cells was computed for the computational model and x, which in these case represents the ISIs. If the firing is more regular, the entropy will be lower, whereas if the firing is more bursty, the entropy will be higher. The model data is correlated with the observed data , and in both cases there was a significant decrease in ISI entropy between 40 and 130 Hz stimulation . Additionally, 130 Hz regular and irregular stimulation achieved ISI entropies that were not significantly different than the cell activity in the intact hemisphere (post-hoc LSD: p < 0.05).The entropy describes how much uncertainty or randomness there is in the variable p < 0.05; post-hoc LSD: p < 0.025). Also, irregular stimulation dampened peak beta band power more than regular stimulation (post-hoc LSD: p < 0.05). These results confirm that pathological activity was reduced with high frequency, irregular stimulus pulse trains, as indicated by the computational model.The power spectrum of the observed LFP data during stimulation was computed in order to identify effects of the STN DBS in the rodent model on beta band activity, since increased beta band activity has been correlated with motor symptoms associated with PD  is effective in treating motor symptoms of PD, whereas low frequency regular stimulation is not effective. Although therapeutic benefit is achieved using regularly spaced pulses, the neural activity is not restored to its non-pathological state and stimulated neurons tend to become pulse-locked, creating a narrowband increase in power in the frequency band around the stimulation frequency.The temporal pattern of stimulus pulses strongly influences the performance of the treatment. Previous work has found that if the inter-pulse time periods are randomly distributed and the density governing the periods allows for long times between pulses, the stimulation is less effective (Dorval et al., in vivo activity characterized by the authors in hemi-parkinsonian rodents with DBS administered unilaterally. In the rodent model, the reduced ISI entropy also coincided with beta band power attenuation, which is associated with improvement in motor symptoms of PD. The construction of essential components in the motor circuit using the biophysical model neurons presented is validated as a potent tool for investigating Parkinsonian activity and promotes the investigation of further stimulation signal design principles for DBS therapy.Using the irregular DBS signal, we found a greater mixture of response in the change in firing rates of the BG neurons that were simulated when compared to using regular DBS of the same average stimulation frequency. This mixture of response, i.e., heterogeneity in the average increase or decrease of a neuron's firing rate, has previously been linked to efficacy of DBS treatment. Both regular and irregular stimulation antidromically modulated activity of the PY cell and reduced ISI entropy. In the Parkinsonian state, cortical cells are more bursty, which means the ISI entropy is high, and irregular DBS maintains the reduction in entropic noise achieved with regular DBS. These results faithfully reproduce The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Apis mellifera) discriminate multiple object features such as colour, pattern and 2D shape, but it remains unknown whether and how bees recover three-dimensional shape. Here we show that bees can recognize objects by their three-dimensional form, whereby they employ an active strategy to uncover the depth profiles. We trained individual, free flying honeybees to collect sugar water from small three-dimensional objects made of styrofoam  or folded paper  and found that bees can easily discriminate between these stimuli. We also tested possible strategies employed by the bees to uncover the depth profiles. For the card stimuli, we excluded overall shape and pictorial features  as cues for discrimination. Lacking sufficient stereo vision, bees are known to use speed gradients in optic flow to detect edges; could the bees apply this strategy also to recover the fine details of a surface depth profile? Analysing the bees’ flight tracks in front of the stimuli revealed specific combinations of flight maneuvers , which are particularly suitable to extract depth cues from motion parallax. We modelled the generated optic flow and found characteristic patterns of angular displacement corresponding to the depth profiles of our stimuli: optic flow patterns from pure translations successfully recovered depth relations from the magnitude of angular displacements, additional rotation provided robust depth information based on the direction of the displacements; thus, the bees flight maneuvers may reflect an optimized visuo-motor strategy to extract depth structure from motion signals. The robustness and simplicity of this strategy offers an efficient solution for 3D-object-recognition without stereo vision, and could be employed by other flying insects, or mobile robots.Honeybees ( Insects show a remarkable complexity of visual performances, in particular in consideration of their comparatively small nervous system. For example, bees use the polarisation pattern of skylight and the analysis of optic flow fields from both eyes to navigate safely through their environment  and In contrast, surprisingly little is known about whether and if so, how bees perceive the three-dimensional form of objects. To recover depth from the 2D retinal image is a major challenge for any visual system and humans exploit a multitude of sources, such as ocular information , pictorial cues , stereopsis and dynamic information from the optic flow field . Most insects, on the other hand, are thought to have a limited access to the three-dimensional aspects of the world because of the fixed optics of the compound eyes and limited binocular field of view. Instead, bees and other insects rely for their navigation in space predominantly on the analysis of the optic flow field –17. The pis mellifera, n = 46) from a nearby bee hive were trained to visit the experimental set up, which was situated outdoors in an open meadow. Two different experimental set ups , and was organized in sessions, each consisting of alternating testing and re-training periods. The initial training, as well as the re-training between the tests was carried out as differential conditioning, i.e. rewarded and unrewarded stimuli were presented simultaneously. No reward was given during the tests. Each test lasted 2 min, and was immediately followed by re-training the bees for 15 min, which allowed 3–4 visits of the bees. In order to avoid that the bees used odour marks, different sets of stimuli were used during training and testing and the background surface was cleaned with 90% ethanol.The experimental conditions were presented in pseudo-randomized order. Discrimination was tested in a two-alternative-choice paradigm, whereby the training stimulus and one of the alternative stimuli were presented simultaneously (discrimination test). During the test period, the choice behaviour of the test-bees was recorded. Landing or briefly touching the stimulus was counted as a decision for that particular stimulus.Two sets of experiments were conducted, testing the discrimination of geometric objects or folded cards, respectively:The set up consisted of a horizontal round turntable  or folded (50 x 60 mm) along the vertical midline in one of two configurations, concave or convex  stimuli, respectively. A 2 x 2 contingency table and the Pearson χ2 test were used in order to assess the significance of the difference of the test-results involving the ball as the training stimulus and the cube as the training stimulus, respectively.We used a two-tailed Apis mellifera) were trained to discriminate between geometric objects such as a ball, a flat cylinder, a cube, and a cuboid. Training stimuli were a ball (in the first experiment) and a cube (in the second experiment), whereby the training object and one of the alternative, unrewarded objects (which was to be discriminated in the following tests) were placed on the horizontal round table  lower discrimination values after training the cube as compared to training the ball: the outline of a cube is different from different viewing directions, whereas the retinal image of a ball is view-point invariant.This result may be surprising given the reported difficulties of bees to discriminate simple geometric 2D shapes when presented horizontally, for example squares vs. triangles –25; howeThe presence or absence  or presence (in the case of the cube) of vertices and their number are strong cues for discriminating between different shapes , 28. In Taken together, the first experiment showed that bees successfully discriminate 3D objects, independently of their height, or the presence of distinct shape features such as vertices. But which properties of the objects did the bees use for discrimination? In the case of two-dimensional stimuli, it has been suggested that bees encode, in addition to overall colour and texture, the global shape, predominantly by detecting the outer edges . In factIn the second set of experiments, we designed the stimuli so that they could not be discriminated based on their outer shape. To that aim, convex, concave or planar paper cards were positioned in small boxes , and preThe results are shown in In the second part of the experiments, we examined which depth cues the bees may use. Perspective cues from texture gradients or shading are powerful cues for depth perception in humans. So, given the bee’s acute pattern recognition , 8, coulA conceivable candidate would be information from the optic flow field; for example, during a lateral movement of the bee, the speed of an image shift on the bees retina from the near sides of the card is larger than the speed from the inner fold of the card which is further away and therefore indicates a concavity. In contrast, a planar card would produce a rather homogenous flow profile across its surface. In order to find out whether the bees could use signals from motion parallax to uncover the depth profiles of the cards, we set up high speed cameras to film the bees during testing and modeled the optic flow patterns obtained during these flights.translation, whereby–within a fronto-parallel trajectory—the body axis is kept rather constant  with an additional change in lateral position , positioned at right angles on top and the side of the turn