The movement in a joint is facilitated by a pair of muscles that pull in opposite directions. The difference in the pair’s muscle force or reciprocal activity results in joint torque, while the overlapping muscle force or the cocontraction is related to the joint’s stiffness. Cocontraction knowingly adapts implicitly over a number of movements, but it is unclear whether the central nervous system can actively regulate cocontraction in a goal-directed manner in a short span of time. We developed a muscle interface where a cursor’s horizontal position was determined by the reciprocal activity of the shoulder flexion–extension muscle pair, while the vertical position was controlled by its cocontraction. Participants made goal-directed movements to single and via-point targets in the two-dimensional muscle space, learning to move the cursor along the shortest path. Simulations using an optimal control framework suggest that the reciprocal activity and the cocontraction may be controlled independently by the CNS, albeit at a rate orders of magnitude slower than the muscle’s maximal activation speed. A muscle pair can also pull against one another or cocontract by arbitrary amounts that result in zero net joint torque. We define cocontraction to be the overlapping muscle force between the flexor and extensor muscles.The human arm has several joints, wherein each joint is, at the very least, controlled by a pair of muscles that pull in opposing directions. Joint torque arises from the difference in the activity of a muscle pair, defined as the 2, to move the hand accurately along a designated path4, and to stabilize the hand’s motion when it is deviated by unpredictable external forces6. The arm’s cocontraction also increases during impacts like when catching a falling object7 or striking a wall8. These increases in the cocontraction serve to augment the arm’s stiffness9, a mechanical property that restores the hand’s position to its unperturbed location without sensory delay. It is particularly useful when the brain cannot react fast enough to the unpredictable environment owing to the delays in proprioceptive or visual feedback.The central nervous system (CNS) knowingly increases the arm’s cocontraction to accurately control the hand’s position during motion. Studies have reported an increase in the arm’s cocontraction at the end of a movement to stop the hand at a smaller target10, but found that the coordination of the arm’s cocontraction between two joints was limited11 and could not be sustained10. Another study found that the cocontraction in the wrist could be controlled to a desired level set by the experimenter12. These studies only tested how the CNS could maintain the cocontraction at a designated constant value, and did not require the participants to modulate their cocontraction to different values in a short span of time. Thus, it is unclear to what extent the CNS can actively control the cocontraction to increase it or decrease it rapidly towards designated values.The participants in the above-mentioned studies controlled their cocontraction to stabilize their arm to fulfil a task; the control of the cocontraction in itself was not the goal, and the participants received no feedback of their cocontraction to control it actively. Some studies have provided visual feedback of the arm’s cocontraction or stiffness to examine whether the CNS can actively control it. One study examined participants who exerted a static force in two dimensions while simultaneously controlling the arm’s stiffness13. Taking the example of catching a ball with the wrist, the CNS need only sustain a minimum threshold of cocontraction to keep the wrist’s position stable when the ball comes in contact with the hand. In such interaction tasks, there is no cocontraction target, but only a threshold to guarantee a successful catch. Additionally, the CNS may struggle to concurrently control reciprocal activity and cocontraction. When exerting a large RA to produce a big joint torque, the antagonist muscle also activates to stabilize the joint14, necessarily increasing the cocontraction. Thus, decreasing cocontraction while increasing RA should prove challenging for the CNS.The active control of cocontraction may be difficult for the CNS as most tasks require only a minimum threshold of cocontraction, and not a specific value per seIn light of this gap in the literature, this study investigates the proficiency of the CNS in actively regulating the cocontraction and the reciprocal activity simultaneously on short time scales, and to examine how the CNS executes the motor plan in muscle space. To test the CNS’ proficiency at regulating RA and cocontraction, we developed a muscle interface where a two dimensional cursor was controlled by shoulder cocontraction along the vertical axis and shoulder RA along the horizontal axis. Participants made goal-directed movements using our muscle interface. A computational simulation using an optimal control framework was used to assess whether the reciprocal activity and the cocontraction were controlled using a strategy to minimize the muscle activity needed to reach the targets in the muscle space.8 right-handed male participants , who all gave written informed consent prior to the experiment, participated in the study, which was approved by the Ethical Review Board for Epidemiological Studies at the Tokyo Institute of Technology. All research was performed in accordance with the relevant guidelines and regulations.The participants were seated facing the KINARM planar robotic manipulandum from BKIN Technologies Fig. a. ParticTwo wireless EMG sensors  were placed on the shoulder flexor  and the shoulder extensor (posterior deltoid). The raw signals from the electromyography sensors were high-pass filtered at 10 Hz, rectified and low-pass filtered at 1 Hz. A second-order Butterworth filter was used for both the high-pass and low-pass filters.In the point-to-point reaching task, participants had to reach and stop at one of either five targets {(i), (ii), (iii), (iv), (v)} Fig. b. One blParticipants were instructed to reach and stop inside the target circles. In the via-point task, they were instructed to pass through the via-point prior to reaching and stopping at the second, final target position. The radius of the final target was 3 cm on-screen while the via-point’s radius was 0.5 cm. The cursor’s velocity had to be below 10N/s and inside the target circle for the trial to succeed, which prevented participants from completing the movement by passing through the target at a high muscle activation rate.R2 = 0.81 ± 0.02.Prior to the main experiment, the filtered EMG was normalized by asking participants to exert a 10N tangential force against the robot using the flexor or the extensor muscle alone 10 times per muscle. Visual feedback of the tangential force was provided continuously to the participant such that they exerted the force using the correct muscle. The data when the measured tangential force t is the time, In the main experiment, the force from each muscle was estimated using,t is the time, and the shoulder cocontraction, defined as the minimum force of the flexor and extensor muscles Participants controlled a cursor’s , and where The control command q is a free parameter whose influence on the simulated RA and cocontraction is examined in greater detail in the next subsection. To simulate the point-to-point movements, the via-point cost matrix The control cost matrix is J isThe control command that minimizes the cost functional Once the control policy is computed, the system is simulated forwards in time by iteratively computing Eq. .τ and q that influence the time-series of the simulated RA and simulated cocontraction in different ways. We systematically observed how the simulated muscle activity time-series changed with each parameter by modifying each parameter while the other was kept constant.The simulation has two free parameters In the simulations of Fig. q described above, and calculated the coefficient of determination q that minimized To identify the parameters that best explained the behavioral data, we simulated the RA and the cocontraction in the two-dimensional parameter space using the ranges of Motor learning of the muscle interface would be exhibited in how the cursor’s trajectory changed as a function of the block number. Figure p = 0.003) and a significant effect of the target  = 24.3, p < 0.001); the interaction between them was also significant  = 4.5, p = 0.006). Post-hoc comparisons using Tukey’s HSD revealed that the trajectory length when reaching targets (ii) (p < 0.001) and (iii) (p < 0.001) shortened with the block number. This learning effect was only observed for targets that required cocontraction, and not those where pure flexion (p = 0.99) or pure extension (p = 0.99) were needed. These results suggest that regulating either flexion or extension alone required little to no learning, while the concurrent control of reciprocal activity and cocontraction benefited from practice.To quantify motor learning, we calculated the trajectory length in each trial, which is charted as a function of the block number Fig. d. The trFigure p = 0.2), but the trajectory did become significantly shorter with the block number  = 5.9, p < 0.046); the interaction between the factors was insignificant  = 1.2, p = 0.3). Thus, participants moved a shorter distance to fulfil the via-point reaching task, but the specific combination of increasing or decreasing RA and cocontraction did not influence the difficulty of the via-point task.Next, we examined the data from the via-point reaching task. Four representative participants’ cursor’s trajectories from the final phase of the via-point reaching task are charted in Fig. p = 0.08), suggesting that the timing of passing the via-point was not dependent on the via-point target.The time-series of the estimated muscle force from the shoulder flexor and extensor muscles Fig. d revealeτ determines the maximum rate at which the simulated RA and the cocontraction can be changed, corresponding to the cut-off frequency of a second-order filter. The weight on the state cost q penalizes the deviation in the simulated RA and cocontraction from the target values at the end of the movement (and at the time when passing through the via-point in the via-point task). We varied each of these parameters while keeping the other constant, and calculated the variance of the RA and the cocontraction explained by the simulation R2 (see Methods for details). For brevity, we only show the simulated RA in reaching the point-to-point target (i) when examining the effect of each free parameter on the time-series of the activity in the muscle space. However, all the point-to-point and via-point targets were simulated when calculating R2.We developed a computational model of the reaching task based on an optimal control framework in the muscle space to determine whether the RA and the cocontraction were independently controlled by the CNS, and to examine how fast the CNS was able to modulate the activity in the muscle space to reach the targets. The simulated RA and the cocontraction were modelled as a damped system with independent control inputs that regulated the rate of change of the RA and the cocontraction. The flexor and the extensor activity were not simulated. The model has two free parameters that change the time-series of the simulated RA and cocontraction in different ways. The time constant R2 increased with a greater time constant, but peaked at The time-series of the simulated RA for different values of the time constant are charted along with the empirical data for comparison Fig. a. R2 incq is plotted in Fig. q. When q is too small the controller is unwilling to increase the muscle activity to minimize the difference between the simulated and the target RA at the end of the trial due to the running cost of the control inputs.The time-series of