Health care professionals seek information about effectiveness of treatments in patients who would be offered them in routine clinical practice. Electronic medical records (EMRs) and randomized controlled trials (RCTs) can both provide data on treatment effects; however, each data source has limitations when considered in isolation.A novel modelling methodology which incorporates RCT estimates in the analysis of EMR data via informative prior distributions is proposed. A Bayesian mixed modelling approach is used to model outcome trajectories among patients in the EMR dataset receiving the treatment of interest. This model incorporates an estimate of treatment effect based on a meta-analysis of RCTs as an informative prior distribution. This provides a combined estimate of treatment effect based on both data sources.The superior performance of the novel combined estimator is demonstrated via a simulation study. The new approach is applied to estimate the effectiveness at 12 months after treatment initiation of acetylcholinesterase inhibitors in the management of the cognitive symptoms of dementia in terms of Mini-Mental State Examination scores. This demonstrated that estimates based on either trials data only  or cohort data only  overestimated this compared with the estimate using data from both sources .It is possible to combine data from EMRs and RCTs in order to provide better estimates of treatment effectiveness. Key MessagesData on a treated cohort from an electronic medical record (EMR) and data from randomized controlled trials (RCTs) can be combined to provide estimates of treatment effects that are less biased and more generalizable than those from either data source alone.This holds true even if both are biased in the same direction.Estimates from either EMRs or RCTs alone overestimate the effects of acetylcholinesterase inhibitors in terms of Mini-Mental State Examination scores at 12 months after treatment initiation.It is possible to combine data from observational and randomized data sources even when the observational data are not comparative.A concerted effort to assemble routine EMR data in a form that can be used to improve real-world inferences from RCTs is required.,,Health care professionals seek knowledge of the effectiveness of treatments in patients who would be offered them in routine clinical practice. Electronic medical records (EMRs) provide potentially valuable representative longitudinal data on treatment outcomes in routine clinical practice.,,Development of methods to combine data from both randomized and observational data sources is an ongoing area of research, with a variety of methods developed in recent years.In this paper, we propose a novel methodology for combined modelling which provides an estimator of treatment effectiveness which overcomes both the lack of an adequate control group in EMR data and the lack of generalizability in RCT data. A Bayesian approach combines these data sources, incorporating RCT estimates as part of an informative prior distribution.The motivating clinical question for this work is the estimation of the effectiveness of acetylcholinesterase inhibitors (AChEIs) in managing the cognitive symptoms of dementia. Dementia is a major health concern, affecting 47 million sufferers worldwide in 2016, predicted to rise to 131 million by 2050.The treated cohort used in this study was extracted from the South London and Maudsley Biomedical Research Centre case register. Patients were included in the cohort if: (i) they had at least one mention of an AChEI  for which the date of treatment offer (approximated by treatment start date which is coded as the earliest date on any AChEI prescription) could be identified; (ii) they had at least one MMSE score with a denominator ≥24 recorded between 1 year before and 3 years after treatment offer (only a single MMSE score was required for inclusion and this could be before or after treatment initiation); and (iii) they had received a primary or secondary diagnosis of dementia excluding diagnoses of Parkinson’s disease dementia and dementia with Lewy bodies. For each eligible patient, all MMSE scores recorded between 1 year before and 3 years after treatment were extracted. MMSE scores with a denominator less than 30 were standardized by calculating an adjusted score as numerator divided by the denominator multiplied by 30. The treated cohort contained 3134 patients with a total of 13 577 scores between them, and covered the period 1 January 2005 to 8 February 2015. A previous systematic review and meta-analysis of trials of AChEIs in managing the cognitive symptoms of dementia forms the RCT dataset.ij, R=1 is the outcome for individual i at time tij if they are offered treatment, and yij, R=0 is the outcome for individual i at time tij if they are not offered treatment. For an individual, the effect of treatment offer (Δi) at a fixed time t = α > 0, is the difference between their outcome at α if they were and were not offered treatment:Each member of the target population, that is patients who receive this treatment in routine clinical practice, can be thought of as having two potential outcome trajectories: the one they would have followed if they were offered treatment, and the one they would have followed if they were not. In practice, only the first of these is observed. Using t to denote time, with time 0 being the point of treatment offer, these two outcomes can be summarized as:where yFor an individual it is possible to observe only one of the two potential outcomes; therefore, the parameter we are interested in estimating is the average effect of treatment offer at t = α, which we call the ARE :In order to be able to estimate this parameter, appropriate expressions for the average trajectory in the population who are offered treatment, and the population who are not, are needed. Previous workAll participants in the cohort were offered treatment, and so an assumption must be made about what would have happened had they not been offered treatment. The assumption made is that they would have continued on their pre-treatment trajectory (A1):α, and may suffer from bias since it relies on assumption A1:Having made this assumption, it is possible to derive an expression for an estimator of treatment effect parameter (ARE). This estimator of treatment effect is denoted θ2 in terms of the other parameters:2 can be substituted into the expected treated trajectory for those who are offered treatment [This expression for βreatment :α) based on data from a cohort who were all offered treatment. Random effects on the coefficients can be incorporated to allow variation between patients:This model can be used to estimate the effect of treatment at time t = α ]. In the presence of two or more random effects, these can be modelled using a multivariate normal distribution with mean zero. Vague priors are used for the covariance matrix. In the case of two random effects, the constituent parts of the covariance matrix can be given vague priors [U for standard deviations and U for the correlation]. In the presence of three or more random effects, an inverse Wishart prior distribution is used for the re-scaled covariance matrix with U priors used for the scaling parameters.To fit this model under a Bayesian framework, prior distributions for each of the parameters were determined. In the absence of additional information, non-informative priors should be used.α is based may be biased, patients may not have continued on their pre-treatment trajectory. This is called projection bias, with the projection bias at time = α denoted φα. The true treatment effect, ARE(α), can be calculated as:The assumption on which the estimator θThis can be substituted into iS, which takes value 1 if individual i is trial eligible and 0 otherwise, to denote whether or not the individual is part of the trial-eligible population:where subscript 1 denotes parameters referring to the trial-eligible portion of the target population and subscript 2 denotes those for the trial not-eligible portion. The trial eligibility parameter is given a Bernoulli distribution:where 0 < π  <  1 is the proportion of the target population that are trial eligible. The overall treatment effect can be calculated as:Data from RCTs can form the basis of an informative prior distribution for ARE(α); however, this is only true for the proportion of the target population who are trial eligible. The model in 1(α). This meta-analysis was performed based on trials identified during a systematic review of the use of AChEIs in the management of dementia.α, can be both positive and negative and so was given a normal prior distribution with mean 0 and large variance. The trial-eligible proportion, π, is a probability and was thus given a uniform prior on the range 0 to 1.As before, each of the parameters in the model is given a prior distribution. An informative prior distributionα, is the same in the trial-eligible and trial not-eligible portions of the target population (A4). These assumptions are weaker than those required when estimating treatment effects based on the treated cohort alone (where A1 is made instead of A3) or trial data alone, where we must assume that the trial and trial-eligible portions of the target population do not differ on any characteristics which predict treatment effect (A2) rather than A4.This proposed combined model relies on two assumptions; first, that there are no treatment effect moderators whose distribution differs between the trial-eligible portion of the target population and the trial samples (A3); and second, that the projection bias, φ1, and the trial not-eligible portion P2. We assumed that P1 could be further split into k mutually exclusive and exhaustive subsets P1j, representing those eligible for each of k trials. Using Zi as an indicator for trial eligibility, Zi = 1 if individual i is trial eligible, 0 otherwise, and setting P(Zi = 1) = π, then the treatment effect for each individual  can be generated using:To investigate the properties of the proposed new estimator, a simulation study was conducted. The target population, P, can be split into the trial-eligible portion P0, i, can similarly be defined as follows:The outcomes for individuals at treatment offer γFor each individual, these values are first generated and the trajectories under treatment offer are derived. The trajectory under no treatment offer is assumed to be:where t = 0 is the point where treatment would have been offered and the trajectory has two slopes. 