table, recorded the flight paths of four individual bees while approaching and discriminating between the different card stimuli. In the following we investigated whether the bees movements in front of the stimuli would have the potential to produce motion parallax patterns which reveal the depth profile of the cards. To this end, we first calculated the angular displacement generated for characteristic points on the folded stimulus cards in a horizontal plane defined by a purely lateral displacement and a cross-section through the stimulus, as an abstraction of the flight paths. Please note that these calculations are based on the idealized situation of a flight trajectory that is parallel to the front plane of the stimulus box and is constant in its height over ground; this is justified by the observation that, in this behavioural context, the bees maintained a largely constant height; furthermore, it should be noted that, although any additional variations in height and distance would change the absolute values of parallax shifts, this would not affect the overall pattern of results. We calculated the parallax shift measured in degrees of visual angle for an overall lateral positions shift of two sizes (LD = 2 or 16 mm) as seen from an average viewing distance VD = 27.5 mm.Image displacement by motion parallax was calculated with a geometric model for motion parallax, for a wide range of conditions. The outcome of the model is illustrated for a subset of typical conditions in It can be seen immediately that the displacement profiles reflect the 3D shape of the stimulus cards in the amount of angular displacements relative to the midline of the stimulus. Notably, the magnitude of the image shift  and its speed (0.04 m/s for the translation), convert to an angular speed of 80 deg/s, which is clearly in a range that easily can be picked up by the bees’ visual system in order to extract such motion parallax profiles. In fact, slowing down in front of the stimuli, the bees flight speed is close to optimum for resolving moving gratings, i.e. 8–10 Hz . Also, tAnother observation may be worth pointing out: bees seem to find it harder to discriminate concave from convex stimuli than concave or convex from the planar stimulus. This correlates with the difference in complexity of the optic flow patterns of the planar stimulus on one hand and the concave and convex stimuli on the other; whereas the planar flow pattern has no abrupt discontinuities, the concave and convex map both have discontinuities; this would support the conclusion that bees identify the depth profile not only from velocity cues in the optic flow patterns but also by detecting features such as discontinuities at edges (see below).magnitudes across space and thus on the bees’ accuracy to discriminate different speeds of the optic flow. For translation plus rotation, on the other hand, the parallax profiles for convex and concave stimuli are characterized by a positive and a negative sign of the displacement: this is because the lateral stimulus regions move behind or in front of the fixated and hence static image point , thus generating image displacements in opposite directions . Thus, bees could base their discrimination on differences in the form of shadows cast by the box on the different card configurations; however, different forms of shadows were also present in the photographic images, but were not used for discrimination, possibly because the shadow boarders were camouflaged by the high contrast random block pattern on the cards. Depth relations may also be revealed by the relative shift of the edges of the stimulus box and their shadow, as the bees move in front of it. However, since the photographic images, too, were placed Numerous studies have shown that bees analyse optic flow patterns for navigation tasks and to identify surfaces in different depth planes. Our results now indicate that bees deploy self-induced motion signals to accurately distinguish planar, convex and concave depth profiles. It is therefore interesting to examine the actual flight maneuvers of the bees in front of the stimuli.translations), but also, importantly, rotations of the body axis in a horizontal plane (yaw). This observation is important because by adding a rotational component to the translational parallax, the distribution of motion signals can be ‘anchored’ relative to a single point (e.g. the centre of the target) that is fixated by means of the rotation, whilst going through the lateral translation. In other words, it provides the static point in the optic flow field (see [and rotations), which we observe in bees flying in front of the stimulus boxes, could reflect an optimized visio-motor strategy to extract the depth structure from optic flow.Recordings of these flight paths revealed characteristic flight maneuvers which show fronto-parallel movement episodes with nearly constant body-axis (eld (see ). This wIt is noteworthy that the flight patterns in front of the stimuli are reminiscent of the so called “turn-back-and-look”behavior  or the In general, bees could use a view-based strategy for object recognition ; that isThe encoding of single object features, as compared to storing the entire visual image, can be understood as an economical strategy of particular importance for animals with small brains, because it would save visual memory. In fact, it has been suggested that the bees visual memory represents objects by a restricted set of features, namely the objects’ outline plus overall colour or texture, but sparing its internal structure . Our finThe experimental results showed that bees can successfully recognize the three-dimensional form of objects and surfaces, independent of pictorial cues or outer shape. We conclude that the bees employ a detailed analysis of optic flow and encode depth profiles in 3D-feature maps. For this performance, bees actively engage in specific flight maneuvers, which seem to be optimized for this task, namely a reduction of their speed of flight, and combinations of translations and rotations. We present a model suggesting that the optic flow generated by these flight maneuvers provides the information necessary to accurately identify the depth profiles. Thus, the depth features of objects can be encoded effectively in a tiny visual system, such as the honeybee’s visual system, using a simple and robust mechanism.S1 TextFigure A. Flight tracks of individual bees during discrimination tests.(DOCX)Click here for additional data file.


This prospective, controlled trial aimed to assess the effect of pharmacist-led medication reviews on the medication safety of psychiatric inpatients by the resolution of Drug-Related Problems (DRP). Both the therapy appropriateness measured with the Medication Appropriateness Index (MAI) and the number of unsolved DRP per patient were chosen as primary outcome measures.Depending on their time of admission, 269 psychiatric patients that were admitted to a psychiatric university hospital were allocated in control (09/2012-03/2013) or intervention group (05/2013-12/2013). In both groups, DRP were identified by comprehensive medication reviews by clinical pharmacists at admission, during the hospital stay, and at discharge. In the intervention group, recommendations for identified DRP were compiled by the pharmacists and discussed with the therapeutic team. In the control group, recommendations were not provided except for serious or life threatening DRP. As a primary outcome measure, the changes in therapy appropriateness from admission to discharge as well as from admission to three months after discharge (follow-up) assessed with the MAI were compared between both groups. The second primary outcome was the number of unsolved DRP per patient after completing the study protocol. The DRP type, the relevance and the potential of drugs to cause DRP were also evaluated.The intervention led to a reduced MAI score by 1.4 points per patient  at discharge and 1.3 points (95% CI: 0.7–1.9) at follow-up compared with controls. The number of unsolved DRP in the intervention group was 1.8 (95% CI: 1.5–2.1) less than in control.The pharmaceutical medication reviews with interdisciplinary discussion of identified DRP appears to be a worthy strategy to improve medication safety in psychiatry as reflected by less unsolved DRP per patient and an enhanced appropriateness of therapy. The promising results of this trial likely warrant further research that evaluates direct clinical outcomes and health-related costs.DRKS00006358Deutsches Register Klinischer Studien (DRKS),  As a result of the high prevalence of risk factors, such as polypharmacy commonly applied by multiple prescribers, several comorbidities and inadequate adherence, psychiatric patients are at significant risk for Drug-Related Problems (DRP) . DRP comDespite the recommendations by the APA, only limited research is available regarding prevention strategies of ADE and medication errors in psychiatric patients ,5,6,8–12Therefore, we aimed to assess the feasibility and the impact of structured, comprehensive medication reviews by clinical pharmacists including the subsequent interdisciplinary discussion of identified DRP on the drug safety of psychiatric inpatients compared with usual psychiatric care in a German university hospital in a prospective, controlled trial. The appropriateness of the therapy, which was measured with the Medication Appropriateness Index (MAI)  at admisThis prospective, non-randomized, open, controlled study was conducted on two non-acute wards in the Department of Psychiatry and Psychotherapy at the University Hospital of Erlangen. Both wards were used as control and intervention wards consecutively. The medication orders were paper-based. Only centralized pharmaceutical services were available by telephone. Pharmaceutical medication reviews were not performed regularly on the study wards prior to the start of the control phase. The detailed pharmaceutical reviews on admission, discharge and post-discharge were firstly implemented in the control phase and were extended during the intervention phase of this study. Usual care for patients admitted to the Department of Psychiatry and Psychotherapy contained consultation of a physician and of a senior psychiatrist once weekly as well as a group counseling once weekly on alternating topics regarding the psychiatric diseases .All patients aged 18 and older who were admitted to one of the