the simulated RA for different values of the weight on the state cost We then conducted simulations in the 2D parameter space, and found that the values of the free parameters that yielded the greatest To examine the ability of the CNS to concurrently control the cocontraction and the reciprocal activity, we developed an interface that mapped a cursor’s movement in two dimensions where the horizontal axis was controlled by RA and the vertical axis was controlled using cocontraction. Muscle activity alone was employed to control the cursor’s position, which was used to reach point targets in the two-dimensional muscle space. The length of the cursor’s trajectory decreased with the block number in the point-to-point reaching task, suggesting that as participants grew familiar with the interface, they gradually decreased the distance travelled by the cursor in reaching equidistant targets. No decrease was observed when solely flexion or extension sufficed to reach the target, indicating that the motor learning occurred primarily in controlling the shoulder cocontraction.17, or a time constant of 0.04 s. The fastest our interface could be controlled was at 1 Hz due to the low-pass filtering of the EMG when estimating the muscle forces. Our results were best explained by a time constant of 5.5 s, corresponding to a cut-off frequency of 0.03 Hz, significantly lower than the maximum rate of 1 Hz which was possible using our interface. This is a limitation of our model, as we had to tune the time constant determining the muscle dynamics, rather than taking the 1 Hz value used in the actual muscle interface.By modifying the time constant of the muscle activity in the simulation, we determined the rate at which the RA and the cocontraction was controlled by our participants. The muscles in the arm can be modelled as a mechanically damped system with a cut-off frequency of 4Hz16 and fatigue18, which could have reduced the participants’ ability to control their RA and the cocontraction. Furthermore, our muscle model is limited at explaining the data as it did not consider signal-dependent noise19 when controlling the RA and the cocontraction. Signal-dependent noise can punish the controller to avoid rapid changes in the muscle space, and may also lower the effective time constant of the muscle activity needed to explain the data20.The large time constant could be due to a number of factors. As the participants rely purely on visual feedback to control the cursor’s position in the muscle space, this could have limited the rate at which the RA and the cocontraction could be controlled. The control in the muscle space could also be slower due to the normalization of the filtered muscle activity, which was linearized prior to the main experiment. The linearization can break down with greater muscle activity12, or to maintain a constant joint torque while modulating the stiffness21. In contrast, our task required simultaneous changes in both RA and cocontraction to reach a target in the muscle space, resembling two-dimensional reaching tasks that have been extensively examined in the field of motor control22. Due to this resemblance with previous studies on reaching movements, we used an optimal control framework commonly used in reaching studies to simulate the control of the RA and the cocontraction15. The control of the RA and the control of the cocontraction must necessarily be independent in the model to explain the data. Our participants were able to reach the point-to-point targets that required only the RA, suppressing cocontraction, and could also increase the cocontraction with nearly null RA. Our model suggests that the participants may have minimized a cost functional used commonly in the motor control literature, wherein the deviation from the target’s position at the end of the movement and the running cost of effort are minimized.To our knowledge, our task is unique in exploring the active control of cocontraction. Related studies in the literature asked participants to maintain either a fixed value of stiffness or cocontractionThe ability to modulate the RA and the cocontraction independently of one another raises the interesting possibility of an additional control input for human–computer interfaces. The cocontraction in the joint could be used as an auxiliary control input to augment human motor function e.g., using the shoulder cocontraction to rotate a platform during soldering. However, the muscle interface in its current form may be too slow to meaningfully control a device. To be viable as a novel human–computer interface, further innovation is needed to boost the rate at which the muscle interface can be controlled.


Erectile dysfunction (ED) is a disorder that affects 152 million men worldwide, and this number is estimated to reach 322 million by the year 2025 . In IPP We aim by this article, to describe a simple surgical technique for the removal of penile prostheses, that avoids the penoscrotal incision and its associated complications. It was developed by an expert andrological team with 10 years’ experience in the domain and became the standard technique at our institution.Between November 2015 and February 2019, 15 patients underwent IPP removal using the same technique, by the same surgical team. Indications for removal were divided into infectious in 12 patients (80%), and non-infectious in 3 cases (20%) related to an unsatisfactory result, patient discomfort or device erosion. The former group had the prosthesis removed between 2 and 36 days from the onset of infection after the failure of conservative treatment. Voluntary removal of the device was performed 10 days after its implantation in the three patients. The demographic characteristics of the patients are detailed in Table After obtaining the patient’s consent, general or spinal anesthesia is applied. The patient is placed in a supine position, and an indwelling urinary catheter is inserted. The skin is shaved and prepped with an alcoholic-iodine solution. A 2 cm transverse incision is performed at each side at the ventral base of the penis Fig. a. A corpBroad-spectrum antibiotics are administered intravenously. We use amoxicillin with clavulanic acid or a fluoroquinolone depending on the patient’s associated risk factors. Pain management is provided during 2 to 3 days of hospitalization. Daily wound care is applied by the injection of a mixture of normal saline and iodine solution in the corrugated drains, followed by normal saline irrigation. The drain is mobilized exteriorly 1 to 2 cm each day starting from the second postoperative day and depending on the secretions. The previously described points are continued at home with a trained nurse whenever the infection is controlled and the patient is ready for discharge. After complete removal of the drains, open wounds at their corresponding sites are left to heal by secondary intention. A close follow up is necessary to examine the healing wounds and to adapt the antibiotics when necessary. The non-absorbable skin sutures are removed 7 to 10 days after the procedure. If distant re-implantation is anticipated, it is best done 2 to 3 months after the resolution of the infection, and the patient is given tadalafil 5 mg daily until the procedure.We think that avoiding the bigger incision needed to remove all the components through the peno-scrotal incision leads to an easier reimplantation procedure, however we did not study the re-implantation results in our patients.The duration of the surgery ranged between 35 and 48 min with a mean of 41 min. All procedures were completed successfully with a smooth course. None of the patients had any residual component of the IPP at the end of the surgery. Neither complications  nor excessive bleeding (> 100 mL) were documented in all patients  that may impair future insertion of IPP. It is simple, safe, reproducible and easy to be performed by junior or unexperienced urologists in urgent cases. Further data and studies are required before the application of this technique as a standard method of removal of an IPP.


This study presents a technique to identify the vibration characteristics in power transmission towers and to detect the potential structural damages. This method is based on the curvature of the mode shapes coupled with a continuous wavelet transform. The elaborated numerical method is based on signal processing of the output that resulted from ambient vibration. This technique benefits from a limited number of sensors, which makes it a cost-effective approach compared to others. The optimal spatial location for these sensors is obtained by the minimization of the non-diagonal entries in the modal assurance criterion (MAC) matrix. The Hilbert–Huang transform was also used to identify the dynamic anatomy of the structure. In order to simulate the realistic condition of the measured structural response in the field condition, a 10% noise is added to the response of the numerical model. Four damage scenarios were considered, and the potential damages were identified using wavelet transform on the difference of mode shapes curvature in the intact and damaged towers. Results show a promising accuracy considering the small number of applied sensors. This study proposes a low-cost and feasible technique for structural health monitoring. Continuous health monitoring of transmission networks is a vital task to prevent sudden failure in power transmission lines. The substations and transmission lines transmit the electricity production of the power plants through various physical, atmospheric, and geographical conditions to the consumption centers. Performance of the transmission lines is sometimes affected negatively by some factors, which may disrupt the power distribution network. Such incidents may cause irreparable damages. The cost of repairing the power transmission lines is very high, at about one million dollars per kilometer . Such toDespite several studies that have studied the vibration characteristics of towers under earthquake and wind loads , the heaIn the present study, a vibration-based technique is presented to identify the spatial location of existing damage in the power transmission towers. An important advantage of this method is that it is a cost-effective method using limited number of sensors compared to other damage detection techniques. This method is based on post-processing the structural responses under ambient vibration .An existing tower was used as case study. First, it was analyzed using a finite element model developed in the SAP2000 software, and the vibration information  were extracted. Next, they were verified through conducting a field measurement test. Finally, in order to simulate a more realistic field condition, a 10% noise was added to the structural responses. To optimize the number of required sensors, a method based on minimizing the non-diagonal entries of modal assurance criterion (MAC) matrix was used. Free vibration response of the structure for all the sensors was obtained using the natural excitation technique (NexT) . SubsequThe structure of the paper is as follows: The first section of literature review, Montejo  comparedDitommaso et al.  proposedGhiasi et al.  presenteKarami-Mohammadi et al.  proposedOn the other hand, there are only a few studies on the application of damage detection techniques in power transmission equipment. According to Qu et al. , power tQu et al.  presenteThis study aims to implement a cost-effective procedure to identify the location of damage in the power transmission towers. The optimum number of sensors, as well as their location is determined by minimizing the non-diagonal entries of the MAC matrix. Subsequently, the modal parameters of the structure will be determined by processing the output signal of the tower under ambient vibration. As a result of structural damage, the vibration anatomy of the towers changes. The proposed method computes the differences