The caloric test is an important tool for the assessment of labyrinthine function.Objective: To compare the nystagmus response in the caloric tests with air at 50°C and 24°C and with water at 44°C and 30°C. Study Design: Randomized crossover clinical trial.Materials and Methods: 40 healthy individuals were submitted to a neurotological evaluation, including caloric tests with air at 50°C and 24°C and water at 44°C and 30°C.Results: Comparing the air and water caloric tests, there were no significant differences among the post-caloric nystagmus slow-phase velocity in relation to the stimulation order, between ears and between the values of unilateral weakness and directional preponderance. The slow-phase velocity values were higher with water , and cold stimulation produced stronger responses (p < 0.001).Conclusion: Comparing 50°C and 24°C air caloric test and 44°C and 30°C water caloric test, we observed similar slow-phase velocity values for both ears, higher responses in the cold temperature and in the test with water, and similar results of unilateral weakness or directional preponderance for post-caloric nystagmus in both tests. The caloric test is usually the most informative part of vestibular evaluation. It is the only procedure which assesses each labyrinth separately, it informs about the affected side and enables characterization of the vestibular lesion intensityHeat stimulation of the labyrinth causes endolymphatic current in the semicircular canals, polarizing or depolarizing the sensorial cells of the ampule crest, triggering the vestibular-ocular reflex. The stimulus generates an ampule current, towards the utricle, exciting the stimulated lateral semicircular canal and causing nystagmus in the same direction of the labyrinth being tested. The cold stimulus results in a current in the opposite direction of the utricle, inhibiting the stimulated semicircular canal and nystagmus in the opposite direction of the assessed labyrinthBesides the convection currents, other mechanisms may be involved in evoking caloric responses, such as the mechanical transduction of the cupule, the heat effect on sensorineural structures and neural adaptation, combined in a non-linear fashionUnder physiological conditions, the vestibular organs are sensitive to stimuli varying between 0.001 Hz and 8 HzThe caloric test enables the assessment of the lateral semicircular canal; defects must be interpreted together with other tests, since they do not necessarily indicate that the labyrinth is involvedMany methods have been created in order to assess vestibular function by means of heat stimulation. Initially, water was the only element employed to evoke the nystagmic responseAir irrigators became commercially available around the 60‘sAir is more comfortable and safer for the test, without contraindications to its use, and it can be used in the assessment of patients with eardrum perforations, patients with external otitis media and mastoidectomy cavitiesThe thermal properties of air and water are significantly different. The capacity to maintain the air temperature is lower than that of waterThe literature discusses the effort of researchers to define the best procedure and to obtain the caloric response with air. The temperatures utilized in the caloric test with hot air varies between 42°C and 51°C and in cold test, they vary between 20°C and 30°C, with air flows between 5 and 13L/min and stimulation time between 60 and 100 secondsIn the irrigation with water, the temperatures employed are 7°C higher and lower than body temperature; 44°C for the warm test and 30°C for the cold one. In the irrigation with air, one needs gradients of 13°C, corresponding to 50°C, for the hot stimulation and to 24°C for the cold one, in order to evoke a response with amplitude similar to the one obtained by water stimulationThe most important parameter for the caloric test quantitative assessment, which can be analyzed thanks to the possibility of recording the response, is the maximum Slow Component Angular Velocity (SCAV), which is proportional to the intensity of the employed stimulusThe caloric stimulation with air was challenged because of response variabilityRecent studied on the caloric test with water and air usually approach topics associated with the findings in vestibular disorders. In our country, in caloric tests with air at 42°C and 18°C and with water at 30°C and 44°C in chronic peripheral vestibular disorders, they found a prevalence of cases with SCAV values abnormalities on labyrinthine predominance and directional preponderanceThe diagnostic importance of the caloric test and the scarce information in our literature on the comparison between thermal labyrinthine stimulations with water and with air motivated this study.The temperatures of 50°C and 24°C of the caloric test with air has been recommended by advanced neurotology centers of numerous countries; and in our country there is no scientific paper comparing the results of this test with the ones from the conventional caloric test with water.The present study can be very practical for the routine assessment of vestibular function and it also opens horizons for other studies with the caloric test with air in these temperatures, enabling a pertaining comparison with the results from the international literature.The goal of the present study is to compare the post-caloric nystagmus of the test with air at 50°C and 24°C with that from the test with water at 44°C and 30°C.The present study was carried out after approval by the Ethics in Research Committee of the institution, under protocol number 0054/09. The informed consent form was signed by all the subjects before the study onset.The study group was made up of 40 volunteers, 25 females and 15 males, with ages between 18 and 40 years, without ear complaints.As for inclusion criteria, we selected healthy individuals without signs and symptoms of body balance disorder and who were not using medication. We carried out a guided interview to rule out a past of neurotological diseases and use of medication. We also excluded healthy individuals with changes in the vestibular test with spontaneous nystagmus with eyes closed and/or pre-caloric, because of the possible influence of these signs on the caloric test.After visually examining the external ear canal, to make sure there was no wax or foreign body, the subjects were submitted to vestibular function assessmentThe individuals were distributed in two groups in a randomized fashion, according to the caloric test, which was carried out first. Group I was initially submitted to the caloric test with air and Group II was initially submitted to caloric test with water, in order to avoid a possible influence in the order of stimulations, habituation and residual effects of one test on the otherBefore the functional assessment of the vestibular system, the patients were instructed to refrain from smoking, eating chocolate, drinking alcoholic or caffeine loaded beverages in the three days before the assessment. On the day of the test, they were instructed to refrain from using makeup, facial cremes or contact lenses.In the exam room, the lighting was dimmed, and the room had air conditioning, keeping the room temperature at about 21°C, to avoid interference from air and water thermal variations in the results.In order to carry out the VENG, the patients had their skins cleaned in order to enable the placement of three active silver chloride leads and one ground lead. The leads were placed in the right external periorbital corner, in the left external periorbital corner and in the frontal midline, using the triangular placement of the leads which enables the identification of nystagmus direction and to check the slow component angular velocity (SCAV) in three recording channelsThe calibration of eye movements was done in the beginning and, when necessary, throughout the test and, systematically before the caloric test to minimize changes to the response amplitude caused by the cornea-retina electrical variation.During the caloric test with water and air, the subject was kept in the supine position with the head tilted at 30°CEach subject was submitted to eight hot and cold caloric stimulations with air or water, carried out in the following order: hot in the right ear, hot in the left ear, cold in the left ear and cold in the right ear. We used strategies such as conversation, naming and the use of mathematical calculations to stimulate mental activity and to avoid the cortical inhibition of the caloric response. Vertigo, SCAV and direction of the post-caloric nystagmus were analyzed with the eyes closed and eyes open. SCAV was chosen as the parameter to assess response intensity.The entire post-caloric nystagmus recording was assessed by selecting the most representative stretch of the post-caloric nystagmus record, with the most intense responses in terms of SCAV. The percentage values of the labyrinthine predominance and directional preponderance of the post-caloric nystagmus were calculated using the SCAV values in the four stimulations with air and in the four stimulations with waterWe did a statistical descriptive analysis to characterize the sample. For the quantitative variables we observed minimum and maximum values and calculated the mean and standard deviation values. For the qualitative variables we calculated the absolute and relative frequencies.We used the chi-square test to assess the homogeneity between the groups I (air-water) and II (water-air) vis-à -vis the age and gender variables.t-Student test was utilized in the comparative analysis of Groups I (air-water) and II (water-air) vis-à -vis the mean SCAV value of the post-caloric nystagmus.The t-Student test in the comparative analysis between the right and left ears in the tests with air at 50 and 24°C and with water at 44°C and 30°C, in the comparative analysis by ear between the tests with air, at 50°C and 24°C, and with water at 44°C and 30°C, in the comparative analysis between the tests with air at 50°C and 24°C and with water at 44°C and 30°C in each ear and in the comparative analysis between the relative values of labyrinthine predominance and nystagmus directional preponderance in the tests with air at 50°C and 24°C and with water at 44°C and 30°C.We used the paired Statistical Package for Social Sciences, version 15.0, 2006) software; the significance level employed was 5% (α= 0.05). The power of the tests was calculated when there was significant difference between the groups; the values found varied between 87% and 100.0%, indicating that the sample size was enough to obtain more than 80% of power.The statistical analyses were done by the SPSS 15.0 for Windows  females and 15 (37.5%) males, with mean age of 26.45 years (ranging between 18 and 39 years) and standard deviation of 5.62 years. All the individuals reported having vertigo upon caloric stimulation with air and with water.p-value of the comparative statistical analysis, considering the order at which the tests were performed. Regardless of such order, there were no statistically significant differences between the post-caloric nystagmus SCAV values with air and there were no statistically significant differences between the post-caloric nystagmus SCAV with water.p < 0.001) between the SCAV values upon comparison of the test with hot air with that of cold air and upon comparing the hot water with the cold water tests in each ear; the cold temperature evoked more intense responses than the hot temperature in the tests with air and water. There was a statistically significant difference  between the caloric test with air in relation to the test with water in all the stimulations; the SCAV values were higher in the stimulations with water than air. There were no statistically significant differences between the values of labyrinthine predominance (p = 0.761) and directional preponderance (p = 0.391) upon comparison of the results from the tests with water and air.Comparing the results from the air-water (Group I) and water-air (Group II) groups, as to the order in which the tests were carried out, there was no statistically significant difference between the post-caloric nystagmus SCAV with air and between the post-caloric SCAV values with water, regardless of which test preceded the other, ruling out a possible effect of the order of post-caloric responses. Similarly to our findings, in another study, there was no evidence of post-caloric nystagmus physiological adaptation in normal individuals, because the order in which the stimulations were done also did not impact response amplitudeThere were no statistically significant differences when we compared the responses from the right ear with those from the left ear in the stimulations at 50°C and 24°C in the caloric test with air and at 44°C and 30°C with water, similarly to what has been reported by other authorsWe noticed that SCAV values were higher with water stimulation when compared to those with air, for both ears. Other authors have also reported higher evoked post-caloric responses with water than airThere was a statistically significant difference in the comparative analysis of the hot stimulations (50°C with air and 44°C with water) and the stimulations with cold temperatures (24°C with air and 30°C with water) in each ear. The cold temperature caused more intense responses than the hot one in both tests: with air and with water. Similarly to our findings, there are reports of higher responses in the cold temperature than in the hot one using waterThere was no significant difference between the relative values of labyrinthine predominance and nystagmus directional preponderance in the caloric tests with air and water, similarly to what was found in other studiesThe use of different configurations of flow, duration and temperature of the thermal stimulus in the assessment of the vestibular functionThe differences found in the post-caloric responses upon comparison with other studies in healthy individuals may be justified by the different thermal properties of water and air as vectors of labyrinthine stimulation. Different responses are expected when using water, since it has a higher specific heat than air and it is capable of keeping the temperature in the external ear canal for longer; air satisfactorily replaced water in 95% of the clinical cases seen in a hospital; the remaining 5% had lower labyrinthine function, confirmed with the use of a more intense stimulus: ice waterConsidering the equivalence between the relative values of labyrinthine predominance and post-caloric nystagmus directional preponderance in the test with air and water in the healthy individuals we assessed, and that such parameters are fundamental to identify vestibular dysfunctions, we can state that both tests are useful in neurotological routine testing.Comparing the tests with air at 50°C and 24°C and with water at 44°C and 30°C, we found two similar values for the slow component angular velocity in both ears to be higher with cold temperature and in the test with water, and similar results of labyrinthine predominance and post-caloric nystagmus directional preponderance in both tests.