two wards between September 2012 and March 2013 (control phase) or May and December 2013 (intervention phase) were eligible for inclusion in the control group or the intervention group, respectively. A randomized, parallel group design was not applied because of the knowledge bias generated in the control group when pharmaceutical recommendations are implemented in the patients in the intervention group on the same ward. Therefore, a consecutive design was conceived. The mean length of stay in the Department of Psychiatry and Psychotherapy was stated to be 21 days. Accordingly, a wash-out period of one month between the two phases should have ensured that all patients in the control group were discharged prior to the start of the intervention. Additional inclusion criteria included the ability to understand and write in German, a psychiatric hospital stay of more than six days and the consent to be contacted after discharge. Patients were excluded if they did not take psychiatric medication. A few days after admission, the patients were fully informed about the content and objectives of the study. Afterwards, written informed consent was obtained for those patients willing to take part in the trial.https://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00006358). The study was registered after enrolment of patients started because the responsible persons were not aware of the need to register before. The full trial protocols in German and English are attached as supplemental files . No significant changes were made to the study protocol after approval of the ethical committee. The trial was registered with the German register of clinical studies , a Drug-Related Problem is “an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes” . DRP comAfter eligible patients gave written consent to take part in the study, both patients in the control group and the intervention group obtained detailed medication reconciliation at admission and medication reviews at discharge and three months after discharge, as well as weekly during the hospital stay by two clinical pharmacists. The reviews at admission, discharge and follow-up included a comprehensive patient interview and the assessment of drug history and ADE by two pharmacists. A standardized form was utilized to assess trade names, dosage, indication, application, duration of use and tolerability of the applied drugs, as well as the patient characteristics, including diagnoses, allergies and laboratory parameters. The medication reviews were conducted subsequent to the physicians’ interviews shortly after admission and shortly before discharge. The noted medication charts were checked for interactions with two drug-drug interaction programs ,27. DRP Recommendations for all identified DRP were compiled immediately after their identification regardless of their severity for patients in the intervention group. The appropriate advices were orally disseminated to the ward staff, discussed with the attending physicians and nurses and implemented if possible within the same day of identification. Recommendations regarding DRP that addressed practical and correct directions or knowledge regarding the individual therapy were also discussed with the patients. Changes in therapy were communicated to the patients by the pharmacists or ward staff. Recommendations for identified DRP of patients in the control group were only disseminated to medical staff if they were serious or life threatening because of ethical considerations.Furthermore, the patients of the intervention group additionally obtained pharmaceutical counseling during the hospital stay with individual drug information leaflets regarding their psychiatric disease and drugs. A discharge medication plan was given and explained to the patients. The patients in the intervention group were also contacted by telephone after discharge at 1.5 and 6 weeks to discuss and solve ongoing problems with their medication.Besides the comprehensive medication reviews at admission, discharge and follow-up patients in the control group received usual psychiatric care as described above.The pharmacists that were responsible for identifying DRP and compiling recommendations were licensed, but did not work in a psychiatric hospital before. Prior to the start of the study, the two pharmacists were first trained intensively regarding psychiatric diseases and medication. Afterwards they joined for three months the physiatrists that were working on the wards.The primary outcome measures were the change of therapy appropriateness measured by the MAI  between The MAI includes ten implicit and explicit criteria to review the appropriateness of each prescribed drug regarding the indication, effectiveness, dosage, correct directions, practical directions, drug-drug interaction, drug-disease interaction, duplication, duration and expense. A weighted scoring system was applied in accordance with Samsa et al . Each quThe demographic data included gender, age, number of prior psychiatric hospital stays, wards, length of hospital stay and number of drugs at admission, discharge and follow-up.The MAI score was calculated on admission, discharge and follow-up. For the estimation of the weighted MAI scores at admission and discharge, the medical records documented in the patient charts at the time of the pharmaceutical medication review shortly after admission and shortly before discharge were used. To assess the follow-up value of the MAI score, the patients in both groups were contacted three months after discharge by telephone, and their medication plan was assessed by the two pharmacists. The patient MAI score was calculated via the summation of the weighted MAI scores for each noted drug the patient received at admission, discharge and follow-up, respectively. The subtraction of the patient MAI score at discharge and follow-up from admission resulted in the assessment of the change in patient MAI score. The MAI scoring was verified independently by a senior psychiatrist.For the estimation of the number of unsolved DRP, all DRP that were identified during the hospital stay by the standardized pharmaceutical medication reviews in control group and intervention group were documented and branded as solved or unsolved depending on whether they were elucidated. Usually, if the physician agreed with the pharmacist’s recommendation, the changes were immediately transferred to patient charts. Occasionally, the medical records were not available or the psychiatrist firstly wanted to discuss the changes in therapy with the patient before they were implemented. In that case, the pharmacists afterwards checked the medical charts of respective patients to verify that the recommendations were implemented. DRP were also marked as solved if the recommended intervention was implemented after discharge but within the study period, which terminated three months after discharge. If a recommendation was not accepted for any reason or accepted but not certainly implemented, the DRP were labeled as unsolved. Furthermore, if a recommended intervention was accepted, but it had not been implemented within the entire study period, it was also marked as unsolved. Only DRP that were identified during the hospital stay were included because the pharmacists did not have access to valid medical information after patient discharge.®-database (APOSTAT) [® system [The identified DRP were classified according to the three-parted Problem-Intervention-Outcome (PIO) system , which iAPOSTAT) . The PIOAPOSTAT) ,32. Base® system , which h® system . Additio® system  database® system . The potThe classification and relevance of the identified DRP were also verified independently by the senior psychiatric physician who was not working on the study wards. If the estimation of the extern reviewer deviated from the pharmacists’ evaluation, classification and relevance of DRP were discussed.Only the patient MAI score was used to perform the power calculation because no data were available for the number of unsolved DRP. According to Hanlon et al , an effeThe patient characteristics, as well as the primary and secondary endpoints at the different time points were presented as the mean  or median  for the continuous variables and as numbers (%) for the categorical variables. As the group allocation was not random but assigned by the time of admission, the group differences at baseline were assessed via Chi squared or Fisher’s exact tests for the categorical variables and Student’s t-test or Mann-Whitney-U test for the continuous variables. Following the intention-to-treat principle, only the patients who were discharged prior to the first pharmaceutical interview were excluded from the analysis.To investigate the efficacy of the intervention on the primary endpoints, we performed a regression analysis to adjust for group differences at admission. For the number of unsolved DRP, which represent the count data, a generalized linear model for the negative binomial distribution with log-link was computed. The number of unsolved DRP served as the response variable; the treatment group, sex, age, gender, comorbidities, number of drugs, length of hospital stays and total number of DRP were included as predictors. Thus, the group variable coefficient represents an adjusted treatment effect and was reported with the 95% confidence interval (CI) and corresponding p-value comparing the effect to 0.For the patient MAI score, which was assessed at admission, discharge and follow-up, we applied a linear mixed-effect model approach to adjust for the longitudinal structure of the data. The outcome variable was the MAI score at the three different time points. This longitudinal modeling approach builds up a design matrix with one row for each measurement instead of for each patient; therefore, a missing outcome at follow-up  does not lead to the deletion of the patient. As predictors, we included the same variables as for the DRP, with an additional interaction between the treatment group and time categories. Thus, the coefficient for the treatment x time interaction represents the adjusted effect of the intervention at the different time points and was reported with the 95% CI and corresponding p-value.http://www.R-project.org/).Statistical analyses were performed using IBM SPSS Statistics for Windows Version 22.0  and the statistical programming environment R 3.0.2  or intervention group (05/2013-12/2013). Prior to the first