between curvature of the mode shapes in the intact and damaged structures. Finally, by implementing the continuous Wavelet transform on residual of the curvature of the mode shapes, the damage location is determined. Since the essence of the proposed procedure is founded on the concept of CWT, a brief theoretical background is presented in this section for those readers less familiar with this topic. The underpinning theory of wavelets is connected to continuous wavelet decomposition of unctions ,27.a is the scale parameter, b is the time location, and a and b. Also, If a and b vary continuously.The CWT of the signal Gaussian, Morlet, Mexican Hat, and Shannon wavelets are models in which the wavelet function, Meyer wavelet is an infinity regular wavelet. It does not have an explicit expression form, but the scaling function does exist, and using DWT is possible (FWT is still unavailable).N, Symlet wavelets of order N, Coiflet wavelet of order N, and Haar wavelet are examples of orthogonal wavelets. They do not have an explicit expression for the wavelet function Daubechies wavelets of order Wavelet functions are divided into two groups: orthogonal and non-orthogonal ones. In dyadic Discrete Wavelet Transform (DWT), as well as the wavelet packet transform, one should select the orthogonal wavelet function. On the other hand, using CWT, one can select either orthogonal or non-orthogonal wavelet functions. Some of the most well-known orthogonal wavelets are: Haar, Daubechies, Coiflets, Meyer, etc . Furthert is time and According to this classification, the mother wavelet to be operated in CWT may or may not take the orthogonal wavelet form. Any signal that satisfies the admissibility condition can be used as a mother wavelet. In this study, two different mother wavelets were adapted, i.e., Morlet and Dibucci. The former one was used to identify the modal parameters of a tower with the following form:a as dilation and b as translation, a son wavelet can be written as:By introducing two new variables: Clearly, it is a cosine signal that decays on both sides by the exponential term. For a digital signal, the sampling rate follows the Nyquist sampling theory; generally the sampling rate can be considered high enough. Then, it will have enough time resolution if the translation unit is equal to the sampling period. It is notable that in Morlet wavelet, parameter Daubechies wavelets are defined by calculating the running averages and differences via scalar products with scaling signals and wavelets. Since the Daubechies wavelets use overlapping windows, the high frequency coefficient spectrum reflects all high frequency changes. It can be used as a proper wavelet to detect the high frequency jumps that occur because of damage in a response signal . TherefoThe cubic spline interpolation was introduced as an engineering tool used to draw smooth curves through a number of points. The cubic spline contains a series of weights attached to a flat surface at the points to be connected. A flexible strip is then bent across each of these weights, approaching a delicately smooth curve. The basic idea of the cubic spline was based on fitting a piece-wise function in the following form:A cubic spline needs to satisfy the following stipulations: (1) The piece-wise function de shape . ConsequThe case study structure was a representative tower out of many, which is installed in the 400 kV line of Bandar Abbas-Sirjan route. This tower was known as S1KL in the power industry. The height of the tower was 46.32 m, see The tower was modeled in the SAP2000 finite element software, see The results of the numerical model were further verified by an ambient vibration test of the real tower. The accelerometers used in this experiment were Novinpardaz sensors with a sensitivity of 0.01 g. These sensors were first calibrated by measuring the natural frequency of the benchmark frame as shown in A parametric study was conducted to investigate the effect of the interaction among multiple towers in-line. For this purpose, the fundamental frequency of a single tower was compared with a series of towers , see First, all the possible locations at which the sensors could be placed were identified .Second, the modal analysis was conducted, and the mode shapes of the structure were obtained for the identified nodes. Next, five intended sensors were placed in locations where the mode shapes have maximum linear in-dependency. In other words, the sensors were placed in such a way that the non-diagonal entries of the MAC matrix approach a minimum value . For thiThis procedure was repeated iteratively for the remaining sensors until the best arrangement was found. Eventually, the optimal location for the sensors was obtained as shown in Since the main objective of this paper was to minimize the number of sensors, the optimal placement of those instruments was very important to obtain the mode shapes of the tower. The team decided to use only five sensors in this research. The small number of sensors was selected based on two objectives: (1) economical constraints and (2) efficient coverage of the entire tower body in case of potential damage. The following steps were followed to find the optimal location:A Gaussian white noise signal was used as an input excitation for the tower. It was a random signal with equal intensity at different frequencies, giving it a constant power spectral density. In other words, a white noise signal had an equal energy at different frequencies . In ordeUsing the random decrement technique (RDT)  and estaExecution of CWT on the free vibration obtained in the previous section provides the wavelet coefficient contours in terms of time and scales coefficients. In this section, we detail how a complex Morlet wavelet was utilized with a central frequency of 4.57 Hz. For instance, Next, the natural frequency and the corresponding modal damping ratio was computed using the Hilbert transform on the free vibration response of each mode. First, the Hilbert transform of the free vibration corresponding to each mode was calculated.Second, the amplitude and phase of the envelope signal (from previous step) was obtained.Third, the slope of amplitude signal was calculated which leads to Finally, the fundamental of structural dynamics was applied to find For instance, in order to determine the first and second natural frequencies and the corresponding modal damping ratios , one should utilize the scaling of 1400 in wavelet coefficient of sixteen-seconds signal for the first mode, and the scaling of 750 in wavelet coefficient of four-seconds signal for the second mode as shown in As it is stated in The same procedure can be implemented to obtain the second mode properties. According to In order to obtain other modal parameters of tower (for other direction), a similar approach should be taken. The information recorded by sensors  usually contains some level of noise. Signal-to-noise ratio (SNR) is defined as the ratio of signal power to the noise power, and is often expressed in decibels (dB). A ratio higher than 1 (more than 0 dB) indicates more signal than noise :(7)SNR=2To simulate a real-world environmental condition, an artificial noise signal should be added to the structural response. In this study, a 10% noise was added to the structural response of tower. This value was at the upper bound value usually used in the literature . Table 3ith mode shape of the structure at the pth degree of freedom. Similar interpretation for pth and qth degrees of freedom at time In this section, a method proposed by Yang et al.  is adaptpth and qth DOF and ith mode. pth and qth degree of freedom at time The authors of Yang et al.  proposedSo far, the previous equation determines only the absolute value of mode shapes. In order to obtain the sign of the mode shape entries the following relations are suggested:Using the above relations, one can determine the mode shape matrix entries based on free vibration response of those modes with significant participating modal mass. ith height step, and The proposed damage detection procedure is founded on the curvature of mode shapes and the CWT method. First, the curvature of the mode shapes in the intact and damaged structures is calculated using the following relation :(11)ϕi″=Normally, a large number of data are required to obtain the curvature of mode shapes. However, this study aims to use only five data points associated with the sensor’s output, and subsequently only five mode shape values were available. To overcome this problem, cubic spline function was used in MATLAB  to generScenario #1; Leg: Stiffness of 12 members of the leg is reduced (in X direction). In order to perception the severity of damage, one can compute the ratio of the damaged element to the total number of elements of the tower. For instance, in this scenario: 12/1978 = 0.61% of the tower’s elements have been damaged,Scenario #2; Trunk: Stiffness of the top members of the trunk is reduced (in X direction),Scenario #3; Body: Stiffness of the main elements of the body  is reduced (in Y direction), andScenario #4; Bridge: Stiffness of the diagonal members of the bridge is reduced (in X direction).In order to verify the proposed procedure, four damage scenarios are defined as follows:Scenario #1: According to Scenario #2: According to Scenario #3: According to Scenario #4: According to For all damage scenarios, In the method proposed by Xu et al. , a totalAs it can be inferred from the results of the present study, the proposed method efficiently detects the damage (both in bottom and top elements). However, it is recommended that in order to make a more reliable decision, this method should be implemented in conjunction with an expert visual inspection. It aims to verify the results obtained through the proposed method by comparing them with physical changes occurred in the structure.In this study, a unique technique based on the curvature of the mode shapes along with continuous wavelet transform is presented to detect the potential damage location in the power transmission tower structures. The developed numerical model in this study is based on information provided by the electrical company responsible for the construction of the tower. This numerical model was verified through modal testing of the actual tower. In order to minimize the number of sensors, which eventually leads to a lower cost of the field measurements, a method based on minimizing the non-diagonal entries of the MAC matrix was used. This method led to the usage of only five sensors through out the height of the tower.The proposed method in this study is based on signal processing of the structure under ambient vibration. In order to simulate the realistic condition of the measured structural response in the field condition, a 10% noise was added to the response of the numerical model. Utilizing the Hilbert–Huang based method, the dynamic characteristics of the tower was identified. The mode shapes were computed based on the method developed by Yang et al. . Four daFinally, by applying CWT to the residual curvature of the intact and damaged structures, the summation of the wavelet coefficient in terms of the scale parameter was determined along the height of the tower. This study showed that the damage scenario #1 to #3 were easily identifiable utilizing the first two mode shapes. However, this was not the case in the scenario #4, which shows the damage using only the second mode shape.The authors suggest performing further experimental and numerical simulations for towers with different sizes and element configurations. The experimental model could be in the form of small-scale laboratory model to identify the damage location. A sensitivity analysis is also required to understand the accuracy of the damage detection method as a function of number of sensors. This further can be coupled with costs associated with damaged sensors to provide the resiliency of the system.