3, thereafter the following expressions for the trajectory under treatment offer can be derived:Assuming that the trajectory under treatment offer has a second change point at t = δ and slope γα, and generalizability bias ζ, are as follows:Expressions for the projection bias φ1, was split evenly among the k trials so that 1j were selected for each trial. For each, their outcome at treatment offer was obtained from 2 participants from the target population P; choosing the time points at which observations are recorded for individual i, tsel, i, to ensure variation in location and number of measurements; and generating potential outcomes at selected time points using Trial samples for each of the k trials were generated by first assuming that the whole trial sample size, n,Input values investigated for each of the parameters are summarized in Three competing estimators were calculated for each simulated dataset: (i) trials only estimator; (ii) cohort only estimator; and (iii) combined estimator. Estimators were compared in terms of absolute bias, standard error (SE) and mean squared error (MSE); 500 sets of data were generated for each combination of input values.IJE online).The impact of varying the generalizability bias parameter (ζ) at α = 0.25 and averaged across all other parameters is summarized in Having demonstrated the favourable performance of the combined model in the simulation study, it was applied to the motivating clinical question. The recent systematic review of AChEIs in the management of dementia identified four trials estimating their effects at 12 months after treatment offer.In this paper we have proposed and evaluated a novel estimator of treatment effectiveness which incorporates data from RCTs to improve the estimates of treatment effect available from analysis of data on a treated cohort. The performance of the novel estimator was compared with that of those based on either data source alone via a simulation study, demonstrating the model to be superior for estimating effectiveness in the presence of bias in one or both of the data sources. The model was applied to estimate the effectiveness of AChEIs 12 months after treatment offer in terms of MMSE scores, and this highlighted an important strength of the new combined model: namely that even when both of the estimates based on a single data source are biased in the same direction, the model can identify and account for these biases.,The combined model used a Bayesian framework, allowing the incorporation of data external to the current dataset in the form of informative prior distributions. This model can be considered an example of the type of bias analysis proposed by Greenland.One limitation of this method is that it does not address potential differences in distribution between the trial-eligible portion of the treated cohort and the trial sample (the requirement for assumption A3 to hold). Approaches to account for these differences,A further limitation which may be encountered in applying such a model is the need to be able to identify patient eligibility in an EMR; however, the availability of such data is increasing.Assumption A4 is analogous to the one made when calculating the linearly extrapolated estimator of treatment effect in Cross Design Synthesis.The approach has been developed for a continuous outcome measure; however, it could be expanded in future for use with in other clinical settings (e.g. where patients are expected to recover permanently as a result of treatment) or other data types (for example binary or time-to-event data). This would require careful consideration of reasonable assumptions for outcomes under control conditions in the EMR data and then using these assumptions to derive an appropriate model with a treatment effect parameter on which a prior could be placed. Simulation studies would be required to investigate the performance of such an expansion of the model. The modelling methods could also be applied in other conditions and to estimate the effectiveness of other treatments.In conclusion, in this paper we have proposed a Bayesian mixed model approach to combining data from trials and a treated cohort to estimate treatment effectiveness, and demonstrated, using a simulation study, the superiority of estimates of effectiveness produced by this model compared with those provided by either data source alone. The new model was also applied to estimate the effectiveness at 12 months after treatment offer of AChEIs in the management of dementia as measured using the MMSE. Several possible avenues for future extensions of this model have also been proposed.The Clinical Record Interactive Search system received ethical approval from the Oxfordshire Research Ethics Committee C as an anonymized data resource.dyac185_Supplementary_DataClick here for additional data file.


The kinematic parameters of reach-to-grasp movements are modulated by action intentions. However, when an unexpected change in visual target goal during reaching execution occurs, it is still unknown whether the action intention changes with target goal modification and which is the temporal structure of the target goal prediction. We recorded the kinematics of the pointing finger and wrist during the execution of reaching movements in 23 naïve volunteers where the targets could be located at different directions and depths with respect to the body. During the movement execution, the targets could remain static for the entire duration of movement or shifted, with different timings, to another position. We performed temporal decoding of the final goals and of the intermediate trajectory from the past kinematics exploiting a recurrent neural network. We observed a progressive increase of the classification performance from the onset to the end of movement in both horizontal and sagittal dimensions, as well as in decoding shifted targets. The classification accuracy in decoding horizontal targets was higher than the classification accuracy of sagittal targets. These results are useful for establishing how human and artificial agents could take advantage from the observed kinematics to optimize their cooperation in three-dimensional space. Typically, the interpretation and predictions about the actions and their intentions represent crucial aspects on which the human behaviour is based. Specifically, by a mechanistic perspective, the kinematic parameters of reach-to-grasp movements are modulated by the action intentions. In fact, the reach and the grasp components are affected by changes in both intrinsic and extrinsic features of the target and prior intentions5. The knowledge that the kinematics of human behaviour is modulated by different motor intentions opens to the possibility of using the observed kinematics as a cue to predict the action intentions. For example, Manera et al.6 showed the possibility to predict the agent’s intention to cooperate or compete with a partner by the observation of the initial reach and grasp phase of the entire movement and without contextual information. Similar results were found by Sartori et al.7 and another study by Cavallo et al.8 showed that the accuracy found in an intention prediction task was significantly related to a specific subset of kinematics features varying across different intentions. Another study showed that the similarity between the kinematics of agents and observers have a positive impact on the accuracy in recognition of intentions9. Furthermore, the use of an object influences the way we reach towards that object and grasp it11. In fact, what the actor intends to do with the object  shapes the grasping kinematics for the same object12. And similarly, the actor’s social intentions such as cooperating with a partner, competing against an opponent, or performing an individual action also modulate the kinematics of reach-to-grasp movements13. Based on the evidence that the action execution is itself shaped by its final goal and/or by the physical properties of its target, the intention and outcome of an observed action can be accurately predicted. In fact, as the action is shaped by its final goal, the information about the goal is available to the observer well before the end of action execution. This can be applied to several ecological motor behaviours spanning from simple actions (e.g. reach-to-grasp an object) to more complex ones 14.Actions require complex cognitive processes that start from abstract action intentions and arrives to the description of motor mechanistic propertiesIn the previously discussed studies, researchers investigated the possibility to predict action intentions or action goals from the kinematics of movement towards targets/objects that remained stable for the entire execution of the movement. However, it is still an open question the effect of an unexpected change in target goal position that occurs at different directions and depths with respect to the body during reaching execution on the prediction of the final goal. In addition, it is unknown the temporal structure of this prediction. In this study, we addressed these questions, and we characterized the information contained in the kinematics of reaching movement towards targets located at different directions and depths with respect to the body in a condition where the targets remained static for the entire duration of the movement and in a condition where the targets shifted to another position during the movement execution. To investigate the effect of reaching perturbation on the predictability of reaching goals and of intermediate positions , a recurrent neural network was used to decode the reaching goals over the trial course  and the intermediate positions of reaching kinematics from the three-dimensional position of the pointing finger and the wrist of human participants.The 3D position of the index finger and the wrist was recorded in each participant during reaching movements performed towards 12 static and shifted spatial positions with 6 different direction angles and 6 different depth levels  and in Experiment 2 (target shift after 100 ms from movement onset). In general, we found that the time course of the accuracy (recognition rate) in predicting static and shifted targets shows similar trends in both horizontal and sagittal dimension and in the two Experiments. No significant differences were found between the time course of decoding accuracy of static targets between Experiment 1 and Experiment 2 suggesting that the two groups presented the same baseline .In Experiment 1 when the target shift occurs at movement onset, the accuracy in the prediction of static horizontal targets was significantly higher than the one of left shifted targets  and also than the one of right shifted targets , see Fig. In Experiment 2, when the target shift occurs 100 ms after movement onset, we found similar results as obtained from Experiment 1, but in wider intervals of movement execution compared to Experiment 1. Specifically, the accuracy in the prediction of horizontal static targets was significantly higher with respect to the one of shifted left targets from 11 to 76% of movement execution, and of shifted right targets from 11 to 77% of movement execution , see Fig. The previous classification analysis enabled to assess the differences in the discriminability of static and shifted targets in the temporal domain. Apparently, no differences are visible from the time course of shifted target classification between the horizontal and sagittal dimension in Experiment 1 and 2. To further address this question, we first calculated at which time of the movement execution the recognition rate reached the chance level (0.5) in each participant when they must execute movement corrections towards targets along the horizontal and sagittal axes, respectively. Figure To further investigate the overall effect of horizontal and sagittal dimension not only in terms of variability in the predictability of final target goals, we calculated the averaged temporal evolution of the accuracy in recognizing static and shifted target positions along the two dimensions considered and in both experiments. As it is shown in Fig. To assess the ability in reconstructing the future trajectory observing the past one and how this was influenced by the offset between past and future observations, RNN-based regressors were trained on sliding windows within the trial course by varying the offset between past (regressor input) and future (regressor output) kinematic values. Figure The focus of this study was to assess whether it was possible to predict static and shifted target goals in the three-dimensional space based on advanced information from the hand kinematics of individual participants. Specifically, we explored (i) at which stage of the movement execution it was possible to make the most accurate predictions about final target goals and (ii) the influence of the offset between past and future observations on the reconstruction of the future trajectory observing the past one.We defined temporal and accuracy differences in predicting static and shifted targets when these were moved at the onset of the movement (Experiment 1) or 100 ms after the onset of the movement (Experiment 2) and when they were located along the horizontal or along the sagittal axis. We found that the accuracy in predicting static targets was higher than the accuracy in predicting shifted targets in both experiments, but an increased variability was visible in predicting shifted targets located along the sagittal axis, particularly, during the execution of Experiment 2.15, Soechting and Lacquaniti (1983)16 and Brenner and Smeets (1997)17 found. In fact, they found the same range of correction time (between 100 and 200 ms) to respond adequately to an unpredictable displacement of the reaching targets during the movement confirming that some corrections can be