pharmaceutical interview four patients were discharged and were excluded from the analysis. The second pharmaceutical interview at discharge was completed by 241 (89.6%) patients. The follow-up period terminated in July 2014 with the last patient’s follow-up interview. The study protocol was completed by 217 (80.7%) patients that were reached by telephone at the follow-up. At this time, ten  patients no longer took medications. One patient’s psychiatric drug was discontinued during the hospital stay. Thus, the evaluation of their MAI scores was not possible. For the analysis of the number of unsolved DRP, all patients who completed the first interview were included .Gender, age and number of comorbidities significantly differed at baseline between the control and intervention groups. Consequently, the analysis of the primary outcomes were adjusted for these variables via regression models. The other demographic data were similar between the groups. The baseline assessment of the MAI score was calculated via the summation of the weighted MAI scores, which were assessed with the scoring system of Samsa et al  of everyThe change in the MAI score and the number of unsolved DRP were chosen as primary outcomes to assess the effect of the pharmaceutical interventions. The procedure of the pharmaceutical interventions is summarized in MAI. The appropriateness of therapy was significantly improved in the intervention group compared with the control group from admission through discharge to follow-up, which correlates with the decrease in the patient MAI scores. An average of 2.3 points (SD: 3.5) in the patient MAI score at admission was reduced to 1.0 (SD: 2.0) at discharge and 0.8 (SD: 1.6) at follow-up in the intervention group. In the patients in the control group, the MAI score slightly decreased from admission  through discharge  to follow-up . The change in the patient MAI score from admission to discharge or follow-up is shown in DRP. In total, 419 and 396 DRP were identified in 134 and 131 patients in the control and intervention groups, respectively,  in the comprehensive medication reviews of medical records at admission, discharge and weekly during the hospital stay. Of the identified DRP, 10.7 and 13.6% were rated as non-preventable ADE in the control and intervention groups, respectively. As shown in The relevance of the identified DRP was typically estimated as minor (43.8%) or moderate (46.9%) in both groups. 45 and 30 major DRP occurred in the control and intervention phases, respectively. 12 identified DRP in the control patients were reported to the ward staff and/or patients by the pharmacist because of the potential to cause serious harm. Examples for DRP that were communicated to the physicians within the control phase were the concomitant prescription of omeprazole and clopidogrel, a patient with major depression that was not treated with an antidepressant or the concomitant use of two benzodiazepines, mirtazapine and risperidone in a patient that was fallen due to this combination.Psychotropic drugs accounted for 54.4% of all detected DRP. Considering their prescribing frequency at admission, the potential to cause DRP of both psychotropic and non-psychotropic drugs were similar with 0.7 DRP per prescribed drug. The potentials of the 10 most commonly applied drugs to cause DRP were calculated and are illustrated in The type of DRP and their outcomes were categorized according to the PIO classification system . The proTo our knowledge, this is the first study in psychiatric patients to provide evidence regarding the impact of a structured, interdisciplinary medicines management on the appropriateness of therapy and the number of DRP as indicators of medication safety compared with usual psychiatric care. Here, the MAI was first used as a valid tool to assess the therapy appropriateness in a psychiatric setting.The trial identified a significant improvement in the appropriateness of therapy, which was sustained after discharge, and substantially less unsolved DRP as a result of our structured, interdisciplinary medication reviews with the subsequent implementation of changes in the therapeutic regimen. Problems that had the potential to cause harm were solved. Common sources of errors were identified and disseminated to the ward staff.Attempts to improve medication safety are typically aimed at the identification and resolution of DRP and the enhancement in drug prescription ,21. TherOther important factors in terms of drug therapy safety are the identification and the resolution of DRP . As confTo minimize the risk of medication-related harm for psychiatric patients, Rothschild et al  claimed A major limitation of our study is that it was designed as a non-randomized but consecutive trial. Assistant physicians alternated during the study period. We cannot rule out that the improvement in prescribing and the decrease in unsolved DRP was caused by the change of ward staff. Nevertheless, the consecutive design attempted to avoid a knowledge bias in the control group when recommendations for the resolution of DRP in the intervention patients on the same ward were compiled and discussed with the attending physicians. For the first investigation to assess the impact of pharmacist-led medication reviews on therapy appropriateness and the number of unsolved DRP in a controlled clinical trial, we chose to abstain from the randomized trial to minimize confounding. Moreover, the applied design did not ensure a comparable structure of patient characteristics at baseline; thus, the analysis of the primary outcome was adjusted for significant differences via a regression model.A one-month washout period between study phases were chosen based on the stated average length of patient stay in the hospital of 21 days. However, this mean length of stay comprised also patient, which stayed only for one or two days in hospital to obtain diagnostic tests for example to detect a dementia. As a hospital stay of less than seven days was an exclusion criterion of our trial, the mean length of stay of our study population was longer with a median of 29.0 and 35.0 days in control and intervention group, respectively. Two patients of the control group were still present at ward for three and seven days, respectively when intervention phase started at 1 May 2014. However, the overlap did not affect the results because the first pharmaceutical interview at admission in the intervention phase was performed on 8 May and therefore after discharge of these two control patients.The scoring of the MAI and the number of identified and unsolved DRP were not assessed by an independent rater, but by the two pharmacists who performed the medication reviews on the wards and recommended changes in the therapy. To avoid an over-estimation of the effect of the intervention, the MAI scoring, the classification and the relevance of the DRP were verified by a senior psychiatrist. However, an inter-rater-reliability-score between the pharmacists and the psychiatrist was not assessed. This second limitation will be addressed in a following evaluation when independent raters retrospectively assess the recorded therapy regimen.As a result of the exploratory nature of our study, indirect measures were applied to assess the impact of an interdisciplinary medicines management in psychiatry. Because a significant benefit was verified, further evaluations should consider the analysis of more direct measurements for patient outcomes, such as the length of hospital stay or readmission rates.Apart from this, the MAI does not address all issues of inappropriate prescribing. Under-prescription, side effects or compliance were not evaluated with the items of the MAI. Therefore, the calculated MAI score does not precisely reflect the appropriateness of therapy. Nevertheless, the MAI with its ten implicit criteria were chosen over other measures of inappropriate prescribing  that employ explicit criteria. When using explicit criteria individual patient preferences and clinical and patient individual knowledge of the prescriber cannot be recognized. Additionally, other measures of inappropriate prescribing such as Beers criteria and STOPP/START criteria were solely developed for the assessment of appropriate therapy in older adults. However, the implicit character of the items of the MAI also allow its use in a younger study population, as we expected to have in our study. Another limitation is the assessment of the MAI score three months after discharge. The calculation of the MAI score based on the medication plan that was verified by the pharmacists in collaboration with the patient by telephonic consultation. However, the pharmacists did not have any other information from community physicians or pharmacies. Therefore, it is possible that the medication plan was incomplete or information were missing.Only two non-acute wards of the same university hospital in Germany were studied. Thus, the generalizability of the results is limited. Additionally, it would have been favorable to estimate the time that was needed for the discussion with the medical team to assess its impact on the workload of the pharmacists. Future studies should focus on this topic. Finally, it was beyond the scope of our evaluation to assess the costs of DRP or additional services . However, the economic aspect is an important factor in the consideration of the permanent implementation of a new care model in the daily clinical routine. Therefore, an economic calculation will also be performed in a subsequent study.In brief, despite several limitations, the structured pharmacist-led medication reviews with subsequent interdisciplinary discussion of DRP has been proven to be an effective tool to identify and solve DRP and therefore enhance the appropriateness of therapy in psychiatric inpatients. Thus, the permanent implementation of the interdisciplinary pharmaceutical care model in psychiatric hospitals appears to be a worthy strategy to improve medication safety in psychiatric patients. The promising results of this trial warrant further research that evaluates the impact of collaborative pharmaceutical care programs regarding direct clinical outcomes and health-related costs in psychiatry.S1 CONSORT Checklist(PDF)Click here for additional data file.S1 File(PDF)Click here for additional data file.S1 Protocol(PDF)Click here for additional data file.S2 Protocol(PDF)Click here for additional data file.