Despite a large amount of materials and methods to make an implant‐supported denture, nowadays there is no gold standard. Every solution has pros and cons that guide the clinician and the technician to choose the best solution for a single case. The aim of this study was to evaluate the mechanical characteristics of the fiber‐reinforced composite superstructure made by using a novel three‐dimensional (3D) printing technology able to create a reinforcing structure patient‐specific, more reliable, structurally optimized, and faster than conventional methods.To evaluate mechanical performances of 3D‐printed fiberglass, mechanical characterization of 3D‐printed material was performed. Before proceeding with the realization of the final prosthesis, five specimens were created on which the tensile test and volumetric fiber content measurement were performed. Then denture reinforcement 3D printing process began. Initially, the robot prints layers of fiber. Finally, the obtained 3D‐printed reinforcement structure was finalized in the lab.The prosthesis obtained through this process was lighter than a traditional prosthesis, there was a greater chemical adhesion between resin and 3D‐printed reinforcement structure and a better result was obtained from an esthetic point of view.The outcomes we obtained endorse its performance both mechanical and esthetic. The entire process is automatic and does not require human operation thanks to specific software programming. This fast polymerization allows the creation of complex geometry reinforcement placed along the arch following the contour and abutment geometries.2To evaluate mechanical performances of 3D‐printed fiberglass a mechanical characterization of 3D‐printed material was performed.Commercially available LuxaPrint Ortho Plus  resin was used as the matrix material. A couple of continuous glass fibers yarn 66 TEX S‐3 HPB , were used as reinforcement, and no additional surface treatments were done. The materials are already certified for dental application. A specific tool head and software were designed to 3D print with a robotic arm KUKA KR10 R900 sixx equipped with a KR C4 Compact controller . The continuous fibers were laid in the longitudinal direction of the specimen. The fibers set in this way can be considered an orthotropic material with the main directions of the fibers aligned with the main directions of the specimen.We tested five specimens. A tensiometer  was used to perform such tensile tests with a crosshead movement speed of 2 mm/s. The specimen configuration was rectangular with end tabs. The dimensions of the specimens are: 2.2To have an estimation of the mechanical properties of the 3D‐printed specimens, the volumetric fiber content of the composite material was measured. Thermogravimetric analysis was performed on a sample of the 3D‐printed material and the result showed the weight percentage of the fibers after all the matrices had been burnt. The volumetric fiber content can be easily calculated from the weight percentage of the fibers as the specific weights of the fibers and the matrix are known. This procedure is performed on a sample and the mean volumetric fiber content of the 3D‐printed material is equal to 45.8%.2.3Starting from the standard triangulation language file of the 3d scanned denture volume, the design of fiber reinforcement denture was obtained by using an algorithm. This algorithm is able to define a useful outline of the 3D scanned part and create a path offsetting the denture geometry and implants contours for all the layers that compose the 3d path Figure .The entire process is automatic and does not require human operation thanks to specific software programming. Initially, the robot prints layers of fiber which are immediately polymerized. This procedure takes about 30 min. Then the structure is placed in a UV oven for 3 min to complete the polymerization. Finally, it is washed with ethanol and ultrasounds to eliminate the uncured excesses. The obtained 3D‐printed reinforcement structure weight was about 2.4 g, and it was finalized by Biartlab  and the elastic modulus of both the fibers (99 GPa) and the matrix , the predicted elastic modulus is 46.5 GPa. By assuming that the tensile strength of the continuous composite in the longitudinal direction is given only by the reinforcing fibers, the Ultimate tensile stress can be estimated as σUc = σUf × Vf. The ultimate tensile stress of the glass fiber is 3300 MPa. The predicted value of the ultimate tensile stress of the composite is about 1504.8 MPa.The mechanical behavior of a composite material can be estimated by means of the use of micromechanical models. The prediction of the longitudinal elastic modulus of an orthotropic continuous fibers composite material is done thanks to the parallel model. Knowing the fiber volume content (Table 3.3The fiber structure obtained using the digital production process shows a great chemical adhesion with the resin used in the finalization, and an opaque layer was not required. Analyzing the final prosthesis from the esthetic point of view, fiber bundles allow great translucency of the entire system, very unique, especially in thin spaces. Furthermore, the fibers impregnated by resin show a behavior very similar to fluorescence because they can reflect UV rays. This reflection is not linear, due to the architecture of the fiber web and to the shape of a single fiber, the radiation is spread in a way very similar to what happens in the natural teeth.4Fiberglass was introduced in the dental prosthesis a long time ago but its usage was not encouraged because it required a manual process, was time‐consuming, not repeatable, strictly dependent on the operator's abilities, and most importantly, uncertified.By the present process of additive manufacturing, we have overcome these limitations and obtained a significant increase in the mechanical strength of the prosthesis, without increasing weight. The fiber paths are optimized as well as their density. Without interrupting the fibers the mechanical behavior is similar to what happens in the bridge steel cables, that sustain and transmit the forces all around the entire structure eventually dissipating before that forces pass through the pillars, in our case the implant connections. The prosthesis as we obtained after the esthetic envelope and teeth mount was completed and it is possible to imagine that it has a very new mechanical behavior with respect to the current solutions because of the chemical linkage between matrices material. We can assume that the entire prosthesis became a new composite structure, moreover, all the constituent materials act in the same way and cooperate with each other in responding to mechanical stress. In other words, all the prostheses became a bearing structure, including the teeth that are crossed by fibers. We can also assume that the novel reinforcement structure presented in this study will react as a shock absorber in the masticatory cycle, generating a better absorbance of loads if compared with a rigid metal or ceramic core prosthesis.endostructure not mesostructure.This particular shape and behavior are more typical of an endoskeleton instead of a more conventional prosthetic framework, for this reason, we prefer to call it Using a fiber bundle width of 0.5 mm and a layer height of 0.295, the final 3D‐printed reinforcement structure can be adopted also in complex cases in which the available space for reinforcement is limited, without compromising the mechanical resistance and aesthetical result.Furthermore, a prosthesis obtained with this method is very easy to reline even intraorally. In conclusion, we can say that the outcomes we obtained endorse its performance both mechanical and esthetic.Andrea Nicali: Conceptualization; writing–original draft preparation. Giulia Pradal: Writing–review and editing, visualization. Andrea Mantelli: software. Gianluca Brandolini: investigation. Marinella Levi: supervision.The authors declare no conflicts of interest.