made during most movements. However, we found that movement corrections to sagittal targets were delayed or not detectable according to the time of the target displacement, respectively. The differences found for movements towards horizontal and sagittal targets are also evident in the target classification in terms of prediction variability of shifted targets and in terms of prediction accuracy of static and shifted targets together . Although in monkey the results showed a reliable decoding of targets goals also in depth from parietal neural discharges22, in humans, when the depth information was added, the decoding of movement became reasonably slower and clumsier23. This can be explainable by the evidence that visual depth perception is distorted and the same binocular disparity can be generated by different objects28. For example, based on disparity information alone, a marble ball that you hold between the fingers and a basketball at a distance of two meters appear virtually identical. In theory, the brain can resolve this ambiguity from an estimate of fixation distance provided by the ocular convergence. However, the brain fails to properly calibrate relative depth, because perceived relative depth is overestimated for objects that are closer from the observer and underestimated for objects that are further29. A similar distortion can be observed also for pointing to visual targets in depth30, so reflecting the kinematics of these types of movements and the accuracy through which the final targets are predicted. However, if the depth distortion perception can explain the differential effect of direction and depth dimension on the classification accuracy of the final targets, the same cannot be considered to explain the absence of the same effect on the accuracy of intermediate kinematics prediction. In this case, similar accuracies were found in our results suggesting that depth and direction are relevant factors for predicting reaching execution as function of the final goals but not for predicting the reaching execution itself.In this study, we found a progressive increase of decoding accuracy of stable targets across the movement execution that goes beyond the chance level before the half 50%) of action execution in both experiments 33 that conducted a double-step reaching task where the shift occurred at either reach onset or peak velocity. They demonstrated that when the target was shifted at movement onset participants compensated for 88–100% of the target displacement. In contrast, when the target was displaced at peak velocity participants were unable to fully account for the change in target position and compensated for only 20–40% of the perturbation33. Liu and Todorov (2007)34 similarly found incomplete corrections to target shifts that occurred considerably after reach onset. They suggested that achieving stability in stopping a reaching movement may potentially compromise the sensorimotor system’s ability to respond to positional errors at the end of the reach34. Present results are in accordance with these pieces of evidence, suggesting that target shifts occurring early in the reach (i.e. 0 ms) were more easily tackled by the neural network than those occurring later in the reach (i.e. 100 ms post reach initiation).Another aspect of the present study is related to the higher classification accuracy found for the target shifts occurring at the movement onset (Experiment 1) with respect to those occurring after 100 ms after the movement onset (Experiment 2). These results are interesting in the framework of models of goal directed reaching, suggesting that targeted reaching movements require several processing stepsThe results of this study provide novel insights into quantitative estimate of the accuracy that is possible to achieve when predicting, from hand kinematics, whether a reaching target goal is located along the horizontal dimension (direction) or the sagittal dimension (depth) of the 3-dimensional space and when the target shift occurs at the onset of the reaching or at later stages in the reach, as a function of time during movement. Furthermore, we also extended this analysis not only for decoding reaching goals but also for intermediate positions, to investigate whether the previous results held also when predicting intermediate kinematics and not only the final goal. We achieved this by exploiting the prediction of a learning system (here a RNN) that provided evidence of the kinematic cues potentially available for predicting final action goals and the intermediate kinematics in reaching targets in the 3D space. Future directions will consider the extension of this framework towards applications in human–robot interaction in which more complicated actions and composite contexts need to be decoded for fruitful human-artificial intelligent agents.A total of 23 naïve volunteers  took part at the study. 12 participants performed Experiment 1 and 11 participants performed Experiment 2. All participants were right-handed, and they had normal or corrected-to-normal vision with no history of neurological or psychiatric disorder. The study was approved by the local ethical committee of University of Bologna and was conducted according to the principles expressed in the Declaration of Helsinki. All participants provided written informed consent.In all trials, the starting position of the hand (dominant right hand) was on a computer mouse placed adjacent to the touchscreen within a square marked with a tape size 12 × 12 cm) in front of the participant’s chest, as sketched in Fig. 2 × 12 cm2. Stimuli were presented on 19-inch touchscreen (ELO IntelliTouch 1939L) laid horizontally on a desk located at waist level with a visible display size of 37.5 × 30 cm and 15,500 touchpoints/cm2. The display had a resolution of 1152 × 864 pixels and a frame rate of 60 Hz.Reaching movements were performed in a dimly illuminated room. The head of participants was supported on a chinrest in order to reduce movements. The stimuli were green (diameter 0.3 cm) and red dots (diameter 1.2 cm) presented at different depths and at different direction with respect to the participant’s midline. The stimuli presented a luminance of ~ 17 cd/m35. Arduino UNO microcontroller  was responsible for triggering the start/stop of the VICON system capture.Reaching movements were recorded using a motion tracking system (VICON motion capture system) by sampling the position of two markers at a frequency of 100 Hz; markers were attached to the wrist (on the scaphoid bone) and on the nail of the index finger (pointing finger). Participant’s eye positions were recorded by a mobile eye-tracking glasses . This device is composed of three cameras: a world camera which records the subject’s field of vision  and two eye-cameras that records the observer’s eye movements . Before each measurement, a binocular calibration process was carried out automatically using five pupil calibration markers (v0.4) located in the touchscreen’s corners and center. The psychophysical experiment was designed and generated with Matlab  with the Psychophysics toolbox extensionThe scheme of the experimental paradigm is illustrated in Fig. http://scikit-learn.org, RRID: SCR_002577) and deep learning  Python packages. Specifically, for hand position data processing and analysis, a custom MATLAB algorithm was used to extract the x, y and z components of the index and wrist trajectories between the onset and the offset of the reaching movement  and Python 3 using open source machine learning  during the entire execution of the movement and for each participant. Then, we compared the lateral velocities of left and right shifted trajectory and those of near and far shifted trajectory in each sample of all participants by a two-tailed t-test (p < 0.05). By this method, we found the sample at which the two shifted trajectory started to become statistically different .Movement accuracy was extracted by endpoints recorded as the x and y coordinates of the touching point acquired by the touchscreen and the x and y coordinates of the target location. The measure of accuracy was extracted for each participant and calculated as follows:Reaction times were calculated as the time interval between the appearance of the reaching target and the movement onset. We compared the reaction times between the two experiments by a two-tailed t-test corrected for multiple comparisons (p > 0.0125).38.As measure of motor strategies along the movement execution, we performed an analysis of the variability of trajectories across trials. For each participant and in each experiment, we calculated standard deviations across trials in both X  and Y dimensions  at a relevant point of the movement corresponding to the peak velocity (point of maximum velocity); then we averaged across participantsDue to the different number of samples of each trial , position trajectories of index and wrist belonging to each trial were normalized between 0 and 100% of the trial duration and resampled to have a fixed number of 100 samples. The x, y, z positions of index and wrist movement effectors were analyzed using two different sliding window decoding approaches, decoding a single chunk of kinematic activity at a time. For both approaches, each input chunk consisted of the In the following, the decoding analyses are described.(i)Classification of reaching goals. In this first decoding analysis, central for this study, classifiers were trained to predict the target endpoint to reach, given the x, y, z coordinates of the index and wrist contained in the chunk mentclass2pt{minimmentclass2pt{minimx and σy of the data.Furthermore, to inspect the differences in classification accuracy between horizontal and sagittal shifted targets in each experiment, we computed the averaged sample at which the accuracy exceeded the chance level (0.5) in recognition. Then, we plotted the percentage of movement towards shifted horizontal targets at which the classification accuracy exceeded the value of 0.5 against the percentage of movement towards shifted sagittal targets exceeded the same value. The differences between the classification accuracy were evaluated by calculating the confidence ellipses for 2D normally distributed data in the two experiments separately. The shape of the confidence ellipses was determined by computing the eigenvectors and the eigenvalues. Eigenvectors represent the direction in which the data varies the most and the eigenvalues correspond to the spread of the data in the direction of the eigenvectors. The area of the ellipses was computed from the length of the major and minor axes defined as standard deviations σ(ii)Regression of future trajectory values. In this analysis, we analyzed to which extent the intermediate kinematic observations  were predictable from past kinematics. Regressors were trained to predict the future position trajectory values recorded during movement, given the x, y, z coordinates of the index and wrist contained in mentclass2pt{minim39 with 100 GRU units was designed. The networks changed only in the adopted output layer across the two decoding approaches. Therefore, in the classification task the output layer was a dense fully-connected layer with one unit for each reaching endpoint, that is, 2 units , followed by a softmax activation function. Conversely, in the regression task, the output layer was a dense fully-connected layer with one unit for each trajectory component, that is, 6 units  did not decrease after 500 epochs. Unless not otherwise specified, the default Keras parameters were used .Furthermore, as concerning network training, RNNs were trained using the categorical cross-entropy and mean squared error as loss functions for the addressed classification and regression tasks, respectively. Adam was used as optimizerLastly, regarding performance evaluation we adopted a fivefold stratified cross-validation scheme, thus, 5 independent models were trained using 48 training trials and 12 test trials within each fold, balanced across classes. Then, performance metrics (accuracy for classification and R squared for regression) scored on the test set were computed and averaged across the 5 cross-validation folds.