Transcranial direct current stimulation (tDCS) is a noninvasive technique that could improve the rehabilitation outcomes in stroke, eliciting neuroplastic mechanisms. At the same time conflicting results have been reported in subacute phase of stroke, when neuroplasticity is crucial. The aim of this double-blind, randomized, and sham-controlled study was to determine whether a treatment with cathodal tDCS before the rehabilitative training might augment the final outcomes  in respect of a traditional rehabilitation for a sample of patients affected by ischemic stroke in the subacute phase. An experimental group  and a control group (sham tDCS plus rehabilitation) were assessed at the beginning of the protocol, after 10 days of stimulation, after 30 days from ending of stimulation, and at the end of inpatient rehabilitation. Both groups showed significant improvements for all the assessed domains during the rehabilitation, except for the manual force, while no significant differences were demonstrated between groups. These results seem to indicate that the cathodal tDCS, provided in an early phase of stroke, does not lead to a functional improvement. To depict a more comprehensive scenario, further studies are needed. Due to increase of life expectancy, adults are progressively more exposed to vascular diseases, as stroke . In the Many of the rehabilitative techniques use knowledge derived by neuroscience to exploit the best outcomes achievable. For many years, the central nervous system (CNS) had been described as a rigid structure. More recently, a large amount of evidence has shown a wide brain cells' activity after damage . This seIn the rehabilitation of patients with stroke, the first period after acute event is crucial for the recovery due to spontaneous neuroplasticity, facilitating neurophysiological repair and cortical reorganization . In factAmong these, noninvasive brain stimulations (NIBS), such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), are techniques gradually obtaining wider interest for being used in clinical settings –13. BothEven from the early studies, it was evident as tDCS was able to produce a polarity-dependent modification of cortical excitability , 15. tDCEven if a certain degree of clinical improvements of motor performances is achieved after tDCS in patients with stroke, very low quality evidence has been demonstrated. In fact, as the principal reviews and meta-analyses have highlighted, there are a wide variability of the patients enrolled into the studies and a disparate use of stimulation parameters, limiting the conclusions on the topic at the moment –19. NeveThere are three possible electrodes' montages for tDCS: anodal, cathodal, or dual. Anodal tDCS facilitates the depolarization of neurons and hence the neural excitability; cathodal tDCS hyperpolarizes the resting membrane potential, reducing the neuronal firing: it can be used to limit the interhemispheric inhibition when mounted on the not damaged brain hemisphere. Dual tDCS combines these two montages . PreviouThe aim of this study was to evaluate the recovery of motor skills outcomes in individuals with stroke undergoing an intensive inpatient rehabilitation and electrical brain stimulation at the early stage of rehabilitation, when neuroplastic mechanisms could be exploited at best.To determine whether the use of electric stimulation at an early phase of stroke may improve the motor outcomes, a double-blind, randomized, and sham-controlled trial was performed.Every patient admitted to our unit was screened according to the diagnosis and evaluated with regard to the inclusion/exclusion criteria reported in the following section (Participants).After obtaining the written informed consent, patients were randomized into 2 groups based on the stimulation . The randomization was created in accordance with a binary sequence previously generated using MATLAB R2007b Software . The experimental treatment was performed in add-on for a total period of stimulation of 10 days, carried out for 2 weeks, 5 consecutive days in each week. The application of cathodal or sham tDCS was provided immediately before the rehabilitative session in order to exploit the after-effects of the stimulation. Patients were assessed before the start of the protocol (T0), after the end of the stimulation period , one month after the end of treatment , and at the end of inpatient rehabilitation .All evaluations were performed for both the groups: cathodal tDCS as experimental group (EG) and sham tDCS as control group (CG). The patient was blind to the type of stimulation, as well as the physician performing the assessments. An unblinded investigator administered the stimulation.This protocol was approved by the local independent ethics committee.All hospitalized patients in our division (Stroke Rehabilitation Unit) were screened per inclusion/exclusion criteria. The inclusion criteria were subjects affected by a first ever stroke, age between 18 and 83 years; an occurrence of ischemic stroke in the territory of middle cerebral artery, as revealed by a magnetic resonance or computerized tomography scan performed before the enrollment; the stroke event occurred within 30 days from the starting of the protocol; no history of moderate to severe cognitive impairment, as evaluated by a neuropsychologist. The exclusion criteria were inability to perform a motor rehabilitation training; the presence of multiple foci of ischemia or a hemorrhagic stroke; the presence in the patient's history of a previous stroke or global cerebral ischemia; a diagnosis of a major psychiatric disorders or epilepsy; a history of tumor independently from location; the presence of pacemaker; uncontrolled arrhythmias or nonstabilized hearth diseases; dementia or severe aphasia that could have compromised the collaboration for the procedures.All enrolled patients gave written informed consent before the beginning of the experimental protocol.2 (5 cm × 7 cm), embedded in a saline-soaked solution. Consequently, we delivered a current density of 0.043 mA/cm2 . Stimulation was preceded by few seconds during which the current increased gradually to the selected intensity (fade-in phase), eliciting transient sensations that disappeared in several seconds and followed by the same few seconds during which current was progressively reduced (fade-out phase). The active electrode was positioned in the primary motor cortex area in the contralateral affected hemisphere . The reference electrode was positioned in a noncephalic side, above the right shoulder, contralateral to the electric circuit of the heart. In this way, only the area below the active electrode was stimulated, focusing the passage of current into the selected treatment area. The system is noninvasive and has been proven safe in the literature [In the EG, tDCS was performed using cathodal montage. The session of cathodal or sham tDCS had a duration of 10 minutes. The Eldith DC Stimulator tDCS model  was supplied to 1.5 mA of electric intensity, by 2 gel-sponge electrodes with a surface area of 35 cmterature .The training session following brain stimulation was that conventionally performed as part of inpatient daily rehabilitation. The motor rehabilitation was scheduled twice a day (in the morning and in the afternoon), lasting 45 minutes for each session and focused on the recovery of the upper limb and locomotor functions. Intensity and type of exercises were tailored on patient's residual abilities. No instrumented therapy was administered in the experimental period of stimulation. To avoid the presence of fatigue, the tDCS was performed before the rehabilitative session of the morning.To evaluate the recovery of motor functions during the inpatient rehabilitation, both instrumented measures and scales were used in order to increase the sensitivity, repeatability, and accuracy of the assessments.For a global evaluation of the patients' condition and abilities in the daily living, Canadian Neurological Scale and the Barthel Index were administered to patients.For the assessment of the upper limb impairments, we used 9-hole peg test, dynamometers for pinch and grasp forces, and Upper Limb Fugl-Meyer Scale.To evaluate the locomotor abilities, we applied the Timed Up and Go Test, the 6-Minute Walking Test, 10-Meter