Outliers are data points that significantly deviate from other data points in a data set because of different mechanisms or unusual processes. Outlier detection is one of the intensively studied research topics for identification of novelties, frauds, anomalies, deviations or exceptions in addition to its use for data cleansing in data science. In this study, we propose two novel outlier detection approaches using the typicality degrees which are the partitioning result of unsupervised possibilistic clustering algorithms. The proposed approaches are based on finding the atypical data points below a predefined threshold value, a possibilistic level for evaluating a point as an outlier. The experiments on the synthetic and real data sets showed that the proposed approaches can be successfully used to detect outliers without considering the structure and distribution of the features in multidimensional data sets. There are various definitions of the term “outlier” in statistics and data science. According to According to the surveys, various methods and approaches have been proposed for outlier detection . All theStatistical outlier detection methods (a.k.a. distribution-based methods) suppose that outliers are the data objects having a low probability of belonging to a modelled distribution, and therefore, deviate from the assumptions of the concerned distribution. In general, they are based on statistical tests, and their efficiencies highly depend on whether the assumptions of statistical models fit to the real data or not. These methods generally cannot be applied on multidimensional data sets, and they also do not work for data sets in which there is no prior information about their distribution .The proximities of data points in a data set can be obtained using the distance or density metrics. The distance-based proximity methods mark a data point as an outlier if it is farther away from other data points in the same data set. On the other hand, density-based proximity methods treat a data point as an outlier if it is located in a low-density region in a data set. In outlier detection, the overall performance of a proximity-based method can be easily affected by the metrics used with it . The advn superior outlier detection method for universally applicable on all kind of data sets. The clustering-based methods can be used in outlier detection practically because they need not prior information about the structure and distribution of data. Furthermore, they are still good candidates for outlier detection in multidimensional data sets and provide advantages to work in incremental mode. Sreevidya argued that the clustering-based outlier detection was more successful than the other types of outlier detection methods with an 88% accuracy rate in an experiment with many data sets  algorithm calculates different membership degrees for each data point to every cluster. When a data point has the same degree of membership to the clusters in a partitioning task it can be evaluated as an outlier. For detection of outliers using fuzzy clustering algorithms, Noise may be present in data sets due to random errors in a feature and they should not be considered as outliers. But they may distort the distribution and mask the distinction between normal objects and outliers. Regarding this kind of problems, the possibilistic algorithms are good candidates for distinguishing outliers more efficiently. For example, n parameter. ROCF detects isolated outliers and outlier clusters based upon a k-NN graph. The idea behind ROCF is that outlier clusters are smaller in size than normal clusters.Even though the main goal of clustering algorithms is to divide data set into homogenous clusters, in recent years, there is an increasing interest to extend them with some approaches for detecting outliers. Although all the algorithms discussed above have their own advantages, they need to select at least one or more parameters. So, using the simple methods which do not require data-dependent parameters may be more useful in outlier detection. Although the typicality degrees from an optimal run of a possibilistic clustering algorithm can be used to identify outlying points, since the fuzzy and possibilistic algorithms are more robust to the noise and coincident clusters problems they can be more successful to detect the outliers. In this study, we used the unsupervised fuzzy possibilistic clustering algorithm by i.e., K-means and its variants, assume that each object belongs to only one cluster; however, clusters may overlap and objects may belong to more than one cluster. In this case, a data point can be a member of several clusters with varying membership degrees between zero and one. The Fuzzy C-means (FCM) clustering algorithm  algorithm has been introduced . Howeverc prototype vectors (vi) and n feature vectors (xk) in Rp features space. uik and tik are the fuzzy and possibilistic membership degree of kth feature vector (xk) to the ith cluster respectively. The UPFC objective function has the constraints which are listed in In m is a fuzziness exponent and the parameter η is a typicality exponent. Both these parameters are usually set to 2. In the objective function in a and b are weighing coefficients for setting the relative importance of fuzziness and typicality respectively. Generally, both of these coefficients are equally set to 1.In the possibilistic algorithms, the parameter JUPFC, the typicality degrees tik and the membership degrees uik are recalculated in each iteration step with To minimize β is is distance variance, and calculated as seen in As seen from the formula in The formula in To find the outliers in multidimensional data sets, we describe the proposed novel approaches in this section. The pseudocode for the proposed approaches is given in Algorithm 1. This algorithm uses the matrix of possibilistic membership degrees . A matrix of possibilistic membership degrees is returned from a UPFC run and passed to the proposed algorithm to find the outliers in the studied data set. In the subsections below the proposed approaches are explained.While the fuzzy clustering algorithms determine the fuzzy membership degree of fuzzy data points to any cluster, they do not evaluate typicality according to their distances from cluster centers. For example, suppose there are two data points A and B, both they have 50% fuzzy membership degree to two different clusters. If their distances from the cluster centers are, say, 2r and 5r, the latter will be a more atypical data point as it is further away from the cluster centers. When compared to fuzzy membership degrees, typicality degrees from the fuzzy and possibilistic clustering algorithms reveal the distinction between the highly atypical and the less atypical members of the clusters. This means that all fuzzy points for a cluster are not equivalent: some are more typical and some are not. This implies that typicality is distinct from a simple similarity to the cluster center because it also involves a dissimilarity notion. Therefore, in our proposed algorithms we used the typicality results from UPFC algorithm.α). This approach checks whether the average typicality of kth feature vector (xk) to all clusters exceeds a threshold level, which is a user-defined possibility degree for evaluating a data point as an outlier.In our first approach, a data point which is not a member of any cluster is evaluated as an outlier. In such case, its average typicality to all clusters should be less than a predefined possibilistic threshold level  is less than α, it is considered as a highly atypical data point and flagged as an outlier in the data set (see in Algorithm 1).The test function in α value is crucial in this approach. According to our tests on several experimental data sets, we determined that a threshold level of 1% (α = 0.01) may be sufficient to find the outliers on the results of UPFC runs, and therefore we recommend to use it as the default value for approach on large data sets. Choosing an appropriate xk for all clusters is less than a user-defined threshold level (α), it is evaluated as an outlier, otherwise, it is normal (see in Algorithm 1). As expected with this function, larger threshold values may lead to less number of outliers whereas smaller ones may lead to much more number of outliers. However, we recommend to use a default threshold typicality level of 5% (α = 0.05) for finding the most probable outliers in data sets, one can increase it to higher levels to make the detection task looser. But, in this case, the probability of treating normal data points as outliers  also increase. In our experiments, a threshold level up to 10% was sufficient to detect the simulated outliers in many runs of UPFC on several synthetic data sets. One can look for an appropriate threshold with trial and error approach for different data sets or can use a prior known level of threshold for a specific application domain. In the second approach, it is assumed that a data point is an outlier if it is atypical for every cluster in ad a data set. As seen in c clusters (n/2c). 2p + 2 can be considered as small outlier clusters. However, the mentioned proposals might be useful for small data sets they may not work well for larger and high dimensional data sets. For computing a more suitable threshold size to determine small clusters (tcs), we propose to use the formula in In some cases, even so, the proposed approaches can find most of the outliers in a data set, collective outliers do exist in it, and their presence should be checked. These are the outlying data points in small or sparse clusters. Thus, all members of small clusters could be seen as the collective outliers according to the third assumption is given in p = 3) and the other with two features (p = 2) for easy demonstration of outlier detection. We generated the first experimental data set by using the R package ‘MixSim’  to ensure the same initialization values between UPFC runs. To determine the success of proposed outlier detection approaches at different number of clusters, UPFC has been started at five levels of number of clusters  on the synthetic data sets. An important subtask in clustering-based outlier detection is to find a good partitioning result for identifying outliers. A reasonable way to find an optimum partitioning is to validate the results obtained at different number of clusters. For this purpose, we used four well-known internal fuzzy indices: Xie-Beni index (XB) In our experiments, we coded the R functions for the proposed outlier detection approaches in R environment . As an iu’ik) to use in validation of clustering results. In this study, the R package ‘fcvalid’, Using The outliers detected from the results of UPFC runs for five different number of clusters for SDS1 are given in c = 2). Except for two points (the points 126 and 128), Approach 2 also detected most of the simulated outliers in SDS1. Using the results from partitioning done for three clusters (c = 3), Approach 1 found twelve outliers that consist of points 1 and 6 in addition to all of the simulated outliers. In the clustering done for three clusters, except two points (the points 124 and 128) Approach 2 also detected the same outliers as those found in the clustering done for two clusters.As seen in For comparison purposes, as the second data set (SDS2), we used the synthetic data set given in c = 2 and c = 3, outlier detection should be based on an optimum clustering result suggested by the fuzzy validation indices. According to the validation indices in Although the proposed approaches were highly successful to identify the simulated outliers from the clustering results at The clusters and the detected outliers are also shown in According to the results in the last row of c = 2). As seen in c = 4). The outliers found with Approach 1 from the clustering done for five clusters (c = 5) were the same with those found in the study on SDS2 data set by As seen in α) as small as 0.05. When it is increased to a higher level, namely to 2 α, Approach 2 could produce the same results with Approach 1. Even though leveraging α to higher values is an option for detecting more outliers, Approach 2 should be applied at lower levels of α to obtain the most possible outliers.Similar to those found for SDS1, Approach 2 detected less number of outliers than Approach 1 for SDS2 too. However, this result was due to the used threshold level  tail of the fitted cumulative distribution function  to those found by