Most in vitro test systems for the assessment of toxicity are based on endpoint measurements and cannot contribute much to the establishment of mechanistic models, which are crucially important for further progress in this field. Hence, in recent years, much effort has been put into the development of methods that generate kinetic data. Real time measurements of the metabolic activity of cells based on the use of oxygen sensitive microsensor beads have been shown to provide access to the mode of action of compounds in hepatocytes. However, for fully exploiting this approach a detailed knowledge of the microenvironment of the cells is required. In this work, we investigate the cellular behaviour of three types of hepatocytes, HepG2 cells, HepG2-3A4 cells and primary mouse hepatocytes, towards their exposure to acetaminophen when the availability of oxygen for the cell is systematically varied. We show that the relative emergence of two modes of action, one NAPQI dependent and the other one transient and NAPQI independent, scale with expression level of CYP3A4. The transient cellular response associated to mitochondrial respiration is used to characterise the influence of the initial oxygen concentration in the wells before exposure to acetaminophen on the cell behaviour. A simple model is presented to describe the behaviour of the cells in this scenario. It demonstrates the level of control over the role of oxygen supply in these experiments. This is crucial for establishing this approach into a reliable and powerful method for the assessment of toxicity. The reasoning for this demand is diverse but several points are crucial in this context: Tests based on animals do not fully reflect all the aspect of human nature, animal tests are expensive and the throughput achievable is rather small5. Finally, ethical concerns have a growing impact on the overall discussion of this subject. This is widely acknowledged and as a result, enormous efforts have been made in recent years to develop methods that do not only give meaningful results but are robust in order to enable a thorough validation. The bulk of recent work has been dedicated to two key components, the cell models9 and the formats of the reactors12, the cells are implemented in. The former is motivated through the necessity to use cells that mimic essential functional details of the related tissue or organs. The format of the cell reactor must enable three major functions: Firstly, it has to provide an environment that is able to maintain status and the vitality of the cells. Secondly, the fluidic system should ensure the supply of medium, the availability of important soluble molecular factors and the controlled immersion of cells with the compounds of interest. Thirdly, access of powerful characterization methods to the cells is crucial for a detailed analysis of their behaviour. In this context, two approaches must be distinguished: Invasive characterization methods are much in use. Although they may provide detailed information about the response of cells, this information describes only a singular point in time and hence it is difficult and/or tedious to elucidate processes that evolve in time. A complementary approach is based on continuous noninvasive monitoring of parameters that are closely related to cell behaviour. This approach produces an abundance of data. Some cases have already been reported in which it helped to decipher cellular mechanism hardly accessible to conventional endpoint measurements, however its value for replacing well established and validated in vitro test formats has still to be demonstrated14.Presently, there is a great demand for in vitro test systems for the elucidation of the mode of action of drug candidates and in particular for the assessment of toxic effects of compounds15. By making use of the advancements of microtechnology in recent years, the focus of this approach lies in optimising the microenvironment of the cells on the chip in order to mimic important features of the human physiology. This comprises the fluidic supply on one hand and on the other hand the establishment of microstructures that can guide the growth of specific tissue-like cell assemblies18. Considerable progress has already been achieved in this respect. Sophisticated fluidic infrastructures do not only supply the cells with precise amounts of medium, signal molecules and compounds to be tested, they also connect cells of different origin and thereby allow the emulation of the exchange of signals between different organs in the human body19.A very prominent part of work in the field is dedicated to the development of so-called organ-on-a-chip devices20. This problem has been mainly addressed using electrochemical methods so far, for example, for monitoring pH or changes of glucose concentration in the medium22. However, these methods are very difficult to implement and are particularly prone to drift of signals and to interference with the many charged entities present in complex biological samples. However, recently it has been demonstrated that long term monitoring of changes of oxygen and lactate concentration caused by the metabolism of single spheroids can be reliably measured23.Despite all these advances, there remain considerable challenges when it comes to the analysis of cell response and development in real time in order to gather quantitative information on these processes25. The advances in employing optical methods for measuring oxygen and related parameters has been substantial over recent years 27. Here we present results that are obtained from real time monitoring of the oxygen consumption of hepatocytes of three different origins using a robust optical detection scheme. The oxygen consumption of the cells is a measure of their metabolic activity and provides crucial information on the vitality of the cells28. The method employed here exploits the oxygen sensitivity of the emission of Ruthenium-Phenanthroline29. The chromophore is immobilised into polymer beads, which provide a very stable matrix. The phosphorescence lifetime of the chromophore is directly related to the local oxygen concentration and can easily be measured using intensity modulated excitation light and a phase sensitive detection scheme. As the signal does not depend on the phosphorescence intensity, the requirements in respect to optical alignment and precision are rather relaxed enabling a very robust measurement scheme. In our reactor, cells and sensor beads are placed into small wells where they are immobilised using a collagen matrix. By carefully controlling the oxygen supply through the medium, the number of cells that consume oxygen and the locations of sensor beads in respect to those of the cells, the dynamic range of this measurement regime can be fully exploited for monitoring the metabolic activity of cells. This approach also enables us to adjust oxygen concentrations that correspond to the physiological conditions in the liver. We do not aim at an utmost miniaturisation with this system, simply because a sufficient number of cells are needed to consume sufficient oxygen and hence we consider our system to be a reactor rather than an organ-on-a-chip. It has been shown that this approach can provide important information on the cellular response of the hepatocyte cell line HepG2 to the exposure to various drugs or compounds known to be hepatotoxic. In the case of the broadly used analgesic and antipyretic acetaminophen, the measurement of oxygen uptake as a function of time revealed two independent time constants indicating for the first time that besides the well-described CYP-dependent toxin mechanism of action a direct mechanism of action on the mitochondrial respiration is present13. The highly controlled perfusion of the cells in this reactor allows to maintain cell viability to more than 4 weeks14.Optical sensors for the measurement of oxygen concentrations provide a valuable alternative to electrochemical methods and offer a number of unique features when it comes to the monitoring of cellular processes30. CYP3A4 is considered to be the most important enzyme in drug metabolism. It metabolises approximately 50% of all clinically used drugs. However its role in metabolising acetaminophen seems to be less prominent in comparison CYP2E1 and CYP1A231. Finally, primary cells from mice are also included as we suppose that their CYP expression exceeds the ones of the cell lines used. Hence, we can make use of three cell types that all show different levels of metabolization of acetaminophen. In addition, the primary cells are known to have a considerably higher oxygen consumption rate, providing us with an additional parameter to vary for characterising our system. In an effort to ensure a high level of control over the microenvironment of the cells, an improved version of the microbioreactor introduced recently has been employed.In this work, we explore and identify conditions in which optimal use of oxygen microsensor beads for the monitoring of oxygen consumption of small cell samples can be made. In particular, in this contribution we focus on the investigation of how cells respond to their exposure to various concentration of acetaminophen when different levels of oxygen supply are present. For this, we employed hepatocytes, the most important cell type for the assessment of toxicity of compounds, from three different sources: The cell line HepG2 is a widely used test system but shows a rather small capability to biotransform drugs in respect to primary hepatocytes, which limits its relevance for toxicity tests. The cell clone HepG2-3A4 overexpresses the enzyme CYP3A4 in comparison to HepG2 parental cellsEach microreactor consists of a cell carrier with three channels, which are open towards the top and are 20 mm long, 0.6 mm high and 2 mm wide. These allow the examination of three different measuring conditions on one unit. Three microcavities per channel are embedded in the channel bottom with a diameter of 1.5 mm and a height of 0.3 mm. The cell carriers were fabricated by soft lithography using the elastomer PDMS , which were moulded in casting stations and cured for two hours at 90 °C. The bottom of the cell carrier was sealed with a cover glass to prevent gas exchange from the environment to the liquid in the microchannel. To bond the cell carrier to the PMMA channel plate, double-side adhesive tape  was used. The PMMA channel plate was fabricated by milling and connects the microchannels to the tubing  via ¼” threads and fluidic adapters .l-glutamine .HepG2 hepatocytes  were cultivated in DMEM containing HEPES (25 mM), FCS (10%), penicillin/streptomycin (1%) and 30 the medium of HepG2 was modified by supplementing 3 µg/ml blasticidin . Both cell lines were cultured at 37 °C and 5% CO2. For subculture, the cells were rinsed twice with PBS and incubated with 0.25% Trypsin/EDTA  for 7 min at 37 °C.For cultivation of HepG2-3A4 32. Briefly, the liver was first perfused with calcium- and magnesium-free Hank's balanced salt solution containing 1 mM EDTA followed by a perfusion with Hank's balanced salt solution containing 0.016 mg/ml Liberase . Hepatocytes were separated from non-parenchymal cells and debris by density centrifugation with 58% Percoll in phosphate buffered saline.Primary mouse hepatocytes were isolated from C57/BL6 mice as described previouslyThe principles of laboratory animal care were followed. Treatment of the animals followed the German animal protection laws and was performed with permission of the state animal welfare committee .6 freshly trypsinized or isolated cells were centrifuged for 5 min at 300×g. Afterwards, the supernatant was removed and the cells were resuspended in 15 μl of ice-cold solution of collagen type I  and 100 µg CPOx-Beads . 