Improvements to the signal-to-noise ratio of magnetic resonance detection lead to a strong reduction in measurement time, yet as a sole optimization goal for resonator design, it would be an oversimplification of the problem at hand. Multiple constraints, for example for field homogeneity and sample shape, suggest the use of numerical optimization to obtain resonator designs that deliver the intended improvement. Here we consider the 2D Lenz lens to be a sufficiently broadband flux transforming interposer between the sample and a radiofrequency (RF) circuit and to be a flexible and easily manufacturable device family with which to mediate different design requirements. We report on a method to apply topology optimization to determine the optimal layout of a Lenz lens and demonstrate realizations for both low- (45 MHz) and high-frequency (500 MHz) nuclear magnetic resonance. For MR measurements, it is important to achieve a high SNR to obtain a high-resolution spectrum or a highly resolved image, which also leads to a reduction in the overall measurement time. The relationship between the SNR and the magnetic field produced by the coil was derived by From the statement above, it is self-evident that reducing the size of the coil will improve its filling factor, which leads to the SNR enhancement, since the strength of Faraday induction increases with a reduction in the distance between the coil and the sample. The miniaturization of coils, as for example discussed by In some cases, the reception coil and its capacitors cannot be placed too close to the sample or specimen, e.g. when performing MRI on small living organisms or for sensitive spectroscopy of small samples. In such scenarios, the improvement of the filling factor is remedied by using a Lenz lens (LL) If we focus our attention on the LL, its design needs to be further investigated to improve the amplified field uniformity and to increase the field amplification for cases where the geometrical space for the LL is limited. Although it was shown by In this paper, we now explore the use of computational optimization to “discover”, via inverse design, a novel distributed metallic track arrangement that produces the same effect as a Lenz lens. The computational procedure will aim to maximize the magnetic field flux (i.e. the lensing effect) in the sample and at the same time aim for a flux distribution that is as constant as possible. As will be shown, these two requirements are in conflict, so a supervisor will have to balance these requirements depending on the application. Furthermore, the design will depart considerably from the Lenz lens topology and may require additional constraints to ensure manufacturability.1.2Topology optimization has been used in various fields for inverse material design, such as for acoustics In the field of electromagnetics, topology optimization has been explored for applications such as photonic crystals However, in surface plasmonics For our problem formulation, we chose the conductivity function as a material property in the domain rather than on the boundary. The conductivity range between which the material property is interpolated was of the order of Using the methodology presented in Sects. The obtained geometries were then characterized, and the simulation results were verified by NMR experiments described in Sect. 2In this section, we consider the electromagnetic wave equation that governs the behaviour of the device, derive the equations of the material distribution method, and formulate the objective function with constraint equations with which to obtain an optimized geometrical configuration corresponding to a spatial material distribution.j represents the imaginary unit  a minimization–maximization process, where the minimization of the objective function The material properties applied to the different domains are represented in Table 3The optimization computations were carried out in the commercial software COMSOL MULTIPHYSICS (V5.4) using its AC/DC and Optimization modules. The simulations were computed using an Intel(R) Xeon(R) Silver 4210 CPU with a processing speed of 2.2 GHz and a RAM size of 64 GB on a 64-bit Windows 10 operating system.i.The material properties were initialized in different domains. ii.The initial value of the design variable value was set to be 0.5. It was filtered using Eqs. (10) and (11). The filtered design variable was then transformed into a projected design variable using a hyperbolic function described in Eq. (12). The projection point iii.The wave equation was solved using the initial value of the design variable, after which it was updated using the method of moving asymptotes (MMA) iv.The tolerance for the objective function error was set to be a very small number to allow the conditions of Eq. (16) to be met before the premature termination of the simulation. If the constraints defined by Eqs. (16) and (17) were not satisfied until The optimization was performed for two frequencies, i.e. at 45 and 500 MHz. The results and more detailed setup for these cases are discussed in the following sub-sections.The computational domains were meshed with linear elements to exploit the efficiency of the linear discretization of the magnetic vector potential. This reduced the total computational cost of the simulations. The simulations were formulated such that they follow an iterative procedure as represented by the flowchart in Fig. 3.1In an MR experiment, the net magnetization of the sample, which is aligned along the The background magnetic vector potential becomes The dimension of the entire computational domain was Figure 3.2A magnetic lens was also designed for an 11.7 The background field was set as defined before in Sect. Figure 4After the designs of OLs were obtained, they were characterized and compared with a wired LL similar to that discussed by To characterize the magnetic field distribution and its enhancement, a second simulation environment was set up where the background field was replaced by the magnetic field produced by a realistic coil geometry. The boundaries of the OLs were truncated by an IBC, and electromagnetic properties of An OL is designed to enhance a unidirectional magnetic field. It focuses the magnetic field for coils exhibiting this property , but for characterization, only a solenoidal coil type was used since the OL properties would be similar to the other coils. Figure To compare the OLs with the LLs, geometries similar to those as shown in the inset of Fig. The OL was then replaced with an LL. The LL had an outer diameter of 19 mm, with an outer to inner diameter ratio of 5.59. The total magnetic flux calculated for this arrangement was 139.55 The LL was found to achieve better enhancement of the field compared to the OL. However, the field distribution for the OL was more uniform. The field uniformity was calculated as the deviation from the By increasing the frequency of operation for this particular arrangement to 500 MHz, the LL produced a magnification of 3, which is slightly higher than at 45 MHz, and the OL produced a magnification of 3.9. As can be seen from the design due to the asymmetric material distribution, with the OL the field distribution of the magnetic field was less central. If the region of interest is reduced such that the variation lies below 10 %, the OL at higher frequencies can still be used; therefore, depending on the application, one can also use the magnetic lens designed for 45 MHz at 500 MHz to get a higher amplification if maintaining uniformity is not a concern or a smaller sample volume can be used. In order to get a uniform field distribution following the same protocol for the optimization as described in Sect. The magnification of the magnetic field produced by the LL depends directly on the ratio of the outer to inner diameter. For 1.05 T (Bruker ICON) measurements, the ratio of the coil size to the sample size was large enough to have a higher amplification by the LL. If we reduce the size of the coil by keeping the sample dimensions the same, as was the case for 11.7 T (Bruker AVANCE (III)) measurements, where a commercially available Bruker's 10 mm saddle coil was used, this leads to a reduction in amplification produced by the LL. The OL designed in Sect. To verify this, the OL and the LL were analysed in a solenoidal coil arrangement. The outer radius of the coil was 6 mm. The two rings were separated by a distance of 3.2 mm. The coils were excited with an alternating current oscillating at a frequency of 500 MHz.The total magnetic flux in the volume of the sample calculated using Eq. (25) without any lens was 179.42 By replacing the OL with an LL whose outer diameter was 7.6 mm and outer to inner diameter ratio 2.24, the total magnetic flux was 322 Therefore, with the reduction in the outer to inner diameter ratio, the total magnification produced by the LL is also reduced. However, the OL was still able to maintain the defined amplification. The maximum variation along the central lines calculated from Eq. (26) for the LL was 19 % along the To summarize the discussion, the LL was found to have a higher magnification, but the field distribution was less uniform. When the ratio of the outer to the inner diameter for the LL is reduced, it produces a lower magnification compared to the optimized magnetic lens albeit the field uniformity of these devices was similar. Table From the above discussion a question arises: why not set a reference field to achieve an amplification of 5 times rather than a mere factor of 2? The reason a reference field was not set higher is that this leads to the material not being properly distributed and we get undefined conductivity values, i.e. at greyscale values besides 0 or 1.5After processing the designs from the simulations, they were fabricated and verified with NMR experiments using distilled water as a test