Approach 1 in the clustering for six clusters in SDS1. Although LOF algorithm detected more outliers when compared to those detected by the proposed approaches in SDS2, most of outliers found were the same. The mvoutlier package resulted with too many outliers for SDS1 (45 outliers), and thus, was not comparable to the other algorithms. But it suggested mostly similar outliers to those of Approach 1 in SDS2. Finally the outliers found by Approach 1 from the clustering done for five clusters (c = 5) were the same with those found by As seen in The performances of suggested approaches have been also tested on the real data sets, which are given in wine) in The Wine data set (b-cancer), letter recognition (letter), pen-based recognition of handwritten text  and Statlog Landstat Satellite (satellite) were imported from the Harvard Dataverse repository (The data sets Wisconsin breast cancer (pository . To use b-cancer), the malignant class in the original data set has been downsampled to 21 points, which are considered as outliers, while points in the benign class are labelled normal data points. This data set includes totally 367 data points with the rate of 2.72% of outliers.The Wisconsin breast cancer data set in UCIML contains the records for benign and malignant cancer types. In the modified version of this data set  in ODDS has been handled by keeping only the digit 8 as the normal class and sample the 10 digits from all other classes as outliers. The pen-global dataset has 16 features and 809 data points  is a modified version of the original Statlog Landsat Satellite data set in UCIML. To create this data set, the smallest three classes have been combined to form the outlier class, while all the other classes have been as the inlier class. The satellite data set consists of 36 features and 5,100 data points.The Satellite data set (c shows the suggested cluster numbers by the fuzzy validation indices for the examined real data sets. According to the outlier detection analyses at these numbers of clusters, Approach 1 at the threshold level of 1% and Approach 2 at the threshold level of 2.5% were completely successful to find all the outliers in b-cancer data set. Both the proposed approaches detected more outliers than the reported number of outliers for the letter data set. Approach 2 with the threshold level of 2.5% produced the nearest result to the numbers of outliers in the letter data set. Approach 1 at the threshold level of 1% successfully detected all of the outliers marked in pen-global data set whereas Approach 2 found the most of them at the same threshold level. Approach 1 with the threshold level of 1% was again successful to find the outliers in the satellite data set while Approach 2 detected less number of outliers for the same data set. Finally, for the wine data set, Approach 1 with the threshold level of 2.5% and the Approach 2 with the threshold level of 5% gave the closest number of outliers to those reported for this data set.In As a general evaluation of the results, we could conclude that when the dimensionality of data sets increases we recommend to use Approach 1 at the lower threshold levels. Working with the threshold level of 1% may practically be enough for detecting outliers in many cases. As explained in the introduction of the approaches in ‘Proposed Approaches for Outlier Detection’, since Approach 2 detects the most probable outliers it will return less number of outliers for the analyzed data sets.In this study, we introduced and tested two novel approaches to detect outliers using the typicality degrees obtained from unsupervised possibilistic and fuzzy clustering algorithms. Based on the experiments, the proposed approaches seem promising in detecting outliers in different kind of multidimensional data sets. Additionally, the proposed approaches are simple to implement and do not need any parameter except only a user-defined alpha value as the threshold typicality level. In this study, although we tested the proposed algorithms on the typicality degrees from UPFC algorithm, they can be applied with the typicality results from the other PCM-like algorithms. Therefore, they can be easily used for achieving considerably good performance in most of the application domains.c is chosen close enough to the real number of clusters in data sets, Approach 2 tends to give a smaller number of outliers, usually at the higher levels of number of clusters used in the runs of the clustering algorithm. Although the outliers could be detected from the partitioning results done for the number of clusters below and above the actual number of clusters, we recommend detecting the outliers by using the partitioning result, which is suggested by the majority of fuzzy internal indices. We also recommend using Approach 1 at the lower threshold levels, i.e., 1%, because it worked well for majority of the analyzed real data sets.However, both of the proposed approaches provide the same results when the parameter In this study, although the proposed approaches have been tested to detect the outliers on some well-known real data sets, we still need some further studies to examine their performances at different densities of outliers in larger data sets. The performance of outlier detection based on clustering is also closely related with the selected values of parameters which are used in the runs of clustering algorithms. Therefore, the efficiency of the proposed approaches should be examined regarding the parameters used by UPFC such as different settings of fuzziness and typicality exponents, different weights of possibilistic part of the objective function, and the different initialization techniques in generation of the prototypes used in UPFC runs.10.7717/peerj-cs.1060/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj-cs.1060/supp-2Supplemental Information 2Click here for additional data file.


The past half century has seen the near eradication of transfusion-associated hazards. Intraoperative cell salvage while widely used still poses significant risks and hazards due to human error. We report on a case in which blood collected from a patient with lung cancer was mistakenly administered to a patient undergoing cardiac surgery who should have received his own collected blood. The initial investigation found that the cause of the patient harm was violations of procedures by hospital personnel. A detailed investigation revealed that not only violations were the cause, but also that the underlying causes included haphazard organizational policies, poor communication, workload and staffing deficiencies, human factors and cultural challenges.On August 14, 2019, a 72-year-old male was admitted to our hospital for angina pectoris and multivessel coronary artery disease. Cardiac surgery was performed using an autologous salvage blood collection system, and there were no major problems other than the prolonged operation time. During the night after the surgery, when the patient’s blood pressure dropped, a nurse retrieved a blood bag from the ICU refrigerator that had been collected during the surgery and administered it at the physician's direction, but at this time neither the physician nor the nurse performed the required checking procedures. The blood administered was another patient's blood taken from another surgery the day before; an ABO mismatch transfusion occurred and the patient was diagnosed with DIC. The patient was discharged 65 days later after numerous interventions to support the patient. An accident investigation committee was convened to analyze the root causes and develop countermeasures to prevent a recurrence.This adverse event occurred because the protocol for intraoperative blood salvage management was not clearly defined, and the procedure was different from the standard transfusion practices. We developed a new workflow based on a human factors grounded, systems-wide improvement strategy in which intraoperative blood collection would be administered before the patient leaves the operating room to completely prevent recurrence, instead of simply requiring front-line staff to do a double-check. Implementing strong systems processes can reduce the risk of errors, improve the reliability of the work processes and reduce the likelihood of patient harm occurring in the future. Autotransfusion of patient blood has been widely used in various surgeries since the early 1970s . IntraopA 72-year-old Patient X with a history of congestive heart failure and chronic atrial fibrillation, requiring dialysis for chronic renal failure due to nephrosclerosis, was admitted to our hospital because of angina pectoris and multi vessel coronary artery disease. The patient’s home medications included warfarin potassium (1 mg), clopidogrel sulfate (50 mg), amiodarone hydrochloride (100 mg), and bisoprolol fumarate (1.25 mg). The patient’s blood type was O RhD positive. The blood was collected by the ASB system and the coronary artery bypass surgery (CABG) was successfully completed. The CABG surgery was prolonged due to a lenghty re-anastomosis of one of the three-vessel cardiac grafts. The operative time was 8 h 19 min, intraoperative blood loss was 790 ml, and no autologous or allogeneic blood transfusions were performed. The hospital usually stocks the collected blood in the intensive care unit (ICU) if the case does not require urgent use of the collected blood. The surgeon usually decides depending on the patient's condition whether to transfuse the blood back to the patient or discard it within 24 h after the operation.The physician in charge on the night after the operation, decided to administer the salvaged blood of the patient due to a decrease in systolic blood pressure. The low blood pressure was attributed to dehydration as the patient was not bleeding, not in shock, and had no abnormalities in cardiac function, blood gases, or their electrocardiogram. The physician instructed nurse A to bring the patient’s blood from the ICU refrigerator. Because nurse A was engaged in the care of another patient, she requested that nurse B to “Bring it to me.” Nurse B went to the ICU refrigerator and picked up a blood bag. However, the bag retrieved by nurse B was not that of Patient X but was collected from another Patient Y, who had undergone thoracic surgery the day before to remove their lung cancer. The blood type of Patient Y was A RhD negative. When stored in the refrigerator, a note with the patient's name and identification (ID) number was supposed to be put on the basket, but this was not present at the time of the incident. The name was written on the pack, but nurse B did not check this because she was in a hurry. Nurse B believed that the blood in her hand was that of Patient X, and handed it directly to the nurse A, who then connected it to the patient's intravenous line and started the infusion without further ascertainment to asure the correct patient's blood identification. The two-person check at the bedside by nurses or physician and nurse was not performed. For a typical blood transfusion, a physician will use a Personal digital assistant (PDA) for verification, but the salvaged blood bag does not have a barcode and is not verified by a PDA.The patient became hypotensive with blood pressures in the range of 50 to 60 mmHg systolic pressure range and vasopressors were initiated. Several minutes after the transfusion began, the patient's blood pressure dropped further, with a systolic pressure consistently in the low 50 s. The blood transfusion was stopped due to growing concern about the possibility of wrong blood transfusion. The volume of blood administered was estimated to be approximately 50 mL. The blood bag was removed from the venous line and the transfusion was stopped. Albumin and noradrenaline drop were administered, and over the next 15–20 min, the patient’s systolic blood pressure increased to the 130 mmHg range. There were no physical findings suggestive of an allergic reaction or hemolytic urine. The surgeon thought that the cause of the hypotension was a low circulating blood volume. One hour later, the patient’s serum hemoglobin level decreased to 9.2 g/dl from 11.4 g/dl preoperatively. The nurse was instructed to restart the transfusion. The nurse connected the blood that was hung on the bedside infusion table to the patient and restarted the transfusion. All residual blood was transfused into the patient. A decrease in the number of platelets was noted the next morning, blood pressures were lower and the patient