0.8 µl of the cell/bead suspension were pipetted in each cavity of the ice cooled cell carrier to achieve a cell concentration of 1 × 105 cells per cavity for HepG2 and HepG2-3A4. The primary mouse hepatocytes were seeded into cavities directly after isolation. In contrast to the cell lines, the cell number of primary mouse hepatocytes had to be adjusted to 3 × 104 cells per cavity due to their high oxygen consumption rates. To alter the amount of cells per cavity, we have regulated the cell concentration with different amounts of collagen. The cell carrier was then incubated for 8 min at 37 °C to polymerize the collagen. Afterwards the cell carrier was ready for connection to the PMMA channel plate. Oxygen measurements were started approximately two hours after seeding.4 × 10https://www.originlab.com).For real-time oxygen detection, an OPAL  was connected to a fully automated Olympus microscope . The 532 nm LED of the OPAL and a filter cube with 531/40 nm (excitation), 607/70 nm (emission) were inserted in the optical light path during measurements. This setup allows quantifying the oxygen concentration via lifetime-based luminescence quenching of a ruthenium-phenanthroline-based phosphorescence dye loaded in microbeads (CPOx-50-RuP). The oxygen measurements were performed by averaging ten seconds exposures of sensor beads in each cavity using a 20 × objective. The cavities were measured consecutively using an automatic routine. All time course experiments were repeated at least three times. The measurement data was further processed and graphically displayed using OriginPro 2015G, 64-bit . The syringes were connected at the outlets of the reactor. Two medium reservoirs were connected to each reactor channel via electrically controllable valves , one reservoir contained medium and the other medium with acetaminophen . The syringes pulled the medium out of the target reservoirs at a flow rate of 20 µl/min in order to supply the cells continuously with oxygen-rich medium. To study the effect of APAP on hepatocytes, the cells were exposed to 0, 1, 4, 8, 12.5, 16 mM for 12, 24 or 48 h. Before and after APAP exposure the cells were continuously supplied with medium. To ensure optimal cell culture conditions, the microreactor and the medium reservoirs are placed into a microscope climate chamber .Figure 33. The resulting altered gene expression can have a major influence on cell metabolism and thus on oxygen consumption.The time course of oxygen concentration in a well filled with primary cells is depicted in Fig. Figure The next phase of the cellular response is dominated by less conspicuous behaviour. In the case of HepG2 and HepG2-3A4 cells at low drug concentrations (1 mM and 4 mM) after a decrease of oxygen uptake the curves again approach the baseline after a few hours. High concentrations of drug cause either no change or moderate rates of increase of oxygen levels during this period of the time course. The primary cells behave somewhat different.13.Oxygen uptake decreases constantly in this part albeit not as fast as during the initial phase. When acetaminophen is withdrawn from the medium some levels of fast recovery occur in nearly all cases (|2|). Only when the primary cells are exposed to 16 mM acetaminophen no recovery is visible. In this case, all cells in the well seem to have died, in accordance what has been reported in previous workN-acetyl-p-benzoquinone imine (NAPQI) which damages or deactivates proteins and affects the mitochondrial respiration of the cell eventually leading to apoptosis and necrosis. The three key enzymes metabolizing acetaminophen are CYP1A2, CYP2E1 and CYP3A4. Although it has been demonstrated that HepG2 cells have considerable higher expression levels of these CYP enzymes when cultivated in a perfusion reactor of similar design as our one in respect to being cultivated in standard cultivation dishes, these levels are still much lower than the expression levels of HepG2-3A4 cells (for CYP3A4 only) or even primary cells. This implies that the production of NAPQI in HepG2 cells is little and the establishment of levels toxic to the cell may take considerable time. On top, NAPQI can be deactivated by glutathione for a while depending on its availability in the cell, so even in primary cells NAPQI leads to irreversible cell damage only after a sufficient period of time. Hence, the graphs of all cell types indicate a complex response pattern. The exposure of all three cell types to acetaminophen leads to a fast reduction of oxygen uptake which has been associated to a NAPQI-independent process where acetaminophen acts directly on the respiration chain13. This first part of the response is linearly dependent on the concentration of acetaminophen. The slowly changing part of the response curve is determined by the production of NAPQI that eventually induces cell death. Cell death reduces the overall oxygen consumption in the wells. The level of recovery of the cells after acetaminophen is withdrawn depends on the amount of acetaminophen that has been metabolised to NAPQI by the cells. We believe that this produces further evidence for the existence of two different toxic modes of action of acetaminophen, one is induced by the production of a toxic metabolite, and the other one directly affects the mitochondrial respiration.In Fig. This conclusion is also supported by data shown in Fig. Repeated dose experiments using the HepG2 cells confirm the reversibility of the fast decrease of oxygen uptake. Figure The data shown in Fig. 5 and 8 × 104 per well, the magnitude of the response remains constant and does not depend on the initial oxygen concentration 34. This compares to a saturated oxygen concentration (100%) in the wells of our reactor at 37 °C to approximately 200 µM . Hence, oxygen concentrations between 15 and 50% correspond to physiological conditions in the liver.Figure 2 from the medium in the channel to the cells must equal the consumption of O2 by the cell. Transport is driven by the concentration gradient of O2 between the medium D is the diffusion constant of oxygen in the medium, A and b stand for the cross section and the depth of a well, respectively, although they do not necessarily describe the real dimensions of a well. They should rather be taken as geometrical parameters. The oxygen consumption by the cells in a well is simply given byN represent the number of cells in a well and We start with the assumption that the oxygen concentration at the position of the cells N is derived. In a graphical representation of this equation, straight lines with the slope N) between the straight line with slope cn(APAP). When comparing these graphs with the graphs obtained from the experimental data, it is clear that the former do not describe the entire set of data. The range of N increases and cells are not able to consume the amount of oxygen N > Ncrit hypoxic conditions prevail at the cells. In the graph this is represented as a straight line with a slope which is lower as Ncrit, they touch the linear graphs with slopes cn(APAP) not restricted by a limiting oxygen supply.Based on this simple model, a linear dependence of see Fig. . Now, th26. At present, this excludes the use of these oxygen microsensor beads for highly miniaturised chip formats. But on the other hand, in our view, there are hardly any clear advantages of reducing the dimensions of the chips to the technological limits. We believe that depending on the questions to be addressed an optimised size regime for the design of a device in respect to a proper performance should be the goal rather than minimising the system to its limits. This implies for our scenario that the supply of cells, the cellular uptake of oxygen and the sensitivity of the sensor elements must be in a particular balance in order to obtain meaningful results. The fact that the readout of the microsensors is based on the detection of visible light provides considerable freedom for the design of a reactor in respect to the geometry of the fluidic components and of the materials as long as they are sufficiently transparent. In addition, as the detection scheme is based on the measurement of phosphorescence lifetime, no focussing of the sensor particles is required, and their positioning tolerates some degree of randomness.The control of all relevant conditions of in vitro tests of toxicity is a crucial issue for a couple of reasons. Firstly, the most obvious one is derived from the demands of reproducibility. Secondly, comparability of the conditions of tests performed in different labs is not always straightforward to maintain. This is a consequence of different designs of test formats, which all have some “hidden” parameters that are hard to characterise but which may be crucial for the outcome of tests. An example for such a parameter is the access of compound to be tested to the cells. Depending on the flow and transport as well as the size and density of cell sample, different parts of the sample may be exposed to different local concentrations of the compound. This may be reduced by a careful design of the fluidic environment and in addition by choosing rather small sample sizes. But the latter implies that highly sensitive probes are available such as the microsensor particles used in this work. However, sensitive sensor elements are only part of the solution for achieving high sensitivity. Close proximity of cells and sensors are vital as minute changes of parameters related to the metabolism of the cells may only be reliably measured in their microenvironment. This is demonstrated by the results shown in Fig. 35. Finally, many endpoint formats are very well established in the field as they are validated and correlated to in vivo tests. In most scenarios, they form an important part of a broader assessment of toxicity36 and the motivation to replace them by more informative methods is rather little. Unfortunately, extending endpoint experiments to formats that allow kinetic data generation is in most cases time-consuming and labor-intensive, since an invasive analysis setup is integrated. This scenario leads to the somewhat unfortunate situation that new innovative formats, which provide a much richer set of information, get stuck in the process of developing novel powerful in vitro tests. In order to overcome this deadlock, we propose to make use of the potential of kinetic measurements for the determination of the time points that should be used in endpoint assays for gathering the most significant data.The most popular formats for in vitro tests for the assessment of the toxicity of compounds are based on endpoint measurements, although they only provide a rather limited amount of information. This is the consequence of the impact of a number of factors, namely the lack of alternatives, the relative ease and straightforwardness of setting up these formats, mechanistic models that would require substantially more information to be tested are not available and hence the content of information provided may be sufficient13. In order to derive the most meaningful information from the measurement, it is therefore necessary to determine suitable time points within the various time courses. In the first place, the possibility of the method described to obtain information on the cellular response from a locally well defined sample in real time minimised the risk of generating artefacts when cell samples are taken in order to identify or measure cell markers using invasive methods. In particular, it allows