sample.5.1The masks for the designs were printed on butter paper using an HP Laserjet Enterprise P3015 dn printer.Using the mask for UV lithographic patterning, the designs were copied onto a positive photosensitized copper board with FR4 laminate with a PCB thickness of 1.6 mm and a The board was etched in a sodium persulfate solution  away from the sample region, designs tend to evolve towards tiny disconnected islands of metal, arranged in a dielectric background or metal patch suspended in air. This would require very advanced 3D printing, and in some cases the designs might not even be pragmatic. We did not pursue such designs in this contribution, but the message should be clear. Optimization must include manufacturing constraints in order to achieve feasible designs.Beyond manufacturability, a design must be practicable in use, which further limits the design freedom, because the sample must be provided with a convenient way in and way out of the sensitive volume of the detector. We found no problems with 2D designs, but 3D designs posed a challenge, resulting in designs that left too little space.The general conclusion is that all aspects of a design must be mathematically expressible as a goal function in order to be considered, but, as more terms are added to the optimization goal, the numerical convergence process slows down, eventually reaching a standstill.Because computational electromagnetics is scale invariant, the topology optimization methodology is applicable to resonator arrangements beyond the range of typical nuclear magnetic resonance frequencies, applications such as the design of magnetic or electric resonators used in electron paramagnetic resonance (EPR), the optimization of individual wavepath components including capacitors and strip lines, and even for wireless energy transfer.10.5194/mr-1-225-2020-supplementThe supplement related to this article is available online at: https://doi.org/10.5194/mr-1-225-2020-supplement.


Epoxy resins coatings are commonly found in corrosion protection coatings but the presence of water can affect their adhesion to the substrate, often weakening the adhesion of the coating to the solid, reducing its efficiency. Nevertheless, small amounts of water can enhance the epoxy/substrate interactions. In this work, the interphase region of an epoxy precursor and metal oxide substrates is investigated using molecular simulations and it is found that water accumulates between the epoxy layer and the solid substrate. At high water concentrations (9 wt %) the interaction between the epoxy precursor and the solid surface is weakened regardless of the nature of the solid, but at low water concentrations the nature of the solid surface becomes important. For hematite, the presence of water decreases the strength of adhesion but for goethite the presence of a small amount of water (3 wt %) enhances the adhesion to the surface resulting in a densification at the interface. Epoxy resin coatings are commonly used to protect metal surfaces from corrosion. Molecular simulations are used to investigate the adhesion in an epoxy resin precursor to hematite and goethite surfaces, as a proxy for steel surfaces and the effect of water ingress. For hematite water always decreases the adhesion whilst for goethite a small amount of water increases adhesion to the surface. Epoxy resins are used as both adhesives and protective coatings with applications across a range of industries including automotive, aerospace, freight, and the oil/gas industry.1, 2 T2O3) (0001) surface and goethite (α‐FeOOH) (100) surface as a proxy for the oxide formation on iron and steel.[Computational approaches have been used to complement experimental methods and can be used to assess the strength of interaction between an epoxy precursor and the solid substrate. Quantum calculations can accurately model the charge transfer in chemisorption and have been widely used to study alumina12, 133O4) is primarily driven by electrostatic interactions between the electronegative atoms in the epoxy matrix and the positive iron sites in the surface. However, in the case of goethite the electronegative atoms in the epoxy matrix can form additional hydrogen bonds with the surface hydroxyl groups. Whilst these results elucidate the binding between the different surfaces and the epoxy precursor, they do not take into account intra‐epoxy interactions that are important when considering the influence of moisture on the binding. In this paper we focus on the effect of water on the binding of a DGEBA molecule within a film on hematite  Figure a on irone Figure b and goee Figure c.We constructed a layer of DGEBA on the selected surface containing 360 molecules, and different water contents , allowing the system to equilibrate at 350 K (unconstrained simulations). We use the OPLS‐AA force fieldz at approximately 3 Å due to favorable interactions between the DGEBA and the positive iron sites in the surface. After this initial peak the density fluctuates around the bulk density of 1.07 g cm−3. Preliminary simulations have validated the model against literature data and details can be found in the Supporting Information. At both 3 wt % and 9 wt % water, the water is located at the interface between the solid and the epoxy precursor, in agreement with experimental studies that suggest that the water is located between the epoxy and the surface[epoxy), the ether (Oether), and the water oxygen (Owater) along with the Owater−Owater. At 0 wt % water there is a large peak in the Oepoxy−Fe RDF at approximately 2 Å and a smaller peak at the same distance in the Oether−Fe RDF. These peaks show the close contacts between the Fe and the adsorbed DGEBA. The epoxide group binds more favorably than the ether group due to the difference in charge (Oepoxy=−0.3343 vs. Oether=−0.2962) and the steric hindrance of the aromatic group for Oether, in agreement with our previous findings.epoxy in blue and the Oether in green (i.e. the closest contacts) where it is clear that more Oepoxy are located at the surface. As the water content increases the water displaces the DGEBA from the surface  has an initial peak in density profile along e surface29, 30water−Owater RDF has much sharper peaks than the hematite case. This ordering is due to the structure of the goethite surface where the surface hydroxyl groups enable the electronegative oxygen atoms in DGEBA to sit in a well and form additional hydrogen bonds alongside the electrostatic interactions.water−Owater RDF which correspond to the Fe spacing on the surface, indicating that the water is located in the wells above the Fe sites.The results on a goethite surface are qualitatitely different from those on the hematite surface. As in the case of hematite, the water forms a  monolayer between the surface and the DGEBA at 3 wt % water and the formation of a second hydration layer at 9 wt % water. The hydration layers on goethite can be seen in both the RDF  we see that the initial peak in the DGEBA density has increased in height from 1.55 to 1.65 g cm−3 at 3 wt % water on the goethite surface indicating that the epoxy precursor has become compressed at the surface. This is contrary to the behaviour observed for hematite which sees the first peak decrease with any water present. By 9 wt % water the first peak in the DGEBA density on both surfaces has decreased and been displaced from the surface by the water.In addition to the formation of a structured water layer in goethite, we can identify some important differences in the film properties of the two materials: (1) we see water displacing the OThe oscillations in the density of the epoxy near the solid interface are characteristic of the formation of an interphase, that is, a region of the polymer with different properties from the bulk.31, 32z direction perpendicular to the interface. This ordering mirror that of the bulk density along z  to remove a single DGEBA molecule from the surface at 300 K shown in Figure The analysis of the structure of the interface and the interphase region, as combined with the PMF calculations show a qualitatively different behavior on hematite and goethite surfaces as models for a steel or iron substrate. On both surfaces the water lies at the interface between the epoxy precursor and the solid. On the hematite the water displaces the DGEBA from the surface, decreasing the interaction and reducing the free energy of adhesion. However, for goethite the presence of a small amount of water increases the free energy of adhesion as the water causes the density of the DGEBA to increase at the surface. By 9 wt % water this enhancement has been overcome by a second hydration layer and both surfaces have a very similar potential of mean force. These results provide insight into the role of water at the interphase region and highlight the complex nature of epoxy adhesion on steel substrates. Water ingress drastically changes the adhesion properties at the surface for an epoxy precursor and increasing our understanding of these systems at the molecular level can aid in the formulation of coatings and adhesives.These results also further explain why the development of suitable tests which results in reliable prediction of coating corrosion protection performance has proved to be very time consuming. It is well understood that in the case of steel the “rust” formed on the steel surface is in fact a complex mixture of different oxide/hydroxides/oxy‐chlorides dependent on the environment and as such specific tests have been developed for specific conditions. This work further reinforces not just the importance of developing the correct rust, but also the role which the environment plays at the coating–steel interphase.The authors declare no conflict of interest.1As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.Supporting InformationClick here for additional data file.