was diagnosed with disseminated intravascular coagulation (DIC) syndrome.The charge nurse discovered during a regular safety check of the ICU refrigerator that the ASB blood, which should have already been administered, was still stored. This revealed that the blood administered to Patient X was that of Patient Y. Patient X was successfully resuscitated and was discharged from the ICU on day 8. The patient was finally discharged home on day 65 due to persistent pleural effusions and positive CRP and had delayed rehabilitation due to severe back pain.An hour after the accident occurred the concerned parties gathered to discuss the best course of action. Three and a half hours after the wrong transfusion was recognized, the surgeon in charge and staff of the patient safety department disclosed the facts of the events to the patient's family and apologized to the family . Nine hoWe describe a completely preventable wrong patient blood transfusion in which a patient was administered another patient’s blood, collected as autologous-salvaged blood (ASB) during cardiac surgery. We review the root cause investigation (RCA) and highlight the systems' issues that emerged and the corrective actions implemented in the hospital to prevent similar adverse incidents.The history of blood supply is one of early, sobering frequency of disease transmission but also remarkable improvement in systems safety in terms of correct blood transitions that is free of infectious agents. Blood product safety has been an improving area of focus over recent decades in many countries . SeveralThe transfusion service is one of the most highly regulated services within the clinical laboratory. The pathway of blood delivery is inherently complex because multiple patient care areas are involved. The goal of the blood delivery pathway is to deliver the right product to the correct patient .Identify the patient with two unique identifiers (ID).Connect the patient identifiers to all prepared lab samples, tests, and blood products.Deliver the right blood product to the right patient at the right time, confirming patient ID again.The pathway can be summarized by three simple steps:These three simple steps comprise numerous processes, each with their own risks of failure, with the highest rates of failure associated with processes outside of the clinical laboratory.The risk of fatality due to an ABO-mismatched red blood cell transfusion is estimated at 1 to 4 per 10,000,000 of each red blood cell unit transfused . But fatThe risks of a lethal hemolytic transfusion reaction were estimated at 1 per 550,000 units transfused for the time period 1976–1985 in the US . Not allWhen estimating the risks, the best information available indicates that most transfusions to the wrong patient occur as a result of potentially avoidable system failures . The mosA linkage diagram Fig.  was creaUnfortunately, but importantly, the linkage diagram shows the patient’s adverse event was not the result of a single error. Most errors are caused by a combination of cascading failures, and it is rare that a single error leads to an incident. Initially, the cause of this accident appeared to be a simple case of rule violation, as the blood was administered by a nurse without checking the name against the blood bag label . HoweverLewin’s equation [the SHELL model [Nurse B's action in "administering the wrong infusion" was considered a possible cause of human error, which was investigated using the RCA (see below). Human error is defined as the failure of planned actions to achieve their desired ends without the intervention of some unforeseeable events, and it is not the cause of the accident; it is the factor that causes the human to make the error that is the cause of the accident . Human bequation  or the SLL model . Figure First, we consider the human factors involved . We explNext, the environmental factors were discussed. The cause of Patient Y's blood being passed into the hands of Nurse A as Patient X's blood was discussed. The probable background factors for how Patient Y's blood got into the hands of Nurse A were as follows: (1) the blood collected from multiple patients was stored in multiple refrigerators in the ICU; (2) the patient’s name and other information were not written on the basket as required when storing the blood bag in the refrigerator; (3) normally, a paper label with the patient's name and ID number must be affixed to the bag after blood collection before usage, but in this case, this label was not used, and the patient's ID number and name were hand written directly on the transfusion bag with a black magic marker; and (4) the thoracic surgeon who salvaged the blood from Patient Y was not familiar with blood salvage protocols and did not make a decision within 24 h to use or discard the blood.It is clear from considering factors 1–3 above, that there were no clear SOPs defined in the ICU. Nurse A administered the incorrect blood unit, believing that the blood unit in her hand belonged to Patient X, when in fact it belonged to Patient Y. The investigation committee determined that the "intraoperative salvaged blood, without starting to administer the blood before leaving theatre, and bringing the bag to the ICU," was the lead root cause of this event.The investigation committee believed that measures addressing the violations of the confirmation process by the staff, background factors such as lack of information sharing, and compliance failures in storage and destruction of bags, while critical, would not have completely prevented this from recurring. Therefore, measures to prevent a recurrence were focused on the upstream causes, which includes how procedures for intraoperative salvaged blood are managed. Transfused salvaged blood is generally recommended to be administered in the operating room but it is not prohibited to be given outside the operating room. However, to prevent blood unit mix-ups, it is necessary to start the ABS administration in the operating room. The draft guidelines for the Implementation of Transfusion of Autologous Salvaged Blood (2020) by the Japanese Society for Autologous Blood Transfusion indicates that “in principle,” administration should be started in the operating room . At our In conclusion, we investigated a serious adverse patient incident in which intraoperatively salvaged blood was transfused to the wrong patient with a different blood type. Under the Human Factors  theory, failures are not satisfactorily explained by demonstrating human deviation from expected behavior. Instead, the circumstances and underlying pressures are meticulously explored, and systemic deficiencies are identified. It is always easier to see the warning signs in hindsight but in reviewing incidents of missed warning signs we are reminded to look for patterns of smaller incidents and to take near-misses seriously. Interventions to improve blood safety should lean towards design improvements, engineering controls, or process simplification and standardization. We developed and implemented a systems' improvement strategy that requires a stringent verification process in collecting and labeling blood specimens. The intraoperative blood collection is administered before the patient leaves the operating room in order to completely prevent a wrong blood administration recurrence, instead of simply requiring front-line staff to check or double-check the blood compatibility. The hospital has been working to improve the reliability of their work processes, enhancing policy and training improvements, and making all efforts to reduce the likelihood of a similar error occurring in the future. While strict rules are a reminder of what not to do, people’s ability to perceive the situation and adapt is the primary source of safety.


We present a series of new implementations that we recently introduced in COBRAMM, the open‐source academic software developed in our group. The goal of these implementations is to offer an automatized workflow and interface to simulate time‐resolved transient absorption (TA) spectra of medium‐to‐big chromophore embedded in a complex environment. Therefore, the excited states absorption and the stimulated emission are simulated along nonadiabatic dynamics performed with trajectory surface hopping. The possibility of treating systems from medium to big size is given by the use of time‐dependent density functional theory (TD‐DFT) and the presence of the environment is taken into account employing a hybrid quantum mechanics/molecular mechanics (QM/MM) scheme. The full implementation includes a series of auxiliary scripts to properly setup the QM/MM system, the calculation of the wavefunction overlap along the dynamics for the propagation, the evaluation of the transition dipole moment at linear response TD‐DFT level, and scripts to setup, run and analyze the TA from an ensemble of trajectories. Altogether, we believe that our implementation will open the door to the easily simulate the time‐resolved TA of systems so far computationally inaccessible. Schematic overview of the protocol implemented in COBRAMM to simulate transient absorption If the incident probe photon covers the UV/vis spectrum as well, the wavepacket can be promoted to a higher‐lying excited state, the so‐called excited state absorption (ESA). Alternatively, the probe pulse can induce the relaxation to the ground state through a radiative decay, the so‐called stimulated emission (SE). A pump‐probe (PP) spectrum is normally recorded with a first measurement performed with the pump turned off and only the probe beam hitting the system, followed by a second measurement with the pump on. In the first measurement only ground state populations is probed, while in the second one part of the total population is on the excited state. The difference in intensity between the ground state absorption in the two measurements gives rise to the so‐called ground state bleaching, which corresponds to the depletion of the ground state population due to the pump pulse.Transient absorption (TA) spectroscopy is a crucial technique to deeply understand the ultrafast dynamics of photoactive systems and can offer a temporal resolution in the order of the femtosecond (fs) time scale.t for an interval τ. More often, a more radical approximation is made, considering only the vertical energy gap between the photoactive state and the remaining states at each delay time t, termed Condon approximation, thus assuming instantaneous dephasing. This approach has been used to successfully reproduce TA spectra using wavefunction methods for the description of the excited states.Despite the powerfulness of the technique, a computational support is often required to confirm and rationalize the time evolution of the system and the chemical and physical nature of the features giving rise to the signals in the TA spectra.In this work, we want to introduce a series of tools implemented in the open‐source academic software developed in our group, Cobramm is Optimized in Bologna to Run Ab‐initio and Molecular‐Mechanics calculations (COBRAMM)22.1EQM) and MM (EMM(tot) and EMM(QM)) part through its own interfaces to MolcasThe QM/MM schemeThe evaluation of the electrostatic interaction between the QM and the MM part is enhanced by the inclusion of the electrostatic embedding term, which allows the polarization of the QM part by the inclusion of the MM charges in the Hamiltonian adopted. Additionally, in case of excited states optimization, minimum energy path exploration or nonadiabatic dynamics, the influence of the QM density on the point charges is considered, with a state‐specific contribution being added to the gradient of the point charges. In the case where the QM‐MM boundary region involves covalent bonds, a link‐atom approach is used. The delicate issue of treating boundary regions and the possibly resulting over‐polarization is automatically handled by COBRAMM internally by charge repartitions, as explained in detail in the original publications.2.2Pj) to hop from a state j to another state is given by the electronic coefficients of the wavefunction:The great popularity of TSHi and j, the hopping between them is driven by the time‐derivative coupling (TDC) Tji which is the dot product of the velocity and the nonadiabatic coupling (NAC) vector. The NAC can be computed at each step along the dynamics or can be approximated by computing the wavefunction overlap (WFO) of the two electronic states involved.S0, which cannot be properly describe with