a precise timing of sample collection and hence helps to establish a strong correlation between kinetic data and possible time points. Secondly, the evaluation of a set of time courses of the cellular response helps to identify the time point or set of time points that contain the most valuable and significant information of the process. In this context, the monitoring of the oxygen consumption of hepatocytes in response to being exposed to acetaminophen in real time provides a very informative example for making the case for this approach.It has already been demonstrated that the continuous monitoring of the oxygen uptake of hepatocytes in real time provides valuable data on the kinetics of their response that helped to identify and to characterise a previously unknown mode of action of the hepatotoxic compound acetaminophenAn instructive example of this reasoning can be derived from the data shown in Figs. 39, its two response mechanism in different time regimes allowed us to highlight the virtues of the new technology. We believe that by complementing end point measurements with methods that provide information on the dynamic behaviour of cells, two goals can be achieved: Firstly, the quality of endpoint measurements can be improved by, for example, a precise identification of suitable time points. Secondly, a validation of in vitro test systems that produce kinetic data can be obtained “en passant”. This may eventually lead to an acceleration of the acceptance of these systems such that the wealth of information can be fully exploited for the advancement of the field of toxicology.Finally, we like to emphasise the utility of continuously monitoring cellular kinetics for the characterization of cellular dynamics. Although, the system chosen has no direct clinical relevance as far as the toxicity of acetaminophen is concernedIn this contribution, we describe an in vitro test system for the continuous monitoring of the oxygen uptake of cells in real time when they are exposed to toxic compounds. In a microreactor up to nine cell samples are accommodated and continuously perfused by the medium and any substance of interest. Microsensor beads allow the measurement of the oxygen concentration in the immediate vicinity of the cells. By adjusting medium flow and sample size, this information can be exploited for the determination of the cellular oxygen uptake, which can serve as a measure for the metabolic activity of the cells. The response of three types of hepatocytes is thoroughly analysed when acetaminophen at various concentrations is used as a test compound. The cells differ by their capacity to metabolise acetaminophen. This has been used to produce further evidence for the existence of two different toxic modes of action of acetaminophen, one is induced by the production of the known toxic metabolite NAPQI, and the other one directly affects the mitochondrial respiration and has only recently been identified using this technology. By making use of the characteristic response pattern of the cells induced by acetaminophen, a detailed analysis of the influence of the mode of application of the compound and of the role of the microenvironment of the cells on the cellular response has been performed. These results may help to refine endpoint measurements, which are still standard in the field of toxicology. Moreover, via this route the establishment of this novel method for the assessment of the toxicity of compounds in the field appears to be conceivable.40, which are induced by hypoxia, can be monitored more precisely through the possibility of determining the oxygen concentration directly in the vicinity of the cells, as shown here.In addition, studies of the processes of vascularization in tumors, as described by Nashimoto et al.Supplementary Information


Transverse deflecting structures (TDSs) are widely used in accelerator physics to measure the longitudinal density of particle bunches. When used in combination with a dispersive section, the whole longitudinal phase space density can be imaged. At the Linac Coherent Light Source (LCLS), the installation of such a device downstream of the undulators enables the reconstruction of the X-ray temporal intensity profile by comparing longitudinal phase space distributions with lasing on and lasing off. However, the resolution of this TDS is limited to around 1 fs rms (root mean square), and therefore, it is not possible to resolve single self-amplified spontaneous emission (SASE) spikes within an X-ray photon pulse. By combining the power spectrum from a high resolution photon spectrometer and the temporal structure from the TDS, the overall resolution is enhanced, thus allowing the observation of temporal, single SASE spikes. The combined data from the spectrometer and the TDS is analysed using an iterative algorithm to obtain the actual intensity profile. In this paper, we present some improvements to the reconstruction algorithm as well as real data taken at LCLS. The electron bunch time-resolved losses match the emitted X-ray temporal profile2, and therefore TDSs are routinely used as diagnostics to measure the X-ray pulse profiles1. However, the limited resolution of a measurement using a TDS imposes an upper limit on the resolution of the temporal reconstruction of photon pulses. As the resolution of an X-band TDS used at an X-ray FEL is typically limited to around 1 fs rms (root mean square), single self-amplified spontaneous emission (SASE) spikes, typically in the range of 0.1 fs to 3 fs, within one photon pulse can often not be resolved. However, the exact knowledge of the temporal structure of SASE radiation is interesting for applications such as “ghost imaging”3.Transverse deflecting structures (TDSs) are used to time-resolve the electron bunch phase spaces downstream of an X-ray free-electron laser (FEL) undulator line to measure the electron bunch energy losses induced by the lasing process4 and the temporal structure from the TDS, the overall resolution can be enhanced, thus allowing the observation of temporal, single SASE spikes in the X-ray range. The combined data from the spectrometer and the TDS is analysed using an iterative algorithm to obtain an estimate of the actual intensity profile. This iterative reconstruction algorithm is published in previous work6.By combining the power spectrum from a high resolution photon spectrometerA schematic of the measurement layout at the Linac Coherent Light Source (LCLS) is shown in Fig. In the following, we will discuss some improvements and adjustments to this iterative reconstruction algorithm that are necessary to analyse real data due to the spectrometer resolution of 0.2 eV during the measurements.6. The blurred temporal profile P(t) is modelled by a convolution with a Gaussian G(t) of fixed standard deviation RtThe iterative reconstruction algorithm is described in detail in previous work5, in this paper we assume that also the power spectrum Rω. This process is also modelled by a convolution with a Gaussian G(ω) of width RωIn contrary to the first publication of the algorithmThe blurred temporal profile Bj(t) in time with varying complex coefficients aj,m, where m is the iteration step,8.The electric field of the photon pulse to be approximated is modelled as a sum of in principle arbitrary base functions 5 are not chirped in time as suggested by the literature11. To accommodate this we introduce an arbitrary linear chirp factor βj to the base functionsσj is the width of the Gaussians centred at times tj, and the ωj can be initially calculated based on the energy profile of the electron phase space. For a linearly chirped electron bunch, we can for example set 12, where ω0 is the main radiation frequency created by electrons with an energy of γ0 and γj is the mean energy of the electrons around tj. Otherwise, they are initialized as ωj = ω0.The Gaussian base functions described in the previous workThese base functions are chosen in a way thatBy setting iβj, Eq.  becomes711 we set Following the literature5. The only change applied to the algorithm is that instead of the actual power spectrum The iteration process and the minimizing is described in detail in the previous work5 the algorithm is tested using simulation data of LCLS at 1.5 nm with a blurred power spectrum using a resolution of Rω = 0.2 eV rms. This value was chosen to match the resolution of the spectrometer used for measurements at LCLS. Therefore, the same tests as in the previous work5 are conducted and showcased in the following using a blurred power spectrum Rω = 0.2 eV. FEL simulations10 for bunch charges of 20 pC, 40 pC, and 150 pC are again used for the testing.Similar to the prior publicationaj,0 are used to construct the initial base functions. Individual results for bunch charges of 20 pC to 150 pC are shown in Fig. P(t) is plotted using a blue line, the blurred intensity profile Rt = 1 fs in these figures. The reconstruction result aj,m, since multiple temporal and spectral profiles may lead to the same blurred profile13. Nonetheless, to obtain a measure for the goodness of the reconstruction the 1 − R2 value known from statistics is used15P(t). This value can of course only be given for simulations as the exact correct result is then known. If the agreement between the reconstruction result P(t) is perfect, the 1 − R2 value is zero. As can be observed, the reconstruction algorithm is still able to retrieve the actual intensity profile very similar to the cases without spectral blurring shown in previous work5. The 1 − R2 values are all in the same region as in5 and also the capabilities and limitations of the algorithm remain the same as before. We therefore conclude that even though an uncertainty due to signal processing remains13, the algorithm enables an improvement of the temporal X-ray reconstruction of FEL pulses.Every reconstruction result is obtained by averaging 50 individual reconstructions, where different random coefficients Rω = 0.2 eV in these figures. The reconstruction result Additionally to the temporal profiles, the result of the spectrum reconstruction for the 20 pC bunch is displayed in Fig. R2 values for the 50 different shots with a charge of 40 pC. Comparing to the prior publication5 it can be seen, that for every shot the 1 − R2 value is in the same order for the perfect and the blurred spectrum, respectively. It can therefore be concluded, that the algorithm performs equally well for both spectral measurements.Figure In summary, the testing results show that the algorithm excels at reconstructing single, isolated spikes and struggles to resolve multiple, dense spikes individually. The existence of adjoining spikes of similar height is retrieved, although the peak power cannot always be correctly determined.A dedicated machine development shift recorded data to be analysed using the iterative reconstruction.16. An overview of the parameters for the measurements shown in the following can be found in Table The measurements were taken at a beam energy of 4 GeV resulting in a wavelength of ~1.7 nm or a photon energy of ~730 eV. The initial charge at the cathode was 40 pC, which is later collimated to either 20 pC or 30 pC prior to the undulator. Using energy collimators in the first bunch compressors, electrons with high energy deviations from the reference energy were truncated17, a gain curve was recorded, see Fig. th undulator (at z = 67 m) to suppress lasing in the downstream undulators. The orbit kick both disrupts overlap between the x-ray waves and electron bunch and degrades electron bunching, interrupting the lasing process18. The chosen configuration provided sufficient signal