Walking Test, the Rivermead Mobility Index, and the Functional ambulation Classification.The Canadian Neurological Scale (CNS) is a validated scale for assessing and monitoring the neurological status of patients affected by stroke, focusing on consciousness, language, and motor functions of both limbs . A totalThe Barthel Index (BI) is the most used scale to measure the performance in activities of daily living (ADL) . The BI The 9-hole peg test (9HPT) is a simple tool to test the hand dexterity . PatientSpecific dynamometers  were used to measure the manual force. Maximum pinch and grip forces were measured in 2 attempts using both hands with the patient seated and the elbow at 90° of flexion and a neutral position of the wrist. This method is well standardized and proved to have a high test-retest reliability and it has been used in similar studies , 30.The Upper Limb Fugl-Meyer Scale (UL-FM) is a validated scale for the assessment of stroke-related upper-limb motor impairment . It is rThe Timed Up and Go (TUG) is a simple test used to assess both static and dynamic mobility balance . PatientThe 10-Meter Walking Test (10MWT) measures the time required to walk 10 meters, with the evaluation of walking speed (m/s) . It has The Six-Minute Walking Test (6MWT) was used to measure walking endurance, as usually described in many studies , 38. PatThe Rivermead Mobility Index (RMI) was used to assess the mobility of patients. It is a scale measuring mobility of subjects with stroke in relationship to many aspects of their static and dynamic balance .The Functional Ambulation Classification (FAC) is a functional 6-point walking scale to evaluate ambulation ability, assessing ambulation status regardless of patients' needing to use a personal assistive device . FAC cant-test was used to compare age and time from event at baseline between the two groups. Parametric statistics, that is, repeated measure analysis of variance, was performed for continuous measures extracted by functional tests. Nonparametric statistics, as Friedman analysis for within subject comparisons along time  and Wilcoxon sign rank test for between subject comparisons . Threshold for statistical significance was set at 0.05. Independently by possible post hoc analyses a direct comparison of the changes occurred between the two groups in the period between T0 and T1  using two-tailed Student t-test for continuous measures and Mann-Whitney U test for clinical ordinal scores. Correlation between these changes and T0 values was performed using Pearson and Spearman correlation coefficients for continuous and ordinal data, respectively.Data were summarized in terms of their mean and standard deviation. n = 7) and control (n = 7) groups. Two patients of EG dropped out from the study (one at the first and the other one at the second session). Also one patient of control group dropped out for an emergency transfer to another hospital. Mean age of the sample of subjects who completed the protocol was 58.36 ± 14.35 years, with a time from stroke event of 19.09 ± 8.04 days, without any statistically significant differences between the groups . Demographical and clinical features of the enrolled patients are reported in Of 115 screened patients admitted in our Unit in the 8 months of this study, fourteen patients matched inclusion/exclusion criteria and accepted to participate to the trial signing the informed consent and were hence enrolled into the study. These subjects were randomized into the experimental  are reported in Analysis of variance conducted on the eleven subjects who completed the study showed a statistically significant improvement along the rehabilitation, independently if experimental or conventional one, for the locomotor tests  and for hand dexterity (9HPT), but not for hand force , as reported in P = 0.931, Wilcoxon sign rank test), FAC-score (P = 0.931), CNS-score (P = 0.792), RMI-score (P = 0.537), and Fugl-Meyer-score (P = 0.444). Both groups showed significant improvements along rehabilitation as shown in The results of clinical scales are shown in In The aim of this study was to determine whether a treatment with cathodal tDCS in adjunction to the traditional motor rehabilitation might improve the outcomes at the end of inpatient rehabilitation for patients affected by a first ever ischemic stroke in a subacute phase. To facilitate the spontaneous mechanisms of neuroplasticity, we developed this experimental protocol at an early phase of stroke rehabilitation (maximum within 30 days from the event). All the main features of motor impairments were assessed during the period of observation. Our results showed no difference in all these assessed domains of motor impairments between the experimental group and the control group.Our trial provided stimulation at an early stage of the stroke rehabilitation, in order to favor the biological mechanisms of neuroplasticity involved in motor recovery. In fact, previous comparative preclinical studies have showed that tDCS could promote the same mechanisms involved in the neuroplastic reorganization . The impP values related to the interactions between treatment and time in the analysis of variance resulted far from the statistically significant threshold. It suggested that the absence of statistically significant differences was related to the similarity of the trends and probably not affected by the small sample size. Analogous results were found for anodal stimulation applied in the acute phase [In the literature, the studies on the role of tDCS in stroke motor recovery are heterogeneous, depicting a fragmented framework. Some of them reported positive results also after a single session , 45, evete phase . Our reste phase .A possible explanation for this lack of effect of tDCS in the stroke rehabilitation could be related to the severity of stroke and the degree of hemiparesis . In theiIt has to be noted that our results differed from those of many other studies in the literature. For example, Kim and colleagues noted significant improvements both of simple and complex motor functions in the activities of daily living after a period of treatments with tDCS , 22. ThiAnalysing the impact of tDCS into rehabilitation of patients with stroke, too many studies were affected by important biases to give definitive indications. Many reviews and meta-analyses concluded suggesting caution into defining tDCS as an effective tool for improving neuromotor rehabilitation in stroke –19, 50. Beyond the methodological considerations, our results about the nonuseful application of cathodal tDCS could be given by the results provided by Iosa and colleagues . In thisAt the moment, all these factors together do not allow a proper evaluation of the value of tDCS in a hypothetical rehabilitation protocol especially if compared to the extensive applications that tDCS has in other therapeutic fields, such as the psychiatric disorders .Our results should be read at the light of the limitation of the study. In fact, the reduced sample size might have affected the power of statistical analyses bringing nonsignificant results. However, our sample size was in line with those of previous similar studies, and all of them highlighted the small number of enrolled subjects as a common limit of studies on cerebral direct current stimulation. To overcome this frequent limit, future studies should be designed as multicenter trials, involving wider and more homogeneous number of patients. For all these reasons, our study could be considered as a pilot. However, despite the reduced number of subjects and the high standard deviations affecting between-group comparisons, the trends of the improvement shown in Figures To verify the present results, next clinical trials should consider the possibility of other types of stimulation , in order to analyze different possible interactions between neuroplasticity and achievable motor outcomes, as well as a prolonged period of stimulation . In the future, as already reported for robotic-assisted rehabilitation , it willIn conclusion, our study showed that an early applied cathodal electrical stimulation did not lead to a higher functional improvement in respect of traditional rehabilitation in patients affected by stroke in subacute phase during their period of inpatient rehabilitation.