linear response TD‐DFT within the adiabatic approximation.1 and S0, at the choice of the user.Beside the energies of state 2.3a, at each time step the TA spectrum can be obtained by calculating vertical excitations from state a. The SE is computed considering the oscillator strength (f) with respect to the ground state, while the ESAs are evaluated considering f of transitions between state a and the higher‐laying excited states calculated. The spectrum at a certain time t is convoluted with a sum of Gaussian functions centered at the ESA and SE energies and with an intensity proportional to f of the transition. The intensity of the ESA from the state a to an excited state e is given by:a to the ground state (gs) is given by:The time‐resolved TA spectrum can be computed from an ensemble of trajectories independently propagated that sample the evolution of the wavepacket along the potential energy surfaces.a in which the system evolves at the time of the interaction with the probe pulse could be observed/simulated. However, these transitions fall very often below the detection limit of the experimental apparatus and it is commonly observed and simulated only the SE to the ground state.In principle, SE to any state below the “active” state t, we obtain the final TA as:Summing over all the trajectories we can obtain the TA for a certain time and convoluting over all the time steps i represents the transition dipole moment vector of the transition promoted by the pump at t0 and TDMj the one promoted by the probe at time t and θ the angle between them. That means that a parallel arrangement leads to a signal three times more intense for transition that have TDM parallel to the one generated by the pump pulse, while the one orthogonal to it will be two times more intense for orthogonal arrangement, and in general indicates a modulation of the relative intensities of the signals; (iii) an additional broadening in the time domain asRegarding the convolution with respect to an experimentally recorded spectrum, some considerations regarding our implementation need to be pointed out: (i) the Gaussian line shape used to convolute the spectrum is artificially broadened by FWHM to smooth the signal, removing the noise; (ii) three possible arrangements of the pump and probe pulses are considered.33.1cobramm.prep), with the advantage of being divided according to the individual task to be performed. This allows to use all of them in serial or independently for particular tasks needed by the user.We implemented a new series of auxiliary scrips in COBRAMM that help the user prepare the system step‐by‐step, and analyze the results of the simulation. These python scripts are added to the already present system‐preparation tool  of the ith electronic state at position r can be written as:Ciar and Φap being the CI coefficients of state i and are the determinants associated with each single excitation from occupied orbital a to virtual orbital p, respectively. With this definition the overlap termi and j at two different geometries r and r′ becomesψpr being the p‐th molecular orbital (MO). The determinant overlap termSa,bp,sSa,bp,s is the overlap matrix of the lowest occupied orbitals (dimension n×n), where the ath row and bth column have been replaced with the pth row and sth column of the full MO overlap matrix (dimension (n+m)×n+m), respectively, and the a,bth element has been replaced by the p,sth elements.In TD‐DFT within the Tamm‐Dancoff approximationr has the form of a unitary matrix , thusr and r′. An unitary transformation of the MOs  does not change the expectation values such as the energy. Making the assumption that the occupied and virtual subsets of MOs present complete orbital sets, it implies that there exist unitary transformation matrices Uocc (dimension n×n) and Uvirt (dimension m×m) which rotate the subsets of the occupied and virtual orbitals at geometry r′ to maximize the overlap with the corresponding subsets at geometry r. The transformational matrices are the inverse of the Socc,occ and Svirt,virt blocks of the full MO overlap matrix.Socc,virt and Svirt,occ. This approximation holds as long as the ground and excited state potential energy surfaces are energetically separated, implying a large energy gap between the occupied and virtual orbitals and, as a consequence, negligible mixing. The approximation breaks at crossings between the ground and first excited state, that is, S1/S0 conical intersection (CoIns) where the frontier orbitals are nearly degenerate and mix strongly. However, this does not present a limitation of the presented method, as single reference methods exhibit convergence problems in the vicinity of the S1/S0 CoIns and the dynamics are interrupted in case such a CoIns region is approached. In fact, the off‐diagonal elements can be used as a diagnostic tool to assess the validity of the approximation.The MO overlap matrix at the same geometry Bavirt denotes the projection of the occupied orbital a at geometry r on the subset of virtual orbitals at geometry r′.r′ are modified by the transformation via the expressionCi is defined as the matrix of CI coefficients of dimension n×m. Since Uocc is unitary matrix, the transpose of its inverse gives the Uocc matrix itself. Thus, only the inverse of the MO overlap matrix of the virtual orbitals needs to be computed. In practice, since the occupied and virtual blocks are not complete, the two expressions  give slightly different results which are related to the quality of the approximation of completeness.Since the single electron excitation requires to exchange an MO from the occupied subset with an MO from the virtual subset, the CI coefficients at geometry r′ it is achieved that the full MO overlap matrix becomes a unitary matrixΦaprΦbsr′ survives only when bra and ket are identical determinants  simplifying the calculation of the wavefunction overlapWith the above MO transformation at geometry The presented approach achieves accuracy comparable to the explicit computation of the overlap via Slater determinants Equation , but acc3.3r the spatial and x the spin‐space coordinates. In case of CIS or TD‐DFT, but only if the TDAω corresponds to the element of the vector X of the Casida equation.The probability and intensity of a transition between two electronic states is proportional to the magnitude of the TDM between them. Consequently, in order to evaluate the ESA, it is necessary to compute the TDM between a currently populated excited state and the higher‐lying states. This can be analytically calculated exactly for wavefunction‐based method. the TDADm,nr=∑j3.4t is extracted, and vertical excitations are computed for the QM part at that geometry, with the inclusion of the point charges in the Hamiltonian. The SE is extracted from the energy and f of the transition from the current active state to the ground state and, analogously, the ESA from the active state to the higher‐lying excited states.Once a statistically relevant number of trajectories are propagated, these can be post‐processed to calculate and convolute the time‐resolved TA spectrum by calculating vertical excitations for time steps of the trajectories within a chosen delay time. This might be in principle done on‐the‐fly along the propagation, but the reasons of the post‐process implementation are the following: (i) along the dynamics a small number of excited states are calculated. In order to keep the calculation as light as possible, usually only few states higher in energy, with respect to the initial active one, are computed. However, the ESA can involve states that are not included along the TSH simulation; (ii) the vertical excitations can be calculated at a higher level of theory, for example using a bigger basis set, to obtain more accurate energies; (iii) the excited states absorption can be evaluated multiple times with different level of theory, using the same propagated geometries without re‐running the trajectories. We implemented the full workflow to obtain TA spectrum from an ensemble of trajectory within a python class in COBRAMM, whose functions are called by two auxiliary scripts, one needed to setup and run the vertical excitations, the other to extract TDM and energies and to convolute the PP spectrum. The workflow is schematized in Figure In a first step, the spectrum is convoluted from the collection of excitations obtained for each time step and subsequently the convolution in time is applied as explained in section Since the full simulation workflow requires many calculations on different steps and levels, we decided to offer individual scripts to setup and run individual tasks. This guarantees a full support throughout the different steps, but leaves the possibility to the user to choose, parametrize, control or restart any part of the workflow individually. That avoids having a full black‐box approach and allows the user to have control over the whole complex workflow.42 state, La in Platt's notation, predicted to be at TD‐DFT level at around 5–5.5 eV. This state is very close in energy with the Lb state that it is populated in an ultrafast timescale (tens of fs). This state is darker but still emits, producing the first emission band. The nature of the second fluorescent signal was under debate for long, but by now the most accepted theory is that the emission comes for a longer time scale  from a different excited state that involved an intramolecular charge transfer following the twisting of the dimethylamine group. These studies included TR spectroscopical measurements and, very recently, the TR‐PP spectrum in acetonitrile (MeCN) has been characterized computationally and reported in literature.S2/S1 decay resembles the second one‐dimensional model original proposed by Tully for the same aim, and already used with this purpose.S2/S1 early relaxation within the first 100 fs. Second, we will test the setup to calculate the TA spectrum on the same 100 fs long trajectories, to map the very first nonadiabatic event during the dynamic of this molecule.The excited states properties and dynamics of DMABN have been intensively studied and properly characterized.4.1S2 for 100 fs with a time step of 0.5 fs. Nonadiabatic couplings were approximated by calculation of wavefunction overlaps with the orbital rotation scheme previously described (section S2 and starts propagating), by calculating 10 roots every fs along each of the trajectories. An artificial broadening of 0.2 eV in the energy domain and 10 fs in the time domain was applied.The initial DMABN geometry was solvated with a box of 24 Å of MeCN molecules. The parameters for MeCN were taken from literature, section . Energy‐4.2S2 to S1.S2/S1 populations in the first 100 fs obtained for the 150 trajectories ran are shown in Figure S1 and S2 in the first 100 fs. Previous dynamics with ab initio multiple spawning and TSH in gas phase at TD‐DFT level, showed the oscillations typical of this behavior in the population profiles.S2, without back hops to that state.S2 population is 20% of the total one after 100 fs.The main feature of the early nonadiabatic dynamics of DMABN is the ultrafast relaxation from S2 surface, forbidding the hops to other states. We computed the time‐derivative coupling between S2 and S1 along these trajectories, as show in Figure We tested the performance computing the time derivative coupling by approximating the NAC by WFN with the two algorithms we implemented in COBRAMM section . We ran As it is visible, the two algorithms give the same result for the WFO, resulting in the same values for the TDC along the trajectories. The main difference stands then in the time needed to compute the WFO. In our implementation, the orbital rotation scheme calculates the TDC in less of a second, for the system used and with the number of roots included, which turned out to be up to 100 times faster along the trajectories studied, suggesting this method as the indicated one, giving identical result in a more efficient way.4.3The TA spectrum of DMABN has been studied both experimentally and computationally,S2 state, which is responsible of the intense spot at 5 eV, to the darker S1 state, that shows the constant band centered at 4.5 eV.The SE signal reflects the ultrafast decay from the bright S1 to higher excited states. The relative intensity of the two signals is also in agreement with previous results, with the strongest signal given by the initial spot of the S2 emission, and the ESA and SE bands from 10 to 100 fs less intense and constant over