In line with the European Paediatric Regulation, the European Medicines Agency (EMA) asks for investigation of a medicine’s acceptability in paediatric medicines development. A standardised acceptability testing method combining the outcome of “swallowability” and “palatability” assessments to a “composite endpoint on acceptability” was recently developed. Before this method’s suitability for selection of the most acceptable drug formulation of a new medicine for children can be broadly recommended, the acceptance and relevance of such established acceptability needs the critical review and input from young patients with understanding of the medicines development methodology. The benefit of involving patients in drug product development, clinical research and innovation is well established.During a focus group meeting with the KIDS Barcelona  the suitability of the “composite endpoint on acceptability” methodology was assessed. Via electronic questionnaires the importance of involving patients in the medicines development and in the acceptability method development was investigated. Questions on how best to determine palatability and swallowability were asked. The relevance of all EMA-listed acceptability elements was assessed via coloured and numbered stickers and questionnaires.The results showed that the involvement of young people in the medicines and acceptability method development was rated high. The group worked out that a 5-point smiley Likert Scale is preferred for assessing acceptability by 6–11 year old patients, while a Visual Analogue Scale is preferred for collecting adolescents’ opinion. The ranking of the EMA-listed acceptability elements showed that palatability and swallowability are the most relevant parameters, while colour of the medicine was rated as least relevant. These results, established face-to-face, were confirmed in a repeat of the ranking through an electronic questionnaire, completed by the participants individually and remotely, 5 weeks later.This work reinforced the need and value to involve young people in the medicines lifecycle, and specifically in this acceptability method development. As next step other focus group meetings with more young people from different European countries are planned.The online version contains supplementary material available at 10.1186/s40900-023-00520-8. Before a new medicine is authorized, its acceptability by children must be investigated according to law. An acceptability testing method combining the outcomes of “swallowability” and “palatability” assessments was recently developed. During a focus group meeting with KIDS Barcelona  their opinion on the suitability of the method and the relevance of patient engagement in the medicines development process were assessed with paper-based and electronic questionnaires. Questions on how best to determine palatability and swallowability were asked. The importance of different elements that typically affect acceptability was rated. The order of relevance of those listed acceptability elements was assessed using coloured and numbered stickers and questionnaires. The results showed that the involvement of young people in the medicines and acceptability method development was rated high. The group worked out that a 5-point smiley Likert Scale that allows for marking a choice between total agreement and total disagreement is preferred for assessing acceptability by 6–11 year old patients. A Visual Analogue Scale  is preferred for collecting adolescents’ (12–18 years) opinion. The ranking of acceptability elements showed that palatability and swallowability of a new medicine are the most relevant parameters, and colour the least. The clarity of the outcome reinforced the benefit of involving young people in the development of medicines relevant for children.The online version contains supplementary material available at 10.1186/s40900-023-00520-8. Evaluation of patient acceptability of a paediatric medicinal product is an integral part of the pharmaceutical and clinical development of a medicine for children as requested in EU , US 2],,2], an IThe Paediatric Regulation EU 1901/2006  requests“Different acceptability methods have been described in literature, which resulted in different outcomes when testing the same medicine in the same patient population” . As knowGiven the importance of the need, an increase of newly developed acceptability assessment methods and evaluation criteria can be observed , 6.In 2021, a public–private multi-stakeholder research group  developed a new acceptability method by statistically combining the outcome of “swallowability” and “palatability” assessments to a new so-called “composite endpoint on acceptability”  was established with the aim to facilitate the involvement of young people in clinical research based on the value that European countries’ diversity brings to research projects but also ensuring the contribution in consultation activities of young people experts. This network is recognized by Enpr-EMA (European Network of Paediatric Research of the European Medicines Agency). YPAGs were created based on the principle that children should transform from research subjects into research partners.In 2017, the European Young Person’s Advisory Groups Network  and to assess in a systematic way whether the methodologies are meeting the patients’ needs and expectations.During a focus group meeting of the research group and the KIDS Barcelona YPAG in December 2022 in Barcelona, Spain, first the suitability of the clinician-observed and patient self-assessed “composite endpoint on acceptability” methodology was reviewed and assessed by 11  adolescents (n = 5) and young adults (n = 7) How do you rate the importance of involving young people in the acceptability method development for paediatric galenic formulations? The next question related to the age group that should be involved in acceptability method development and in self-assessment of acceptability. The young people were asked to answer the following two questions by selecting an age group in the electronic questionnaire:12–18 years (12–18 años)10–18 years (10–18 años)8–18 years (8–18 años)6–18 years (6–18 años)Which age group should give input into acceptability method development? 12–18 years (12–18 años)10–18 years (10–18 años)8–18 years (8–18 años)6–18 years (6–18 años)Which age group of young people should do self-assessment of the acceptability of galenic formulations? Subsequently, the participants were asked to give their opinion on six questions concerning palatability on a 10 (highest) to 1 (lowest) rating scale in an electronic questionnaire:How suitable do you consider the 5-point smiley Likert Scale to assess palatability in the age group 12–18 years? How suitable do you consider the 5-point smiley Likert Scale to assess palatability in the age group 6–11 years? In your opinion, how attractive is the Visual Analogue Scale of 10 cm for the assessment of palatability for the age group 12–18 years? In your opinion, how attractive is the 5-point Likert Scale without any icons for the assessment of palatability for the age group 12–18 years? In your opinion, how attractive is the 5-point Likert Scale with other icons for the assessment of palatability for the age group 12–18 years? In your opinion, how attractive is the YES–NO question for the assessment of palatability for the age group 12–18 years? This was followed by the request to answer 6 questions on swallowability on the 10 (highest) to 1 (lowest) scale in the electronic questionnaire:7.In your opinion, how suitable is the investigator-assessed swallowability method for young people aged 12–18 years? 8.In your opinion, how suitable is the investigator-assessed swallowability method for young people from 6 to 11 years? 9.In your opinion, rate the Visual Analogue Scale of 10 cm for the assessment of swallowability for young people: 10.In your opinion, rate the 5-point Likert Scale without any icons for the assessment of swallowability for young people: 11.In your opinion, rate the 5-point Likert Scale using other icons for the assessment of swallowability for young people: 12.In your opinion, rate the YES–NO question for the assessment of swallowability for young people: Then the group of young people was asked to answer the following question in the electronic questionnaire:Young people were asked to rate the importance of paediatric patient involvement presented in the following 2 questions on a 10 (highest) to 1 (lowest) scale in a bilingual (English and Spanish) electronic questionnaire (Google Form):Yes, I expect big differences in teenagers Yes, I expect big differences in children of 6–11 years Yes, but I expect only minor differences in teenagers Yes, but I expect only minor differences in children of 6–11 years No, I expect no differences in teenagers No, I expect no differences in children of 6–11 years In the second part of the meeting the patient’s view on the relevance of all eight EMA-listed elements of acceptability was assessed. The EMA parameters [Palatability, swallowability Appearance Complexity of the modification to be conducted by the child or its caregivers prior to administrationThe required dose The required dosing frequency and duration of treatmentThe selected administration deviceThe container closure systemThe actual mode of administration to the child and any related pain or discomfortThe adolescents and young adults were asked to answer the question: “Which EMA parameter is the most important and which is the least important?” They were asked to put a green sticker for the most and a red sticker for the least relevant parameter behind the respective item presented on a flip chart. This exercise was done in person on December 16th, 2022, during the focus group meeting, and repeated individually on January 27th, 2023, to investigate the consistency of the judgements of the young people directly after the explanations within the group meeting and with a time lag of 5 weeks. The second assessment in January 2023 was done individually by the young people completing a paper questionnaire at home.“Do you think that there are cultural differences to be expected when children and teenagers from different countries will answer the previous questions?”  