To assess the budgetary impact of switching from screen-film mammography to full-field digital mammography in a population-based breast cancer screening program.A discrete-event simulation model was built to reproduce the breast cancer screening process  combined with the natural history of breast cancer. The simulation started with 100,000 women and, during a 20-year simulation horizon, new women were dynamically entered according to the aging of the Spanish population. Data on screening were obtained from Spanish breast cancer screening programs. Data on the natural history of breast cancer were based on US data adapted to our population. A budget impact analysis comparing digital with screen-film screening mammography was performed in a sample of 2,000 simulation runs. A sensitivity analysis was performed for crucial screening-related parameters. Distinct scenarios for recall and detection rates were compared.th year and 2,866,124€  in the 20th year, representing 4.5% and 8.1% of the overall cost associated with screen-film mammography. The sensitivity analysis showed net savings in the long term.Statistically significant savings were found for overall costs, treatment costs and the costs of additional tests in the long term. The overall cost saving was 1,115,857€  in the 10Switching to digital mammography in a population-based breast cancer screening program saves long-term budget expense, in addition to providing technical advantages. Our results were consistent across distinct scenarios representing the different results obtained in European breast cancer screening programs. In Spain, all resident women aged 50–69 are actively invited to participate in the population-based breast cancer screening program by written letter every 2 years. A screening mammogram (a type of low-dose x-ray examination used to detect breast cancer) is offered, allowing women who begin screening at 50–51 years up to a maximum of 10 screening mammograms. Breast cancer screening in Spain adheres to the European Guidelines for Quality Assurance in Mammographic Screening Several studies have shown that digital mammography is more expensive than screen-film mammography In Spain, screening units are increasingly switching to digital mammography as a consequence of digitalization of radiology departments. The US Preventive Services Task Force recommendations Budget impact analysis aims to estimate the impact of introducing a new technology in the budgets for the coming years In light of current findings, the economic impact of switching to digital mammography needs to be assessed. This impact includes not only the costs of mammography itself, but also the costs derived from performing a population-based screening program involving millions of women and tests, i.e., the costs of additional diagnostic tests and those of cancer treatment. The objective of the present study was to estimate the long-term impact on costs and health outcomes of switching from screen-film mammography to full-field digital mammography in a population-based breast cancer screening program from the perspective of a National Health System.This study was approved by the ethics committee of Hospital del Mar. The need for written informed consent was waived because all data was analyzed anonymously.Discrete-event simulation has been defined as “a flexible modeling method characterized by the ability to represent complex behavior within, and interactions between individuals, populations, and their environments” Parallel to the events related to the screening program, each woman was assigned a natural history of breast cancer. These events consisted of the start of the pre-clinical stage (when the cancer appears but it is asymptomatic), the start of the clinical stage (when the cancer is symptomatic), and death . The modThe time units were years. A simulated time horizon of 20 years (from 2010 to 2029) was chosen to encompass the life history of a woman entering a screening program (from 50 to 69 years) and to allow the budget impact to be analyzed in the long term. Individual women were simulated. Two identical groups of women with the same pattern of screening participation were simulated: one group by using the parameters estimated for screen-film mammography and the other by using parameters for full-field digital mammography. The times until an event of the natural history of breast cancer were also the same unless modified by cancer detection. All women underwent biennial screening from 50 to 69 years of age. Women aged 70 years or older were followed-up until 2029 only if they were diagnosed with cancer between the ages of 50 and 69 years or with an interval cancer in the last mammogram.The simulation model was implemented by using Arena (Rockwell Software) version 13.9.The target population at the beginning of the simulation included 100,000 women aged 50-69 years undergoing biennial screening. Every 2 years, women aged 50–51 years old entered the target population, following the age structure of the Spanish population Breast cancer incidence Age of death from any cause was modeled using the number of women and the number of deaths, by age, of the Spanish population in 2008 We assumed that if a woman enters the clinical stage, the cancer is detected on the basis of symptoms. Currently available data did not allow modeling the natural history of breast cancer based on progression through cancer stages, occurrence of symptoms or recurrences. Thus, the cancer stage was assigned according to the distributions described in the The participation profile for each woman was generated at the beginning of the simulation in order to ensure the same participation profile for digital and screen-film screening. Participation was treated as a probabilistic parameter  tests is assigned to the woman. Tests include additional mammographic projections, ultrasound, fine-needle aspiration cytology (FNAC), core biopsy, and open surgical biopsy. By using the Breast Cancer Screening Program database, the relative frequencies of the existing combinations of tests were calculated, stratifying by digital or screen-film mammography as well as by initial or successive screening.In our model cancer is detected inside and outside the screening program. The latter refers to nonparticipating women and interval cancers. The distribution of cancer stage at detection differs according to age and the screening round  as well as according to the detection setting. Clinical detection refers to cancers detected by clinical symptoms  and screening detection refers to those detected through a screening program (participating women). The stage distribution of screen-detected cancers differed according to digital or conventional mammography but that of clinical detected cancers was the same. In all cases, stage distribution was treated as a probabilistic parameter. See The study was carried out from the perspective of a National Health System that includes in its portfolio both preventive programs and clinical treatments, as it is the case of Spain and the majority of European countries. That means that the same payer bears all the preventive and curative costs. The costs of both screen-film and digital mammography were obtained from the accounting system of a Spanish program The cost of diagnostic and screening mammograms was assumed to be the same, according to expert opinion. The reason is that, although a screening mammogram needs to be read by two radiologists and needs a higher number of projections, it takes an average of 3 minutes to read, while a diagnostic mammogram needs fewer projections and is read by one radiologist but reading takes longer.The costs of breast ultrasound, FNAC, core needle biopsy and open surgical biopsy were obtained from the cost accounting systems of several Spanish hospitalsThe cost of treatment was obtained from a study Crucial parameters such as sensitivity, specificity, the stage distribution of detected cancers and participation were included as probabilistic parameters , the participation rate, the mean age of invited women, the number of mammograms over time , the recall rate, cancer detection rate, false-positive rate, false-negative and interval cancer rate, the distribution of additional tests, the distribution of cancer stage , and life expectancy. Validation results were shown to the research team using graphics through time and compared to published and unpublished data on Spanish programs. The distributions of the probabilistic parameters were also shown and its relationship with outcomes explained, as well as published data from other countries was presented to contextualize the need to include them as probabilistic parameters. The research team checked the validation results and the model was considered as valid, credible and useful for the purposes of the study.Budget impact analysis requires the inclusion of the entire population involved in a system each year The model started with a target population of 100,000 women aged 50–69 years. Over the 20 simulated years, 151,960 women were dynamically incorporated into the target population, making a total of 251,960 women invited to the program and resulting in more than 731,400 screening mammograms, of which 15.3% corresponding to initial screening .The recall rate was 6.1% for digital and 6.6% for screen-film mammography. Fewer additional tests were required with digital mammography . The falth year, data not shown).The results of runs with a better detection rate and a higher proportion of noninvasive cancers with digital mammography showed higher costs of digital mammography in the short term, but significant savings in the long term , despite excess costs in the short term.Our model shows that, although the differences in recall rate between digital and screen-film mammography are small in magnitude, they result in substantial cost savings in the long term as the lower recall rate with digital mammography results in fewer adverse events and additional tests with a consequent reduction in the negative impact on women. The most frequent additional test with digital mammography was one ultrasound scan (about 30%), while for conventional mammography a combination of ultrasound and FNAC was used (about 22%). Because the differences in recall and detection rate between screen-film and digital mammography are controversial, sensitivity and specificity were included as probabilistic parameters, meaning that some simulations were run with better sensitivities and/or specificities for digital mammography, others were run with better sensitivities and/or specificities for screen-film mammography, other simulations were run combining opposite directions for each parameter and still others were run with similar parameters. The results of the sensitivity analysis performed with the results of detection and recall rates demonstrated that, for all subgroups, the switch to digital mammography produced significant net savings in the long term, indicating that our results are consistent and robust concerning differences in the detection and recall rates between digital and screen-film mammography. The sensitivity analysis stratified by excess detection of carcinoma The model's parameters were mostly obtained from Spanish breast cancer screening programs that followed the standards of the European guidelines, thus conferring homogeneity to the model. However, the parameters related to the natural history of the disease, such as the sojourn time in the pre-clinical stage, although adapted to our population, were based on US data.Treatment costs may have been underestimated because medication criteria corresponded to 2000–2005 and costs to 2005 and more expensive chemotherapy treatments have been introduced since then. In addition, treatment costs included those of women with cancers detected within the simulation horizon only. Although this consideration did not pose a limitation to our objective of comparing digital with screen-film mammography screening, it did lead to underestimation of treatment and overall costs, especially in the short term.Given that our objective was to compare the population-based screening program using one technology versus the same program using the other, the costs and inefficiencies associated to the process itself of switching from screen-film to digital mammography have not been included In conclusion, switching from screen-film to digital mammography within a population-based breast cancer screening program reduces expense in the long term in addition to providing technical advantages. The higher expense of digital screening is offset by the reduction in additional tests. These results were consistent across distinct scenarios representing the different results obtained in European breast cancer screening programs.Appendix S1Supporting information to: Budget impact analysis of switching to digital mammography in a population-based breast cancer screening program.(DOCX)Click here for additional data file.Table S1Beta distributions for probabilistic sensitivity analysis.(DOCX)Click here for additional data file.Table S2Parameters of the Dirichlet distributions for cancer detection stages by age, detection setting, type of mammography and screening number.(DOCX)Click here for additional data file.