this time.S1 minimum is expected to rise, but we stopped our trajectories after 100 fs, since the goal was only to verify and proof the applicability of the workflow implemented and presented, which will be soon applied to simulate the ultrafast TA spectra of other molecules, whose ultrafast dynamics is less clear and might be only simulated at the TD‐DFT level, due to the size of the chromophore. However, the lower computational cost of this protocol would allow at the same time to run longer trajectories with reasonable computational effort. Nonetheless, in the spectrum reported here, the computational flexibility of TD‐DFT allowed us to obtain a convolution using a statistically relevant number of trajectories (150) and vertical excitation (150.000) otherwise not feasible that alleviates the weight of the approximation used. At this point, we can apply the additional post‐processing tools, in order to disentangle the contributions of the transitions to the spectrum. We can first observe the spectrum for different delay times. In particular, we can decompose the spectrum in signals obtained every 20 fs of delay time from the pump and the probe pulse ,On the other hand, the ESA signal centered at 1.8 eV shows a relative lower intensity at time 0 fs, where only In Figure S0 ‐ > S2 and S2 ‐ > S0 TDMs, and that results in a more intense signal at the beginning of the dynamics, in the first 10 fs, and when the population comes back to S2. The ESA band is enhanced as well in the main signal at 1.75 eV, while in case of orthogonal arrangement, the relative intensity of the blurred band between 2 and 3 eV is enhanced with respect of the main signal, indicating the role of different transitions, which in this case have a TDM orthogonally oriented with respect of the S0 ‐ > S2 excitations.This is because of the parallel orientation of the In order to finally disentangle the role of different excited states involved in the ESA band, a decomposition of the that band is performed at the magic angle orientation Figure .S1 ‐ > Sn transition and S2 ‐ > Sn transitions. This is practically done by convoluting the spectrum considering only the S1 (or S2) to higher states transitions individually, for each step in which the initial state of interest is also active one. We can identify six different sub‐signals  due to the close vicinity in energy along the dynamics. The first sub‐signal (a) is centered at 1.75 eV and is obtained from excitations from S1 to S3 and S4. These components are the relatively most intense ones among the whole set of transitions considered and their absorption represents the main contribution to the ESA signal. Transitions from S1 give rise also to the other part of the band. Excitations to S5 – S7 give a weak signal centered at 2 eV (b), while the S1 ‐ >S8 absorption is centered at 2.25 eV (c) and finally the upper blurred contribution of the total ESA signal is obtained from transition to S9 and S10 (d). Although it is rapidly depopulated, the S2 relative population along the dynamics still produces some contribution to the total ESA band. Transitions to S3 and S4 do not contribute at any time along the dynamics, while a first contribution from this state is found where it is excited to S5 − S8 (e), which excitations contribute in minor part to the main signal at 1.75 eV. Additional absorption is found for S2 – >S9 and S5 – >S10, which is centered slightly above 2.0 eV. Individual transitions maintain their intensities along the dynamics and confirm the back‐hops between the two excited states along the simulation.We reported the single contributions of the s Figure  that alts Figure . SignalsS1 – >S3 and S1 – >S4 transitions to the ESA signal, and the relative contributions of the other excited states absorption to the other parts of the total band. The total results show how such type of post‐processing tools might turn out as a crucial tool to disentangle more complex TA signals.This analysis gives a complete overview on the ESA of DMABN in the first 100 fs, unveiling the main contribution of 5In this work, we presented some of our most recent implementations in COBRAMM, a software developed in our group to simulate photochemistry in complex environment. The new functionalities of the software range from (i) the automatization of the important and delicate task of setup of initial conditions; (ii) the implementation of an internal routine to evaluate fast and efficiently the WFO and compute the TDC; (iii) post‐production tools to analyze the results of TSH simulations; (iv) the evaluation of TDM between excited states at TD‐DFT level; (v) setup, run and convolution of TA spectra resolved in time at the TD‐DFT level; (vi) post‐production analysis including convolution according to different polarization schemes and decomposition of the signal in single transition contributions. Additionally, the efficiency of COBRAMM has been enhanced by rewriting the interfaces for AMBER, for force field‐based calculations, and Gaussian, for TD‐DFT calculations, in an object‐oriented compliant way. The interface with the output and wavefunction analyzer Multiwfn allows the evaluation of the TDM at the TD‐DFT level and opens the opportunities of additional implementations to exploit many of the potentiality of that software, like real‐time excited states characterization along the dynamics, or automatic reparameterization of the chromophore partial charges to account the change in electronic density after promotion and propagation on excited states surfaces. In terms of outlook, the new initial condition preparation toolkits can be additionally increased in flexibility and capabilities to offer an always stronger support to the user in such a delicate task. With this work, we offer for the first time the possibility of simulating TA spectra resolved in time at the TD‐DFT level with a QM/MM scheme, which means, within the limitations of the method, opening the doors of such a type of simulation to medium‐to‐big systems, without losing the effect on the environment, included within the QM/MM formalism, and obtaining a reliable and accurate comparison with experiments, giving insight otherwise impossible to obtain for the ultrafast dynamics of these molecules. In perspective, with all the theoretical considerations of the case, our interface might be adapted to couple different levels of theory for different steps of the protocol, that is, propagating the dynamics on TD‐DFT surfaces and compute the vertical excitations with a multireference wavefunction‐based method, for example in cases where double excitations might be relevant in the TA. We aim to extend the workflow to methods like ADC(2),


The objective of this article is to present the design and manufacture of a scaled railroad track to be used as a laboratory track for the study of different railway applications. It could be a guideline for future laboratory railroad tracks. The ideal concept was based on possible future studies and, according to them, design requirements have been specified. The main characteristic of the track is that its geometry can be mechanically modified and irregularities can be introduced under controlled conditions in any kind of track sections: straight, curved and transition ones. Finally, the current installed track is shown and the performed quality controls are described. An example of this improvement is the speed record of 159.67 m/s (574.80 km/h) reached by TGV Alstom in 20072. Several benchmarks7 have allowed to compare agreement between different codes giving confidence on results, acknowledging that no analytical solution is known. Although computational models are very useful, it is important to experimentally validate the numerical results to ensure that the model is sufficiently accurate in the simulation of reality. To this end, validation requires experimental data from real vehicles to be obtained. Due to the difficulty of having access to this type of data, laboratory solutions exist for certain studies. Two examples of these laboratory solutions are full and reduced-scale roller rigs, and full and scaled vehicle-track systems. A state of the art of the scaled roller rigs can be found in10. Each roller rig design is unique and strongly depends on the goals of experiments, as it is highlighted in11. In relation to full scale vehicle- track systems, there is an important facility in USA, the Transportation Technology Center, in Pueblo, Colorado, that has been testing vehicles and track components since 1970s12. New facilities will be operational within 202213. Another full scale system can be found in Japan, MIHARA test center14. In relation to scaled vehicle-track systems, if the main purpose is to obtain results extrapolated to a full-scale system, the problem of scale correlation and similarity laws implies that experimental results in the scaled track cannot be directly extrapolated to results in a full-scale track16. It allows, however, the validation of computational models as its main advantage. In this sense, roller rigs have proven to be an effective experimental tool for the study of wheel-rail contact and other issues in railway vehicle dynamics17. However, roller rigs present certain disadvantages versus the use of test tracks due to some differences described as follows: 19.The curvature of the roller alters the geometry of the contact area between wheel and roller, the contact patch being shorter in the direction of motion. This difference will influence the magnitude of the creep forcesThe lateral and vertical structural stiffness of rollers may be different from the track stiffness.8.Wear patterns: in tracks, testing wear is more uniformly distributed whilst in a roller rig it is more concentrated in the roller surface20, as Chengdu and Japan (RTRI) roller rig.Introducing track irregularities in roller rigs is complex and tedious since it implies an additional source of vibrations to the roller. Some examples of roller rigs that simulate track irregularities in curved tracks can be found inIt is complex for a roller rig to simulate a transition curve. Owing to this, studies are limited to straight or constant-radius curved tracks.When studying railway dynamics, the behaviour of railway vehicles can be simulated in a virtual environment using commercial programmes. A list of the main available programmes can be found inR = 3.3 m), transition curve and a straight one. In this track, whose description can be found in23, the transition curves are sinusoidal. Also, in25 it is explained the construction of a testbed for the development and testing of active steering systems of railway vehicles, and it includes a 1/5 scaled track model with no cant angle and two straight tracks (6.41 m length each one) connecting a curved track with R = 20 m and 14.30 m length. In26, a 1/5 scaled wheel-rail test rig is used. It is a beam mounted on a central pivot with a single wheel at one end of the beam, and a circular track with a diameter of 2.5 m. In29, a rail track assembly is described. It includes different subassemblies as the components of a railway track structure, which is bended around a central pivot to provide a circular rail ring with a diameter of 4 m. Another example of a scaled track is that of Stapleford in Leicestershire (UK), which is used for training purposes by the railway division of the Institution of Mechanical Engineers through the RailwayChallengeCompetition. This competition is focused on the knowledge of the complete cycle of the design and manufacture of a prototype supported by academic and industry mentors. Participants should design and build a scaled locomotive that can travel on a 0.26 m (10 1/4”) gauge track following strict rules and specified technical details. The locomotives are tested on the aforementioned track.To the best of the authors’ knowledge, there is very little bibliography describing construction for research purpose. The University of Tokyo has the Chiba Experiment Station, IIS, with a 25 m length scaled track (1/10) formed by the following segments: a straight section, transition curve, curved track . The possibility of lateral movement will allow the track gauge deviation and irregularities in the alignment to be reproduced. The vertical displacement will allow the irregularities of cross-level and vertical profile to be reproduced and vertical slopes to be modified.Possibility to generate an arbitrary cant angle is required.The method of varying the track geometry should be easily applied.Rails should be