by choosing from the options:Afterwards, the adolescents and young adults were asked to rank the eight EMA guideline parameters from 1 (most) to 8 (least) important by sticking the numbers (1) to (8) behind the parameters; this was done on December 16th, 2022. On January 27th, 2023, this ranking exercise was repeated by requesting the participants to individually complete the online version of the questionnaire.The importance of involving adolescents and young adults in the medicines development process and more specifically in the acceptability method development are given in Table The results on the question which age group should be involved in acceptability method development and in self-assessment of acceptability testing are given in Fig. Most young people suggested that 6–18-year-old patients should give input into acceptability method development and that self-assessment of the acceptability of galenic formulations is best suited for the age group 8–18 years.The results of the six questions on how to measure palatability are given in Table The results demonstrate a high value for the suitability of the 5 point smiley Likert Scale and seem to suggest a preference for a Visual Analog Scale of 10 cm for young people.The results of the six questions on how to measure swallowability are given in Table Anticipated influence of cultural differences.The answers to the question on cultural differences are listed in Table The results indicate that the investigator-assessed swallowability method is suited for the younger age group from 6 to 11 years, while a Visual Analogue Scale of 10 cm is preferred for young people. 3.5. 10 out of 11participants answered this question. 9 out of 10 participants expect differences, the majority expect minor differences when teenagers from different countries will answer the questions raised before, one participant expects no differences.In the second part of the focus group meeting, the research group wanted to collect the opinion of the young people on the relevance of the 8 parameters of acceptability listed in the EMA guideline. This was done in two ways. First, the young people were asked to select the most and the least important parameter in their opinion. In a second step, they were asked to rank the 8 parameters. Also, these questions were asked a second time 5 weeks later.The answers to the question on which is the most important and which is the least important EMA-listed parameter for acceptability are shown in Fig. The results show that palatability and swallowability were considered to be the most relevant parameters when assessing acceptability and that appearance is the least important parameter defining acceptability. This outcome was the same when conducted in December 2022 and repeated in January 2023. But a little variance in the outcome can be detected: From December to January palatability and swallowability as most relevant aspects of acceptability lost one green point while the opinion on appearance as least relevant aspect increased by two red points.It must be noted that the method of opinion collection for both questions differed between these two occasions: In December during the joint focus group meeting the participants were asked to physically place colored dots/numbers behind the parameters, and in January 2023 they filled in an individual paper-based questionnaire at home. The results are given in Fig. The results show again that palatability and swallowability are the most important EMA parameters for the young people and appearance the least important parameter. As second choice “the actual mode of administration to the child and any related pain or discomfort” was chosen in both, the sticker method as well as the paper-based questionnaire method.Beyond this clear choice, no significant differences in ranking between the parameters “Complexity of the modification to be conducted by the child or its caregivers prior to administration”, “The required dose ”, “The required dosing frequency and duration of treatment”, and “The selected administration device” could be detected.The relevance of the “Container closure system” was rated relatively low.In general, the method of physical placing of coloured and numbered stickers showed weaknesses over the individual paper-based questionnaire, as not 11 ratings were given per parameter but sometimes more than 11 or less than 11 ratings. With the individual paper-based questionnaire 11 ratings per parameter were given, so it seems that this method was better suited to determine the ranking of the EMA acceptability parameters.The benefit of involving patients as advisors in different aspects of the medicines development process is widely accepted . TailoreThe used classification of children and adolescents in the questions asked (6–11 years and 12–18 years) corresponds to the common classification in paediatrics, according to ICH Guideline E11 .To enable comprehensive information on the acceptability research methodology as well as direct observation of the reactions and responses to the questions, a face-to-face focus group meeting with a group of adolescents and young adults aged 16–23 years educated in the medicines development methodology was considered essential. The KIDS Barcelona YPAG was willing to collaborate with the research team on these topics because they felt that patient involvement in a research topic that is so relevant to develop a suitable paediatric medicine is important. National groups of young people of different age that are educated in clinical trials, clinical research and innovation like the KIDS Barcelona group are organized in the European YPAG network (eYPAGnet) [To ensure detailed planning and concrete understanding of the research approach, a “Young People Involvement Plan” was developed by the research group and the leader of the Spanish YPAG. This plan presented the background and rationale as well as a detailed description of the opinion gathering activities in the focus group. In an introductory presentation in lay language this “Young People Involvement Plan” was presented to the young people and triggered their interest in forming opinions on the different aspects raised. The concretely formulated questions on the composite endpoint on acceptability methodology were presented in an electronic questionnaire in English and in the adolescents and young adults’ Spanish mother tongue. It offered scales from 1 to 10 and defined age ranges to facilitate the expression of the patients’ ratings and recommendations. The handling of the electronic questionnaires was considered easy and was well accepted by all involved. Therefore, it seemed to be an appropriate and efficient method to get feedback on several different topics as the questions and answers could easily be tailored.The method of selecting the most and least important aspects of acceptability by physically sticking colored dots behind the respective acceptability parameters presented on a flip chart at the wall worked well as all eleven red and all eleven green stickers were placed on the flip chart.In the ranking exercise, however, the method of physical sticking of numbers behind the different parameters showed its limitations: Not always 11 ratings were given per parameter but sometimes more than 11 or less than 11 ratings, as the participants did not always remember where they had already placed their stickers. The most and least relevant and ranking exercises were repeated five weeks later with a paper-based questionnaire that the participants completed at home. Here the 11 participants delivered 11 complete rankings for the eight EMA parameters. Therefore, this method seemed to be better suited for a ranking exercise.In the subsequent discussion among the young people during the focus group meeting it became clear that the ranking of the EMA parameters could be impacted by the participants’ disease and treatment experience.The involvement of young patients in the medicines development and specifically in the acceptability method development was rated as very important by all young people. But opinions differed for example on the age as of which self-assessment method should start and which self-assessment method would be best for the respective age groups.Interestingly, the young people rated swallowability and palatability as the most important acceptability elements in the EMA list of parameters while appearance—expected to be high-ranking as well—was the least important. The same results were found with both assessment methods.This was the first investigation with a limited number of young people, from one country and with just one age group (16–23 years). Therefore, and based on the experiences made, the research team and other YPAGs members of eYPAGnet intent to replicate this patient involvement activity in further focus group meetings with more young people from different European countries and to include different age groups. As an alternative approach the research team considers developing a remote strategy with a video of the introductory method explanations and a toolkit to answer the questionnaires online. The results from the two different strategies will be compared. Once more data will be available from a larger number of young people from different regions and from different age groups, the research team will report on the experiences made with this method of young patient involvement and recommend the most efficient young patient contribution process in the acceptability assessment methodology. The composite endpoint on acceptability was validated based on a validation study in patients 1–6 months and 6–18 years. Publication of the results is currently ongoing.This young patient involvement project reinforced the need for systematically enabling the contributions of young people with knowledge about the medicines development process to the research and development processes. Such contribution can help to enable concrete patient-relevant input in the suitability of the acceptability assessment method developed by clinicians and researchers for new paediatric oral dosage forms aiming that the scales and methods are appropriate, suited, understandable, and well-designed for the relevant patient population.Additional file 1. GRIPP 2 Short form.