The most important asset of semisupervised classification methods is the use of available unlabeled data combined with a clearly smaller set of labeled examples, so as to increase the classification accuracy compared with the default procedure of supervised methods, which on the other hand use only the labeled data during the training phase. Both the absence of automated mechanisms that produce labeled data and the high cost of needed human effort for completing the procedure of labelization in several scientific domains rise the need for semisupervised methods which counterbalance this phenomenon. In this work, a self-trained Logistic Model Trees (LMT) algorithm is presented, which combines the characteristics of Logistic Trees under the scenario of poor available labeled data. We performed an in depth comparison with other well-known semisupervised classification methods on standard benchmark datasets and we finally reached to the point that the presented technique had better accuracy in most cases. Classification task is an integral part of machine learning algorithms, trying to separate and thereafter match each tested pattern or object into distinct categories or classes. The classes vary according to the application domain of each problem. For example, the classes could represent the different origin among the tested speakers in a Speech Identification problem or different objects at several pictures in various backgrounds in a Pattern Recognition problem.The default scenario of classification is the supervised, in which all the available labeled data are used in order to build a classification model. Using the information of the labeled data, the trained supervised classification model will assign to each new instance a class label. Unsupervised techniques can be also used for the same problems. The main characteristic of unsupervised techniques is the lack of need for labeled data . HoweverFriedhelm and Edmondo  proposedSun  reviews In many application domains, the labeling of the training instances requires high cost in labor and/or time . The majL) and the unlabeled (U) set. The mathematic expression of the instances that are included in each of these subsets is as follows:In particular, SSC methods demand only a small proportion of the whole amount of data to be labeled for accomplishing their task. This attribute is widely known as labeled ratio and is usually provided in percentage values: Tanha et al.  suggesteThe aim of our work was to present a self-trained Logistic Model Tree (LMT) algorithm and compare it with other well-known semisupervised classification methods on standard benchmark datasets. To achieve this, we performed statistical comparisons of the proposed method with other algorithms and represented an illustrative visualization for recording the behavior of each algorithm against the others. Our proposed technique presented higher accuracy in most cases and a better overall performance in different scenarios, rendering this algorithm as a robust tool.In Self-training is usually called a wrapper method that constitutes a great tool for semisupervised learning tasks. It is a simple scheme based on four stages . In the p-dimensional feature space, whereas p is the dimension of the feature vector (p × 1). By evaluating a hypothesis test, they finally discard any example whose output of the test was negative.Self-Training with Editing (SETRED) method is a modified approach to self-training proposed by Li and Zhou . Their pCotraining is an equally important scheme that can be considered as a different variant of self-training technique . Its maiWang et al.  proposedRASCO  does notTri-training scheme uses three classifiers using different bootstrap sample of the same dataset to label each unlabeled instance. If two of the three classifiers agree on the categorization of an instance, then this is considered to be labeled and is added to the training set . An imprHuang et al.  proposedn values, the node has n child nodes, and examples are sorted down one of the n branches depending on their feature's value. For numerical features, the node has two child nodes and the test consists of comparisons of the feature value with a threshold. The LogitBoost algorithm is used to produce a linear regression model at every node in the tree [Our proposed algorithm combines self-training scheme with Logistic Model Tree (LMT) algorithm. A LMT is a decision tree that has linear regression models at its leaves to provide a piecewise linear regression model . As in othe tree . The subthe tree . As for the tree .Decision trees can generate estimates for the class membership probabilities: the probability for a particular class is just the fraction of the instances in the region which are labeled with that class. In terms of probability estimates, LMT outperforms all other simple decision trees and related algorithms included in the experiments . In thisU to L is based on estimation of class probabilities. If the probability of the most probable class exceeds the predefined threshold T, then this instance is assigned a label. In the proposed algorithm, experimental results that were performed by the authors showed that a good option for the threshold parameter is the value of 0.9, which gave decent results irrespective of the dataset. It was noticed that only a small amount of instances per class in each iteration meets the restriction above.Removal of data points from For the implementation, we used the open-source environments of Weka  and KEELThe experiments are based on standard classification datasets taken from the KEEL-dataset repository  coveringSubsequently, we compared the proposed method with other state-of-the-art algorithms into the KEEL tool  such as http://www.math.upatras.gr/~sotos/Self_LMT_Results.xlsx.The classification accuracy of each tested algorithm using 10%, 20%, 30%, and 40% as labeled ratio is presented in Tables Here, we present only the best 10 of these algorithms, according to their classification accuracy. A short comment follows each experiment about the general behavior of the proposed algorithm in comparison with the most effective one of the rest. We also provide a more representative visualization of the average accuracy ability of the proposed algorithm in comparison with the rest 21 algorithms, presented in In this experiment, self-trained LMT and Co-Forest presented 8 wins in an amount of 52 datasets, being followed by self-training (C45), cotraining (C45), and APSSC with 5 victories. Despite the low labeled ratio of instances, self-trained LMT managed to achieve the best average accuracy, assuring its robust behavior.During the experiment of 20% labeled rate, self-trained LMT algorithm succeeded with 15 victories, while the next in victories' rank were Co-Forest algorithm with 5 and cotraining (SMO) with 4, respectively.Similar to the previous experiment, self-trained LMT performed 17 wins out of 52 datasets, while cotraining (SMO) and Rel-Rasco (NB) achieved 7 and 6 best accuracy values, respectively.Finally, self-trained LMT algorithm outperformed the rest of algorithms managing to score the best accuracy value in 19 different datasets, while democratic-co achieved 5 victories.An interesting point which comes out from As a result, the proposed algorithm gives statistically better results among all the tested algorithms. This is due to better probability-based ranking and higher classification accuracy which allow selection of the high-confidence predictions in the selection step of self-training.It is promising to implement techniques that use both labeled and unlabeled instances in classification tasks. The limited availability of labeled instances makes the learning process difficult, as supervised learning methods cannot produce a learner with worthy accuracy.LMT produces a single tree containing binary splits on numeric features, multiway splits on categorical ones, and logistic regression models at the leaves, and the algorithm ensures that only relevant features are included in the latter. The produced classifier is not so easy to interpret as a standard decision tree, but much more legible than an ensemble of classifiers or Kernel-based estimators.In this work, a self-trained LMT algorithm has been proposed. We performed a comparison with other well-known semisupervised learning methods on standard benchmark datasets and the presented technique had better accuracy in most of the tested datasets. Due to the encouraging results obtained from these experiments, one can expect that the proposed technique can be applied to real classification tasks giving slightly better accuracy than the traditional semisupervised approaches.In spite of these results, no general method will work always. The main drawback of the semisupervised schemes is the needed time in the training phase. Some techniques that could enhance this property by saving both valuable operation time and computational resources are the feature selection algorithms which search for a subset of relevant features by removing the less informative of the initial features . Buildin