discretely supported by sleepers with elastomeric material as in most conventional tracks.Each rail section should be as long as possible to reduce the number of discontinuities in the final track.Vertical and lateral step in the rail joints (minimum mismatch of position permitted between the sections in contact with consecutive sections of rail) should not affect the dynamics of the railway vehicle much when passing through consecutive rail sections. Welded connections are not allowed to permit easy substitution of rails .Separation between consecutive rail sections is not allowed to minimize the influence on the dynamics of the railway vehicle as it passes through the joints, except for the consideration of expansion joints that absorb the length variation of the rails due to temperature effects.The track should include a bridge-like structure. The bridge allows the vehicles to experience a change in the track stiffness with respect to the general track base structure.The rails must not be permanently deformed by the usual loads they are subjected to. Low-weight railway vehicles (approximately 50 kg) will be tested on the track.The design requirements due to the location and available space are the following: 5-inch track gauge (127 mm). This implies a length scaling factor with respect to a standard 1435 mm track gauge of 1/11.3.Impact on the roof where the track is installed should be minimal. In this sense, roof should not be perforated.The structure should guarantee sufficient stability to avoid the displacement of the track and should allow the evacuation of rainwater from the roof of the building.The material of the support mechanisms should be adequate to avoid corrosion, taking into account that the track will be installed outdoors.The main design requirements for research purposes are the following: In this section, the track final design will be described. The design of three parts in the track are described next: infrastructure, support mechanisms and rails.39. However, due to the limitations at the location of the track (the roof of an Engineering School and the restrictions established by the University of Seville), metallic tables simply supported on the roof are considered.With the specifications required for the infrastructure, one of the most proper solutions would be the use of a concrete foundation that simulates a slab track40, to provide them with adequate protection against corrosion. There are 47 tables along the circuit. The size of each table has been limited to a maximum length of 2 m to facilitate individual handling. Each structure is bolted with the adjoining ones, forming a continuous chain to assure rigidity and stability. Due to the drainage slopes of the roof, the tables supports are adjustable which allows to compensate differences in elevation and inclination. The average height of the tables is 0.7 m and the higher level of the rail runs at a height of 0.825 m. The advantages offered by this system compared to a system such as conventional ballast or slab scaled tracks are the following: The impact on the roof of the building is minimal. A structure similar to the conventional ones would affect the drainage of rainwater which would increase the risk of leaks in the building.A great reduction on the dead load added to the roof with respect to a concrete foundation is achieved. In this sense, a concrete foundation would add around 630 kg/m versus the 50 kg/m of the proposed infrastructure.The proposed system allows a positioning of the support mechanisms more accurate than any other system, such as the drilling of the concrete foundation, mainly because the positioning and verticality of the drills could be questioned.The method chosen to manufacture the base structure makes the process of moving from 3D-design to manufacturing straightfoward. This makes it easy to obtain complex geometries, as is the layout of the different straight, constant curvature and, specially, transition sections of the track.The design allows pre-assembly tasks to be carried out in mechanical workshops.The geometry and extension of the track could be easily modified by adding or removing tables.Maintenance tasks are also easier than in other systems, as the base structure tables could be replaced in the future if necessary.On the tables, constituted by a structure of electro-welded steel tubes and equipped with adjustable feet, a 6 mm thick steel plate cover is screewed with a series of perforations intended to receive the fastening screws of the support mechanisms that will serve as the support for the rails. Both the structures of the tables and their surfaces are built in hot-dip galvanised steel according to UNE-EN-ISO 1461: 2010Straight section of 20 m length. This section includes the bridge-like structure of 2 meters length.Transition of 3 m length.Section of constant curvature of 26 m length and 24 m radius.Transition of 3 m length.Straight section of 6 m length.Transition of 3 m length.Section of constant curvature of 12 m length and 6 m radius.Transition of 3 m length.Straight section of 12 m length.Given the dimensions of the area of the roof available for the installation of the track, the ideal route that maximizes its length, consists of an open circuit of about 88 meters length constituted by straight, transition, and curved sections, as shown in Fig. Horizontal section of the first 75.91 m.Section with ascending slope of 3.75Horizontal section of the following 2 m.Section with descending slope of 5Horizontal section of 2 m to the end of the track.The track is completely horizontal except for the last 12 meters of straight section, in which a height change of 0.15 m is included. The characteristics of the elevation of the track are specified below: To avoid abrupt changes in slope, vertical transition sections are used, with a minimum radius of curvature of 20 m. That is why the radii of the vertical transition sections should be D1, D2 and D3 according to the standard EN1384832. In addition to varying the geometry of the track and allowing long wavelength irregularities to be reproduced, the support mechanisms can correct possible imperfections in the geometrical layout resulting from the manufacture or installation of the track. The support mechanisms (sleepers) are equidistant 0.1 m in the longitudinal direction while in conventional tracks are equidistant around 0.6 m. The distance between the support mechanisms is greater than what corresponds to the length scaling factor of 1/11.3 in order to facilitate the access and to vary the geometry easily.The support mechanisms serve as sleepers and also let the geometry of the track to include track irregularities in the ranges of The support mechanisms are described below, each part being indicated by a number in parentheses corresponding to the number shown in Fig. Y-lateral direction of ± 0.008 m and in Z of ± 0.008 m  is not scaled since only the railhead profile keeps contact with the wheels. The rail cross-section is shown on Fig. The material used for the rails is AISI 304 stainless steel, milled in a CNC machine. To join consecutive rails, their ends are bevel-cut at 45The scaled track is shown in the upper left corner of the building in Fig. Figure Certain quality controls were carried out after the installation of the scaled track. (1) A study of the response of the track due to vertical and lateral loads, and (2) a track geometry measurement with a topographic equipment to know the real geometry of the track. The obtained results are shown in the following subsections.XX corresponds to the number that identifies the structure  in Fig. Test 3: lateral load on the bridge. Different loads were applied in the middle of the 2-m length bridge and measured with a dynamometer . The results obtained are displayed in Fig. Test 4: vertical load on the bridge. Different masses were placed in the middle on the bridge over the support mechanisms, and the vertical displacement  in Fig. With the different applied experiments, it was observed that the structure does not suffer permanent deformation in lateral and vertical directions. It is also observed that the bridge, which is the least stiff part of the track, experiences a linear trend behaviour in its middle point. Test results support that the rigid track assumption is reasonable. That conclusion is taken after considering the forces and displacements that would occur when a 70 kg vehicle runs on the small radius curve (R = 6 m) with the relatively high velocity of 3 m/s. In that scenario, the centrifugal force is 105 N and the lateral displacement of the vehicle is 3.2 mm if the track is assumed rigid. This value of the lateral displacement is the wheel-rail clearance. If the track is flexible, using the stiffness obtained in the experimental tests, the increment in lateral diplacement due to the track flexibility would be 0.2 mm . For each measured point, the lateral and vertical distance to the theoretical position that each point should have according to the initial design are calculated, in order to determine the initial irregularities that the track has. This experimental procedure is described inA global criterion: The absolute distance from a point to its position in the design geometry should not exceed 0.05 m. This value was selected so that there is a clearance between the track and the surrounding building.D1 level according to EN13848-532), the maximum lateral and vertical distance to the design points should not exceed 2 mm.An irregularity criterion: Upon application to the irregularities obtained from topographic measurements of a 4th order band-pass Butterworth filter, with wavelengths Gauge criterion: the track gauge irregularity, measured with the absolute distance between the internal faces of the rails, should not be less than -1 mm nor greater than 2.5 mm.The criterion established for the track gauge is based on the limits established by UNE-EN 13848-532. In this standard, for speeds below 120 km/h, isolated defects of the track gauge range from The following three criteria are established to evaluate the quality of the manufacturing and installation of the track: 42.Figures This article presents the process of design, manufacture and installation of a scaled railroad track that allows to introduce track irregularities to its reference geometry such as gauge variation, cross-level, alignment and vertical profile. The main advantage of the scaled track presented in this article is that it allows the development of different methods that can be extrapolated to conventional systems. Some examples of these extrapolatable methods which are developed using this scaled track, are the methods that monitor the geometry and detect irregularities that will improve the maintenance of railway tracks, and methods that allow to study the effect of the irregularities in the dynamics of the vehicles. The track is not designed to directly extrapolate the dynamics effects obtained at the scaled size to the full-scaled one. The scaled track allows an easy access to experimental trials under controlled conditions that are not easily accessible on conventional tracks. It is based on design specifications and, based on them, the design carried out is explained. The results obtained after the manufacture and installation of the track are shown in this article. Some studies that can be carried out with the track have been specified. However, it allows the use of more different studies, such as the study of the effect of different fasteners, the introduction of specific short-wavelength surface rail irregularities or the addition of track segments containing switches and crossings. In those cases, simple but new elements designs are required, which shows the broad range of applications of this facility. Various tests are carried out to check the quality of the track; they include load tests in vertical and lateral direction, and the measurement of the geometry of both rails. The load tests have shown that the response of the base structure and the support mechanisms will not undergo permanent deformations for the applied loads and that the stiffness of the bridge, which is the most flexible part of the track, has a linear trend behaviour. Also, test results support that the rigid track assumption is reasonable. In addition, it is shown that the irregularities measured at the track meet the specified requirements.Informed consent was obtained from all participants for the publication of identifying images in an online open-access publication.