We derive the most general homogeneous and isotropic teleparallel geometries, defined by a metric and a flat, affine connection. We find that there are five branches of connection solutions, which are connected via several limits, and can further be restricted to the torsion-free and metric-compatible cases. We apply our results to several classes of general teleparallel gravity theories and derive their cosmological dynamics for all five branches. Our results show that for large subclasses of these theories the dynamics reduce to that of closely related metric or symmetric teleparallel gravity theories, while for other subclasses up to two new scalar degrees of freedom participate in the cosmological dynamics. Various cosmological observations, such as the tension between late-time and early-time measurements of the Hubble parameter , show inentclass1pt{minima studied . Most co studied . Further studied . Several studied –10.In order to study the cosmological dynamics of any given gravity theory, one usually assumes that all dynamical fields present in the theory exhibit cosmological symmetry, i.e., homogeneity and isotropy, and are thus invariant under spatial rotations and translations. For the metric, this leads to the well-known Friedmann–Lemaître–Robertson–Walker form, while, e.g., a scalar field is assumed to be constant along hypersurfaces of constant time. For teleparallel gravity theories, one of the dynamical fields is a flat, affine connection, and so one must also impose homogeneity and isotropy on this field for consistency. Previous works in this direction have shown that the most general homogeneous and isotropic affine connection is described by five functions of time, two of which can be associated with torsion, while three are related to nonmetricity , 12. If The aim of this article is to continue the aforementioned line of studies and determine the most general homogeneous and isotropic teleparallel geometry, defined by a metric and a flat, affine connection, where the latter is restricted only by the condition of vanishing curvature, but may possess both torsion and nonmetricity, and to study the physical consequences of our findings in the context of different general teleparallel gravity theories. Moreover, we study how a coupling between matter and the teleparallel connection, which gives rise to a hypermomentum described as a cosmological hyperfluid , enters The outline of this article is as follows. In Sect. G in the action is defined asB,We start by giving a brief review of the class of general teleparallel gravity theories. In their metric-affine formulation, the dynamical fields are given by a Lorentzian metric mentclass2pt{minimquations 12\documeIn GR the famous Bianchi identity states that the Einstein tensor is automatically covariantly conserved, and so is the energy–momentum tensor of matter by the Einstein equation. Here we want to derive the Bianchi identity of a general teleparallel theory and look at the consequences for hypermomentum conservation.S the full action then S we will have S the full action Let us assume again we have an action mentclass2pt{minimu can be real or imaginary; this choice of the parameter will turn out to be more practical than the more common curvature parameter Setting For Assuming We start by assuming We then continue with the spatially curved case We see that there are five different branches, in each of which the flat, cosmologically symmetric connection is determined by two functions of time. In the following, however, it will turn out to be more convenient to introduce a different parametrization, which is based on the expressionst, which serve as an alternative parametrization to the previously introduced In the branch For For For u in the parametrization such that u will give the same result with the replacement For Finally, for For the spatially curved case In this section we derive the most general teleparallel geometry which is compatible with the assumption of cosmological symmetry, following closely the approach used for the metric and symmetric teleparallel cases –15. Usinivatives 31\documementclasspt{minima tensors , 16, whef of time. In terms of these quantities, the parametrizations simplify, and take the form summarized in Table To further simplify the parametrizations, it turns out to be convenient to introduce rescaled quantitiesIt is worth discussing how these different branches of cosmologies are related to each other. For the spatially curved branch 2a, we see that mentclass2pt{minimosmology , 14. Simosmology . These rIn the following sections, we will apply the conditions of homogeneity and isotropy to the matter source and gravitational field equations of teleparallel gravity theories.We apply the conditions of cosmological symmetry introduced in the previous section to the generic form  of the gthe form 58\documef(G) class of theories, whose Lagrangian is given by an arbitrary function f of the GTEGR Lagrangian G. Another class of theories based on the most general Lagrangian which is quadratic in torsion and nonmetricity is studied in Sect. We now apply our findings to a few classes of general teleparallel gravity theories and study their cosmological dynamics. In Sect. G denotes the scalar  theories; while the spatially curved case  gravity become identical to the vector branch of the metric teleparallel f(T) class of theories [f and not a new degree of freedom. Similarly, setting f(T) cosmology. Any remaining solutions, given by G, but since in our cosmological setup G depends only time all terms are proportional to G contains first derivatives of f and its derivatives evaluated at f(G) gravity does not involve a dynamical connection. Either G.The situation is similar, yet different for the remaining branches. For the spatially curved case 2b, the metric cosmological field equations become theories , 19. Sintions in  again, aThe next class of teleparallel gravity theories we study is known as general teleparallel quadratic gravity . Its actthe form 90and91\dR action . We now Another type of conditions on the parameters can be obtained that the two fields ondition  of a proThe propagation of two massles spin-2 fields can also be achieved by imposing transverse diffeomorphisms and Weyl symmetry as an additional gauge symmetry. The former gives the condition ondition  yields aAs the last example, we consider a class of scalar-teleparallel gravity theories, which is defined by the action , 20110\dWe then take a look at the cosmological dynamics. For the branch 2a the metric and scalar field equations become at limit .We continue with the spatially curved branch 2b. In this case the metric field equations become For theories which satisfy the condition  gravity . The telquations  of motioThe field equations  are alsoquations , and theequation , which iFor quations  can alsoquations  and the quations  reduce tIn summary, we find that for all branches of cosmologically symmetric teleparallel geometries the cosmological dynamics of the class of scalar-teleparallel gravity theories defined by the action  gravity in the absence of hypermomentum. Here we want to show another simple case exemplifying effects of the connection and hypermomentum on the metric. We consider the general quadratic gravity in the simple branch 2a. One can show that one can find the exact solution of the connection equationsWe have already seen some example solutions of the connection equations of motion in We have derived the most general class of homogeneous and isotropic teleparallel geometries, defined by a metric and a flat, affine connection, which are invariant under spatial rotations and translations. We find that there are five branches of such geometries, two of which exhibit a non-vanishing spatial curvature for the metric Levi-Civita connection, while the remaining three spatially flat cases arise as particular limits from the spatially curved cases. We have also shown how these branches are related to the more restricted classes or metric and symmetric teleparallel geometries, in which nonmetricity or torsion are imposed to vanish. Our findings show that in addition to the lapse and scale factor appearing in the homogeneous and isotropic Robertson-Walker metric, the flat affine connection is described by two further functions of time, which may participate in the cosmological dynamics for a suitable gravity theory which couples to these degrees of freedom.f(G) class of theories, general teleparallel quadratic gravity and a simple class of scalar-teleparallel gravity theories. We have seen that for the different branches of cosmologically symmetric teleparallel geometries, which are distinct only by the flat, affine connection, one finds, in general, qualitatively different cosmological dynamics, such as a different number of dynamical functions appearing in the cosmological field equations or a different differential order of these equations. Further, our findings show that for the f(G) and scalar-teleparallel theories the cosmological dynamics fully reduces to that of related metric teleparallel or curvature based gravity theories, in which nonmetricity and possibly torsion are absent, such that the results found for the cosmological dynamics of these simpler theories also apply to their general teleparallel counterparts as follows: f(G) gravity reduces to general relativity with a cosmological constant  gravity or scalar-torsion gravity (STG)) in the “axial” branch [In the branch 2a, the dynamics reduces to that of the metric teleparallel counterpart (” branch , and to For the spatially curved branch 2b and the two flat branches 1b and 1c, one finds that if It follows that the only possibility to obtain new dynamics in the aforementioned classes of theories is to consider a non-trivial coupling between matter and the teleparallel connection, leading to non-vanishing hypermomentum. For more general theories, new dynamics is obtained. As an explicit example, we have shown this for the class of general teleparallel quadratic gravity theories, but one may also consider theories with a more general dependence of the Lagrangian on the teleparallel geometry or more general scalar field couplings.We have then applied our findings to a number of general teleparallel gravity theories and derived their cosmological dynamics. In particular, we have considered the Our results allow for several directions of further research. Starting from the homogeneous and isotropic teleparallel geometries we have determined, one can derive and study the cosmological dynamics of further general teleparallel gravity theories. Also among those classes of theories whose cosmological field equations we have derived in this article we find several classes of general teleparallel quadratic gravity theories whose cosmological dynamics qualitatively differs from the previously studied metric and symmetric teleparallel theories, and deserves further attention. Finally, going beyond the cosmological background dynamics one may consider perturbations of the teleparallel geometry around this background and study their dynamics. For a general flat connection one finds that the perturbations are of the formtheories , 21–26, theories . We leav