for the spectrometer to work and fulfilled the requirement of being close to the saturation point so that a meaningful reconstruction of the photon pulse power from the energy loss and the energy spread increase of the electron bunch can be performed17. The orbit downstream of the undulator section was restored stable by using a closed three-bump20.As the reconstruction has to be performed using bunches that are not yet saturated or close to the saturation pointEon,off(ti), the energy spread I(ti) in each time slice ti17. The subscript denotes, whether the quantity was taken from a measurement with lasing on or lasing off. The influence of the FEL process on the bunch current is negligible, therefore, this quantity does not have a subscript. For each time slice, the energy loss and the energy spread increase comparing the lasing-on and lasing-off measurement is then calculatedTo obtain the photon pulse power the longitudinal phase space density of an electron bunch producing light (lasing on) has to be compared to one where the lasing process is suppressed (lasing off). The longitudinal phase space densities are then divided into slices along the time dimension to get the time-dependent beam parameters such as the mean energy 17From these quantities the radiation power in each slice can be determined. When using the energy loss method, the radiation power in each slice is21When using the energy spread method, the radiation power in each slice is24.To determine the total radiation power an additional, independent measurement of the total pulse energy is necessary. This can for example be accomplished using a calibrated gas detectorTo see if the algorithm reconstructs the photon pulse correctly both the power profile obtained from the energy loss and the energy spread method are used as target power profiles for the reconstruction algorithm. By then comparing the reconstructed temporal power profiles one can observe the similarities and differences to check if even though the inputs might be slightly different the algorithm ends up with the same temporal power profile.σj was chosen to be 0.1 fs as well as their spacing In the following, the photon pulses obtained from the reconstruction using only the TDS and the corresponding reconstruction methods are displayed as dashed-dotted lines. The reconstructions using the energy loss method are plotted in black and those using the energy spread method are plotted in blue. 50 different initial guesses serve as starting points for the reconstruction algorithm. These 50 reconstructions are averaged to obtain the final reconstructed photon pulses (solid lines). The mean reconstruction is surrounded by a dark gray and a light gray shaded area which is one standard deviation for the energy loss and the energy spread method, respectively. For the reconstruction the width of the Gaussian base functions We first apply the reconstruction algorithm the experimental data with a charge of 30 pC at the undulator entrance. The parameter overview can be found in the left column of Table Examples of reconstructed photon pulses can be found in Fig. For the power profiles in Fig. The position and height of most of the main SASE spikes is also very similar for both target profiles shown in Fig. Figure Secondly, bunches with a charge of 20 pC at the undulator entrance are used for the reconstruction. The settings are the same as in the previous section, but the bunches are truncated even further using energy collimators in the first bunch compressor. The resulting parameters can be found in the right column of Table Figure The reconstruction found in Fig. The second example for this setting can be found in Fig. An example where the iterative algorithm did not reconstruct successfully can be found in Fig. 5 was improved and applied to real measurement data taken at LCLS.In this paper, the reconstruction algorithm previously publishedThe results show how the reconstruction algorithm using both TDS and spectral information can improve the X-ray pulse profile reconstruction over the established method using only the TDS measurement. The reconstruction accuracy is currently limited by the achievable resolution of the TDS implemented at LCLS. For future upgrades an even better accuracy can be expected. The algorithm excels at reconstructing single, isolated spikes. Multiple, adjacent spikes of similar height are more difficult to be retrieved individually.


Coronavirus pandemic causes stress and anxiety for pregnant women worldwide. The present study was conducted for the path analysis of the relationship among fear and anxiety caused by coronavirus, pregnancy experience, and the mental health of pregnant women.This cross‐sectional study was conducted on 222 pregnant women who were referred to Kamali Hospital in Alborz province in 2020. The eligible individuals entered the study through convenience sampling, and data were collected using five questionnaires including the Fear of COVID‐19 Scale, the Anxiety of COVID‐19 Scale, the pregnancy experiences Scales, Depression Anxiety Stress scale, and demographic checklist. The obtained data were then analyzed using SPSS‐16 and Amos software.According to results of the path analysis, the anxiety of COVID‐19 and concerns during pregnancy were variables that were positively and significantly correlated with mental health only through one path, which was direct, and anxiety of COVID‐19 had also the highest positive direct correlation among them (B = 0.32). The next variable was the happiness during pregnancy experiencing, which had a significantly negative and direct correlation with mental health disorder (B = 0.29). Moreover, fear of COVID‐19 through the mediating concerns of pregnancy experiences was shown to have a significant positive relationship with mental health through an indirect path (B = 0.05).Based on the result of this study, it is necessary to pay more attention to the mental health of pregnant women during a pandemic. In addition, it is recommended to provide a virtual training group to reduce anxiety caused by coronavirus and pregnancy concerns, as well as emphasizing the feeling of enjoying happiness caused by pregnancy experience during a pandemic. This paper is path analysis method for explain mental health during pregnancy. Pregnant women are often concern about fetal health and the outcome of childbirth. Besides the anxiety resulted from pregnancy, there are several other risk factors associated with the high anxiety prevalence during pregnancy . This Hospital serves as the main referral center for pregnant women in Alborz. For the purpose of the study, the researcher visited Kamali Hospital, identified the eligible women, and explained the study objectives for them. The study questionnaires were then distributed among the participants. Sampling took place through the convenience method until reaching the determined sample size.2.1n=Z1‐α/2+Z1‐β/0.5ln1‐r/1+r2+3, the sample size has been obtained as 194. To increase the accuracy by 10% and considering the potential sample loss, the sample size was estimated as 220 participants.According to the study by Que et al. , Corona Disease Anxiety Scale (CDAS), Depression Anxiety Stress scale (DASS‐21), Pregnancy experience Scale (PES), and a demographic checklist.2.5Fear of the COVID‐19 Scale (FCV‐19S) consists of 7 items measuring the emotional fear reactions toward the COVID‐19 pandemic, and its scoring is on a five‐point Likert‐type scale from 1 to 5. The sum of the scores of these items shows higher level of fear (7–35). Designing and testing validity and reliability of this tool were done by Ahorsu et al.  in Iran 2.6Corona‐related anxiety is an 18‐item tool that measure corona‐related anxiety in two dimensions, namely psychological symptoms and physical symptoms, and the items are answered on a Likert scale from zero to 3. Each participant receives a score from 0 to 54. The validity and reliability of this questionnaire have been assessed in Iran by Alipour et al. in 2020. Moreover, the Cronbach's alpha for the whole questionnaire was reported (α = 0.919) . Accordingly, each subscale consists of seven items, which are measured using a 4‐point Likert scale (“Never” = 0 point to “Almost Always” = 3 points). In Iran, this scale was psychometric by Asghari, Saed, and Dibajnia , and the2.8The Pregnancy Experiences Scale‐Brief Version is a 20‐item tool that measures happiness and concerns of pregnancy in two dimensions (each one contains 10 items), and these items are rated on a Likert scale from 0  to 3 . Ebadi et al.  determin2.9An ethics code was obtained from the Ethics Committee of Alborz University of Medical Sciences (IR.ABZUMS.REC.1399.028). The written informed consent was then obtained from the included participants. Also, they were assured regarding their information confidentiality. Moreover, all the spiritual and financial rights of mothers were respected.2.10This study examined the fit of a conceptual model of path analysis Figure  to deter3r = .362, p < .001)  compared to positive emotions and took more care of themselves with negative emotions (Fakari & Simbar, Other studies have also shown that, during public health emergencies like SARS, several negative emotional responses such as high levels of anxiety have been occurred (Li, Wang, Xue, Zhao, & Zhu, The results of the present study show that fear of corona during pregnancy could affect the anxiety caused by corona as well as indirectly affecting the mental health during this period by affecting the concerns of pregnancy.One of the main causes that increase anxiety during the pandemic period is the fear of COVID‐19, and one of the most common of which is the fear of infecting others or infecting beloved ones with the disease (Colizzi et al., The results of some previous studies have shown that women usually are more afraid of COVID‐19 than men, and these high levels of fear in women can be due to the gender differences in sensitivity and susceptibility to stress, and the increased risk of mental health problems following the occur of stressful life events (Bitan et al., During the coronavirus pandemic, pregnant women feel fear from their illness and their family members when commuting to hospitals, and because of these stress and anxiety, they want to terminate their pregnancies prematurely or by cesarean. These pregnant women feel fear and anxiety on the health of their fetus and baby during the pandemic period (Ahorsu et al., The results of the present study show that pregnancy concern as the second variable was directly related to maternal mental health disorders during this period.At the end of pregnancy period, women experience high levels of anxiety and signs of fear about the unpredictability of childbirth (Qiu et al., The occurrence of stressful events during pregnancy, such as the death of relatives, exposure to natural disasters or the occurrence of a pandemic that cause interpersonal imbalances, lack of contact with relatives, occupational problems, etc., could increase the concerns during pregnancy (Holditch‐Davis et al., The results of the present study show that happiness caused by pregnancy experience has a direct inverse effect on mental health disorder during pregnancy, which is a factor that increases its experience during pregnancy and also reduces the problems of maternal mental health during this period.The results of a previous study showed that the occurrence of COVID‐19 pandemic initially caused negative emotions in people, but positive emotions were then increased, which were caused by the group cohesion of people in belief and prayer compared to the conditions created (Li et al., In this study, the feeling of happiness from pregnancy was a hope source of for mothers, and by more emphasizing on this experience, mental health can be improved compared to the conditions created.According to the vulnerability of pregnant mothers in the pandemic period and their susceptibility to infection, it is recommended to pay special attention to their fears and to identify the mental disorders of women during this period.Therefore, according to the direct effect of anxiety caused by coronavirus on the mental health disorder of pregnant mothers during the pandemic period, it is recommended to conduct a qualitative study on identifying the causes of maternal anxiety during this period.One of the limitations of this study was the lack of measuring fear and anxiety of fathers during the pregnancy of their wives and the amount of support for wife in the pandemic period, which is considered as an important and influential factor on maternal mental health, so it is recommended to conduct more studies in this field.Another limitation of the study was the type of study. In this regard, in some studies, the cross‐sectional method has been mentioned to be weak in explaining the conditions needed for testing mediation; however, due to the pandemic conditions of the COVID‐19 and the stress and anxiety of pregnant women, we decided to design a study with less time consumption. Therefore, it is recommended to perform more prospective studies to investigate the effect of fear and anxiety of the coronavirus on the mental health and pregnancy experience of mothers.5The results of this study show that anxiety caused by corona directly and the fear caused by corona indirectly and by affecting pregnancy worries are related to the mental health of pregnant women. So, providing information on increasing maternal awareness of coronavirus, its risk factors, and its impact on the fetus and baby is essential. Also, according to the effect of happiness caused by pregnancy experience on mental health during this period, and recommending to reduce the number of care during this period and commuting restrictions in healthcare centers, it is necessary to provide group virtual training for reducing anxiety caused by corona and pregnancy concerns. Also, the feeling of enjoying happiness caused by pregnancy experience during a pandemic should be emphasized.No conflict of interest.Sara Esmaelzadeh is a supervisor who designed and performed the study; Leili Salehi designed and consulted about the proposal and sampling; Mitra Rahimzadeh is a biostatistician and gave consultation on sampling and analysis of data; Elham Molaei performed sampling; and Hamideh Zaheri performed the study and sampling.https://publons.com/publon/10.1002/brb3.1835.The peer review history for this article is available at


A general method to calculate the elastic deformation and X-ray diffraction curves of arbitrarily shaped, toroidally bent crystal wafers based on the free-energy minimization is presented. Toroidally and spherically bent single crystals are widely employed as optical elements in hard X-ray spectrometry at synchrotron and free-electron laser light sources, and in laboratory-scale instruments. To achieve optimal spectrometer performance, a solid theoretical understanding of the diffraction properties of such crystals is essential. In this work, a general method to calculate the internal stress and strain fields of toroidally bent crystals and how to apply it to predict their diffraction properties is presented. Solutions are derived and discussed for circular and rectangular spherically bent wafers due to their prevalence in contemporary instrumentation. For example, Seidler et al.  when taken out of the backscattering condition (angle of incident X-rays <90°) which can cause aberrations in imaging and issues with detectors with small active areas. The problem may be partly averted with toroidally bent crystal analysers (TBCA) which have different sagittal and meridional bending radii. Notwithstanding, TBCAs are encountered rarely as they are more difficult to manufacture than SBCAs and need to be tuned for a specific Bragg angle which incurs increased expenses, especially if the spectrometer setup is meant to be used for a wide range of photon energies. However, at least some of these problems can be avoided by using vacuum-forming optics , the partial derivatives of the displacement vector field need to be known over the diffraction domain.The propagation of electromagnetic radiation in a crystalline medium strained by external forces is mathematically described by a group of partial differential equations known as the Takagi–Taupin equations  so that z = 0 is located at the midplane of the wafer and the radii of curvature R1 and R2 are aligned with the x and y axes as presented in Fig. 1x, y) dimensions of the crystal are typically small compared with R1 and R2, we may approximate the vertical (z) deflection ζ of the wafer with a paraboloidal surface:et al., 1994ijS be the Cartesian components of the compliance matrix of an elastically anisotropic crystal in the Voigt notation.ijS are rotated to match the orientation of the crystal directions of the wafer. As detailed in Section S1 of the supporting information, the partial derivatives of the displacement vector et al., 2009et al., 2014bet al., 2017d spacing of the Bragg planes due to the non-zero Poisson ratio and thus the diffraction curve of the TBCA. In the scope of linear elasticity, the total strain tensor is iju.Consider an arbitrarily shaped, toroidally bent crystal wafer with the thickness i.e. the transverse dimensions of the wafer are considerably larger than its thickness d), the total energy can be written as the sum of the pure bending energy and the stretching energy. Since the pure bending solution is already known, it is sufficient to concentrate on the minimization of the stretching energy given byx and y. Using the Hooke’s law ij as a function of χ = χ, also known as the Airy stress function, so thatiju can be assumed to be constant with respect to the z coordinate given by equation 14.1 (p. 51) in the work by Landau et al. (1986P (per unit area) between the wafer and substrate is the only external force acting on the wafer, we require that its integral over the surface has to vanish in order the wafer to stay stationary, i.e.supporting information.The deformation of the wafer can be found by minimizing the mechanical strain energy under the toroidal bending constraint. If we assume that the wafer is thin  which minimizes equation  in our previous work 1/2 which implies radial symmetry of χ. This allows us utilize the general solution to ∇4χ = 0 known as the Mitchell solution  by quadratic summing in accordance with the central limit theorem. Usually the full width at half-maximum (FWHM) is used instead of the standard deviation, in the case whereby σ is to be multiplied by 2(2ln2)1/2. This underestimates the true FWHM of equation . The derivation presented in this work is theoretically more sound and thus expected to be physically more accurate. However, it should be noted that the original approach leads to the same solution if the integrated contact force is required to vanish.For the anisotropic case, we ought to not assume k > 0 is a proportionality constant andB/A are presented in Fig. 3B = 0, the isocurves of ΔE are circular as in the isotropic circular case. For non-zero values of B, the isocurves become elliptical and are intercepted by the circular edge as illustrated in Fig. 4E distribution, the prominence of which is proportional to the B/A ratio. The standard deviation of equation , Si(555) and Si(731) reflections with selected in-plane crystal directions as presented in Fig. 9e.g. Si(008)] can cause a significant effect to the resolution curve of the crystal. Nevertherless, as it is evident from equations  analysers manufactured using the anodic bonding techinique were reported in the work by Rovezzi  al. 2017. The str4.pyTTE and tbcalc, are provided for the low-threshold adoption of the methods to predict the resolution functions of the bent isotropic and anisotropic crystal wafers presented in Section 3pyTTE calculates 1D X-ray diffraction curves of elastically anisotropic crystals with a depth-dependent deformation field in Bragg and Laue geometries by solving the 1D Takagi–Taupin equation using the variable-coeffient ordinary differential equation solver (VODE) with the backward differential formula (BDF) method  and including it in the integrals of free energy and contact force. Such an approach should work well without further modification if d can be written as a low-order polynomial, like in the case of Johansson-type analysers which are ground after bending so their surfaces follow the Rowland circle exactly, but may require additional higher-order terms in the expansion of χ. Alternatively, if the variation in d is small, a perturbative approach could be easier to apply. The latter approach could also be used to include also the figure and slope errors from the perfect toroidal surface due to, for example, imperfections in bonding or shape of the substrate  to tune the optical parameters of the analyser. More theoretical and computational work is needed to quantify the magnitude of imperfections to the diffraction properties.One of the main assumptions in calculating the transverse stretching is that the wafer is (infinitely) thin and of even thickness throughout. However, in practice the wafer is of finite thickness which may vary along the wafer. This variation may be purposeful such as in the case of Johansson-type analysers (Johansson, 1932 al. 2011, the metzzu which is a clear indication that transverse stretching can have an effect on the focusing properties of the analyser as well. However, combining the presented method with optical simulations has not been explored in depth for the time being.In addition to its energy or angular resolution, another important figure of merit of an crystal analyser is its focusing properties. As presented in the top panel of Fig. 12From a general perspective, the energy resolution of TBCAs worsens with increasing photon energy. On the other hand, higher photon energies would be important to utilize in IXS experiments at synchrotrons because the inelastic scattering cross section increases with increasing photon energy while photoelectric absorption decreases. Higher-energy photons would also have higher penetration capability for condensed samples when combining imaging and IXS spectroscopy. These requirements with standard TBCAs are in conflict with each other. Development for higher-resolution TBCAs that operate with higher photon energies would thus be an important goal. Our results are expected to work towards that goal, giving a framework with which the optimization of the crystal analyzers can be accomplished.6.In this work, we have presented a general approach to model the internal strain and stress fields of arbitrarily shaped, toroidally bent crystal wafers and how they can be utilized to predict the diffraction properties of the wafer. Isotropic and anisotropic analytical solutions were derived for circular and rectangular wafers and their properties were discussed in detail, focusing on the special case of spherical bending. Comparisons to the available experimental data show that the models can make quantitatively accurate predictions. An open source implementation of the method was discussed and provided.7.supporting information: Amenzade (1979The following references are cited in the zade 1979; Lide (2zade 1979.10.1107/S2052252520014165/hf5943sup1.pdfSupporting information, equations and figures. DOI: